rhodium-catalyzed asymmetric carbon-carbon bond … · this thesis describes the ... 2.3.2...

Rhodium-Catalyzed Asymmetric Carbon-Carbon Bond Formation Leading to the Development of Rhodium/Palladium Multi-Metal Catalysis

by

Lei Zhang

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy

Department of Chemistry University of Toronto

© Copyright by Lei Zhang 2015

ii

Rhodium-Catalyzed Asymmetric Carbon-Carbon Bond Formation

Leading to the Development of Rhodium/Palladium Multi-Metal

Catalysis

Lei Zhang

Doctor of Philosophy

Department of Chemistry University of Toronto

2015

Abstract

This thesis describes the development of rhodium-catalyzed asymmetric ring opening of strained

alkenes and the subsequent use of rhodium and palladium catalysis in the development of

domino reactions. The contents are divided into 4 chapters.

Chapter 1 describes the rhodium-catalyzed asymmetric ring opening (ARO) of strained bicyclic

alkenes using silyl enolates. The development of this method achieved a highly enantioselective

addition of alkyl fragments onto bicyclic alkenes, affording broad scope, mild reaction

conditions, and high functional group tolerance. The synthetic utility of the method was

demonstrated through functionalization of the ARO products to a number of core scaffolds of

natural products.

Chapter 2 describes the development of a domino rhodium/palladium-catalyzed synthesis of

dihydroquinolines. The use of two different ligands in the reaction led to a mechanistic

investigation that revealed metal-ligand interactions that were crucial to the success of this

domino reaction. The mechanistic insights facilitated reaction optimization, leading to an

expansion of the reaction scope, including the synthesis of chromenes.

iii

Chapter 3 describes the importance of time resolution and ligand interference in the development

of enantioselective domino rhodium/palladium catalysis employing chiral and achiral ligands.

The development of this method provided access to chiral C4-substituted dihydroquinolinones in

a direct manner, affording high yields and enantioselectivities. Current work on developing

multicomponent enantioselective rhodium/palladium catalysis is also disclosed.

Chapter 4 describes the development of multi-metal-catalyzed multicomponent reactions

(MC)2R. The development of a highly compatible rhodium/palladium catalyst system allowed

the incorporation of a third catalyst, copper, achieving a three-component one-pot reaction.

Current work on the development of the use of other metal combinations to achieve (MC)2R is

also disclosed.

iv

Acknowledgments

Five years, I can't believe how fast it passed by. There are so many things to say and recall. At

this moment of reflection, I would like to acknowledge those that have made this journey

possible.

I would like to acknowledge Professor Mark Lautens, my supervisor, for giving me this

invaluable opportunity. Mark, you have my deepest gratitude for this experience. From the first

day to now, I have changed. I have learned chemistry and research. Your high expectations for

excellence and constructive criticisms always kept me on my toes. I'm glad I had this chance to

challenge myself, realize my weaknesses, and work toward improvement continually. Every day

I am working toward realizing my full potential. Thank you for the enduring presence for times

of difficulty. There are many times of challenge throughout this journey, but I have learned to be

stronger in the face of defeat. You gave me the freedom to explore, to take matters into my own

hands. From inception to conception, I felt motivated and empowered. These values I will take

on in my future. From the highs and lows, the times at work, the times of interacting with

colleagues, to the few precious times to catch up and reflect, there was not a moment of

boredom. I live with purpose.

I would like to thank the members of my supervisory committee: Professors Mark Taylor, Andrei

Yudin, and Robert Morris for their guidance, advice, and company. I would also like to thank

Professor Andre Charette (Universite de Montreal) for being the external examiner on my

defense committee. I would like to thank Professor Andre Beauchemin (University of Ottawa),

for his passion for chemistry inspired me to go down this path.

I would like to thank the people that I worked with, for they have made this work possible. Jane

Panteleev, thank you for being a great collaborator and having faith in me. To Marie Cubizoles,

Jason Stacey, Theo Bruun, Lorenzo Sonaglia, Christine Le, Zafar Qureshi, and Alvin Jang. I

have learned so much from you. Thanks to Jennifer Tsoung for being a great cubicle mate.

Thanks to Gavin Tsui, for being a great fellow dancing colleague. Thanks to all the Lautens

group members current and past. I would like to thank Dave Petrone and Simon Kim, for the late

night company, drinks, food runs, and friendship. With all of you I have shared so many

memories. You were my travelling company on this road.

v

Janet, thank you for your friendship and getting me into dancing, I am grateful. Teddy, thank you

for the gift of dancing. I have never felt so much joy and elation. Even on the hard days, the great

music, dance, and partnership made everything about life worth living. Thank you for the

wonderful people on your team. I am forever in your debt for realizing this lifelong passion.

I would like to thank the departmental staff, Dr. Darcy Burns and Dmitry Piguchin (NMR), Dr.

Matthew Forbes (MS), Dr. Alan Lough (Xray), and Ken Greaves (Stores). A special thanks to

Anna-Liza Villavelez, for the unwavering support and courtesy throughout all the administrative

procedures.

Lastly, I would like to thank my parents. You are always there for me.

vi

“...the overflow of my brain would probably, in a state of freedom, have evaporated in a

thousand follies; it needs trouble and difficulty and danger to hollow out various mysterious and

hidden mines of human intelligence. Pressure is required, you know, to ignite powder: captivity

has collected into one single focus all the floating faculties of my mind; they have come into

close contact in the narrow space in which they have been wedged. You know that from the

collision of clouds electricity is produced and from electricity comes the lightning from whose

flash we have light amid our greatest darkness.”

-Abbe Faria

vii

To George and Wei,

and Providence

viii

Table of Contents

Chapter 1 Rhodium-Catalyzed Enantioselective Alkylative Ring Opening of Oxa/Azabicylic Alkenes Using Silyl Ketene Acetals and Enol Ethers ................................................................ 1

1 Rhodium-Catalyzed Enantioselective Alkylative Ring Opening of Oxa/Azabicylic Alkenes Using Silyl Ketene Acetals and Enol Ethers ................................................................ 2

1.1 Introduction ......................................................................................................................... 2

1.2 Research plan ...................................................................................................................... 8

1.3 Optimization of the addition to benzofused oxabicyclic alkenes ..................................... 10

1.4 Scope of the rhodium-catalyzed ARO of oxabicyclic alkenes using silyl nucleophiles ... 11

1.5 Conclusions ....................................................................................................................... 17

1.6 Experimental section ......................................................................................................... 17

Chapter 2 Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of Dihydroquinolines ........ 50

2 Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of Dihydroquinolines ...................... 51

2.1 Introduction ....................................................................................................................... 51

2.1.1 Modes of multiple metal catalysis ........................................................................ 52

2.2 Research plan .................................................................................................................... 61

2.3 Stepwise reaction optimization ......................................................................................... 62

2.3.1 Rh-catalyzed formal alkyne hydroarylation .......................................................... 62

2.3.2 Pd-catalyzed C-N cross coupling .......................................................................... 68

2.4 Mechanistic analysis and reaction development ............................................................... 72

2.5 Scope of the Rh/Pd-catalyzed domino synthesis of dihydroquinolines ............................ 81

2.6 Conclusion ........................................................................................................................ 86

2.7 Experimental section ......................................................................................................... 86

Chapter 3 Enantioselective Sequential Multi-Metal Catalysis in the Presence of Achiral Ligands: Time Resolution and Orthogonal Ligand Affinity Enabled Synthesis of Heterocycles ........................................................................................................................... 129

ix

3 Enantioselective Sequential Multi-Metal Catalysis in the Presence of Achiral Ligands: Time Resolution and Orthogonal Ligand Affinity Enabled Synthesis of Heterocycles ........ 130

3.1 Introduction ..................................................................................................................... 130

3.1.1 Time resolution ................................................................................................... 130

3.1.2 Ligand interference ............................................................................................. 133

3.2 Research plan .................................................................................................................. 137

3.2.1 Synthetic access to C4-substituted dihydroquinolinones .................................... 137

3.3 Reaction optimization ..................................................................................................... 140

3.4 Scope of the enantioselective Rh/Pd-catalyzed sequential synthesis of dihydroquinolinones ....................................................................................................... 145

3.5 Future work: multi-metal-catalyzed multicomponent reactions (MC)2R: enantioselective Rh/Pd-catalyzed bidirectional functionalization and Rh-catalyzed domino conjugate addition/α-arylation ........................................................................... 149

3.6 Conclusions ..................................................................................................................... 153

3.7 Experimental section ....................................................................................................... 154

Chapter 4 The Development of Multi-Metal-Catalyzed Multicomponent Reactions: (MC)2R 182

4 The Development of Multi-Metal-Catalyzed Multicomponent Reactions: (MC)2R ............. 183

4.1 Introduction ..................................................................................................................... 183

4.2 Research plan .................................................................................................................. 185

4.3 Reaction optimization ..................................................................................................... 186

4.4 Reaction scope ................................................................................................................ 188

4.5 Current and future work: copper/palladium catalyzed (MC)2R: synthesis of fully substituted 1,2,3-triazoles ............................................................................................... 192

4.6 Conclusions ..................................................................................................................... 198

4.7 Experimental section ....................................................................................................... 198

x

List of Publications

Parts of this thesis have been published in scientific journals as listed below.

Lei Zhang, Jane Panteleev, and Mark Lautens. “Metal-Ligand Binding Interactions in Rhodium

/Palladium-Catalyzed Synthesis of Dihydroquinolines”. J. Org. Chem. 2014, In press.

Lei Zhang, Zafar Qureshi, Lorenzo Sonaglia, and Mark Lautens. “Enantioselective Catalysis in

the Presence of an Achiral Ligand: Rh/Pd Sequential Bond Formation Leading to

Dihydroquinolinones”. Angew. Chem. Int. Ed. 2014, 53, 13850-13853.

Lei Zhang, Christine M. Le, and Mark Lautens. “The Use of Silyl Ketene Acetals and Enol

Ethers in the Catalytic Enantioselective Alkylative Ring Opening of Oxa/Aza Bicyclic Alkenes”.

Angew. Chem. Int. Ed. 2014, 53, 5951-5954.

Lei Zhang, Lorenzo Sonaglia, Jason Stacey, and Mark Lautens. “Multi-Component Multi-

Catalyst Reactions (MC)2R: One Pot Synthesis of 3,4-Dihydroquinolinones”. Org. Lett. 2013,

15, 2128-2131.

Jane Panteleev, Lei Zhang, and Mark Lautens. “Domino Rhodium-Catalyzed Alkyne

Arylation/Palladium-Catalyzed N-Arylation: A Mechanistic Investigation”. Angew. Chem. Int.

Ed. 2011, 50, 9089-9092.

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List of Tables

Table 1.1 Reaction optimization .................................................................................................. 11

Table 2.1 Optimization of the Rh-catalyzed hydroarylation ........................................................ 67

Table 2.2 Scope of Rh-catalyzed hydroarylation ......................................................................... 68

Table 2.3 Optimization of the Pd-catalyzed amidation ................................................................ 71

Table 2.4 Control reactions for domino catalysis ........................................................................ 74

Table 2.5 Effect of relative ligand loading in the domino reaction .............................................. 79

Table 2.6 Scope of nitrogen protecting groups ............................................................................ 82

Table 2.7 Scope of arylboronic acids in the domino reaction ...................................................... 83

Table 2.8 Scope of substitutions on substrate .............................................................................. 84

Table 2.9 Synthesis of chromenes ................................................................................................ 85

Table 3.1 Catalyst competition studies in Rh-catalyzed ARO with exogenous metal and ligand additives. ..................................................................................................................... 136

Table 3.2 Reaction optimization of the domino Rh/Pd-catalyzed dihydroquinolinone synthesis ................................................................................................................................. 142

Table 3.3 Reaction scope with respect to arylboronic acids ...................................................... 145

Table 4.1 Optimization of Rh/Pd-catalyzed conjugate addition/amidation ............................... 188

Table 4.2 Scope of the Rh/Pd-catalyzed dihydroquinolinone synthesis .................................... 189

Table 4.3 Scope of the Rh/Pd catalysis with respect to the Michael acceptor ........................... 190

Table 4.4 Optimization of the arylation of dihydroquinolinones. .............................................. 191

Table 4.5 Two-step one-pot Rh/Pd/Cu-catalyzed (MC)2R ........................................................ 192

xii

List of Schemes

Scheme 1.1 Regiodivergent resolution of unsymmetrical oxabicycles .......................................... 3

Scheme 1.2 Regiodivergent synthesis of Rotigotine and (S)-8-OH-DPAT ................................... 4

Scheme 1.3 Proposed mechanism of the rhodium-catalyzed ARO with soft nucleophiles ........... 5

Scheme 1.4 Proposed mechanism of the rhodium-catalyzed ARO with arylboronic acids ........... 7

Scheme 1.5 Scope of the rhodium-catalyzed ARO of benzofused oxabicyclic alkenes. ............. 12

Scheme 1.6 Oxabicyclic alkene scope .......................................................................................... 13

Scheme 1.7 Ligand screening in the ARO of azabicyclic alkenes with silyl ketene acetal ......... 14

Scheme 1.8 Azabicyclic alkene scope and derivatization ............................................................ 15

Scheme 1.9 Functionalization of the alkylated oxabicyclic alkenes ............................................ 16

Scheme 2.1 The catalytic cycle of the Sonogashira cross coupling. ............................................ 54

Scheme 2.2 Dual V/Pd-catalyzed Meyer-Schuster rearrangement/allylic alkylation. ................. 55

Scheme 2.3 Blum’s report on Au/Pd-catalyzed butenolide synthesis. ......................................... 56

Scheme 2.4 Enantioselective Rh/Pd-catalyzed allylation of cyanoesters. ................................... 57

Scheme 2.5 Catalytic cycle of the Wacker process. ..................................................................... 58

Scheme 2.6 Ir/Mo-catalyzed alkane metathesis. .......................................................................... 60

Scheme 2.7 Ru/Pt-catalyzed carbocyclization/cyclopropanation. ................................................ 60

Scheme 2.8 Rh-catalyzed formal hydroarylation of alkynes ........................................................ 63

Scheme 2.9 Synthetic route towards the alkyne substrates for Rh-catalyzed hydroarylation ...... 64

Scheme 2.10 Catalytic cycle of the C-N cross coupling. ............................................................. 69

Scheme 2.11 Buchwald’s multi-ligand catalyst system for selective sequential diamination. .... 70

Scheme 2.12 Domino Rh/Pd-catalyzed synthesis of dihydroquinolines ...................................... 72

Scheme 2.13 Time-resolved domino sequence and competitive reaction pathways .................... 73

Scheme 2.14 Ligand-specific binding of [Rh(cod)OH]2 to BINAP ............................................. 74

Scheme 2.15 Proposed domino catalytic cycles ........................................................................... 81

xiii

Scheme 3.1 Ru/Pt-catalyzed cross metathesis/hydrogenation sequence for the synthesis of lactones. .................................................................................................................................. 132

Scheme 3.2 Time-resolved domino Rh/Pd-catalyzed hydroarylation/C-N cross coupling ........ 132

Scheme 3.3 Preferential Rh-BINAP association over XPhos .................................................... 133

Scheme 3.4 Access to aryl acrylamides for the Rh/Pd enantioselective catalysis ..................... 140

Scheme 3.5 Reaction scope of aryl acrylamides ........................................................................ 146

Scheme 3.6 Lack of time resolution on the Rh/Pd catalysis for pyridine containing substrates 148

Scheme 3.7 Derivatization of dihydroquinolinones. .................................................................. 148

Scheme 4.1 Cu/Pd-catalyzed synthesis of fully substituted 1,2,3-triazoles ............................... 194

Scheme 4.2 Pd-catalyzed direct arylation of iodotriazoles ........................................................ 196

xiv

List of Figures

Figure 1.1 Biologically active targets synthesized via the ARO ................................................... 3

Figure 1.2 Access to cyclohexenes and aminodihydronaphthalenes via the ARO of less-strained bicyclic alkenes ............................................................................................................ 8

Figure 2.1 Scope of reactions available for the ligand-dependent multi-metal catalysis............. 52

Figure 2.2 Shibasaki’s catalyst architecture and proposed mechanism of stereoinduction. ........ 53

Figure 2.3 Ligands screened for hydroarylation and C-N/O cross coupling ............................... 66

Figure 2.4 31P NMR spectra of Rh and ligand mixtures in benzene ............................................ 73

Figure 2.5 Effect of Pd and XPhos as additives in the hydroarylation step. ................................ 75

Figure 2.6 Effect of BINAP and ligand exchange on the amidation reaction ............................. 77

Figure 2.7 Influence of [Rh(cod)OH]2 and BINAP in the amidation reaction ............................ 78

Figure 2.8 Determination of optimal catalyst ratios for the domino reaction .............................. 79

Figure 2.9 Effect of relative ligand loading on the formation of 2.2b in the domino reaction. ... 80

Figure 2.10 Effect of relative ligand loading on the formation of 2.3b in the domino reaction. . 80

Figure 3.1 Bioactive C4-substituted tetrahydroquinolines. ........................................................ 138

Figure 3.2 Unsuccessful substrates in the Rh/Pd catalysis. ....................................................... 147

Figure 4.1 One-pot Rh/Pd/Cu (MC)2R: synthesis of N-aryl dihydroquinolinones. ................... 186

Figure 4.2 Bioactive dihydroquinolinones ................................................................................. 186

xv

List of Appendices

Appendices 1-4 .......................................................................................................................... 218

Appendix 1: Rhodium-Catalyzed Enantioselective Desymmetrization of Oxabicyclic Alkenes Using Silyl Ketene Acetals/Enol Ethers .................................................................. 219

Appendix 2: Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of Dihydroquinolines ... 319

Appendix 3: Enantioselective Sequential Multi-Metal Catalysis in the Presence of Achiral Ligands: Time Resolution and Orthogonal Ligand Affinity Enabled Synthesis of Heterocycles ........................................................................................................................... 387

Appendix 4: The Development of Multi-Metal-Catalyzed Multicomponent Reactions: (MC)2R ................................................................................................................................... 439

xvi

List of Abbreviations

[α]D specific rotation measured at 589 nm Ac acetyl aq aqueous Ar aryl ARO asymmetric ring opening atm atmosphere BINAP 1,1’-binaphthalene-2,2’-diphenylphosphine Bn benzyl Boc tert-butoxycarbonyl Bpin 4,4,5,5-tetramethyl-1,3,2- dioxaborolane Bu butyl Bz benzoyl °C degrees centigrade Calcd calculated Cbz benzyloxycarbonyl COD or cod 1,5-cyclooctadiene Conv. conversion Cp cyclopenta-2,4-dien-1-ide Cp* 1,2,3,4,5-pentamethyl cyclopenta-2,4-dien-1-ide Cy cyclohexyl DART Direct Analysis in Real Time dba dibenzylideneacetone 1,2-DCE dichloroethane DCM dichloromethane δ chemical shift d day(s) d.r. diastereomeric ratio DIBAL diisobutylaluminum hydride Diox. 1,4-dioxane DMAP 4-(dimethylamino)pyridine DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide DPPB diphenylphosphinobutane DPPE diphenylphosphinoethane DPPF diphenylphosphinoferrocene DPPM diphenylphosphinomethane DPPP diphenylphosphinopropane E or E+ electrophile EDG electron donating group ee enantiomeric excess EI electron impact Eqn equation

xvii

e.r. enantiomeric ratio ESI electrospray ionization equiv molar equivalent(s) Et ethyl Et3N triethylamine Et2O diethyl ether EtOAc ethyl acetate EWG electron withdrawing group g gram(s) h hour(s) iPr isopropyl Josiphos (R,S)-PPF-PtBu2

(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tertbutylphosphine.

Hex hexanes HRMS high-resolution mass spectrum Hz hertz L.A. Lewis acid LAH lithium aluminum hydride IR infrared m meta M metal, or molar concentration Mandyphos (R,R)-(+)-2,2'-Bis[(S)-(N,N-dimethylamino)(phenyl)methyl]-1,1'-

bis(di(2-methylphenyl)phosphino)ferrocene (MC)2R multi-metal-catalyzed multicomponent reaction Me methyl MeCN acetonitrile MeOH methanol mg milligram(s) min minute mL millilitre mmol millimole M.p. melting point Ms methanesulfonate MS molecular sieves naphth or nap naphthyl NMR nuclear magnetic resonance NOE nuclear Overhauser effect Ns 2- or 4-nitrophenylsulfonyl Nuc nucleophile o ortho p para PG protecting group Ph phenyl

xviii

PhB(OH)2 phenylboronic acid Phen 1,10-phenanthroline Piv pivaloyl PPh3 triphenylphosphine ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl quant. quantitative R generic alkyl group Rf retardation factor r.r. regioisomeric ratio r.t. room temperature RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl sat. saturated SDS sodium dodecyl sulfate SM starting material SNAr nucleophilic aromatic substitution SPhos 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl t time T temperature TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl tBu tert-butyl Tf trifluoromethanesulfonyl THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TOF time of flight Tol tolyl Trost ligand (R,R)-DACHphenyl

(1R,2R)-(+)-1,2-diaminocyclohexane-N,N"-bis(2-diphenylphosphinobenzoyl)

Ts tosyl, para-toluenesulfonyl X generic halide/heteroatom Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

1

Chapter 1 Rhodium-Catalyzed Enantioselective Alkylative Ring Opening of

Oxa/Azabicylic Alkenes Using Silyl Ketene Acetals and Enol Ethers

2

1 Rhodium-Catalyzed Enantioselective Alkylative Ring Opening of Oxa/Azabicylic Alkenes Using Silyl Ketene Acetals and Enol Ethers

The work described in this chapter was performed in collaboration with a fellow graduate

student, Christine M. Le. The project development and the majority of the experimental work

was carried out by the author, and the experiments conducted by C. M. Le are labeled as such.

1.1 Introduction

In the past two decades, the Lautens group has developed a general approach toward the

asymmetric ring opening (ARO) of strained bicyclic alkenes via RhI catalysis to efficiently

access chiral dihydronaphthalene building blocks with high enantioselectivity.1 A number of soft

heteroatom nucleophiles, such as alcohols,2a amines,2b,c malonates,2b,c carboxylates,2d and thiols2e

were successfully employed in the ARO. Using a RhI catalyst with Josiphos, these soft

nucleophiles open the bicycle in a SN2’ manner, affording a 1,2-trans disubstituted

dihydronaphthalene (Eqn 1.1).2a This trans stereochemical relationship provided access to a

number of important biologically active compounds (Figure 1.1).

[Rh(cod)Cl]2 (0.125 mol %)

(R,S)-PPF-PtBu2

(0.025 mol %)

Nuc (5 equiv)

THF, reflux

OH

Nuc

1.11.3

OFe

PPh2

PtBu2

(R,S)-PPF-PtBu2

Josiphos

Nuc = ROH, up to 99% ee

R1R2NH, up to 95% ee

(1.1)

1 For reviews, see: (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48-58. (b) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169-196. (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829-2844. (d) Lautens, M.; Fagnou, K. Proc. Natl. Acad. Sci. USA 2004, 101, 5455-5460. (e) Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions, Wiley-VCH, Weinheim, 2005. 2 For selected examples, see: (a) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122, 5650-5651. (b) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170-7171. (c) Lautens, M.; Fagnou, K.; Yang, D. J. J. Am. Chem. Soc. 2003, 125, 14884-14892. (d) Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067-5072. (e) Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194-2196.

3

Figure 1.1 Biologically active targets synthesized via the ARO

Recently, R. Webster in the group also developed a regiodivergent resolution via the ARO of

unsymmetrical oxabicycles (Scheme 1.1).3a,c As the starting oxabicycle was racemic, the chiral

catalyst reacted divergently with respect to each enantiomer, creating two different regioisomers

with high ee.

Scheme 1.1 Regiodivergent resolution of unsymmetrical oxabicycles

The two enantioenriched products could be separated by chromatography. This method was

applied toward the synthesis of two different neuroactive compounds, Rotigotine and (S)-8-OH-

DPAT (Scheme 1.2).3b Other soft nucleophiles that were recently developed for the ARO that

afforded products with the 1,2-trans stereoconfiguration include sodium isocyanate,4 water,5 and

fluoride.6

3 (a) Webster, R.; Böing, C.; Lautens, M. J. Am. Chem. Soc. 2009, 131, 444-445. (b) Webster, R.; Boyer, A.; Fleming, M. J.; Lautens, M. Org. Lett. 2010, 12, 5418-5421. (c) Nguyen, T. D.; Webster, R.; Lautens, M. Org. Lett. 2011, 13, 1370-1373. 4 Tsui, G. C.; Ninnemann, N. M.; Hosotani, A.; Lautens, M. Org. Lett. 2013, 15, 1064-1067. 5 Tsui, G. C.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 5400-5404. 6 Zhu, J.; Tsui, G. C.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 12353-12356.

4

Scheme 1.2 Regiodivergent synthesis of Rotigotine and (S)-8-OH-DPAT

Extensive mechanistic studies were conducted in the Lautens group, and the catalytic cycle of

the ARO with soft nucleophiles was proposed (Scheme 1.3).1 The dimeric rhodium catalyst 1.3.0

first dissociated to form the active monomeric species 1.3.1, which oxidatively inserted into the

enantiotopic bridgehead carbon-oxygen bond in the oxabicycle 1.3.2. This was the

enantiodiscriminating step. The protonation of the rhodium alkoxide 1.3.3 occurred to give 1.3.4.

Subsequent attack of the nucleophile in an SN2’ manner afforded the product 1.3.5 with the

observed trans configuration and regenerated the active catalyst.

5

ClRhRh

Cl P

P

P

P**

ClRh

solP

P* O

ORh

PPCl*

ORh

PPCl*

H

Nuc-H

Nuc

OH

Nuc-

Nuc-

1.3.0

1.3.1

1.3.2

1.3.31.3.4

1.3.5

Scheme 1.3 Proposed mechanism of the rhodium-catalyzed ARO with soft nucleophiles

Amine nucleophiles have been extensively studied and were able to open a wide class of bicyclic

alkenes, including non-benzofused oxabicycles2b,c and azabicycles.7 However, these less reactive

substrates generally required more forcing conditions, such as elevated temperatures, increased

catalyst/ligand loadings, and with a proton source. Other than amines, the ring opening of less

reactive bicyclic alkenes with soft nucleophiles is very rare. Methods for the ARO of these

bicyclic alkenes are predominantly based on hard nucleophiles, such as hydrides8 and

organometallic reagents.9 The carbon-based hard nucleophiles provided products with the 1,2-cis

7 (a) Lautens, M.; Fagnou, K.; Zunic, V. Org. Lett. 2002, 4, 3465-3468. (b) Cho, Y.-H.; Zunic, V.; Senboku, H.; Olsen, M.; Lautens, M. J. Am. Chem. Soc. 2006, 128, 6837-6846. 8 (a) Lautens, M.; Rovis, T. Tetrahedron 1998, 54, 1107-1116. (b) Lautens, M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 11090-11091. 9 (a) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804-1805. (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett. 2000, 2, 1971-1973. (c) Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2002, 4, 2703-2705. (d) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437-1447. (e) Zhang, W.; Wang, L.-X.; Shi, W.-J.; Zhou, Q.-L. J. Org. Chem. 2005, 70, 3734-3736. (f) Yoshida, K.; Toyoshima, T.; Akashi, N.; Imamoto, T.; Yanagisawa, A. Chem. Commun. 2009, 2923-2925. (g) Ogura, T.; Yoshida, K.; Yanagisawa, A.; Imamoto, T. Org. Lett. 2009, 11, 2245-2248. (h) Bos, P. H.; Rudolph, A.; Perez, M.; Fañanás-Mastral, M.; Harutyunyan, S. R.; Feringa, B. L. Chem. Commun. 2012, 48, 1748-1750.

6

stereoconfiguration under rhodium or palladium catalysis. Among the most versatile

nucleophiles used in the ARO to access the 1,2-cis stereoconfiguration are arylboronic acids. The

addition of arylboronic acids to a wide class of oxa/azabicyclic alkenes could be achieved under

either palladium or rhodium catalysis.10 For example, Lautens and coworkers reported a seven

step synthesis of (+)-homochelidonine via a Pd-catalyzed ARO of an azabicycle with an

arylboronic acid (Eqn 1.2).10c,d

A different catalytic cycle was proposed to account for the cis selective addition of hard

nucleophiles and arylboronic acids (Scheme 1.4). The monomeric catalyst 1.4.1 first underwent

transmetalation with the arylboronic acid, forming the organo-rhodium species 1.4.2.

Enantioselective carborhodation of the oxabicycle subsequently occurred to form 1.4.3, which

beared the cis stereoconfiguration observed in the products. The alkyl rhodium species then went

through a β-oxy elimination to form a rhodium alkoxide 1.4.4, which protonated to release the

product and regenerate the catalyst.

10 (a) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314. (b) Lautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695-3698. (c) McManus, H. A.; Fleming, M. J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433-436. (d) Fleming, M. J.; McManus, H. A.; Rudolph, A.; Chan, W. H.; Ruiz, J.; Dockendorff, C.; Lautens, M. Chem. Eur. J. 2008, 14, 2112-2124. (e) Tsui, G. C.; Tsoung, J.; Dougan, P.; Lautens, M. Org. Lett. 2012, 14, 5542-5545.

7

Scheme 1.4 Proposed mechanism of the rhodium-catalyzed ARO with arylboronic acids

In comparison, the addition of alkyl groups to strained bicyclic alkenes, or the alkylative ARO, is

not as general, as the organometallic reagents employed lacked functional group tolerance,

stability, and availability. Consequently, only simple alkyl fragments that lack functional group

handles have been reported. For example, Feringa and coworkers reported an enantioselective

Cu-catalyzed addition of a number of alkyl lithiums and alkyl zincs to benzofused oxabicycles

(Eqn 1.3, 1.4).9c,h

The use of copper and a phosphoramidite ligand could access products with the trans

stereoconfiguration. However, the use of a functionalized alkyl lithium such as TMSCH2Li

8

afforded low yields and ee.9c Grignard reagents could also be employed in the ARO under

copper catalysis, but the reaction exhibited limited nucleophile scope and low to modest

enantioselectivities.9e In addition, the enantioselective alkylative ring opening of the less-strained

oxabicyclo-[2.2.1]heptanes and azabicyclic alkenes has only been achieved with the use of

dimethyl- and diethylzinc.9

1.2 Research plan

Since the initial development of the ARO using alcohol and amine nucleophiles, significant

efforts have been invested in the development of the ring opening of strained, benzofused

oxabicyclic alkenes to access dihydronaphthalene cores. Reports on the ARO of the less-strained

non-benzofused oxabicyclo-[2.2.1]heptanes and azabicyclic alkenes are considerably rare.

Overcoming the lack of reactivity of these challenging bicyclic alkenes is desirable as this would

provide access to enantioenriched highly substituted cyclohexenes and

aminodihydronaphthalenes (Figure 1.2). Due to the inherent lack of reactivity of these bicyclic

alkenes, stronger nucleophiles were used. However, the drawbacks of strong nucleophiles such

as organometallic reagents include accessibility, functional group tolerance, and scope. Thus far,

only arylboronic acids and amines exhibited general reactivity towards both strained and less-

strained bicyclic alkenes. Therefore, we were interested in the development of soft carbon

nucleophiles that can ring open a wide class of bicyclic alkenes. In so, we could also address the

nucleophile limitations of the alkylative ARO.

O

OROR

RN

oxabicyclo-[2.2.1]heptanes

azabicyclicalkenes

OH

Nuc

NHR

NucRO

RO

Figure 1.2 Access to cyclohexenes and aminodihydronaphthalenes via the ARO of less-strained bicyclic alkenes

Our aim was twofold: the nucleophile should have elevated reactivity to expand the bicyclic

alkene scope and yet mild enough to allow broad nucleophile scope. With that perspective in

mind, we looked at enolate equivalents. While the use of malonates in the alkylative ARO has

been reported,2b,c these nucleophiles are limited in scope and reactivity by requirement for α,α-

disubstitution of electron withdrawing groups (Eqn 1.5).

9

Thus, to effect the addition of an acetate fragment would entail reaction with malonate followed

by decarboxylation. Interestingly, the use of Meldrum’s acid in the ARO led to an intramolecular

lactonization and decarboxylation to afford a 5-membered lactone (Eqn 1.6).2b,c

With the favourable reactivity observed for malonates, we considered the use of more reactive

and versatile enolate equivalents, such as silyl ketene acetals and enol ethers. In comparison to

organometallic reagents, these nucleophiles are stable, can be prepared in a concise manner, react

under mild conditions, and are more functional group tolerant.11 These highly useful reagents are

well-studied in the Mukaiyama aldol reaction.12 In addition, the use of rhodium catalysis in the

Mukaiyama aldol has also been reported (Eqn 1.7, 1.8).12b,c Good to high yields could be

achieved, but stereoselectivity remained an unresolved issue. The authors invoked a rhodium

enolate in the mechanism of the catalysis.

11 For selected reviews and preparation, see: a) Brownbridge, P. Synthesis 1983, 1, 1-84. (b) Brownbridge, P. Synthesis 1983, 1, 85-104. (c) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181-187. (d) Poirier, J. M. Org. Prep. & Proc. Intl. 1988, 20, 317-369. 12 (a) Kobayashi, S.; Murakami, M.; Mukaiyama, T. Chem. Lett. 1985, 1535-1538. For examples of Rh-catalyzed aldol type reactions with silyl enol ethers, see: (b) Sato, S.; Matsuda, I.; Izumi, Y. Tetrahedron Lett. 1986, 27, 5517-5520. (c) Sato, S.; Matsuda, I.; Izumi, Y. Tetrahedron Lett. 1986, 28, 6657-6660.

10

The utility of these reagents has been demonstrated by Narasaka in the ring opening of

unsymmetrical oxabicyclic alkenes using a Lewis acid (Eqn 1.9).13 The opening of these

unsymmetrical bicycles occurred in a 1,4-manner, affording high stereoselectivity.

The literature precedence implied that it would be possible to develop the ring opening of

bicyclic alkenes with silyl enolates. In addition to the development of a general method, we also

wanted to demonstrate its utility, as the added alkyl fragments would provide handles for further

derivatization to access core motifs of chiral naphthoquinone and sesquiterpene lactone natural

products (Eqn 1.10).

1.3 Optimization of the addition to benzofused oxabicyclic alkenes

We began our study on the ARO with a Rh catalyst, Josiphos, oxabicycle 1.1, and silyl ketene

acetal 1.2 in THF at 70 °C (Table 1.1). Screening of Rh catalysts suggested the importance of

cationic [Rh(cod)2]OTf over neutral RhI precursors for providing the desired reactivity (entries 1-

4). We observed a 77% yield by 1H NMR with full conversion (entry 4) and silyl group

13 Yamamoto, I.; Narasaka, K. Chem. Lett. 1995, 1129-1130.

11

migration. Due to the nonpolar nature of the ring opened products, the enantiomeric ratios of the

products were measured after the cleavage of the silyl protecting group. Excellent e.r. (>99:1)

was observed. While lowering the temperature of the reaction to 50 °C did not affect the

reaction, lowering the catalyst loading had a deleterious effect (entry 5). Optimal reactivity was

observed with 2.5 equivalents of the silyl ketene acetal (entry 6), affording the desired product in

90% yield while maintaining the excellent enantioselectivity. Deviation from THF as the solvent

gave poorer results.

Table 1.1 Reaction optimizationa

Entry [Rh] Sol Equiv 2.2 % Yield e.r.

1 [Rh(cod)Cl]2 THF 1.5 0 -

2 [Rh(cod)OH]2 THF 1.5 0 -

3 [Rh(CO)2Cl]2 THF 1.5 0 -

4 [Rh(cod)2]OTf THF 1.5 77 >99:1

5b [Rh(cod)2]OTf THF 1.5 8 n.d.

6c,d [Rh(cod)2]OTf THF 2.5 95 (90) >99:1

7c [Rh(cod)2]OTf Dioxane 2.5 47 n.d.

8c [Rh(cod)2]OTf PhMe 2.5 0 -

9c [Rh(cod)2]OTf MeCN 2.5 0 - a Representative reaction conditions: [Rh] and Josiphos were added to a 2 dram vial under Ar atmosphere and 0.5 mL of solvent

added. The mixture was stirred for 10 min. 1.1 and 1.2 were dissolved in 1.5 mL of solvent and introduced into the vial via syringe.

The mixture was stirred at the described temperature and time. Yields were determined by 1H NMR spectroscopy. b [Rh] (2.5 mol

%), Josiphos (3 mol %) were used. c Reaction conducted at 50 °C. d Reaction time 3 h. Isolated yield in parenthesis.

1.4 Scope of the rhodium-catalyzed ARO of oxabicyclic alkenes using silyl nucleophiles

Having established a high yielding and enantioselective method, we examined the scope of the

reaction with respect to the nucleophile (Scheme 1.5). In general, silyl ketene acetals displayed

higher reactivity, affording 1.3a and 1.3b. For silyl enol ethers, we found improved results upon

adding Zn(OTf)2 as a co-catalyst. We suspected that Zn2+ either served as a Lewis acid that

activated the bridgehead oxygen for the Rh oxidative insertion,9c or it could activate the

12

nucleophile, forming a zinc enolate intermediate.14 Various aryl silyl enol ethers underwent

smooth reaction (1.3c-1.3f) and the reaction was amenable to scale up, at lower catalyst loading

and under modified conditions (1.3e). An X-ray crystal structure of the enantiomer of 1.3i after

silyl deprotection revealed the absolute and relative stereoconfiguration (See Appendix 1). Alkyl

silyl enol ethers also reacted in lower yields; however, the enantioselectivity remained excellent.

While the diastereoselectivity remained to be improved (1.3b), we observed good to high yields

while retaining the excellent enantioselectivity.

R

OSi+

[Rh(cod)2]OTf (5 mol %)

(R,S)-PPF-PtBu2 (6 mol %)

THF, 50 C, 3 h

OSi

1.1 1.2 1.3

O

RO

OTBS

OEt

O

1.3a90% yield>99:1 e.r.

OTBS

Ph

O

1.3c85% yield>99:1 e.r.

OTBS

O

OMe

1.3e92% yield>99:1 e.r.

3 mmol scale2 mol % [Rh]

O

OMe

O

1.3ba

77% yield

2 : 1 d.r.

>99:1 e.r.

TMS

1.3db

69% yield

>99:1 e.r.

OTBS

O

F OTBS

O OMe

1.3fb

78% yield

>99:1 e.r.

O

O

Ph

TMS

1.3h77% yield>99:1 e.r.

OTBS

O

1.3g32% yield>99:1 e.r.

OTBS

O

1.3ib

78% yield

>99:1 e.r.

Scheme 1.5 Scope of the rhodium-catalyzed ARO of benzofused oxabicyclic alkenes. E.r. based silyl deprotection of product using TBAF, see Experimental section a Reaction conducted using silyl ketene acetal 8:1 (E/Z). b Examples reported by C. M. Le.

14 (a) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 11176-11177. (b) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182-5191.

13

The favourable ring opening of oxabicyclic alkene 1.1 led us to examine various oxabicycles,

including less reactive substrates. A variety of oxabicyclic alkene substrates reacted favourably

with the silyl ketene acetals (Scheme 1.6). Both electron poor and rich substrates (1.3j-1.3l) were

tolerated in the reaction. Efforts were invested in the opening of oxabicyclo[2.2.1]heptanes.

Employing the previously established conditions did not give any conversion. Extensive

screening of additives, bases, and solvents, including Zn(OTf)2, fluoride sources (CsF), toluene,

and dioxane, were carried out. However, the most effective adjustments were the elevation of

temperature and catalyst loading. The reaction could also be conducted on gram scale, again with

reduced catalyst loading (1.3o). Excellent yields and enantioselectivities were maintained

throughout. Direct access to the tetrasubstituted cyclohexenes was readily achieved.

Scheme 1.6 Oxabicyclic alkene scope. E.r. based on silyl deprotection of product using TBAF, see Experimental section. a Examples reported by C. M. Le. b 1.2 (3 equiv), [Rh(cod)2]OTf (7.5 mol %), (R,S)-PPF-PtBu2 (9 mol %), 70 °C, 15 h. c E.r. based on 1.3i, Scheme 1.4. d [Rh(cod)2]OTf (3.5 mol %), (R,S)-PPF-PtBu2 (4.5 mol %).

We next examined the reaction scope with respect to azabicyclic alkenes. This class of substrates

presented yet another challenge. At lower reaction temperatures (50 °C), no conversion was

observed. The elevated temperatures employed in the opening of oxabicyclo[2.2.1]heptanes

afforded the aminodihydronaphthalene in quantitative yield, but with no enantioselectivity

(Scheme 1.7). Ligand screening of the chiral ferrocene ligand classes was carried out. Other

14

members of the Josiphos family provided trace conversions and no enantioselectivity. The

Taniaphos and Walphos class of ligands also provided meagre conversions and no e.r. We were

delighted when Ferriphos afforded a high yield with a good enantioselectivity.

Scheme 1.7 Ligand screening in the ARO of azabicyclic alkenes with silyl ketene acetal

Upon examination of previous reports on the ARO of azabicycles, Y.-H. Cho in our group

described the use of Ferriphos with amine nucleophiles. Importantly, excess loading of the ligand

to the metal (2.2 L/Rh ratio) was crucial in conferring high enantioselectivity.7b Mechanistic

studies were conducted to explain this puzzling effect. The authors observed that the association

of the nucleophile to the catalyst prior to the enantiodiscriminating C-N bond oxidative insertion

step caused loss in enantioselectivity. However, the excess ligand served to displace the

nucleophile prior to the C-N bond insertion. The proposed dual ligand-bound complex was

responsible for high enantioinduction (Eqn 1.11).7b

Thus, further ligand screening within the Ferriphos family with elevated ligand loadings was

carried out. Under the optimized conditions, we observed high yields and enantioselectivity

employing the MandyPhos ligand (Scheme 1.8). The sulfonyl aryl nitrogen protecting groups

15

displayed the best reactivity (1.3p). N-Boc-azabicyclic alkenes did not undergo the desired

reaction as the Lewis acidic reaction conditions promoted Boc-cleavage. With the addition of

Zn(OTf)2 as a co-catalyst, silyl enol ethers participated in the ring opening to afford 1.3q and

1.3r. While silyl group migration was observed in the crude product, the labile N-silylated

product underwent deprotection upon treatment with silica gel. The ARO product 1.3pa was

hydrogenated to access the 2-alkyl-1-amino-tetralin core 1.3t with the trans-stereoconfiguration.

This method offered a complementary approach to the asymmetric hydrogenation of

tetrasubstituted cyclic enamides derived from tetralones,15 which would provide these cores with

the corresponding cis stereoconfiguration.

Scheme 1.8 Azabicyclic alkene scope and derivatization. Absolute stereoconfiguration of 1.3q determined by X-ray crystallography. See Appendix 1 for details.

We wanted to demonstrate the utility of this method by performing a number of modifications of

the ring opening products that would allow access to diverse structural motifs (Scheme 1.9). For

15 (a) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem. 1999, 64, 1774-1775. (b) Chen, X.; Hu, X.-Y.; Shu, C.; Zhang, Y.-H.; Zheng, Y.-S.; Jiang, Y.; Yuan, W.-C.; Liu, B.; Zhang, X.-M. Org. Biomol. Chem. 2013, 11, 3089-3093.

16

the chiral dihydronaphthalene products, the alkene served as a useful handle for derivatization.

For example, adduct 1.3a was converted to iodolactone 1.4 or epoxide 1.5. These scaffolds are

derivatives of chiral naphthoquinones such as glycoquinone16 or Avicennone G,17 which are

congeners of podophyllotoxins,18 and exhibit anti-bacterial and anti-proliferative properties.

Scheme 1.9 Functionalization of the alkylated oxabicyclic alkenes. a Example reported by C. M. Le.

16 Ito, C.; Kondo, Y.; Rao, K. S.; Tokuda, H.; Nishino, H.; Furukawa, H. Chem. Pharm. Bull. 1999, 47, 1579-1581. 17 Han, L.; Huang, X.; Dahse, H.-M.; Moellmann, U.; Fu, H.; Grabley, S.; Sattler, I.; Lin, W. J. Nat. Prod. 2007, 70, 923-927. 18 (a) Damayanthi, Y.; Lown, J. W. Curr. Med. Chem. 1998, 5, 205-252. (b) Canel, C.; Moraes, R. M.; Dayan, F. E.; Ferreira, D. Phytochemistry 2000, 54, 115-120. (c) Xu, H.; Lv, M.; Tian, X. Curr. Med. Chem. 2009, 16, 327-349.

17

The silyl protecting group could also be removed efficiently with high yields (1.6). However,

keeping the silyl ether may be advantageous as saponification and amide coupling can proceed to

afford 1.8. In addition, lactonization of the ring opening products can access structural motif 1.7,

found in sesquiterpene lactones, such as eudesmanolides.19

1.5 Conclusions

We have successfully employed silyl ketene acetals and enol ethers as reactive and functional

group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of

a range of oxa/azabicyclic alkenes. This method provided access to enantioenriched

dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward

core motifs of napthoquinone and sesquiterpene natural products.

1.6 Experimental section

General Experimental Procedures: Unless otherwise noted, reactions were carried out under

argon atmosphere, in single-neck, round bottom flasks fitted with a rubber septum, with

magnetic stirring. Air- or water-sensitive liquids and solutions were transferred via syringe or

stainless steel cannula. Organic solutions were concentrated by rotary evaporation at 23–40 °C

under 40 Torr (house vacuum). Analytical thin layer chromatography (TLC) was performed with

Silicycle™ normal phase glass plates (0.25 mm, 60-A pore size, 230-400 mesh). Visualization

was done under a 254 nm UV light source and generally by immersion in acidic aqueous-

ethanolic vanillin solution, or in potassium permanganate (KMnO4), followed by heating using a

heat gun. Purification of reaction products was generally done by flash chromatography with

Silicycle™ Ultra-Pure 230-400 mesh silica gel, as described by Still et al.20

19 In various reported syntheses of a number of members in this class, the lactone core was α-functionalized to access natural products in this family. For selected examples, see: (a) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.; Marinovic, M. J. Am. Chem. Soc. 1977, 99, 5773-5780. (b) Wender, P. A.; Lechleiter, J. C. J. Am. Chem. Soc. 1980, 102, 6340-6341. (c) Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756-1757. (d) Still, W. C.; Murata, S.; Revial, G.; Yoshihara, K. J. Am. Chem. Soc. 1983, 105, 625-627. (e) Chen, J.; Chen, J.; Xie, Y.; Zhang, H. Angew. Chem. Int. Ed. 2012, 51, 1024-1027. 20 Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.

18

Materials: Unless otherwise indicated, starting materials, ligands, and catalysts were obtained

from Aldrich, Strem or VWR and used without further purification. Solvents DCM, THF,

dioxane, PhMe, MeCN were freshly distilled under N2 prior to use.

Instrumentation: Proton nuclear magnetic resonance spectra (1H NMR) and carbon nuclear

magnetic resonance spectra (13C NMR) were recorded at 23 °C with a Varian Mercury 400 (400

MHz/100 MHz) NMR spectrometer equipped with a Nalorac4N-400 probe, a Bruker Avance III

400 MHz, an Agilent DD2 500 MHz, or a Varian 400 (400 MHz/100 MHz) NMR spectrometer

equipped with ATB8123-400 probe. Recorded shifts for protons are reported in parts per million

(δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR

solvents (CHCl3: δ 7.26, CHDCl2: δ 5.29, C6HD5: δ 7.15, CD2HOD: δ 3.30). Chemical shifts for

carbon resonances are reported in parts per million (δ scale) downfield from tetramethylsilane

and are referenced to the carbon resonances of the solvent (CDCl3: δ 77.0, CH2Cl2: δ 53.8, C6D6:

δ 128.0, CD3OD: δ 49.2). Data are represented as follows: chemical shift, integration,

multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintuplet, sx = sextet, sp =

septuplet, dd = doublet of doublets, m = multiplet, br = broad), and coupling constant (J, Hz).

Infrared (IR) spectra were obtained using a Shimadzu FTIR-8400S FT-IR spectrometer as a neat

film on a NaCl plate or using a Perkin-Elmer Spectrum 100 instrument equipped with a single-

bounce diamond / ZnSe ATR accessory as a powder. Data is presented as follows: frequency of

absorption (cm–1). High resolution mass spectra were obtained from a SI2 Micromass 70S-250

mass spectrometer (EI), or an ABI/Sciex Qstar mass spectrometer (ESI), or JMS-T1000LC mass

spectrometer (DART). Melting points were taken on a Fisher-Johns melting point apparatus and

are uncorrected. Optical rotations were measured in a 5.0 cm cell with a Rudolph Autopol IV

polarimeter digital polarimeter equipped with a sodium lamp source (589 nm), and are reported

as follows: [α]DT°C (c = g/100 mL, solvent). The HPLC system was a HP 1100 Series modular

system from Agilent, operated by a ChemStation LC 3D software, v. 10.02. The details of

column type and run conditions are described below in the characterization section.

General procedure A for the ARO with silyl enolates

A 2-dram vial equipped with a stir bar was charged with [Rh(cod)2]OTf (4.7 mg, 5 mol %) and

(R, S)-PPF-PtBu2 (6.5 mg, 6 mol %). When silyl enol ethers were employed as nucleophiles,

ZnOTf2 (14.5 mg, 20 mol %) was added to the same vessel. The vial was purged with argon,

19

THF (0.5 mL) was added, and the catalyst solution was stirred at r.t. for 10 min. A separate vial

was charged with oxabicyclic alkene (0.2 mmol, 1.0 equiv) and silyl enolate (2.5 equiv). The

reagents were taken up in THF and transferred to the reaction vessel via syringe such that the

final reaction concentration = 0.1 M with respect to the oxabicyclic alkene. The vial was sealed

with a Teflon-lined PTFE cap and heated at 50 °C until TLC analysis showed full conversion.

The crude mixture was filtered through a plug of silica gel, concentrated under reduced pressure,

and purified by silica gel chromatography.

General procedure B for the silyloxy ether deproctection of ARO adducts

A dry 2-dram vial equipped with a stir bar was charged with the ARO adduct and distilled THF

(0.2 M). To the solution was added TBAF (1.0 M in THF, 1.2 equiv) dropwise and the solution

was stirred until TLC indicated reaction completion. The mixture was quenched with a drop of

water, concentrated under reduced pressure, and purified by silica gel chromatography.

General procedure C for ARO of azabicyclic alkenes

A 2-dram vial equipped with a stir bar was charged with [Rh(cod)2]OTf (2.3 mg, 5 mol %) and

(S,S)-(-)-2,2'-Bis[(R)-(N,N-dimethylamino)(phenyl)methyl]-1,1'-

bis(diphenylphosphino)ferrocene (MandyPhos) (10 mg, 12 mol %). When silyl enol ethers were

employed as nucleophiles, ZnOTf2 (14.5 mg, 20 mol %) was added to the same vessel.

Azabicylic alkene (0.2 mmol, 1.0 equiv) and silyl enolate (5 equiv) were subsequently

introduced. The vial was purged with argon, THF (2mL, 0.1M) was added, and the catalyst

solution was stirred at r.t. for 10 min. The vial was sealed with a Teflon-lined PTFE cap and

heated at 80 °C for 15 h. The crude mixture was filtered through a plug of silica gel, concentrated

under reduced pressure, and purified by silica gel chromatography.

I. Characterization of ARO products:

ethyl 2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)acetate 1.3a

20

Prepared according to General Procedure A using oxabicycle 1.1 (29 mg, 0.2 mmol) and tert-

butyl((1-ethoxyvinyl)oxy)dimethylsilane (101 mg, 0.5 mmol, 2.5 equiv). Purified by silica gel

chromatography (5% Et2O:Hex) and isolated as a colourless oil (31.2 mg, 90%). 1H NMR (400

MHz, CDCl3) δ 7.31 – 7.14 (m, 3H), 7.07 (dd, J = 7.1, 1.6 Hz, 1H), 6.49 (dd, J = 9.6, 1.3 Hz,

1H), 5.95 (dd, J = 9.6, 4.4 Hz, 1H), 4.59 (d, J = 6.2 Hz, 2H), 4.14 (qd, J = 7.1, 1.6 Hz, 2H), 3.04

– 2.90 (m, 1H), 2.42 (dd, J = 15.5, 6.5 Hz, 1H), 2.21 (dd, J = 15.5, 8.7 Hz, 1H), 1.25 (t, J = 7.1

Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), -0.02 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.4, 136.1,

133.1, 129.8, 128.1, 127.4, 127. 3, 127.1, 126.4, 72.5, 60.6, 39.6, 35.9, 26.0, 18.3, 14.4, -4.1, -

4.2.; IR (NaCl, CHCl3, cm-1) 2957, 2930, 2888 2857, 1732, 1603, 1464, 1362, 1252, 1153, 1067,

1034, 943, 895, 837, 775.; HRMS (DART+): 347.20383 [M+H]+ (calc’d 347.347.20425 for

C20H31O3Si). For (R, S)-enantiomer: [α]D20 = 163° (c = 0.39, CHCl3). The absolute configuration

was assigned by analogy with compound 1.3i’.

ethyl 2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)acetate 1.3aa’

Prepared according to General Procedure B using 1.3a (69 mg, 0.2 mmol). Purified by silica gel

chromatography (20% EtOAc:Hex) and isolated as a beige solid (43 mg, 94%). 1H NMR (400

MHz, CDCl3) δ 7.47 – 7.38 (m, 1H), 7.31 – 7.19 (m, 2H), 7.10 (dd, J = 6.5, 2.2 Hz, 1H), 6.51

(dd, J = 9.6, 1.6 Hz, 1H), 5.93 (dd, J = 9.6, 4.1 Hz, 1H), 4.58 (s, 1H), 4.15 (qd, J = 7.1, 1.9 Hz,

2H), 3.11 – 2.93 (m, 1H), 2.50 (dd, J = 15.6, 7.0 Hz, 1H), 2.36 (dd, J = 15.6, 7.5 Hz, 1H), 2.19

(s, 1H), 1.26 (t, J = 7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.6, 135.9, 132.3, 129.4,

128.5, 128.1, 127.5, 127.0, 126.6, 72.5, 60.8, 39.4, 36.9, 14.3.; IR (NaCl, CHCl3, cm-1) 3061,

3034, 2897, 1976, 1597, 1580, 1484, 1449, 1408, 1360, 1272, 1240, 1210, 1182, 1160, 1120,

1033, 1001, 945, 902, 781, 772, 750.; M.p. 35-36 °C.; HRMS (DART+): 250.14449 [M+NH4]+

(calc’d 250.14432 for C14H20NO3).; The e.r. was measured by HPLC: Chiralpak AD-H column,

flow 0.8 mL/min, hexane/2-propanol = 80/20, tR = 14.0 min (major) 14.7 min (minor).; For (R,

S)-enantiomer: [α]D20 = -611° (c = 0.19, CHCl3) for >99:1 e.r. The absolute configuration was

assigned by analogy with compound 1.3i’.

21

Methyl 2-((1S,2S)-1-((trimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)propanoate 1.3b

Prepared according to General Procedure A using oxabicycle 1.1 (29 mg, 0.2 mmol) and (E)-((1-

methoxyprop-1-en-1-yl)oxy)trimethylsilane (80 mg, 0.5 mmol, 2.5 equiv). Purified by silica gel

chromatography (5% Et2O:Hex) and isolated as an inseparable mixture of diastereomers and

colourless oil (46.7 mg, 77%). 1H NMR(400 MHz, CDCl3) δ 7.26 – 7.18 (m, 9H), 7.11 – 7.01

(m, 3H), 6.59 – 6.50 (m, 3H), 5.98 – 5.88 (m, 3H), 4.86 (d, J = 6.2 Hz, 2H), 4.62 (d, J = 6.8 Hz,

1H), 3.66 (s, 3H), 3.59 (s, 6H), 3.00 – 2.84 (m, 1H), 2.74 – 2.67 (m, 2H), 2.67 – 2.51 (m, 3H),

1.15 (d, J = 7.1 Hz, 9H), 0.15 (d, J = 1.7 Hz, 25H).; 13C NMR (101 MHz, CDCl3) δ 176.2, 175.4,

136.5, 136.4, 133.0, 132.9, 128.2, 128.1, 127.8, 127.7, 127.6, 127.6, 127.5, 127.2, 127.1, 126.5,

126.4, 71.4, 71.1, 51.8, 51.6, 46.2, 45.1, 39.9, 39.7, 15.1, 13.7, 0.78, 0.67, 0.1.; IR (NaCl,

CHCl3, cm-1) 3036, 2953, 2902, 2846, 1722, 1489, 1464, 1436, 1352, 1250, 1197, 1050, 951,

893, 840, 780, 749, 686.; HRMS (DART+): 322.18519. [M+NH4]+ (calc’d322.18384 for

C17H28NO3Si). The absolute configuration was assigned by analogy with compound 1.3i’. The

diastereoisomeric ratio was determined by the integration ratio of peaks 3.66 and 3.59 ppm in the 1H NMR spectrum (1:2)

(R)-methyl 2-((1S,2S)-1-hydroxy-1,2-dihydronaphthalen-2-yl)propanoate 1.3b’

Prepared according to General Procedure B using 1.3b (14 mg, 0.046 mmol). Purified by silica

gel chromatography (10% EtOAc:Hex) and isolated as an inseparable mixture of diastereomers

and colourless oil (10 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.33 (m, 3H), 7.31 – 7.21

(m, 7H), 7.15 – 7.07 (m, 3H), 6.64 – 6.51 (m, 3H), 5.97 – 5.81 (m, 3H), 4.78 (s, 2H), 4.58 (s,

1H), 3.66 (s, 3H), 3.60 (s, 6H), 3.02 – 2.87 (m, 3H), 2.74 – 2.54 (m, 3H), 2.15 (s, 2H), 1.80 (s,

1H), 1.23 – 1.10 (m, 9H).; 13C NMR (75 MHz, CDCl3) δ 175.9, 136.4, 132.3, 128.7, 128.4,

128.23, 128.15, 128.14, 127.9, 127.1, 127.1, 126.73, 126.70, 126.65, 71.0, 70.0, 51.9, 51.8, 45.5,

22

45.1, 41.0, 40.6, 14.1, 14.0.; IR (NaCl, CHCl3, cm-1) 3435, 3033, 2979, 2950, 2890, 1722, 1713,

1709, 1436, 1381, 1352, 1269, 1222. 1200, 1170, 1115, 1071, 1048, 1040, 996, 946, 906, 882,

783, 770, 746.; HRMS (DART+): 250.14444 [M+NH4]+ (calc’d 250.14432 for C14H20NO3).; The

e.r. was measured by HPLC: Chiralpak OD-H column, flow 0.5 mL/min, hexane/2-

propanol/diethylamine = 90/10/1, tR = 18.2, 27.6 min (major), 25.6, 35.7 min (minor); >99:1 e.r.

The absolute configuration was assigned by analogy with compound 1.3i’. The diastereoisomeric

ratio was determined by the integration ratio of peaks 3.66 and 3.60 ppm in the 1H NMR

spectrum (1:2)

2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)-1-phenylethanone

1.3c


butyldimethyl((1-phenylvinyl)oxy)silane (116 mg, 0.5 mmol, 2.5 equiv). Purified by silica gel


MHz, CDCl3) δ 7.91 (dd, J = 8.3, 1.1 Hz, 2H), 7.61 – 7.50 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.26

(t, J = 6.6 Hz, 2H), 7.23 – 7.18 (m, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 6.03

(dd, J = 9.6, 4.5 Hz, 1H), 4.64 (d, J = 5.8 Hz, 1H), 3.27 – 3.16 (m, 1H), 3.12 (dd, J = 16.7, 5.9

Hz, 1H), 2.85 (dd, J = 16.7, 8.5 Hz, 1H), 0.90 (s, 9H), 0.15 (s, 3H), -0.00 (s, 3H).; 13C NMR

(125 MHz, CDCl3) δ 198.9, 137.0, 136.1, 133.3, 133.2, 130.6, 128.7, 128.2, 128.1, 127.6, 127.3,

126.7, 126.4, 72.7, 39.9, 39.0, 26.0, 18.3, -4.0, -4.2.; IR (NaCl, CHCl3, cm-1) 3066, 3033, 2955,

2928, 2987, 2855, 1679, 1598, 1489, 1472, 1464, 1447, 1407, 1390, 1360, 1353, 1318, 1255,

1231, 1213, 1201, 1181, 1122, 1062, 1033, 1002, 989, 893, 878, 850, 837, 813, 751, 690.;

HRMS (DART+): 396.23623 [M+NH4]+ (calc’d 396.23588 for C24H34NO2Si).; For (S, R)-

enantiomer: [α]D20 = -251° (c = 0.47, CHCl3). The absolute configuration was assigned by

analogy with compound 1.3i’.

23

2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-1-phenylethanone 1.3c’

Prepared according to General Procedure B using 1.3c (38 mg, 0.1 mmol). Purified by silica gel

chromatography (20% EtOAc:Hex) and isolated as white solid (23.5 mg, 90%). 1H NMR (500

MHz, CDCl3) δ 7.95 – 7.89 (m, 2H), 7.60 – 7.52 (m, 1H), 7.47 – 7.37 (m, 3H), 7.32 – 7.23 (m,

3H), 7.13 (dd, J = 7.1, 1.6 Hz, 1H), 6.53 (dd, J = 9.6, 1.5 Hz, 1H), 6.03 (dd, J = 9.6, 4.4 Hz, 1H),

4.62 (t, J = 6.7 Hz, 1H), 3.33 (dtdd, J = 7.7, 6.2, 4.4, 1.5 Hz, 1H), 3.18 (dd, J = 17.2, 6.5 Hz, 1H),

3.01 (dd, J = 17.2, 7.4 Hz, 1H), 2.04 (d, J = 7.4 Hz, 1H).; 13C NMR (125 MHz, CDCl3) δ 199.0,

136.9, 135.8, 133.4, 132.5, 130.2, 128.7, 128.6, 128.3, 128.0, 127.3, 127.1, 126.7, 72.6, 40.8,

38.5.; IR (NaCl, CHCl3, cm-1) 3458, 3061, 3029, 2917, 2862, 1668, 1597, 1448, 1400, 1350,

1270, 1241, 1193, 1119, 1087, 1010, 1002, 741, 748, 688.; M.p. 118-119 °C.; HRMS (DART+):

282.14854 [M+NH4]+ (calc’d 282.144940 for C18H20NO2).; The e.r. was measured by HPLC:

Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 80/20, tR = 14.2 min (major),

12.8 min (minor).; For (S, R)-enantiomer: [α]D20 = -187° (c = 0.81, CHCl3) for >99:1 e.r. The

absolute configuration was assigned by analogy with compound 1.3i’.

2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)-1-(4-

fluorophenyl)ethanone 1.3d


butyl((1-(4-fluorophenyl)vinyl)oxy)dimethylsilane (221 mg, 0.875 mmol, 2.5 equiv). Purified by

silica gel chromatography (10% Et2O:Hex) and isolated as a colourless oil (95.8 mg, 69%). 1H

NMR (400 MHz, CDCl3) δ 7.95 – 7.89 (m, 2H), 7.30 – 7.16 (m, 2H), 7.14 – 7.02 (m, 3H), 6.49

(d, J = 9.6 Hz, 1H), 6.01 (dd, J = 9.6, 4.6 Hz, 1H), 4.62 (d, J = 5.7 Hz, 1H), 3.24 – 3.14 (m, 1H),

3.07 (dd, J = 16.6, 5.9 Hz, 1H), 2.80 (dd, J = 16.6, 8.5 Hz, 1H), 0.89 (s, 9H), 0.14 (s, 3H), -0.01

(s, 3H).; 13C NMR (100 MHz, CDCl3) δ 197.3, 165.9 (d, J = 254.8 Hz), 136.0, 133.5 (d, J = 3.0

24

Hz), 133.2, 130.9 (d, J = 9.3 Hz), 130.4, 128.2, 127.6, 127.3, 126.8, 126.5, 115.8 (d, J = 21.9

Hz), 72.7, 39.8, 39.0, 26.0, 18.3, -4.0, -4.2.; 19F NMR (377 MHz, CDCl3) δ -105.10 (dq, J = 8.2,

5.6 Hz).; IR (NaCl, neat, cm-1) 2955, 2928, 2891, 2856, 1688, 1599, 1506, 1472, 1410, 1360,

1236, 1200, 1155, 1123.; HRMS (DART+): 414.22740 [M+NH4+] (calc’d 414.22646 for

C24H33FNO2Si).; For (S, R)-enantiomer: [α]D20 = -246° (c = 0.81, CHCl3). The absolute

configuration was assigned by analogy with compound 1.3i’.

1-(4-fluorophenyl)-2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)ethanone 1.3d’

Prepared according to General Procedure B using 1.3d (20 mg, 0.05 mmol). Purified by silica gel

chromatography (10% Et2O:DCM) and isolated as a white solid (12.7 mg, 90%). 1H NMR (600

MHz, CDCl3) δ 7.98 – 7.93 (m, 2H), 7.42 – 7.38 (m, 1H), 7.32 – 7.26 (m, 2H), 7.15 – 7.08 (m,

3H), 6.53 (dd, J = 9.6, 1.2 Hz, 1H), 6.02 (dd, J = 9.6, 4.4 Hz, 1H), 4.61 (t, J = 6.8 Hz, 1H), 3.35

– 3.27 (m, 1H), 3.14 (dd, J = 17.1, 6.4 Hz, 1H), 2.98 (dd, J = 17.1, 7.5 Hz, 1H), 2.01 (d, J = 7.4

Hz, 1H).; 13C NMR (100 MHz, CDCl3) δ 197.3, 166.0 (d, J = 255.1 Hz), 135.8, 133.4 (d, J = 3.0

Hz), 132.4, 131.0 (d, J = 9.3 Hz), 130.1, 128.8, 128.1, 127.4, 127.2, 126.8, 115.9 (d, J = 21.9

Hz), 72.7, 40.8, 38.6.; 19F NMR (376 MHz, CDCl3) δ -104.86 – -104.95 (m).; IR (NaCl, neat,

cm-1) 3474, 1674, 1595, 1505, 1451, 1404, 1366, 1236, 1157, 1036, 1011.; M.p. 128-130 °C.;

HRMS (DART+): 300.14025 [M+NH4+] (calc’d 300.13998 for C18H19FNO2).; The e.r. was

measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 80/20, tR

= 13.5 min (major), 15.3 min (minor); For (S, R)-enantiomer: [α]D20 = -302° (c = 0.71, CHCl3)

for >99:1 e.r. The absolute configuration was assigned by analogy with compound 1.3i’.

25


methoxyphenyl)ethanone 1.3e


butyl((1-(4-methoxyphenyl)vinyl)oxy)dimethylsilane (1.98 g, 7.5 mmol, 2.5 equiv). Purified by

silica gel chromatography (15% Et2O:Hex) and isolated as a colourless oil (1.127 g, 92%). 1H

NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 7.31 – 7.16 (m, 3H), 7.12 – 7.06 (m, 1H),

6.89 (d, J = 8.9 Hz, 2H), 6.48 (d, J = 9.6 Hz, 1H), 6.02 (dd, J = 9.6, 4.6 Hz, 1H), 4.62 (d, J = 5.8

Hz, 1H), 3.85 (s, 3H), 3.24 – 3.14 (m, 1H), 3.05 (dd, J = 16.3, 5.9 Hz, 1H), 2.78 (dd, J = 16.3,

8.5 Hz, 1H), 0.89 (s, 9H), 0.14 (s, 3H), -0.01 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 197.4,

163.6, 136.1, 133.3, 130.8, 130.5, 130.2, 128.1, 127.6, 127.2, 126.6, 126.4, 113.8, 72.7, 55.6,

39.5, 39.1, 26.0, 18.3, -4.1, -4.2.; IR (NaCl, CHCl3, cm-1) 3061, 3034, 2955, 2929, 2897, 2855,

1679, 1601, 1576, 1511, 1498, 1472, 1464, 1419, 1401, 1368, 1304, 1260, 1215, 1169, 1060,

1033, 987, 940, 894, 852, 776.; HRMS (ESI+): 431.2017 [M+Na]+ (calc’d 431.2013 for

C25H32NaO3Si).; For (S, R)-enantiomer: [α]D20 = -624° (c = 0.22, CHCl3). The absolute


2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-1-(4-methoxyphenyl)ethanone 1.3e’

Prepared according to General Procedure B using 1.3e (49 mg, 0.12 mmol). Purified by silica gel

chromatography (10% Et2O:Hex) and isolated as a white solid (33.1 mg, 92%). 1H NMR (400

MHz, CDCl3) δ 7.91 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 6.5 Hz, 1H), 7.27 (pd, J = 7.5, 1.6 Hz, 2H),

7.11 (d, J = 6.7 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 6.51 (d, J= 9.6 Hz, 1H), 6.00 (dd, J = 9.6, 4.3

Hz, 1H), 4.61 (t, J = 6.1 Hz, 1H), 3.85 (s, 3H), 3.38 – 3.23 (m, 1H), 3.11 (dd, J = 16.9, 6.6 Hz,

1H), 2.96 (dd, J = 16.9, 7.3 Hz, 1H), 2.27 (s, 1H).; 13C NMR (100 MHz, CDCl3) δ 197.6, 163.8,

26

135.9, 132.5, 130.60 130.4, 130.0, 128.6, 128.0, 127.3, 127.0, 126.7, 113.9, 72.7, 55.6, 40.6,

38.7.; IR (NaCl, CHCl3, cm-1) 3453, 3052, 2917, 2848, 1672, 1599, 1575, 1508, 1452, 1419,

1361, 1316, 1259, 1221, 1170, 1113, 1014, 837, 773.; M.p. 130-132 °C.; HRMS (ESI+):

317.1155 [M+Na]+ (calc’d 317.1148 for C19H18NaO3).; The e.r. was measured by HPLC:


15.8 min (minor).; For (S, R)-enantiomer: [α]D20 = -308° (c = 0.23, CHCl3) for >99:1 e.r. The



methoxyphenyl)ethanone 1.3f


butyl((1-(2-methoxyphenyl)vinyl)oxy)dimethylsilane (231 mg, 0.875 mmol, 2.5 equiv). Purified

by silica gel chromatography (20% Et2O:Hex) and isolated as a white solid (111.6 mg, 78%). 1H

NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 7.7, 1.8 Hz, 1H), 7.43 (ddd, J = 8.4, 7.3, 1.8 Hz, 1H),

7.28 – 7.15 (m, 4H), 7.06 (dd, J = 7.1, 1.4 Hz, 1H), 6.99 (td, J = 7.6, 0.9 Hz, 1H), 6.92 (d, J = 8.4

Hz, 1H), 6.46 (d, J = 9.5 Hz, 1H), 5.96 (dd, J = 9.5, 4.1 Hz, 1H), 4.61 (d, J = 6.0 Hz, 1H), 3.80

(s, 3H), 3.22 – 3.08 (m, 2H), 2.92 – 2.82 (m, 1H), 0.89 (s, 9H), 0.13 (s, 3H), -0.01 (s, 3H).; 13C

NMR (101 MHz, CDCl3) δ 201.5, 158.5, 136.6, 133.5, 133.4, 131.1, 130.4, 128.7, 127.9, 127.4,

127.1, 126.5, 126.2, 120.8, 111.6, 72.7, 55.6, 45.0, 39.1, 26.0, 18.3, -4.1 (diastereotopic

(CH3)2Si- have identical chemical shifts).; IR (NaCl, neat, cm-1) 2955, 2928, 2856, 1668, 1598,

1484, 1462, 1287, 1246, 1058.; M.p. 81-82 °C.; HRMS (ESI+): 431.2015 [M+Na]+ (calc’d

431.2013 for C25H32O3NaSi).; For (S, R)-enantiomer: [α]D26 = -263° (c = 0.77 , CHCl3). The


27

2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-1-(2-methoxyphenyl)ethanone 1.3f’

Prepared according to General Procedure B using 1.3f (20.4 mg, 0.05 mmol). Purified by silica

gel chromatography (10% Et2O:DCM) and isolated as a white solid (13.2 mg, 90%). 1H NMR

(400 MHz, CDCl3) δ 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.30 – 7.22 (m, 2H),

7.15 – 7.07 (m, 1H), 7.03 – 6.97 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 9.6, 1.1 Hz, 1H),

5.97 (dd, J = 9.6, 4.2 Hz, 1H), 4.62 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.33 – 3.23 (m, 1H), 3.18

(dd, J = 17.0, 7.0 Hz, 1H), 3.05 (dd, J = 17.0, 6.7 Hz, 1H), 2.17 (d, J = 7.1 Hz, 1H).; 13C NMR

(101 MHz, CDCl3) δ 201.6, 158.6, 136.2, 133.8, 132.6, 130.7, 130.5, 128.4, 128.4, 127.9, 127.2,

127.0, 126.6, 120.9, 111.7, 72.8, 55.6, 46.2, 39.0.; IR (NaCl, neat, cm-1) 3430, 3031, 2942, 2838,

1667, 1597, 1484, 1464, 1436, 1288, 1245.; M.p. 94-97 °C.; HRMS (DARTˉ): 293.11701 [M-

H]ˉ (calc’d 293.11777 for C19H17O3).; The e.r. was measured by HPLC: Chiralpak AD-H

column, flow 0.8 mL/min, hexane/2-propanol = 80/20, tR = 17.5 min (major), 19.6 min (minor).;

For (S, R) enantiomer: [α]D26 = -277° (c = 0.77, CHCl3) for >99:1 e.r. The absolute configuration

was assigned by analogy with compound 1.3i’.

1-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)-3-methylbutan-2-

one 1.3g


butyldimethyl((3-methylbut-1-en-2-yl)oxy)silane (100 mg, 0.5 mmol, 2.5 equiv). Purified by

silica gel chromatography (5% Et2O:Hex) and isolated as a colourless oil (22.1. mg, 32%). 1H

NMR (400 MHz, CDCl3) δ 7.31 – 7.13 (m, 4H), 7.08 (d, J = 7.1 Hz, 1H), 6.46 (d, J = 9.5 Hz,

1H), 5.92 (dd, J = 9.5, 4.7 Hz, 1H), 4.48 (d, J = 5.2 Hz, 1H), 3.11 – 2.96 (m, 1H), 2.64 – 2.40 (m,

2H), 2.31 (dd, J = 17.0, 8.6 Hz, 1H), 1.05 (d, J = 6.9 Hz, 6H), 0.86 (s, 9H), 0.12 (s, 3H), -0.04 (s,

3H).; 13C NMR (100 MHz, CDCl3) δ 213.4, 135.9, 133.2, 130.6, 128.2, 127.8, 127.2, 126.5,

28

126.4, 72.6, 41.5, 41.3, 38.4, 26.0, 18.3, 18.2, -4.1, -4.2.; IR (NaCl, CHCl3, cm-1) 3034, 2958,

2929, 2887, 2857, 1710, 1464, 1454, 1360, 1257, 1125, 1062, 1032, 893, 837, 813, 797, 775.;

HRMS (DART+): 362.25217 [M+NH4]+ (calc’d 352.25153 for C21H36NO2Si).; For (R, S)-



1-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-methylbutan-2-one 1.3g’

Prepared according to General Procedure B using 1.3g (10.7 mg, 0.031 mmol): Purified by silica

gel chromatography (10% Et2O:Hex) and isolated as a beige solid (6.4 mg, 90%). 1H NMR (500

MHz, CDCl3) δ 7.42 – 7.36 (m, 1H), 7.30 – 7.23 (m, 2H), 7.11 (dd, J = 7.1, 1.7 Hz, 1H), 6.49

(dd, J = 9.6, 1.5 Hz, 1H), 5.90 (dd, J = 9.6, 4.3 Hz, 1H), 4.49 (d, J = 5.0 Hz, 1H), 3.18 – 3.05 (m,

1H), 2.64 (dd, J = 17.4, 6.8 Hz, 1H), 2.57 (dt, J = 13.9, 6.9 Hz, 1H), 2.49 (dd, J = 17.4, 7.2 Hz,

1H), 1.12 – 1.04 (m, 6H).; 13C NMR (125 MHz, CDCl3) δ 213.7, 135.9, 132.4, 130.3, 128.6,

128.0, 127.2, 127.1, 126.7, 72.8, 42.8, 41.3, 38.2, 18.31, 18.25.; IR (NaCl, CHCl3, cm-1) 3177,

3043, 2960, 2906, 1710, 1450, 1383, 1305, 1264, 1195, 1118, 1084, 992, 961, 902, 851, 792,

776, 601.; M.p. 88-89 °C.; HRMS (DART+): 248.16464 [M+NH4]+ (calc’d 248.16505 for

C15H22 NO2).; The e.r. was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min,

hexane/2-propanol = 90/10, tR = 13.1 min.(major), 15.0 min (minor).; For (S, R)-enantiomer:

[α]D20 = -233° (c = 0.21, CHCl3) for >99:1 e.r. The absolute configuration was assigned by


29

(E)-4-phenyl-1-((1S,2R)-1-((trimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)but-3-en-2-one

1.3h

Prepared according to General Procedure A using oxabicycle 1.1 (29 mg, 0.2 mmol) and (E)-

trimethyl((4-phenylbuta-1,3-dien-2-yl)oxy)silane (109 mg, 0.5 mmol, 2.5 equiv). Purified by

silica gel chromatography (10% Et2O:Hex) and isolated as a colourless oil (55.8 mg, 77%). 1H

NMR (500 MHz, CDCl3) δ 7.58 – 7.46 (m, 3H), 7.41 – 7.36 (m, 3H), 7.31 – 7.19 (m, 3H), 7.11

(d, J = 7.1 Hz, 1H), 6.72 (d, J = 16.2 Hz, 1H), 6.52 (dd, J = 9.6, 1.4 Hz, 1H), 6.01 (dd, J = 9.6,

4.4 Hz, 1H), 4.66 (d, J = 6.3 Hz, 1H), 3.15 (ddd, J = 8.1, 4.4, 1.7 Hz, 1H), 2.83 (dd, J = 16.3, 6.2

Hz, 1H), 2.60 (dd, J = 16.3, 8.3 Hz, 1H), 0.18 (s, 9H).; 13C NMR (125 MHz, CDCl3) δ 198.9,

143.0, 136.0, 134.5, 133.1, 130.7, 130.4, 129.1, 128.4, 128.2, 127.5, 127.4, 126.9, 126.5, 126.3,

72.7, 42.1, 38.9, 0.7.; IR (NaCl, CHCl3, cm-1) 3061, 2956, 1699, 1661, 1609, 1576, 1496, 1451,

1401, 1358, 1326, 1251, 1201, 1180, 1125, 1100, 1055, 1032, 976, 898, 871, 785, 748.; HRMS

(ESI+): 385.1605 [M+Na]+ (calc’d 385.161594 for C23H26NaO2Si).; For (R, S)-enantiomer: [α]D20

= -680° (c = 0.21, CHCl3). The absolute configuration was assigned by analogy with compound

1.3i’.

(E)-1-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-4-phenylbut-3-en-2-one 1.3h’

Prepared according to General Procedure B using 1.3h (62 mg, 0.17 mmol). Purified by silica gel

chromatography (20% EtOAc:Hex) and isolated as a white solid (44 mg, 90%). 1H NMR (400

MHz, CDCl3) δ 7.59 – 7.47 (m, 3H), 7.45 – 7.35 (m, 4H), 7.32 – 7.22 (m, 2H), 7.12 (dd, J = 7.0,

1.7 Hz, 1H), 6.73 (d, J = 16.2 Hz, 1H), 6.52 (dd, J = 9.6, 1.1 Hz, 1H), 5.98 (dd, J = 9.6, 4.3 Hz,

1H), 4.59 (t, J = 6.2 Hz, 1H), 3.30 – 3.18 (m, 1H), 2.87 (dd, J = 16.7, 6.8 Hz, 1H), 2.72 (dd, J =

16.7, 7.3 Hz, 1H), 2.23 (s, 1H).; 13C NMR (101 MHz, CDCl3) δ 199.0, 143.4, 135.9, 134.5,

132.5, 130.8, 130.2, 129.1, 128.7, 128.5, 128.1, 127.4, 127.2, 126.7, 126.3, 72.7, 43.1, 38.7.; IR

30

(NaCl, CHCl3, cm-1) 3418, 3060, 3029, 1682, 1656, 1651, 1646, 1608, 1575, 1495, 14, 85, 1450,

1403, 1360, 1330, 1261, 1203, 1172, 1103, 1035, 1000, 977, 771, 749, 690.; M.p. 122-124 °C.;

HRMS (ESI+): 313.1205 [M+Na]+ (calc’d 313.1199 for C20H18O2Na).; The e.r. was measured by

HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 90/10, tR = 14.9 min

(major), 16.6 min (minor); For (S, R)-enantiomer: [α]D20 = -354° (c = 0.23, CHCl3) for >99:1 e.r.

The absolute configuration was assigned by analogy with compound 1.3i’.

2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)-1-(naphthalen-2-

yl)ethanone 1.3i


butyldimethyl((1-(naphthalen-2-yl)vinyl)oxy)silane (249 mg, 0.875 mmol, 2.5 equiv). Purified

by silica gel chromatography (10% Et2O:Hex) and isolated as a colourless oil (117.0 mg, 78%). 1H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H), 8.01 (dd, J = 8.6, 1.7 Hz, 1H), 7.90 (d, J = 8.1 Hz,

1H), 7.87 (t, J = 8.0 Hz, 2H), 7.60 – 7.58 (m, 1H), 7.55 – 7.52 (m, 1H), 7.30 – 7.25 (m, 2H), 7.24

– 7.19 (m, 1H), 7.14 – 7.08 (m, 1H), 6.52 (d, J = 9.5 Hz, 1H), 6.08 (dd, J = 9.5, 4.2 Hz, 1H), 3.31

– 3.22 (m, 2H), 3.00 – 2.91 (m, 1H), 0.90 (s, 9H), 0.17 (s, 3H), 0.02 (s, 3H).; 13C NMR (100

MHz, CDCl3) δ 198.8, 136.1, 135.7, 134.4, 133.3, 132.6, 130.6, 130.0, 129.7, 128.62, 128.59,

128.2, 128.0, 127.8, 127.3, 126.9, 126.7, 126.5, 124.0, 72.7, 39.9, 39.2, 26.0, 18.3, -4.0, -4.2.; IR

(NaCl, neat, cm-1) 3059, 3034, 2955, 2928, 2891, 2855, 1682, 1628, 1472, 1389, 1360, 1277,

1256.; HRMS (ESI+): 451.2067 [M+Na+] (calc’d451.2064 for C28H32NaO4Si).; For (S, R)-



31

2-((1S,2R)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-1-(naphthalen-2-yl)ethanone 1.3i’

Prepared according to General Procedure B using 1.3i (21 mg, 0.05 mmol). Purified by silica gel

chromatography (10% Et2O:DCM) and isolated as a white solid (13 mg, 83%). 1H NMR (400

MHz, CDCl3) δ 8.42 (s, 1H), 8.02 (dd, J = 8.6, 1.7 Hz, 1H), 7.95 – 7.84 (m, 3H), 7.63 – 7.57 (m,

1H), 7.57 – 7.51 (m, 1H), 7.43 (dd, J = 6.9, 1.2 Hz, 1H), 7.34 – 7.28 m, 2H), 7.15 (dd, J = 7.1,

1.4 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 6.08 (dd, J = 9.6, 4.4 Hz, 1H), 4.67 (t, J = 6.6 Hz, 1H),

3.43 – 3.37 (m, 1H), 3.31 (dd, J = 16.9, 6.5 Hz, 1H), 3.15 (dd, J = 16.9, 7.3 Hz, 1H), 2.10 (d, J =

7.3 Hz, 1H).; 13C NMR (100 MHz, CDCl3) δ 198.9, 135.8, 135.8, 134.3, 132.6, 132.5, 130.3,

130.1, 129.7, 128.74, 128.71, 128.64, 128.1, 127.9, 127.5, 127.1, 127.0, 126.8, 123.9, 72.7, 40.9,

38.7.; IR (NaCl, thin film, cm-1) 3497, 3019, 1663, 1630, 1472, 1400, 1364, 1215, 1121, 1074,

1036, 1009.; M.p. 142-144 °C.; HRMS (ESI+): 337.1212 [M+Na+] (calc’d 337.1199 for

C22H18O2Na).; The e.r. was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min,

hexane/2-propanol = 80/20, tR = 17.5 min (major), 28.0 min (minor); For (S, R)-enantiomer:

[α]D26 = -354° (c = 1.07, CHCl3) for >99:1 e.r. The absolute stereoconfiguration was determined

by single-crystal X-ray analysis of the enantiomer of 1.3i’ (see Appendix 1).

ethyl 2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-5,8-dimethoxy-1,2-dihydronaphthalen-2-

yl)acetate 1.3j



chromatography (10- 20% Et2O:Hex) and isolated as a colourless oil (48.8 mg, 60%). 1H NMR

(400 MHz, CDCl3) δ 6.87 (d, J = 9.8 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H),

32

6.05 (ddd, J = 9.8, 6.0, 1.3 Hz, 1H), 4.97 (t, J = 1.4 Hz, 1H), 4.21 – 4.03 (m, 2H), 3.79 (s, 3H),

3.78 (s, 3H), 2.99 – 2.93(m, 1H), 2.12 (dd, J = 7.8, 2.2 Hz, 2H), 1.24 (t, J = 7.1 Hz, 4H), 0.79 (s,

9H), 0.10 (s, 3H), -0.11 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.3, 151.5, 149.4, 129.0,

123.5, 122.7, 120.3, 110.9, 109.8, 64.4, 60.5, 56.2, 55.4, 38.8, 35.9, 26.0, 18.3, 14.4, -4.6, -4.8.;

IR (NaCl, neat, cm-1) 2955, 2929, 2854, 2835, 1733, 1484, 1470, 1464, 1453, 1450, 1438.;

HRMS (ESI+): 429.2053 [M+Na]+ (calc’d 429.2067 for C22H34O5NaSi).; For (S, R)-enantiomer:

[α]D26 = -147° (c = 0.91, CHCl3). The absolute configuration was assigned by analogy with

compound 1.3i’.

ethyl 2-((1S,2R)-1-hydroxy-5,8-dimethoxy-1,2-dihydronaphthalen-2-yl)acetate 1.3j’

Prepared according to General Procedure B using 1.3j (20 mg, 0.05 mmol). Purified by silica gel


MHz, CDCl3) δ 6.90 (dd, J = 9.8, 0.8 Hz, 1H), 6.82 – 6.73 (m, 2H), 6.06 (ddd, J = 9.8, 5.5, 1.1

Hz, 1H), 4.98 (s, 1H), 4.19 – 4.04 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.16 – 3.07 (m, 1H), 2.29

(dd, J = 15.6, 7.0 Hz, 1H), 2.24 (d, J = 5.3 Hz, 1H), 2.18 (dd, J = 15.6, 8.3 Hz, 1H), 1.23 (t, J =

7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.0, 151.6, 149.7, 128.5, 123.3, 122.0, 120.5,

111.5, 110.8, 65.0, 60.6, 56.3, 56.2, 38.0, 36.8, 14.3.; IR (NaCl, neat, cm-1) 3501, 2939, 2917,

2836, 1729, 1486, 1464, 1436, 1370, 1260.; HRMS (ESI+): 315.1195 [M+Na]+ (calc’d315.1202

for C16H20O5Na).; The e.r. was measured by HPLC: Chiralcel OJ column, flow 0.8 mL/min,

hexane/2-propanol = 85/15, tR = 19.0 min (major), 14.0 min (minor).; For (S, R) enantiomer:

[α]D26 = -215° (c = 1.30, CHCl3) for 98:2 e.r. The absolute configuration was assigned by


33

ethyl 2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-6,7-dimethyl-1,2-dihydronaphthalen-2-

yl)acetate 1.3k

Prepared according to General Procedure A using oxabicycle 1.1 (34.4 mg, 0.2 mmol) and tert-



MHz, CDCl3) δ 7.03 (s, 1H), 6.85 (s, 1H), 6.43 (d, J = 9.7 Hz, 1H), 5.87 (dd, J = 9.7, 4.5 Hz,

1H), 4.53 (d, J = 6.0 Hz, 1H), 4.19 – 4.09 (m, 2H), 2.97 – 2.88 (m, 1H), 2.39 (dd, J = 15.4, 6.6

Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 2.23 – 2.16 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H),

0.11 (s, 3H), -0.01 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.5, 136.0, 135.5, 133.5, 130.7,

129.1, 128.7, 127.8, 126.9, 72.3, 60.6, 39.8, 36.1, 26.1, 19.8, 19.6, 18.3, 14.4, -4.06, -4.14.; IR

(NaCl, neat, cm-1) 2956, 2929, 2895, 2889, 2857, 1735, 1473, 1360, 1255, 1249, 1160, 1153.;

HRMS (ESI+): 397.2167 [M+Na]+ (calc’d 397.2169 for C22H34O3NaSi).; For (S, R)-enantiomer:

[α]D25 = -162° (c = 0.93 , CHCl3). The absolute configuration was assigned by analogy with

compound 1.3i’.

ethyl 2-((1S,2R)-1-hydroxy-6,7-dimethyl-1,2-dihydronaphthalen-2-yl)acetate 1.3k’

Prepared according to General Procedure B using 1.3k (19 mg, 0.05 mmol). Purified by silica gel


MHz, CDCl3) δ 7.17 (s, 1H), 6.89 (s, 1H), 6.47 (d, J = 9.6 Hz, 1H), 5.88 (dd, J = 9.6, 4.4 Hz,

1H), 4.52 (t, J = 6.6 Hz, 1H), 4.23 – 4.06 (m, 2H), 3.08 – 2.96 (m, 1H), 2.44 (dd, J = 15.6, 7.2

Hz, 1H), 2.32 (dd, J = 15.6, 7.6 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 1.95 (d, J = 7.3 Hz, 1H), 1.26

(t, J = 7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.6, 136.8, 136.5, 133.1, 129.9, 128.8,

128.3, 128.1, 127.2, 72.3, 60.8, 39.6, 36.9, 19.8, 19.6, 14.4.; IR (NaCl, neat, cm-1) 3386, 2978,

2921, 2860, 1733, 1711, 1412, 1371, 1299, 1255, 1242, 1173, 1153, 1031, 1022.; M.p. 79-80

34

°C.; HRMS (DART+): 278.17610 [M+NH4]+ (calc’d 278.17562 for C16H24NO3).; The e.r. was


= 8.4 min (major), 11.7 min (minor); For (S, R) enantiomer: [α]D26 = -209° (c = 0.75, CHCl3) for

99:1 e.r. The absolute configuration was assigned by analogy with compound 1.3i’.

ethyl 2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-6,7-difluoro-1,2-dihydronaphthalen-2-

yl)acetate 1.3l

Prepared according to General Procedure A using oxabicycle 1.1 (63 mg, 0.2 mmol) tert-



MHz, CDCl3) δ 7.08 (dd, J = 10.7, 7.9 Hz, 1H), 6.88 (dd, J = 10.6, 7.7 Hz, 1H), 6.38 (d, J = 9.6

Hz, 1H), 5.96 (dd, J = 9.6, 4.3 Hz, 1H), 4.53 (d, J = 6.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.98 –

2.88 (m, 1H), 2.41 (dd, J = 15.7, 6.5 Hz, 1H), 2.22 (dd, J = 15.7, 8.5 Hz, 1H), 1.26 (t, J = 7.1 Hz,

3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.1, 149.9 (dd, J

= 246.7, 12.8 Hz), 149.2 (dd, J = 247.7, 12.4 Hz), 133.2 (dd, J = 4.8, 3.7 Hz), 130.7 (d, J = 2.6

Hz), 129.88 (dd, J = 6.3, 3.9 Hz), 125.4 (t, J = 1.9 Hz), 116.4 (d, J = 18.3 Hz), 115.0 (d, J = 17.7

Hz), 71.6, 60.8, 39.2, 35.6, 25.9, 18.2, 14.4, -4.1, -4.2.; 19F NMR (377 MHz, CDCl3) δ -139.18 –

-139.42 (m), -139.94 – -140.18 (m).; IR (NaCl, neat, cm-1) 2956, 2931, 2897, 2888, 2858, 1733,

1599, 1509, 1500, 1311, 1258, 1156, 1114.; HRMS (DART+): 383.18540 [M+H]+

(calc’d383.18540 for C20H29F2O3Si).; [α]D26 = -148° (c = 0.98, CHCl3). The absolute


35

ethyl 2-((1S,2R)-6,7-difluoro-1-hydroxy-1,2-dihydronaphthalen-2-yl)acetate 1.3l’

Prepared according to General Procedure B using 1.3l (19 mg, 0.05 mmol): Purified by silica gel

chromatography (10% Et2O:DCM) and isolated as a white solid (12 mg, 90%). 1H NMR (400

MHz, CDCl3) δ 7.30 (dd, J = 10.6, 7.9 Hz, 1H), 6.90 (dd, J = 10.5, 7.7 Hz, 1H), 6.40 (dd, J = 9.7,

1.9 Hz, 1H), 5.91 (dd, J = 9.7, 3.7 Hz, 1H), 4.56 (t, J = 7.6 Hz, 1H), 4.17 (qd, J = 7.1, 0.8 Hz,

2H), 3.05 – 2.94 (m, 1H), 2.54 (dd, J = 15.8, 7.3 Hz, 1H), 2.44 (dd, J = 15.8, 6.9 Hz, 1H), 2.30

(d, J = 7.2 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 172.7, 150.1 (dd, J

= 247.6, 12.9 Hz), 149.7 (dd, J = 249.0, 12.8 Hz), 133.4 (dd, J = 5.1, 3.6 Hz), 130.3 (d, J = 2.6

Hz), 129.3 (dd, J = 6.4, 4.0 Hz), 115.9 (d, J = 18.3 Hz), 115.2 (d, J = 17.9 Hz), 71.9, 61.1, 39.2,

36.9, 14.3.; 19F NMR (377 MHz, CDCl3) δ -138.16 – -138.39 (m), -139.45 – -139.69 (m).; IR

(NaCl, neat, cm-1) 3442, 2963, 1722, 1511, 1505, 1370, 1311, 1284, 1258, 1215, 1178, 1156.;

M.p. 76-77 °C.; HRMS (DART+): 286.12576 [M+NH4]+ (calc’d286.12547 for C14H18F2NO3).;

The e.r. was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol

= 93/7, tR = 15.2 min (major), 16.5 min (minor).; For (S,R) enantiomer: [α]D20 = -135° (c = 0.95,

CHCl3) for >99:1 e.r. The absolute configuration was assigned by analogy with compound 3i’.

ethyl 2-((1R,4R,5S,6S)-6-((tert-butyldimethylsilyl)oxy)-4,5-bis(methoxymethyl)cyclohex-2-

en-1-yl)acetate 1.3m

Prepared according to General Procedure A using oxabicycle (37 mg, 0.2 mmol), [Rh(cod)2]OTf

(6.6 mg, 7 mol %), (R,S)-PPFPtBu (9.8 mg, 9 mol %), and tert-butyl((1-

ethoxyvinyl)oxy)dimethylsilane (121 mg, 0.6 mmol, 3 equiv) at 70 °C. Purified by silica gel


MHz, CDCl3) δ 5.67 (d, J = 9.9 Hz, 1H), 5.53 (d, J = 10.1 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.75

36

– 3.66 (m, 1H), 3.59 – 3.47 (m, 2H), 3.40 (t, J = 8.5 Hz, 1H), 3.32 (s, 4H), 3.27 (s, 3H), 2.52 (dd,

J = 14.3, 4.1 Hz, 2H), 2.43 (s, 1H), 2.12 (dd, J = 14.7, 8.6 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 0.89

(s, 9H), 0.11 – 0.02 (m, J = 3.2 Hz, 6H).; 13C NMR (100 MHz, CDCl3) δ 172.7, 128.2, 128.0,

74.7, 72.4, 70.0, 60.5, 58.8, 58.7, 41.0, 39.4, 39.0, 37.7, 26.0, 18.1, 14.4, -4.5, -4.7.; IR (NaCl,

CHCl3, cm-1) 2977, 2956, 2929, 2892, 2858, 2809, 2362, 2333, 1739, 1729, 1471, 1464, 1387,

1370, 1255, 1203, 1189, 1156, 1114, 1099, 1037, 1006, 962, 879, 838, 776, 751.; HRMS

(DART+): 387.25606 [M+H]+ (calc’d 387.25667 for C20H39O5Si).; For (R,R,S,S)-enantiomer:

[α]D20 = -341° (c = 0.37, CHCl3). The absolute configuration was assigned by analogy with

compound 1.3i’.

ethyl 2-((1R,4R,5S,6S)-4,5-bis((benzyloxy)methyl)-6-((tert-butyldimethylsilyl)oxy)cyclohex-

2-en-1-yl)acetate 1.3n

Prepared according to General Procedure A using oxabicycle (67.3 mg, 0.2 mmol),

[Rh(cod)2]OTf (6.6 mg, 7 mol %), (R,S)-PPFPtBu (9.8 mg, 9 mol %), and tert-butyl((1-



MHz, CDCl3) δ 7.38 – 7.27 (m, 10H), 5.79 (d, J = 10.0 Hz, 1H), 5.56 (dt, J = 10.1, 2.5 Hz, 1H),

4.59 – 4.34 (m, 4H), 4.14 (q, J = 7.1 Hz, 2H), 3.76 (dd, J = 6.8, 2.9 Hz, 1H), 3.72 – 3.60 (m, 2H),

3.49 (dt, J = 18.3, 8.8 Hz, 2H), 2.72 – 2.61 (m, 1H), 2.55 (dd, J = 15.0, 4.5 Hz, 1H), 2.46 (s, 1H),

2.26 – 2.07 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H).; 13C NMR (100 MHz,

CDCl3) δ 172.7, 138.8, 138.7, 128.42, 128.38, 127.9, 127.74, 127.73, 127.54, 127.52 (2C), 73.3,

73.2, 72.6, 67.4, 60.5, 41.3, 39.7, 39.1, 37.6, 26.0, 18.1, 14.4, -4.4, -4.7.; IR (NaCl, CHCl3, cm-1)

3061, 3034, 2955, 2928, 2897, 2885, 2857, 1733, 1498, 1472, 1464, 1454, 1401, 1368, 1304,

1257, 1205, 1156, 1097, 1078, 1036, 1029, 879, 837, 756.; HRMS (DART+): 539.31828

[M+H]+ (calc’d 539.31827 for C32H47O5Si).; For (R,R,S,S)-enantiomer: [α]D20 = -282° (c = 0.33,

CHCl3). The absolute configuration was assigned by analogy with compound 1.3i’.

37

ethyl 2-((1R,4R,5S,6S)-6-((tert-butyldimethylsilyl)oxy)-4,5-bis(((4-

methoxybenzyl)oxy)methyl)cyclohex-2-en-1-yl)acetate 1.3o

Prepared according to General Procedure A using oxabicycle 1.1 (79 mg, 0.2 mmol),

[Rh(cod)2]OTf (6.6 mg, 7 mol %), (R,S)-PPFPtBu (9.8 mg, 9 mol %), and tert-butyl((1-


chromatography (10% Et2O:Hex) and isolated as a colourless oil (98.2 mg, 82%; 1.70 g, 95% on

3 mmol scale). 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 13.4, 8.5 Hz, 4H), 6.94 – 6.71 (m,

4H), 5.74 (d, J = 9.9 Hz, 1H), 5.52 (d, J = 10.1 Hz, 1H), 4.48 – 4.27 (m, 4H), 4.13 (q, J = 7.1 Hz,

2H), 3.80 (s, 6H), 3.72 (d, J = 4.0 Hz, 1H), 3.68 – 3.57 (m, 2H), 3.42 (dt, J = 18.4, 8.8 Hz, 2H),

2.61 (s, 1H), 2.52 (d, J = 14.8 Hz, 1H), 2.43 (s, 1H), 2.25 – 2.04 (m, 2H), 1.23 (q, J = 7.0 Hz,

3H), 0.88 (d, J = 16.0 Hz, 9H), 0.06 (s, 6H).; 13C NMR (100 MHz, CDCl3) δ 172.7, 159.2 (2C),

131.0, 130.9, 129.3 (2C), 128.5, 127.8, 113.84, 113.81, 72.9, 72.8, 72.3, 67.1, 60.5, 55.4 (2C),

41.3, 39.6, 39.0, 37.6, 26.0, 18.1, 14.4, -4.4, -4.7.; IR (NaCl, CHCl3, cm-1) 2956, 2929, 2902,

2856, 2358, 2331, 2323, 2313, 1727, 1616, 1587, 1505, 1456, 1369, 1303, 1249, 1171, 1160,

1091, 1037, 879, 836, 776.; HRMS (DART+): 559.33959 [M+H]+ (calc’d 599.34040 for

C34H51O7Si).; For (R,R,S,S)-enantiomer: [α]D20 = -205° (c = 0.48, CHCl3). The absolute


ethyl 2-((1R,4R,5S,6S)-6-hydroxy-4,5-bis(((4-methoxybenzyl)oxy)methyl)cyclohex-2-en-1-

yl)acetate 1.3o’

Prepared according to General Procedure B using 1.3o (898 mg, 1.5 mmol): Purified by silica gel

chromatography (25% EtOAc:Hex) and isolated as a colourless oil (649 mg, 89%). 1H NMR

(500 MHz, CDCl3) δ 7.21 (dd, J = 8.8, 4.6 Hz, 4H), 6.87 (d, J = 8.7 Hz, 4H), 5.62 (d, J = 10.1

38

Hz, 1H), 5.47 (d, J = 10.1 Hz, 1H), 4.39 (t, J = 5.7 Hz, 3H), 4.33 (d, J = 11.4 Hz, 1H), 4.21 –

4.10 (m, 3H), 3.80 (s, 6H), 3.64 (t, J = 9.0 Hz, 1H), 3.59 – 3.49 (m, 2H), 3.35 (dd, J = 9.4, 5.4

Hz, 1H), 3.30 (dd, J = 9.4, 6.2 Hz, 1H), 2.65 (ddd, J = 29.9, 13.7, 4.7 Hz, 3H), 2.53 (dd, J = 5.8,

2.7 Hz, 1H), 2.21 (dd, J = 15.2, 8.3 Hz, 1H), 1.62 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H).; 13C NMR

(125 MHz, CDCl3) δ 172.8, 159.39, 159.36, 129.9, 129.7, 129.6, 129.5, 129.2, 127.2, 113.89,

113.87, 73.3, 72.9, 72.8, 69.4, 69.0, 60.4, 55.3 (2C), 39.3, 38.34, 38.26, 38.19, 14.3.; IR (NaCl,

CHCl3, cm-1) 3444, 2956, 2906, 2866, 2838, 1733, 1722, 1716, 1700, 1697, 1607, 1587, 1505,

1464, 1441, 1373, 1348, 1303, 1248, 1243, 1218, 1211, 1174, 1162, 1085, 1035, 849, 820, 758,

667.; HRMS (DART+): 485.25470 [M+H]+ (calc’d 485.25393 for C28H37O7).; The e.r. was


= 15.9 min (major), 17.0 min (minor).; For (R,R,S,S)-enantiomer: [α]D20 = -247° (c = 0.22,

CHCl3) for 97:3 e.r. The absolute configuration was assigned by analogy with compound 1.3i’.

ethyl 2-((1S,2R)-1-(4-methylphenylsulfonamido)-1,2-dihydronaphthalen-2-yl)acetate 1.3pa

Prepared according to General Procedure C using azabicycle (30 mg, 0.1 mmol) and tert-

butyl((1-ethoxyvinyl)oxy)dimethylsilane (101 mg, 0.5 mmol, 5 equiv). Purified by silica gel

chromatography (0-30% Et2O:Hex) and isolated as a white solid (36.5 mg, 95%). 1H NMR (400

MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 7.0 Hz, 1H), 7.01

(dd, J = 17.3, 7.6 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 4.76 (d, J = 7.5 Hz, 1H), 4.33 – 4.23 (m,

1H), 4.12 (q, J = 7.1 Hz, 2H), 2.74 (dd, J = 11.4, 6.0 Hz, 2H), 2.46 (s, 3H), 2.43 – 2.30 (m, 2H),

2.19 – 2.09 (m, 1H), 2.09 – 1.97 (m, 1H), 1.68 – 1.58 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C

NMR (100 MHz, CDCl3) δ 172.6, 143.6, 138.3, 136.8, 134.7, 129.9, 129.3, 129.2, 127.8, 127.3,

126.6, 60.6, 56.5, 36.6, 36.5, 26.1, 24.2, 21.7, 14.3.; IR (NaCl, CHCl3, cm-1) 3278, 3106, 2983,

2926, 2857, 1727, 1715, 1607, 1529, 1427, 1373, 1350, 1312, 1165, 1092, 1023, 952, 913, 845,

794, 746, 686, 632, 607.; M.p. 99-101 °C.; HRMS (DART+): 403.16828 [M+H]+

(calc’d403.16915 for C21H27N2O4S).; The e.r. was measured by HPLC: Chiralpak AD-H column,

flow 0.8 mL/min, hexane/2-propanol = 70/30, tR = 11.5 min (major), 13.5 min (minor); For

39

(S,R)-enantiomer: [α]D20 = -173° (c = 0.57, CHCl3) for 95:5 e.r. The absolute configuration was

assigned by analogy with compound 1.3q.

ethyl 2-((1S,2R)-1-(4-nitrophenylsulfonamido)-1,2,3,4-tetrahydronaphthalen-2-yl)acetate

1.3pb


butyl((1-ethoxyvinyl)oxy)dimethylsilane (101 mg, 0.5 mmol, 5 equiv). Purified by silica gel

chromatography (0-20% EtOAc:Hex) and isolated as a white solid (20.4 mg, 49%). 1H NMR

(400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H),

7.03 (t, J = 6.9 Hz, 2H), 6.87 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 9.6 Hz, 1H), 5.93 (dd, J = 9.5, 5.5

Hz, 1H), 5.28 (d, J = 8.1 Hz, 1H), 4.50 (dd, J = 8.2, 2.7 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.98

(dd, J = 5.4, 2.8 Hz, 1H), 2.20 (d, J = 7.5 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).; 13C NMR (75 MHz,

CDCl3) δ 171.4, 149.8, 147.2, 131.90, 130.91, 129.2, 128.7, 128.5, 128.2, 128.1, 127.9, 126.9,

124.2, 60.9, 55.4, 37.3, 35.6, 14.2.; IR (NaCl, CHCl3, cm-1) 3268, 2981. 1729, 1718, 1599, 1454,

1424, 1332, 1160, 1095, 1030, 914, 743.; M.p. 139-140 °C.; HRMS (ESI+): 439.0937 [M+Na]+

(calc’d439.0934 for C20H20N2O6NaS).; The e.r. was measured by HPLC: Chiralpak AD-H

column, flow 0.8 mL/min, hexane/2-propanol = 60/40, tR = 12.4 min (major), 14.1 min (minor).

For (S,R)-enantiomer: [α]D20 = -74° (c = 0.40, CHCl3) for 94:6 e.r. The absolute configuration

was assigned by analogy with compound 1.3q.

4-methyl-N-((1S,2R)-2-(2-oxo-2-phenylethyl)-1,2-dihydronaphthalen-1-

yl)benzenesulfonamide 1.3q

40


butyldimethyl((1-phenylvinyl)oxy)silane (116 mg, 0.5 mmol, 5 equiv). Purified by silica gel

chromatography (0-30% EtOAc:Hex) and isolated as a white solid (30.5 mg, 73%). 1H NMR

(400 MHz, CDCl3) δ 7.81 (dd, J = 8.3, 1.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.54 (t, J = 7.4 Hz,

1H), 7.41 (t, J = 7.7 Hz, 2H), 7.25 – 7.19 (m, 3H), 7.14 – 7.03 (m, 2H), 6.95 (d, J = 7.5 Hz, 1H),

6.50 (d, J = 9.6 Hz, 1H), 6.00 (dd, J = 9.6, 5.0 Hz, 1H), 4.91 (d, J = 8.2 Hz, 1H), 4.42 (dd, J =

8.3, 4.8 Hz, 1H), 3.30 – 3.16 (m, 1H), 2.97 – 2.75 (m, 2H), 2.40 (s, 3H).; 13C NMR (100 MHz,

CDCl3) δ 197.9, 143.4, 138.4, 136.7, 133.4, 132.6, 132. 5, 130.1, 129.8, 128.8, 128.7, 128.3,

128.20, 128.16, 127.6, 127.2, 126.8, 77.5, 77.2, 76.8, 56.0, 40.8, 36.6, 21.7.; IR (NaCl, CHCl3,

cm-1) 3282, 3064, 3031, 2922, 1683, 1598, 1496, 1450, 1424, 1332, 1305, 1289, 1158, 1094,

1062, 1028, 913, 815, 789, 732, 690, 665.; M.p. 170-171 °C.; HRMS (ESI+): 440.1286 [M+Na]+

(calc’d 440.1291 for C25H23NNaO3S).; The e.r. was measured by HPLC: Chiralpak AD-H

column, flow 0.8 mL/min, hexane/2-propanol = 60/40, tR = 18.9 min (major), 21.8 min (minor).;

For (S,R)-enantiomer: [α]D20 = -211° (c = 0.23, CHCl3) for 92:8 e.r. The absolute configuration

was determined by X-ray analysis.

N-((1S,2R)-2-(2-(4-methoxyphenyl)-2-oxoethyl)-1,2-dihydronaphthalen-1-yl)-4-

methylbenzenesulfonamide 1.3r


butyl((1-(4-methoxyphenyl)vinyl)oxy)dimethylsilane (132 mg, 0.5 mmol, 5 equiv). Purified by

silica gel chromatography (0-40% EtOAc:Hex) and isolated as a white solid (23.7 mg, 53%). 1H

NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.9 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.22 (dd, J = 10.4,

4.4 Hz, 3H), 7.12 – 7.01 (m, 2H), 6.96 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 6.48 (d, J =

9.6 Hz, 1H), 4.97 (s, J = 7.7 Hz, 1H), 4.41 (dd, J = 8.3, 5.0 Hz, 1H), 3.85 (s, 3H), 3.20 (t, J = 5.7

Hz, 1H), 2.82 (d, J = 6.8 Hz, 2H), 2.39 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 196.5, 163.7,

143.3, 138.4, 132.7, 132.5, 130.5, 130.3, 129.8, 129.7, 128.8, 128.3, 128.1, 127.5, 127.1, 126.8,

113.8, 56.1, 55.6, 40.4, 36.7, 21.7.; IR (NaCl, CHCl3, cm-1) 3276, 3064, 3034, 2957, 2925, 2841,

41

2255, 1704, 1668, 1576, 1511, 1454, 1419, 1330, 1318, 1305, 1261, 1243, 1160, 1094, 1029,

913, 816, 781, 734, 666, 649.; M.p.128-130 °C.; HRMS (DART+): 465.18358 [M+H]+ (calc’d

465.18480 for C26H29N2O4S).; The e.r. was measured by HPLC: Chiralpak AD-H column, flow

0.8 mL/min, hexane/2-propanol = 60/40, tR = 21.3 min (major), 26.6 min (minor).; For (S,R)-

enantiomer: [α]D20 = -211° (c = 0.23, CHCl3) for 91:9 e.r. The absolute configuration was


NHTs

O

F

N-((1S,2R)-2-(2-(4-fluorophenyl)-2-oxoethyl)-1,2-dihydronaphthalen-1-yl)-4-

methylbenzenesulfonamide 1.3s


butyl((1-(4-fluorophenyl)vinyl)oxy)dimethylsilane (126 mg, 0.5 mmol, 5 equiv). Purified by

silica gel chromatography (0-30% Et2O:Hex) and isolated as a white solid (31. mg, 71%). 1H

NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 9.0, 5.4 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.23 (M, J =

9.0, 4.4, 1.0 Hz, 3H), 7.10 – 7.04 (m, 4H), 6.90 (dd, J = 7.5, 0.6 Hz, 1H), 6.50 (d, J = 9.6 Hz,

1H), 5.99 (dd, J = 9.6, 4.9 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.41 (dd, J = 8.4, 4.8 Hz, 1H), 3.26

– 3.19 (m, 1H), 2.87 (qd, J = 17.2, 7.0 Hz, 2H), 2.41 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ

196.3 (s), 165.9 (d, J = 255.0 Hz), 143.4 (s), 138.4 (s), 133.2 (d, J = 3.0 Hz), 132.4 (d, J = 1.0

Hz), 130.9 (d, J = 9.3 Hz), 130.0 (s), 129.8 (s), 128.9 (s), 128.23 (s), 128.17 (s), 127.6 (s), 127.2

(s), 126.9 (s), 115.8 (d, J = 21.9 Hz), 55.9 (s), 40.7 (s), 36.7 (s), 21.7 (s).; 19F NMR (376 MHz,

CDCl3) δ -104.88 (tt, J = 8.4, 5.4 Hz).; IR (NaCl, CHCl3, cm-1) 3279, 3071, 3044, 2924, 2850,

2368, 1700, 1683, 1598, 1506, 1409, 1332, 1234, 1157, 1094, 913, 814, 781, 732, 665.;

M.p.179-181 °C.; HRMS (ESI+): 458.1194 [M+Na]+ (calc’d 458.1197 for C25H22FNNaO3).; The

e.r. was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol =

60/40, tR = 22.3 min (major), 24.4 min (minor); For (S,R)-enantiomer: [α]D20 = -174° (c = 0.2.2,

CHCl3) for 85:15 e.r. The absolute configuration was assigned by analogy with compound 1.3q.

42

Hydrogenation of 1.3pa for the synthesis of 1.3t

In a flask was charged with 1.3pa (63.7 mg, 0.165 mmol) and Pd/C (10% wt) (6.4 mg). The

mixture was suspended in 1.7 mL of EtOAc and the flask was evacuated and back-filled with H2

(3x). A balloon of H2 was fitted on top of the flask and the contents were stirred for 2 h. The

mixture was diluted with EtOAc and filtered through a celite pad. The solution was concentrated

to afford the product (63.4 mg, 99%) as a white solid.

1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 7.0

Hz, 1H), 7.01 (dd, J = 17.3, 7.6 Hz, 2H), 6.78 (d, J = 7.7 Hz, 1H), 4.76 (d, J = 7.5 Hz, 1H), 4.33

– 4.23 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.74 (dd, J = 11.4, 6.0 Hz, 2H), 2.46 (s, 3H), 2.43 –

2.30 (m, 2H), 2.19 – 2.09 (m, 1H), 2.09 – 1.97 (m, 1H), 1.68 – 1.58 (m, 1H), 1.25 (t, J = 7.1 Hz,

3H).; 13C NMR (100 MHz, CDCl3) δ 172.6, 143.6, 138.3, 136.8, 134.7, 129.9, 129.3, 129.2,

127.8, 127.3, 126.6, 60.6, 56.5, 36.6, 36.5, 26.1, 24.2, 21.7, 14.3.; IR (NaCl, CHCl3, cm-1) 3283,

3062, 3024, 2981, 2930, 1736, 1714, 1599, 1494, 1454, 1436, 1332, 1304, 1289, 1183, 1159,

1094, 1035, 915, 815, 747, 665.; M.p. 121-123 °C.; HRMS (ESI+): 410.1399 [M+Na]+ (calc’d

410.1397 for C21H25O4NNaS).; The e.r was measured by HPLC: Chiralpak AD-H column, flow

0.8 mL/min, hexane/2-propanol = 80/20, tR = 11.8 min (major), 13.8 min (minor); For (S,S)-



II Product derivatization

Saponification and iodolactonization: Synthesis of 1.4

OTBS

O

OEt

OTBS

O

OH

OTBS

OO

I

LiOH.H2O

MeOH, 50 °C

I2, NaHCO3, KI

MeCN/H2O (1:1)0 °C to r.t.

1.3a' 1.41.3a94%

50%

43

Procedure:

A solution of 1.3a (152 mg, 0.44 mmol) in MeOH (2 mL) was added to a round bottom flask

charged with LiOH•H2O (89 mg, 2.2 mmol). The flask was equipped with a reflux condenser

and heated to 50 °C for 5 h. The crude mixture was filtered to remove excess insoluble

LiOH•H2O and concentrated under reduced pressure. The residue was redissolved in Et2O (5

mL), diluted with H2O (5 mL), and acidified with concentrated HCl (pH ≈ 1). The aqueous layer

was separated from the organic layer and extracted with Et2O (3 x 5 mL). The combined organic

layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and

purified via flash silica gel chromatography (eluent = 1:1 EtOAc:Hexanes, spiked with 1%

AcOH) to yield 1.3a’as a light yellow oil (131 mg, 94%).

To a solution of 1.3a’(20 mg, 0.064 mmol) in MeCN (0.7 mL) was added a solution of NaHCO3

(7.6 mg, 0.09 mmol) in H2O (0.7 mL) at 0 °C. After stirring for 5 min, KI (13.8 mg, 0.083 mmol)

and I2(21 mg, 0.083 mmol) were added sequentially. The reaction mixture was gradually warmed

to r.t. and stirred until the starting material was fully consumed by TLC analysis. The crude

mixture was diluted with EtOAc (4 mL) and quenched with saturated Na2S2O3 (5 mL). The

aqueous layer was separated from the organic layer and was extracted with EtOAc (3 x 5 mL).

The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced

pressure, and purified by flash silica gel chromatography to yield 1.7 as a colourless oil (14.2

mg, 50%).

2-((1S,2R)-1-((tert-butyldimethylsilyl)oxy)-1,2-dihydronaphthalen-2-yl)acetic acid 1.3a’

1H NMR (400 MHz, CDCl3) δ 7.30 – 7.18 (m, 3H), 7.10 – 7.06 (m, 1H), 6.51 (d, J = 9.5 Hz,

1H), 5.97 (dd, J = 9.6, 4.3 Hz, 1H), 4.60 (d, J = 6.5 Hz, 1H), 3.02 – 2.92 (m, 1H), 2.51 (dd, J =

16.0, 6.4 Hz, 1H), 2.27 (dd, J = 16.0, 8.7 Hz, 1H), 0.89 (s, 9H), 0.11 (s, 3H), -0.02 (s, 3H) (Note:

Carboxylic acid proton too broad to observe by 1H NMR).; 13C NMR (100 MHz, CDCl3) δ

179.0, 136.0, 133.0, 129.5, 128.1, 127.44, 127.37, 127.29, 126.4, 72.5, 39.3, 35.7, 26.0, 18.3, -

4.1, -4.2.; IR (NaCl, thin film, cm-1) 3036, 2956, 2929, 2894, 2858, 1708, 1472, 1463, 1453,

44

1410, 1278, 1257, 1124, 1063.; HRMS (DART+): 319.17246 [M+NH4]+ (calc’d 319.17295 for

C18H27O3Si).

(3aR,4S,9S,9aS)-4-((tert-butyldimethylsilyl)oxy)-9-iodo-3a,4,9,9a-tetrahydronaphtho[2,3-

b]furan-2(3H)-one 1.4

1H NMR (400 MHz, CDCl3) δ 7.49 – 7.42 (m, 1H), 7.36 – 7.29 (m, 2H), 7.24 (dd, J = 5.5, 3.5

Hz, 1H), 5.48 (d, J = 3.5 Hz, 1H), 5.32 (dd, J = 8.6, 3.5 Hz, 1H), 4.67 (d, J = 4.7 Hz, 1H), 3.16

(dddd, J = 10.4, 8.6, 7.2, 4.7 Hz, 1H), 2.77 (dd, J = 18.5, 10.4 Hz, 1H), 2.23 (dd, J = 18.5, 7.2

Hz, 1H), 0.95 (s, 9H), 0.18 (s, 3H), 0.00 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 174.8, 136.4,

134.6, 130.9, 129.3, 128.8, 127.9, 85.2, 71.8, 42.1, 32.2, 25.9, 21.3, 18.1, -4.2, -4.7.; IR (NaCl,

thin film, cm-1) 2954, 2929, 2857, 1784, 1767, 1472, 1462, 1415, 1361, 1327, 1253, 1176, 1122,

1093. 1073, 1055.; HRMS (DART+): 462.09624 [M+NH4]+ (calc’d 462.09614 for

C18H29INO3Si).

Epoxidation: synthesis of 1.5

Procedure:

In a 2-dram vial equipped with a stir bar was charged with 1.3a (67 mg, 0.2 mmol) followed by 1

mL of anhydrous DCM. The solution was cooled to 0 °C in an ice bath and freshly prepared

DMDO (~60 mM) in acetone 3 mL was added dropwise. The solution was brought to r.t. and

stirred for 18 h. TLC indicated reaction completion and the solution was concentrated and

purified with silica gel chromatography (20% Et2O:Hex) to afford the product as a clear

colourless oil (54.7 mg, 78%).

45

ethyl 2-((1aR,2R,3S,7bS)-3-((tert-butyldimethylsilyl)oxy)-1a,2,3,7b-tetrahydronaphtho[1,2-

b]oxiren-2-yl)acetate 1.5

1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.4, 1.1 Hz, 1H), 7.37 (td,

J = 7.6, 1.3 Hz, 1H), 7.27 (dt, J = 7.4, 1.0 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 4.26 – 4.14 (m,

2H), 3.94 (d, J = 4.3 Hz, 1H), 3.75 (d, J = 4.3 Hz, 1H), 3.03 (dd, J = 16.0, 3.4 Hz, 1H), 2.58 (dd,

J = 16.0, 11.3 Hz, 1H), 2.31 (td, J = 10.9, 3.4 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.03 (s, 9H), 0.17

(s, 3H), 0.13 (s, 3H).; 13C NMR (150 MHz, CDCl3) δ 172.8, 140.0, 131.7, 129.0, 128.6, 127.0,

124.7, 68.9, 60.8, 55.7, 54.4, 38.4, 35.2, 26.2, 18.4, 14.4, -3.77, -3.83.; IR (NaCl, CHCl3, cm-1)

2954, 2934, 2898, 2859, 1738, 1473, 1464, 1418, 1390, 1368, 1348, 1310, 1254, 1232, 1213,

1192, 1162, 1130, 1112, 1087, 1046, 1028, 1006, 984, 939, 901, 882, 836, 807, 777, 760, 740.;

HRMS (DART+): 363.19937 [M+H]+ (calc’d 363.19916 for C20H31O4Si).

Silyl Ether Deprotection: synthesis of 1.6

ethyl 2-((1R,4R,5S,6S)-4,5-bis((benzyloxy)methyl)-6-hydroxycyclohex-2-en-1-yl)acetate 1.6

Prepared according to General Procedure B (62 mg, 0.12 mmol): Purified by silica gel

chromatography (10% EtOAc:Hex) and isolated as a colourless oil (45.4 mg, 93%). 1H NMR

(400 MHz, CDCl3) δ 7.39 – 7.20 (m, 10H), 5.63 (d, J = 10.1 Hz, 1H), 5.49 (d, J = 10.0 Hz, 1H),

4.53 – 4.35 (m, 4H), 4.13 (dt, J = 9.9, 6.8 Hz, 3H), 3.70 (t, J = 9.0 Hz, 1H), 3.58 (dd, J = 9.3, 6.8

Hz, 2H), 3.36 (ddd, J = 20.8, 9.4, 5.9 Hz, 2H), 2.77 – 2.60 (m, 3H), 2.57 (s, 1H), 2.23 (dd, J =

14.9, 8.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 172.9, 137.9, 137.8,

129.3, 128.59, 128.58, 128.01, 127.96, 127.94, 127.91, 127.2, 73.8, 73.4, 73.1, 69.9, 69.4, 60.5,

39.4, 38.53, 38.45, 38.2, 14.4.; IR (NaCl, CHCl3, cm-1) 3494, 3029, 2903, 2861, 2364, 1786,

1729, 1714, 1454, 1368, 1258, 1206, 1158, 1095, 1075, 1028, 735, 698.; HRMS (DART+):

46

425.23245 [M+H]+ (calc’d 425.23280 for C26H33O5).; The e.r. was measured by HPLC:


15.0 min (minor); For (R,R,S,S)-enantiomer: [α]D20 = -240° (c = 0.35, CHCl3) for 97:3 e.r. The


Synthesis of lactone 1.7

OH

OEt

O

PMBO

PMBORO

RO

OO

MsCl, NEt3

CH2Cl20 C - r.t., 3 h

quant

OMs

OEt

O

PMBO

PMBO

LiOH•H2O,

MeOH/H2O50 C, 5 h

71%1.3o' 1.3o'' 1.7

To a solution of 1.3o’ (145 mg, 0.3 mmol) in distilled Et3N (3 mL) cooled to 0 °C was added a

solution of MsCl (69 mg, 0.049 mL, 0.6 mmol, 2 equiv) in anhydrous DCM (1.5 mL) dropwise.

The mixture was warmed to r.t. and stirred for 16 h. The reaction was diluted with 2 mL of DCM

and quenched with 3 mL of water. The aqueous phase was extracted with DCM (3x) and the

organic phases were combined, washed with water and brine, dried over MgSO4, filtered and

concentrated. The crude was purified with silica gel chromatography (10% EtOAc in Hex) to

afford 1.3o’’ (166 mg, quant) as a colourless oil.

To solution of 3o’’ (56mg, 0.1 mmol) in MeOH/H2O (10:1, 2.2 mL) was added LiOH·H2O (42

mg, 10 equiv). The mixture was stirred at 50 °C for 5 h. The mixture was partitioned with EtOAc

and 3 mL of 1N HCl. The aqueous phase was extracted with EtOAc 3 x 2 mL, and the organic

portions were combined, washed with water, and brine. The solution was dried over MgSO4,

filtered, and concentrated under reduced pressure to afford the crude. The crude was purified

with silica gel chromatography (20% EtOAc:Hex) to afford the product 1.7 (31.0 mg. 71%) as a

colourless oil.

47

ethyl 2-((1R,4R,5S,6S)-4,5-bis(((4-methoxybenzyl)oxy)methyl)-6-

((methylsulfonyl)oxy)cyclohex-2-en-1-yl)acetate 1.3o’’

1H NMR (500 MHz, CDCl3) δ 7.22 (dd, J = 8.8, 3.1 Hz, 4H), 6.86 (dd, J = 8.7, 3.8 Hz, 4H), 5.77

(d, J = 10.2 Hz, 1H), 5.57 (d, J = 10.1 Hz, 1H), 4.86 (dd, J = 6.4, 3.1 Hz, 1H), 4.45 – 4.33 (m,

4H), 4.14 (q, J = 7.2 Hz, 2H), 3.80 (s, 6H), 3.61 – 3.54 (m, 3H), 3.39 (dd, J = 9.2, 8.2 Hz, 1H),

2.99 (s, 3H), 2.85 (d, J = 3.7 Hz, 1H), 2.75 – 2.65 (m, 1H), 2.57 – 2.45 (m, J = 15.8, 7.9 Hz, 2H),

2.30 (dd, J = 16.0, 7.9 Hz, 1H), 1.57 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).; 13C NMR (125 MHz,

CDCl3) δ 171.6, 159.20, 159.18, 130.4, 130.3, 129.4, 129.3, 128.7, 126.7, 113.8, 113.8, 81.6,

72.80, 72.76, 71.0, 66.4, 60.8, 55.3 (2C), 38.6, 38.4 (2C), 37.2, 36.5, 14.2.; IR (NaCl, CHCl3,

cm-1) 3027, 2935, 2906, 2865, 2838, 1729, 1613. 1586, 1514, 1464, 1455, 1417, 1356, 1338,

1303, 1249, 1174. 1092, 1034, 927, 867, 850, 819, 759.; HRMS (DART+): 580.25918

[M+NH4+] (calc’d 580.25803 for C29H42NO9S).; For (R, S)-enantiomer: [α]D

20 = -245° (c = 0.22,

CHCl3).

(3aR,6R,7S,7aR)-6,7-bis(((4-methoxybenzyl)oxy)methyl)-3,3a,7,7a-tetrahydrobenzofuran-

2(6H)-one 1.7

1H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 8.4 Hz, 4H), 6.87 (d, J = 8.5 Hz, 4H), 5.71 (ddd, J =

10.1, 2.9, 1.8 Hz, 1H), 5.57 (d, J = 10.0 Hz, 1H), 4.88 (t, J = 6.4 Hz, 1H), 4.45 – 4.25 (m, 4H),

3.80 (d, J = 0.6 Hz, 6H), 3.54 – 3.36 (m, 4H), 2.97 (s, 1H), 2.78 (td, J = 5.6, 2.6 Hz, 1H), 2.72

(dd, J = 17.3, 8.9 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.28 (dd, J = 17.3, 5.2 Hz, 1H).; 13C NMR (150

MHz, CDCl3) δ 176.6, 159.4, 159.3, 130.4, 130.3, 129.4, 129.3, 128.8, 126.6, 113.9, 113.9, 79.0,

73.0, 72.8, 69.6, 66.9, 55.4 (2C), 37.5, 35.2, 33.7, 33.5.; IR (NaCl, CHCl3, cm-1) 3029, 3001,

48

2954, 2933, 2910, 2859, 2836, 1778, 1768, 1761, 1612, 1585, 1513, 1464, 1420, 1365, 1302,

1248, 1180, 1174, 1160, 1110, 1089, 1033, 819, 743.; HRMS (DART+): 456.24020 [M+NH4]+

(calc’d 456.456.23861 for C26H34NO6).

Saponification and amide coupling: Synthesis of Compound 1.8

OTBSHN

O

O

O

Ph

OTBS

OEt

O

O

O

1) LiOH•H2OMeOH/H2O, 50 C

2) DCC, PhNH2DMAP, CH2Cl2, 0 C - r.t

69%.1.3m 1.8

To a solution of 1.3l (38.1 mg 0.1 mmol) in MeOH/H2O (10:1, 1.1 mL) was added LiOH·H2O

(21 mg, 5 equiv). The mixture was stirred at 50 °C for 5 h. The mixture was partitioned with

EtOAc and 3 mL of 1N HCl. The aqueous phase was extracted with EtOAc 3 x 2 mL, and the

organic portions were combined, washed with water, and brine. The solution was dried over

MgSO4, filtered, and concentrated under reduced pressure to afford the crude carboxylic acid.

The acid was dissolved in distilled DCM (1 mL) in a dry 5 mL round bottom flask and aniline

(11 mg, 0.011 mL, 0.12 mmol, 1.2 equiv) and DMAP (1.2 mg, 0.1 equiv) were added. The

solution was cooled to 0 °C and DCC (24 mg, 1.2 equiv) was added. The reaction was warmed to

r.t. and stirred for 16 h. The mixture was concentrated and purified using silica gel

chromatography (10% EtOAc in Hex) to afford the product as a clear colourless oil (29.3 mg,

69%)

2-((1R,4R,5S,6S)-6-((tert-butyldimethylsilyl)oxy)-4,5-bis(methoxymethyl)cyclohex-2-en-1-

yl)-N-phenylacetamide 1.8

1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H), 7.31 (t, J = 7.9 Hz, 2H),

7.10 (t, J = 7.4 Hz, 1H), 5.73 (d, J = 9.8 Hz, 1H), 5.63 (dt, J = 10.1, 2.4 Hz, 1H), 3.79 (s, 1H),

3.59 – 3.50 (m, 2H), 3.42 (dd, J = 9.0, 7.6 Hz, 1H), 3.38 – 3.31 (m, 4H), 3.29 (s, 3H), 2.58 (d, J

= 20.5 Hz, 3H), 2.12 (dd, J = 13.4, 9.1 Hz, 2H), 1.80 (s, 1H), 0.90 (s, 9H), 0.08 (d, J = 2.9 Hz,

49

6H).; 13C NMR (125 MHz, CDCl3) δ 170.0, 138.0, 129.1, 128.6, 128.1, 124.4, 119.9, 74.7, 72.3,

69.9, 58.81, 58.77, 41.4, 39.6, 26.0, 18.1, -4.50, -4.54.; IR (NaCl, CHCl3, cm-1) 3299, 2955,

2892, 2857, 1662, 1600, 1549, 1539, 1533, 1501, 1495, 1472, 1462, 1444, 1436, 1360, 1312,

1256, 1189, 1112, 1099, 1046, 1031, 962, 878, 837, 776, 752, 692.; HRMS (DART+):

434.27248 [M+H]+ (calc’d 4334.27266 for C24H40NO4Si).; The e.r. was measured by HPLC:

Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 95/5, tR = 14.6 min.; For (R, S)-


assigned by analogy with compound 1.3i’.

50

Chapter 2 Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of

Dihydroquinolines

51

2 Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of Dihydroquinolines

The work described in this chapter was completed in collaboration with former graduate student,

Dr. Jane Panteleev. The author was responsible for the initial development of the project, with

contributions to optimization, mechanistic studies, and reaction scope. The contributions of J.

Panteleev are noted in text and labeled as such.

2.1 Introduction

The use of multiple catalysts in a reaction vessel in organic synthesis has recently gained

significant interest, as multi-catalytic systems can achieve superior reactivity and synthetic

efficiency that are unmatched with single catalytic systems. Important advantages include new

modes of substrate activation, new bond forming transformations, and efficient complexity

generation processes that lead to waste reduction in synthesis and minimized environmental

impact. For example, the use of multiple metals in catalysis has provided powerful

transformations such as the Wacker process and the Sonogashira cross coupling. Thus, in

comparison to the traditional approach of using a single metal catalyst to perform a reaction,

taking the multi-metal catalysis approach toward synthesis can be highly effective (Figure 2.1).

However, concerns over incompatibility and complexity of multiple catalytic cycles have

hindered their development. Consequently, examples of multi-metal catalysis generally employ

one ligand or ligand-less metals. As ligands are integral in controlling regio- and stereoselectivity

in metal-catalyzed reactions, their exclusion imposes significant limitations on reaction

discovery and scope. Therefore, the development of multi-metal-ligand domino catalysis may

enable a broad range of useful transformations in a more practical way. The use of multiple

ligands in multi-metal catalysis can facilitate optimization, improve reaction efficiency, and

allow systematic ligand screening to fine-tune reactivity. Taking advantage of the dynamics and

reactivity of multiple metal-ligand interactions may unlock new reactions in a variety of modes

of multi-metal catalysis.

52

Figure 2.1 Scope of reactions available for the ligand-dependent multi-metal catalysis

2.1.1 Modes of multiple metal catalysis

Of the existing reports on the use of multiple metal catalysts in synthesis, there are generally 4

modes of catalysis: bimetallic catalysis, cooperative dual metal catalysis, “restorative” co-

catalysis, and tandem/domino multi-metal catalysis.21

2.1.1.1 Bimetallic catalysis

This mode of catalysis involves the use of hetero- or homodinuclear bifunctional catalysts.22

Shibasaki and coworkers provided notable contributions to the development to these catalysts,

21 For reviews on the various modes of multiple metal-catalyzed reactions, see: (a) Lee, J. M.; Na, Y; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302-312. (b) Bruneau, C.; Dérien, S.; Dixneuf, P. H. Top Organomet. Chem. 2006, 19, 295-326. (c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633-658. (d) Park, J.; Hong, S. Chem. Soc. Rev. 2012, 41, 6931-6943. 22 For a review, see: (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209. For selected examples of the bimetallic catalysis mode, see: (b) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418-4420. (c) H. Sasai, T. Suzuki, N. Itoh, M. Shibasaki, Tetrahedron Lett. 1993, 34, 851-854. (d) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 1871-1873. (e) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. (f) Sawada, D.; Shibasaki, M. Angew. Chem. Int. Ed. 2000, 39, 209-213. (g) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521-10532. (h) Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733-736. (i) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194-6198. (j) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett.1996, 37, 5561-5564. (k) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557-7558. (l) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043-4044. (m) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60, 6656-6657. (n) Gröger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 9291-9292. (o) Gröger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 3089-3103. (p) Schlemminger, I.; Saida, Y.; Gröger, H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043-4044. (q) Schlemminger, I.; Saida, Y.; Gröger, H.; Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818-4825.

53

whereby a combination of rare-earth (Ln) and alkali (M) metals with BINOL were incorporated

in the catalyst architecture in the form of M3[Ln(binol)3] (Figure 2.2). The rare-earth metal

served as a Lewis acid that activated an electrophile while the alkali metal facilitated the

deprotonation of a nucleophile. The proximity of both metal centers provided enhanced rates of

reactivity, enantioinduction, and mild reaction conditions. An application of this catalyst system

was the first highly enantioselective nitroaldol reaction employing La and Li in combination with

BINOL LLB (Eqn 2.1).22b,c Proposed mechanism of the catalysis involved the coordination of La

to the carbonyl oxygen to activate the aldehyde and Li to the nitro group to facilitate

deprotonation of the nitroalkane (Figure 2.2).

Figure 2.2 Shibasaki’s catalyst architecture and proposed mechanism of stereoinduction

The catalyst-enabled dual activation provided the direct nitroaldol addition without the need for

the use of stoichiometric amounts of base. Importantly, the combination of rare-earth metals and

alkali metals along with the BINOL ligand could be modified to achieve a variety of

transformations such as the direct Aldol addition,22d-h conjugate Michael addition,22i-l and

hydrophosphonylation.22m-p The versatility of Shibasaki’s catalyst framework set an important

precedent for the development of the ligand-dependent multi-metal catalysis.

2.1.1.2 Cooperative (Synergistic/Contemporaneous/Catalyzed) dual metal catalysis

This mode of catalysis involves two metal catalysts that simultaneously activate substrates

separately and couple upon activation.21c The dual activation strategy offers opportunities for the

construction of novel bonds and provides unique disconnections for synthesis. For example,

54

using Pd/Cu catalysis, the Sonogashira cross coupling couples an aryl halide with a terminal

acetylene, forging a bond between a sp2 and a sp carbon center (Scheme 2.1).23a

Cu R2

CuI

H R2

CuI

H R2

NR3 HI

NR3

Pd0

ArI

PdII I

Ar

PdII

Ar

R2Ar

R2

2.1.12.1.2

2.1.3

Scheme 2.1 The catalytic cycle of the Sonogashira cross coupling

The catalytic cycle of this reaction involved the Pd-mediated oxidative insertion into the aryl

halide (2.1.1). Separately, the Cu facilitated the deprotonation of the alkyne by the base to form a

copper acetylide 2.1.2. Transfer of the acetylide from Cu on to Pd occurred in the

transmetallation step (2.1.3), which was followed by reductive elimination to furnish the cross

coupling product.

Recent reports on cooperative dual metal catalysis include the work of Trost23j,k and Blum.23g,h

For example, Trost reported a V/Pd catalytic system in the coupling of propargyl alcohols with

allyl carbonates to afford α,β-disubstituted enones (Scheme 2.2). The dual activation involved an

23 For selected examples of cooperative metal catalysis, see: (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-4470. (b) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605. (c) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem. Int. Ed. 2004, 43, 1132-1136. (d) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309-3310. (e) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928-9929. (f) Gooßen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662-664. (g) Shi, Y.; Peterson, S. M.; Haberaecker, W. W.; Blum, S. A. J. Am. Chem. Soc. 2008, 130, 2168- 2169. (h) Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc. 2009, 131, 18022-18023. (i) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674-3675. (j) Trost, B.; Luan, X. J. Am. Chem. Soc. 2011, 133, 1706-1709. (k) Trost, B.; Luan, X.; Miller, Y. J. Am. Chem. Soc. 2011, 133, 12824-12833. (l) Gu, Z.; Herrmann, A. T.; Zakarian, A. Angew. Chem. Int. Ed. 2011, 50, 7136-7139. (m) Motoyama, K.; Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Organometallics 2012, 31, 3426-3430. (n) Shirakawa, E.; Ikeda, D.; Masui, S.; Yoshida, M.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 272-279.

55

interrupted Meyer-Schuster rearrangement, where V activated the propargyl alcohol to generate

an allenoate 2.2.1. Concomitantly, Pd inserted into the allyl carbonate to form the reactive π-allyl

complex 2.2.2. The addition of the allenoate to the π-allyl complex resulted in an enone bearing

an α-allyl substituent. It was noted that the optimal catalyst loading was very important in this

reaction, as each catalyst could individually lead to undesired reaction pathways. For example, V

alone would lead to the Meyer-Schuster rearrangement without incorporation of an α-allyl

substituent and Pd alone would lead to the allylation of the propargyl alcohol.

Scheme 2.2 Dual V/Pd-catalyzed Meyer-Schuster rearrangement/allylic alkylation

Blum and coworkers described an Au/Pd catalytic system in the synthesis of butenolides and

isocumarins from allyl esters (Scheme 2.3).23g,h The pathway was initiated as Au activated an

olefin such as alkyne or allene, promoting the addition of the ester carbonyl oxygen to form a

vinylgold species 2.3.1. The cationic nature of the intermediate allowed the transfer of the allyl

group onto Pd to generate the Pd π-allyl complex 2.3.2. The π-allyl complex was trapped by the

vinylgold to afford the allyl migration observed in the reaction.

56

Me

•R2R1

OO

O+

OMe

Ph3PAuR1

R2

O

OMe

Ph3PAuR1

R2

PdII

Pd0

O

OMe

PdII R1

R2

O

OMe

R1

R2

PPh3Au+

2.3.1

2.3.2

Scheme 2.3 Blum’s report on Au/Pd-catalyzed butenolide synthesis

Ito and coworker23d also took advantage of the generation of Pd π-allyl complex and trapped it

with a prochiral nucleophile activated by Rh (Scheme 2.4). While Pd alone with the ligand could

catalyze the reaction, the dual combination was essential in conferring enantioselectivity. As the

authors observed that a chiral Pd π-allyl complex could not induce enantioselectivity in the

reaction, they proposed that Rh acted as a Lewis acid that coordinated the nitrile group on the α-

cyanoester, facilitating the formation of the enolate. The chiral environment created by the ligand

bound to Rh was responsible for exerting enantioselectivity. The chiral enolate added to the π-

allyl complex to afford α-allyl cyanoesters and constructing a chiral all-carbon substituted

quaternary stereocenter with high enantioselectivity. As the Lewis acid-like activation was

crucial in this reaction, it was observed that the reaction was highly temperature dependent, as

the ee deteriorated dramatically once the reaction was conducted at 0 °C.

57

NC

Me

Oi-Pr

O

O O

O

CF3

CF3+

[Rh(acac)CO]2 (1 mol %)

Pd(Cp)( 3-C3H5) (1 mol %)

AnisTRAP (2 mol %)

THF, -40 C

Oi-Pr

O

Me CN

93% yield99% ee

Rh only: 0% yieldPd only (with L): 91% yield, 0% ee

Fe

Fe Me

PAr2

Me

Ar2P

Ar = p-MeOPhAnisTRAP

Scheme 2.4 Enantioselective Rh/Pd-catalyzed allylation of cyanoesters

2.1.1.3 “Restorative” Co-catalysis

This mode of catalysis, while still not strictly defined, can be mechanistically viewed

analogously to the Wacker processes.24a The catalytic activity responsible for the organic

24 For selected examples of “restorative co-catalysis”, see: (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Rüttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176.-182. (b) Stille, J. K.; Divakaruni, R. J. Am. Chem. Soc. 1978, 100, 1303-1304. (c) Bäckvall, J. E.; Akermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411- 2416. (d) Murahashi, S.-I.; Naota, T.; Hirai, N. J. Org. Chem. 1993, 58, 7318-7319. (e) Éll, A. H.; Closson, A.; Adolfssom, H.; Bäckvall, J.-E. Adv. Synth. Catal. 2003, 345, 1012-1016. (f) Jonsson, S. Y.; Adolfsson, H.; Bäckvall, J.-E. Chem. Eur. J. 2003, 9, 2783-2788. (g) Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. Angew. Chem. Int. Ed. 2001, 40, 4619-4623. (h) Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. J. Org. Chem. 2003, 68, 1736-1746. (i) Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 11257-11260. (j) Wickens, Z. K.; Skakuj, K.; Morandi, B.; Grubbs, R. H. J. Am. Chem. Soc. 2014, 136, 890-893.

58

transformation is promoted by one of the metal constituent; the other metal is responsible for

regeneration or “restoration” of the active catalyst after each cycle. For example, in the Wacker

process (Scheme 2.5), PdII complexed with an olefin and facilitated the addition of water onto

the olefin (2.5.1). Subsequent β-hydride elimination, hydropalladation, and β-hydride elimination

afforded the oxidized ketone. The PdII-hydrido complex 2.5.2 could generate Pd0, which was

catalytically inactive. However, the presence of a co-catalyst such as CuII could re-oxidize Pd0 to

PdII, allowing the Pd catalyst to turn over. The advantage of Cu was that the reduced CuI species

could be readily oxidized by oxygen back to CuII, in essence catalyzing the oxidation of Pd by

molecular oxygen, the cheapest and cleanest oxidizing reagent. While the co-catalyst does not

play a role in the organic transformation, its restorative capabilities are highly enabling,

especially in light of greener chemical processes required in industry.

Scheme 2.5 Catalytic cycle of the Wacker process

Recent advances in the Wacker-type reactions are still of research interest. Grubbs24i,j reported

the use of AgNO3, a second co-catalyst that reversed the high Markovnikov selectivity in the

59

conventional Wacker process, achieving good selectivity for the synthesis of aldehydes (Eqn

2.2).

2.1.1.4 Tandem/Domino (Cascade/Sequential) Multi-Metal Catalysis

This mode of multi-metal catalysis evokes independent catalytic events that occur in a reaction.25

The reaction pathway can occur in a defined sequence, as in a domino sequence. Or, varying

pathways can occur simultaneously but eventually converge to one desired product, as in a

tandem reaction. As a multitude of transformations is occurring in the sequence, the types of

reactions that are reported as well as the degree complexity generated in the reactions are broad.

This mode of catalysis has been applied in metathesis and polymerization reactions, including

the works of Goldman,25e Bazan,25a and Cossy.25c For example, Goldman and coworkers25f

reported the use of an Ir-pincer complex and Schrock catalyst in the oligomerization of alkanes

into higher order alkanes (Scheme 2.6). The Ir catalyst first dehydrogenated the alkane to reveal

a terminal alkene. Two of these alkenes underwent metathesis catalyzed by the Schrock catalyst.

The internal alkene product was then hydrogenated by the Ir catalyst. The dehydrogenation-

25 For examples of cascade/domino/sequential/tandem multi-metal catalysis, see (a) Komon, Z. J. A.; Diamond, G. M.; Leclerc, M. K.; Murphy, V.; Okazaki, M.; Bazan, G. C. J. Am. Chem. Soc. 2002, 124, 15280-15285. (b) Ko, S.; Lee, C.; Choi, M.-G.; Na, Y.; Chang, S. J. Org. Chem. 2003, 68, 1607-1610. (c) Cossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459-462. (d) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem. Int. Ed. 2003, 42, 2681-2684. (e) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2004, 126, 16066-16072. (f) Goldman, A. S.; Roy, A. H.; Huang, Z.; Ahuja, R.; Schinski, W.; Brookhart, M. Science 2006, 312, 257-261. (g) Kammerer, C.; Prestat, G.; Gaillard, T.; Madec, D.; Poli, G. Org. Lett. 2008, 10, 405-408. (h) Zhang, M.; Jiang, H.-F.; Neumann, H.; Beller, M.; Dixneuf, P. H. Angew. Chem. Int. Ed. 2009, 48, 1681-1684. (i) Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124-3125. (j) Takahashi, K.; Yamashita, M.; Ichihara, T.; Nakano, K.; Nozaki, K. Angew. Chem. Int. Ed. 2010, 49, 4488-4490. (k) Takahashi, K.; Yamashita, M.; Nozaki, K. J. Am. Chem. Soc. 2012, 134, 18746-18757. (l) Yuki, Y.; Takahashi, K.; Tanaka, Y.; Nozaki, K. J. Am. Chem. Soc. 2013, 135, 17393-17400. For examples of multi-ligand multi-metal catalysis, see: (m) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220-10221. (n) Panteleev, J.; Zhang, L.; Lautens, M. Angew. Chem. Int. Ed. 2011, 50, 9089- 9092. (o) Friedman, A. A.; Panteleev, J.; Tsoung, J.; Huynh, V.; Lautens, M. Angew. Chem. Int. Ed. 2013, 52, 9755-9758. (p) Zhang, L.; Sonaglia, L.; Stacey, J.; Lautens, M. Org. Lett. 2013, 15, 2128-2131. (q) Tsoung, J.; Panteleev, J.; Tesch, M.; Lautens, M. Org. Lett. 2014, 16, 110-113. (r) Zhang, L.; Qureshi, Z.; Sonaglia, L.; Lautens, M. Enantioselective Catalysis in the Presence of an Achiral Ligand: Rh/Pd Sequential Bond Formation Leading to Dihydroquinolinones. Angew. Chem. Int. Ed. 2014, In press.

60

polymerization-hydrogenation sequence may provide a solution for access to fuels from low

molecular weight alkane feedstocks.

Scheme 2.6 Ir/Mo-catalyzed alkane metathesis

Nishibayashi and Uemura25e also demonstrated the use of Ru/Pt in carbocyclizations to afford

cyclopropanes (Scheme 2.7). The catalytic sequence is remarkable given the complexity of the

transformations proposed by the authors. The Ru catalyst reacted with the propargyl alcohol

moiety to form an allenylidene 2.7.1, which underwent an ene cyclization to afford the eneyne

2.7.2. Pt subsequently activated the alkyne for cycloisomerization to form the cyclopropane ring.

Scheme 2.7 Ru/Pt-catalyzed carbocyclization/cyclopropanation

Recently, the Nozaki group25j-l has also applied Rh/Ru in the synthesis of alcohols via a

hydroformylation/hydrogenation sequence from alkenes and syngas (Eqn 2.4).

61

Given the breadth of transformations reported in multi-metal catalysis, reports on the use of

multiple ligands are substantially rare, and the potential for development remains to be realized.

One of the first examples of multi-metal catalysis that employed a combination of ligands was

reported by Jeong and coworkers (Eqn 2.5).25m The authors described a Rh/Pd-catalyzed allylic

alkylation/Pauson-Khand cyclization for the synthesis of cyclopentenones. The reaction

efficiently accessed products with high yields, though with a limited scope. The optimal ligand

combination was found to be dppb and dppp. The similarity in the ligands invokes the question

whether ligand exchange was occurring between the two metal catalysts, as both metals do

possess the capability to catalyze the allylic alkylation and Pauson-Khand cyclization.

However, Jeong’s report did demonstrate the utility and potential of developing multi-metal

catalysis based on a Rh/Pd system and that the use of ligands can play an impact in influencing

specific catalyst reactivity.

2.2 Research plan

Our interest in the development of multi-metal catalysis originated from our group’s

longstanding expertise in transition metal catalysis and their use in constructing molecular

complexity in a diverse and highly efficient manner. Particularly, rich bodies of work have been

accomplished with Rh and Pd catalysis. Extensive research into ligands has enabled powerful

transformations with the use of these two metals including conjugate additions, hydrogenation,

62

allylic alkylation, and cross coupling.26 It is foreseeable that utilizing these two metals in a

tandem/domino reaction with combinations of ligands and conditions can achieve a wide range

of reactions. As a model reaction (Eqn 2.6), we were interested in the Rh-catalyzed formal

hydroarylation of alkyne 2.1. Functionalization of the alkyne would deliver alkene 1.2 for a Pd-

catalyzed cross coupling. Combining Rh/Pd catalysis would provide efficient access to

heterocyclic structures 2.3.

2.3 Stepwise reaction optimization

2.3.1 Rh-catalyzed formal alkyne hydroarylation

Our work began with the development of Rh-catalyzed formal hydroarylation of propargyl

amines with arylboronic acids. The use of arylboronic acids in the addition of aryl groups across

alkynes was first reported by Hayashi and Miyaura (Scheme 2.8).27 The reaction featured

predominantly symmetrical alkynes or yielded regioisomeric mixture of products.

26 For a review on Rh-catalyzed enantioselective conjugate addition, see: (a) Berthon, G.; Hayashi, T. Rhodium- and Palladium-Catalyzed Asymmetric Conjugate Additions. In Catalytic Asymmetric Conjugate Reactions; Cordova, A., Ed.; Wiley-VCH: Weiheim, Germany, 2010; pp 1- 70. For reviews on Rh-catalyzed asymmetric hydrogenation, see: (b) Chi, Y.; Tang, W.; Zhang, X. Rhodium-Catalyzed Asymmetric Hydrogenation. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weiheim, Germany, 2005; pp 1-31. (c) Etayo, P.; Vidal-Ferran, A. Chem. Soc. Rev. 2013, 42, 728-754. For a review on Pd-catalyzed asymmetric allylic alkylation, see: (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921-2944. (d) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59-72. For a review on Pd-catalyzed cross coupling reactions, see: (e) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062-5085. 27 (a) Sakai, M.; Hayashi, T.; Miyaura, N. Organometallics, 1997, 16, 4229-4231. (b) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123, 9918-9919.

63

R R

[Rh]-OH

R

[Rh]Ar

ArB(OH)2

[Rh]-Ar

R

Ar

R R

H2O

2.7.1

2.7.1

Scheme 2.8 Rh-catalyzed formal hydroarylation of alkynes

In the mechanism, the catalytic cycle commenced with the transmetallation of the aryl group

from the boronic acid onto Rh, forming an organorhodium species 2.7.1. Carborhodation

occurred across the alkyne, forming a vinylrhodium intermediate 2.7.2. Protonation of the

organorhodium afforded the product alkene and regenerated the active Rh catalyst. The overall

transformation was a formal hydroarylation of the alkyne.

Following Hayashi’s work, our group addressed the regioselectivity of this reaction and

developed a Rh-catalyzed hydroarylation of pyridyl alkynes in water.28 The pyridyl group was

proposed to direct the addition of the aryl group, conveying high regioselectivity. Based on our

28 (a) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358-5359. (b) Lautens, M.; Yoshida, M. J. Org. Chem. 2003, 68, 762-769. (c) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123-125. (d) Tsui, G. C.; Lautens, M. Angew. Chem. Int. Ed. 2010, 49, 8938-8941.

64

findings, we hypothesized that by appending a nucleophilic group on the alkyl substituent and a

halogen on the aromatic group on the alkyne substrate 2.1 (Scheme 2.9), the hydroarylation

could afford products with useful functional groups that would allow further synthetic

manipulation using Pd catalysis.

X

R1

2.1

NHR I

X

R1 NHR+

Scheme 2.9 Synthetic route towards the alkyne substrates for Rh-catalyzed hydroarylation

These aryl alkyne substrates could be accessed via the Sonogashira cross coupling in a direct

manner from the corresponding iodoarene and propargyl amine or alcohol. Extensive efforts

were invested in search of a suitable substrate and optimal conditions for Rh catalysis. Initial use

of bromopyridyl alkynes did not provide desired reactivity and significant decomposition was

observed under various sets of conditions (Eqn 2.8). Changing the pyridyl group to phenyl did

not produce any benefit.

Although the complex decomposition reaction mixture remained a difficulty in analysis, we

investigated the source that likely contributed to the problem. Of the two added functional

groups on the substrates, the propargyl amine did not cause significant issues with reactivity.

Studies by Jane Panteleev29 and contemporary work by Marinelli30 on the hydroarylation

revealed smooth conversion using substrates without halogen substitution (Eqn 2.9). Extensive

optimization of the bromine containing substrates achieved a tandem hydroarylation and Suzuki-

Miyaura cross coupling catalyzed by a cationic Rh species. However, the products arising from

only the hydroarylation step could not be observed (Eqn 2.10). The Rh-catalyzed Suzuki-

29 Panteleev, J.; Huang, R. Y.; Lui, E. K. J.; Lautens, M. Org. Lett. 2011, 13, 5314-5317. 30 Acardi, A.; Aschi, M.; Chiarini, M.; Ferrara, G.; Marinelli, F. Adv. Synth. Catal. 2010, 352, 493-498.

65

Miyaura reaction necessitated that the Rh underwent oxidative insertion31 into the aryl bromide

bond. Though rare, this phenomenon has been observed and may provide precedence for further

development.

However, the observation of the hydroarylation and Suzuki-Miyaura cross coupling suggested

that switching to a less activated halogen may give the desired reactivity. Indeed, the switch from

bromide to chloride provided the hydroarylation product in an initial yield of 44% (Table 2.1,

entry 4). While conducting an extensive ligand, solvent, and base screening, we looked for

conditions in the hydroarylation step that would be suitable for the subsequent Pd-catalyzed C-N

coupling. Employing [Rh(cod)OH]2, BINAP (L1), PhB(OH)2, and K2CO3, we observed

favorable reactivity in either toluene (entry 3) or dioxane. The solvent effect was very important

in the reaction, as the use of EtOH/H2O reported by Marinelli30 did not afford the desired

reactivity (entry 1). Screening of ligands L1 to L6 (Figure 2.3, Table 2.1, entries 4-8)

demonstrated that BINAP L1 as the ligand of choice for the hydroarylation. Considering that the

pyridine directing group was absent in the substrate, the hydroarylation afforded good

regioselectivity, but the yields were still moderate. We subsequently explored the use of

additives to increase the yield. There were a number of studies on the Rh-catalyzed 1,4-conjugate

arylation that utilized additives such as methanol, which significantly enhanced the yield and

31 (a) Larock, R. C.; Narayanan K.; Hershberger, S. S. J. Org. Chem. 1983, 48, 4377-4380. (b) Ueura, K.; Satoh T.; Miura, M. Org. Lett. 2005, 7, 2229-2231. (c) Kantam, M. L.; Roy, S.; Roy, M.; Sreedhar, B.; Choudary B. M.; De, R. L. J. Mol. Catal. A: Chem. 2007, 273, 26-31. (d) Harada, Y.; Nakanishi, Y. Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766-5771. (e) Zhang L.; Wu, J. Adv. Synth. Catal. 2008, 350, 2409-2413. (f) Yu J.-Y.; Kuwano, R. Angew. Chem. Int. Ed. 2009, 48, 7217-7220. (g) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.; Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.; Chatani, N.; Nishioka, T. Org. Lett. 2009, 11, 1777-1780.

66

enantioselectivity.32 Indeed, we observed the beneficial effects of MeOH on the hydroarylation.

A notable increase in yield was achieved and the regioselectivity of the hydroarylation was

significantly enhanced as no arylation α to the arene was seen (>25:1 vs. 10:1, Table 2.1, entries

10-12).

Figure 2.3 Ligands screened for hydroarylation and C-N/O cross coupling

32 (a) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588-13589. (b) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 13168-13169. (c) Shintani, R.; Hayashi, T. Org. Lett. 2011, 13, 350-352. (d) Shintani, R.; Takeda, M.; Soh, Y.-T.; Ito, T.; Hayashi, t. Org. Lett. 2011, 13, 2977-2979.

67

Table 2.1 Optimization of the Rh-catalyzed hydroarylationa

Entry Ligandb Solvent Additivec Convd (%) NMR Yielde (%)

(2.2a:2.4a)

1 L3 EtOH (95%) 100 Trace

2 L1 THF H2O 100 40 (11:1)

3 L1 PhMe H2O 100 45 (>25:1)

4 L1 Dioxf H2O 100 44 (10:1)

5 L5 Diox H2O 77 50 (>25:1)

6 L6 Diox H2O 0

7 L4 Diox H2O 0

8 L2 Diox H2O 0

9 L1 Diox 100 44 (10:1)

10g L1 Diox MeOH 100 65 (>25:1)

11 L1 Diox MeOH 100 77h (>25:1)

12i L1 Diox MeOH 100 69 (19:1) a [Rh(cod)OH]2 with ligand were mixed in 1 mL dioxane for 15 min and then added to a vial containing 2.1a (0.2 mmol), PhB(OH)2,

K2CO3 and 0.1 mL of additive. The mixture was stirred at 70 oC for 16 h. b 5.2 mol % for bidentate ligands, 10.4 mol % for

monodentate ligands. c 10:1 solvent:additive. d Conv = conversion. e Yield of 2.2a. Yield and regioselectivity were determined by 1H

NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard introduced into the crude mixture. f Diox = 1,4-dioxane. g

Reaction conducted at 60 °C. h Isolated yield. i Reaction conducted at 80 °C.

We evaluated the scope of the Rh-catalyzed hydroarylation (Table 2.2) and found the reaction

tolerated various substitutions on the arylboronic acid, including electron rich (entry 7), electron

poor (entry 5), and thiophene or pyridine-containing heteroarylboronic acids (entries 8, 9).

Substrates bearing hydroxyl groups are also tolerated (entries 10, 11), though the sulfonamide

group gave the highest yields. The unprotected amine did not participate well in the reaction.

68

Table 2.2 Scope of Rh-catalyzed hydroarylationa

Cl

NHR

[Rh(cod)OH]2 (2.5 mol %)BINAP (5.2 mol %)

ArB(OH)2 (2 equiv), K2CO3 (2.2 equiv)Dioxane, MeOH, 70 °C, 16 h

Cl

Ar

NHR

Cl NHTs

Cl NHTs

Cl NHSO2Ph

Cl NHTs

Cl NHBoc

Cl OH

OMe

CF3

69

70

51

73

70

49

Cl NHMs

77b

entry entryproduct yield (%) product yield (%)

1

2

3

4

5

6

7

2.2a

2.2bc

2.2cc

2.2dc

2.2e

2.2f

2.2g

Cl

2.2hc

Cl NHTs

N Cl

2.2ic

OH

8

9

77

51

Cl NHMs

S

77

10

2.2j

Cl NHTs

2.2k

11

64

2.1 2.2

entry product yield (%)

a See Experimental section for reaction procedures. Reactions conducted on 0.2 mmol scale. b Reaction conducted at 60 oC. c

Reaction performed by J. Panteleev.

2.3.2 Pd-catalyzed C-N cross coupling

The adduct 2.2a following the hydroarylation was shown to undergo a Pd-catalyzed

intramolecular amidation (Table 2.3) to access dihydroquinolines of biological interest.33 The

Pd-catalyzed C-N cross coupling of amines and aryl halides is an important method for the

33 (a) Matsuda, M.; Mori, T.; Kawashima, K.; Nagatsuka, M.; Kobayashi, S.; Yamamoto, M.; Kato, M.; Takai, M.; Oda, T. (Santen Pharam Co. Ltd., JP). Novel 1,2-dihydroquinoline derivative having glucocorticoid receptor binding activity. Patent WO2,007,032,556. March 22, 2007. (b) Klein, E.; Johnson, A.; Standeven, A.; Beard, R. L.; Gillet, S. J.; Duong, T. T.; Nagpal, S.; Vuligonda, V.; Teng, M.; Chandraratna, R.; (Allergan Sales Inc., US). Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities. US Patent US5,877,207. March 02, 1999.

69

synthesis of aryl amines and has received considerable attention.34 Significant contributions to

the development and mechanism elucidation of this reaction were made by Buchwald and

Hartwig. The general mechanism (Scheme 2.10) involves the oxidative insertion of the Pd0

catalyst into an aryl halide 2.10.1, followed by transmetallation with the amine 2.10.2, and

subsequent reductive elimination furnishes the C-N bond and regenerates the Pd0 catalyst. The

use of palladium catalysis has been extended to C-O cross coupling for the synthesis of aryloxy

ethers as well.

Scheme 2.10 Catalytic cycle of the C-N cross coupling

The use of ligands has played a pivotal role in achieving reactivity with various aryl halides and

amines. Depending on the nature of the coupling partners, the catalyst-ligand combination can be

quite specific. Utilizing the specificity of ligands in this catalysis, Buchwald and coworkers

demonstrated a multi-ligand palladium catalyst system that could perform two sequential

amination reactions selectively (Scheme 2.11).35 Based on the preference for reactivity dictated

by the ligands, the Pd-BrettPhos complex first catalyzed the amination of a primary amine with

34 For reviews on C-N/C-O coupling see: (a) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041-20. (b) Schlummer, B.; Scholtz, U. Adv. Synth. Catal. 2004, 346, 1599-1626. (c) Carril, M.; SanMartin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639-647. For C-N coupling see: (d) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338-6361. (e) Aubin, Y.; Fischmeister, C.; Thomas, C. M.; Renaud, J.-L. Chem. Soc. Rev. 2010, 39, 4130-4145. For C-O coupling see: (f) Frlan, R.; Kikelj, D. Synthesis 2006, 2271-2285. (g) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912-4924. 35 Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 15914–1591.

70

an aryl bromide. The resulting secondary amine then readily participated in a coupling with an

aryl chloride catalyzed by Pd-RuPhos. Interestingly, the authors reported the use of a single Pd

precursor in the reaction to achieve reactivity. After a series of mechanistic analysis, they

concluded that ligand exchange must be occurring in the system such that both catalytic species

of Pd had to be present in order to achieve catalysis. The ligand exchange mechanism observed

by Buchwald that led to specific domino aminations provided an important precedent for the

development of a domino multi-metal reaction.

NH2

NH2

Br Cl

+ +

(0.2 mol %)L10 (0.2 mol %)

NaOtBu, dioxane110 °C, 24h

HN

NH

N N

L11 BrettPhos

Preferential aryl chlorideand primary amine coupling

L10 RuPhos

Preferential aryl bromideand secondary amine coupling

OMe

MeO

i-Pr i-Pr

i-Pr

PCy2

i-PrO Oi-Pr

PCy2

TPD, hole transport agent

Pd

NH2

ClL11

Pd-L11 Pd-L10

Scheme 2.11 Buchwald’s multi-ligand catalyst system for selective sequential diamination

While we were able to achieve an Rh-catalyzed hydroarylation with substrates bearing the aryl

chloride group, the inherent lowered reactivity of aryl chlorides was a concern in the Pd-

catalyzed amidation step. Although intermolecular amination of aryl chlorides have been

reported,36 examples with deactivated amides such as sulfonamides were rare, and secondary

36 For selected examples of C-N coupling with aryl chlorides, see: (a) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413-2415. (b) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.; Nolan, S. P. J. Org. Chem. 2006, 71, 3816-3821. (c) Sheng, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109-4112. For the sulfonamidation of aryl chlorides, see: (d) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001-13007. (e)

71

sulfonamides even more uncommon.36d-f Among these examples, the typical reaction used

inorganic bases and polar aprotic solvents at elevated temperatures. We optimized the

hydroarylation to suit those constraints. To effectively promote the amidation, J. Panteleev

screened a number of commercially available biarylphosphine ligands (Figure 2.3) that were

reported by Buchwald for coupling of aryl chlorides (Table 2.3). In combination with palladium,

we noted that the ligand used in the hydroarylation reaction, BINAP (L1), was not capable of

catalyzing the amidation (entries 1, 8). Using dioxane and carbonate bases, we were pleased to

observe a smooth conversion of the adducts from Rh-catalysis 2.2a and 2.2b into

dihydroquinolines 2.3a and 2.3b using Pd(OAc)2 and XPhos (L8, entries 4-6) as the catalyst

system.

Table 2.3 Optimization of the Pd-catalyzed amidationa

Entry R Ligand T (°C) Convb (%)

1 Ts L1 100 0

2 Ts L2 100 34

3 Ts L7 100 53

4 Ts L8 100 100

5 Ts L8 90 100c

6 Ms L8 90 100c

7 Ts L9 90 0c

8 Ms L1 90 16c a Reactions conducted by J. Panteleev. Pd(OAc)2 and ligand were mixed in 1 mL dioxane for 15 min and transferred to a vial

containing 2.2a (0.2 mmol), Cs2CO3 (91 mg, 0.28 mmol). The mixture was stirred at 90 oC for 3 h. b Determined by 1H NMR

spectroscopy. c With 10:1 dioxane:MeOH.

Establishing a two-step route provided access to dihydroquinolines 2.3a and 2.3b with a

favorable overall yield of 61 and 71% respectively (Scheme 2.12). Having developed very

similar reaction conditions for both steps, we subsequently shifted our focus to determining the

viability of an “all-in-one” domino process, which would provide a direct access to

dihydroquinoline scaffolds with substantially increased synthetic efficiency. For consistency in

Hicks, J. D.; Hyde, A. M.; Martinez Cuezva, A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720-16734. (f) Rosen, B. R.; Ruble, J. C.; Beauchamp, T. J.; Navarro, A. Org. Lett. 2011, 13, 2564-2567.

72

the reaction protocol, we prepared the ligand-metal solutions separately and added them to the

reactants prior to heating (See Experimental section). Performing the reaction without premixing

the catalyst-ligand mixtures can achieve the desired transformation, but with ca. 5% diminished

yield. The domino transformation proceeded smoothly in a comparable yield to the two-step

reaction sequence (69 vs 71%, Scheme 2.12).

Pd(OAc)2

XPhos, 90 C92%

[Rh(cod)OH]2

BINAP, PhB(OH)2, 60 C77%

2.1b

2.2b

2.3b

[Rh(cod)OH]2, BINAP, PhB(OH)2

PdOAc2, XPhos, 90 °C, 20 h69%

Cl

NHMs

N

Ph

Ms

Scheme 2.12 Domino Rh/Pd-catalyzed synthesis of dihydroquinolines

2.4 Mechanistic analysis and reaction development

Although the sequence of transformations for this reaction was simple, the selective formation of

the desired dihydroquinoline product implied that the reaction pathway must be highly

controlled. Having both catalysts and ligands in at the same time, a number of undesired

transformations could occur under the reaction conditions. For example, a scrambling of metal-

ligand complexes and the formation of inactive or less active catalyst-ligand combinations was

possible. Another concern is that the presence of arylboronic acids, arylhalides, and palladium

could lead to an undesired Suzuki-Miyaura cross coupling (Scheme 2.13).37 Consequently, a

time-resolved reaction sequence with defined catalytic cycles was clearly present in this domino

process. With the exception of the report from Jeong and coworkers,25m the development of a

domino reaction with a rhodium-palladium multi-ligand system catalyzing mutually exclusive

transformations has remained unexplored.

37 For the use of Pd/XPhos in Suzuki reactions, see: a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696. For the use of Pd/BINAP in C-N/C-O coupling, see: b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333-10334. c) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 3584-3591.

73

Scheme 2.13 Time-resolved domino sequence and competitive reaction pathways

To investigate the metal-ligand interactions of a domino process, we initially probed the effects

of BINAP and XPhos on rhodium by 31P NMR. In solution, we observed complexation of

rhodium with BINAP. However, to our surprise, [Rh(cod)OH]2 did not bind with XPhos, even

with extended heating (Figure 2.4, entries 1,2).38,39 As a result, by adding BINAP to a solution of

[Rh(cod)OH]2 and XPhos, we observed selective binding of [Rh(cod)OH]2 to BINAP (entry 4).

This unanticipated specificity had implications in realizing a number of tandem/domino

reactions, including enantioselective variants that we have recently reported (Scheme 2.14).25o,r

We also attempted to investigate the multi-ligand multi-catalyst mixture with Rh/BINAP and

Pd/XPhos directly via 31P NMR. However, the mixture decomposed over time or with heating,

posing difficulties in deducing the catalytic species present in the complex mixture.

Figure 2.4 31P NMR spectra of Rh and ligand mixtures in benzene

38 In addition, in situ hydrogenation of the cod ligand with H2 did not yield any observable Rh/XPhos complexation. 39 For formation of [Rh(BINAP)OH]2, see: Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052-5058.

1

2

3

4

Entry

[Rh(cod)OH]2 + XPhos, r.t., 15 min

[Rh(cod)OH]2 + XPhos, 50 °C, 1 h

[Rh(cod)OH]2 + (R)-BINAP, 50 °C, 1 h

[Rh(cod)OH]2 + XPhos, then (R)-BINAP, 50 °C, 2 h

(R)-BINAP

XPhos

[Rh((R)-BINAP)OH]2

74

Scheme 2.14 Ligand-specific binding of [Rh(cod)OH]2 to BINAP

Several control experiments were carried out by J. Panteleev, and the outcomes corroborated

with our observations from 31P NMR studies (Table 2.4). In the hydroarylation reaction, Rh and

BINAP were responsible for catalysis (entry 2). BINAP was essential as no hydroarylation

occurred in reactions with [Rh(cod)OH]2 on its own or with added XPhos (entries 1, 3).

Pd(OAc)2 was not an effective catalyst for the hydroarylation (entry 4). In fact, if only palladium

and XPhos were present in a mixture of the alkyne 2.1b and phenylboronic acid, Suzuki-Miyaura

cross coupling was observed in high yield (entry 5). Since the hydroarylation occurred at 70 °C

while the Suzuki-Miyaura cross coupling was sluggish at that temperature, the fast consumption

of phenylboronic acid in the Rh-catalysis in the domino process prevented the Suzuki-Miyaura

coupling from occurring. The rate difference conferred the “time-resolution” that was crucial to

the success of the domino process.

Table 2.4 Control reactions for domino catalysisa

Cl

NHMs

Catalyst, LigandPhB(OH)2 (2.0 equiv)

K2CO3 (2.2 equiv)Dioxane, MeOH

90 °C, 20 h

Ph

NHMsClN

Ph

2.1b

2.2b 2.3b

Ms

Ph

NHMs2.5b

Entryb Catalyst (mol %) Ligand (mol %) 2.1b (%) 2.2b (%) 2.3b (%) 2.5b (%)

1 [Rh(cod)OH]2 (2.5) 0c 0 0 0

2 [Rh(cod)OH]2 (2.5) L1 (5) 0 77 0 0

3 [Rh(cod)OH]2 (2.5) L8 (10) 56 6 0 0

4 Pd(OAc)2 (2) L1 (2) 96 0 0 0

5 Pd(OAc)2 (2) L8 (4) 6 0 9 76 a Reactions conducted by J. Panteleev. See Table 2.6 for reaction procedures. b Yields determined by 1H NMR spectroscopy. c

Decomposition was observed.

Subsequently, we tested the impact of added Pd(OAc)2 and XPhos on the efficiency of the

hydroarylation step (Figure 2.6). The Rh-catalyzed addition gave 70% conversion in 30 min at

70 °C (entry 1). The addition of XPhos had no effect, further supporting that this ligand had

75

minimal interaction with rhodium. However, adding Pd(OAc)2 to the reaction caused a

significant decrease in conversion (entry 3). It appeared that palladium may competitively bind

BINAP, thus stripping it from rhodium and diminishing the catalytic efficiency. Consequently,

the addition of both Pd(OAc)2 and XPhos to the reaction was essential in negating the

competitive BINAP binding effect of added Pd(OAc)2. As a result, high conversion was restored

for the Rh-catalyzed hydroarylation (entry 4). At 5 mol % Pd(OAc)2 and 10 mol % XPhos

loading (equivalent Rh:Pd loading), traces of the Suzuki cross coupling 2.5b and domino

products 2.3b appeared. As the loading of the palladium and XPhos increased, the amount of

Suzuki coupling products 2.5b became significant (entry 5). From the conversion studies, we

noted that fine tuning the catalytic components would be important in realizing the domino

reaction.

[Rh(cod)OH]2 (2.5 mol %), BINAP (5 mol %)PhB(OH)2 (2 equiv), K2CO3 (2.2 equiv)

Dioxane, MeOH, 70 °C, 30 min

Additives: Pd(OAc)2, XPhos (L8)

2.1b 2.2b

Figure 2.5 Effect of Pd and XPhos as additives in the hydroarylation step. Yields determined by 1H NMR spectroscopy. Reactions conducted by J. Panteleev.

With these initial studies, we proceeded to examine the Pd-catalyzed amidation step. Even in the

presence of phenylboronic acid, full conversion of 2.2b to the amidation product 2.3b was

observed without the formation of the Suzuki-Miyaura coupling product 2.6b (Eqn 2.11). The

intramolecular cyclization outcompeted the intermolecular cross coupling reaction.

1 Entry 432 5

76

Driven by the control in selectivity observed during the amidation step in the presence of boronic

acids, we proceeded to probe the influence of ligands XPhos and BINAP on palladium. As noted

earlier, palladium and BINAP were ineffective for catalysis. Thus, the addition of BINAP

attenuated the Pd-catalyzed amidation step, (Figure 2.6). As the loading of BINAP increased

from 4 mol % (2:1 L:Pd) to 8 mol %, the reaction became so slow that only trace conversion was

observed (entries 3, 4). The preferential binding of BINAP with palladium likely diminished the

amount of active [Pd(XPhos)] species in the reaction medium. In an experiment where Pd(OAc)2

and BINAP (1 or 2 equiv to Pd) were premixed to form the [Pd(BINAP)OAc2]40 complex, and

then added to the substrate and XPhos mixture, cyclization of 2.2b still occurred, albeit in a

lower conversion (entries 5 and 6). To gain more insight into the catalyst system, the palladium-

ligand complexes in the catalyst mixtures were examined by 31P NMR (Eqn 2.12, see Appendix

2). While it was evident that BINAP could displace XPhos bound to PdII, the reverse reaction

could not be observed by NMR. To determine if the oxidation of BINAP under the reaction

conditions led to the release of Pd0 and allowing the formation of the active catalyst, a control

experiment using Pd-BINAP-GIII, a Pd0-BINAP precursor 41 was conducted. In the presence of

XPhos and this catalyst, full conversion of 2.2b to 2.3b was observed (Eqn 2.13). It was likely

that although palladium formed an observable complex with BINAP, some equilibration between

the two metal-ligand species did occur under the reaction conditions, thereby generating

sufficient amounts of [Pd(XPhos)] to catalyze the C-N coupling reaction.

40 For formation of [Pd(BINAP)(OAc)2] and [Pd(BINAP)2] see: a) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177-2180. b) Ozawa, F; Kubo, A.; Matsumoto, Y.; Hayashi, T. Organometallics 1993, 12, 4188-4196. c) Grushin, V. V. J. Am. Chem. Soc. 1999, 121, 5831-5832. d) Grushin, V. V. Organometallics 2001, 20, 3950-3961. 41 Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916-920.

77

Figure 2.6 Effect of BINAP and ligand exchange on the amidation reaction. Pd(OAc)2 and XPhos were premixed for 30 min to fully form the ligand-bound species (observed via 31P NMR, see Appendix 2). BINAP was subsequently added and the mixture stirred for an additional 30 min. The catalyst-ligand mixture was then subjected to the reaction.a Pd(OAc)2 and BINAP were premixed for 30 min to form [Pd(BINAP)(OAc)2] (

31P NMR) followed by addition of XPhos and stirring for additional 30 min prior to subjecting to the reaction.

At higher BINAP loading, the conversion of the Pd-catalyzed amidation step was significantly

hindered. However, the addition of [Rh(cod)OH]2 along with BINAP (Figure 2.7, entry 4)

reduced this inhibition, similar to the beneficial effect of adding both Pd(OAc)2 and XPhos in the

hydroarylation step. This result suggested that excess BINAP could be effectively sequestered by

rhodium, thereby preventing formation of the inactive [Pd(BINAP)] species. However, the

loading of rhodium and BINAP relative to palladium and XPhos was also important. When it

1 Entry 4 3 2 5a 6a

78

was increased to 10 mol % (5:1 Rh:Pd), the amount of BINAP available to complex onto

palladium increased as well, leading to inhibition (entry 5).

Figure 2.7 Influence of [Rh(cod)OH]2 and BINAP in the amidation reaction

With a better understanding of metal-ligand interactions, we studied the effect of changing the

relative equivalents of the catalysts in the domino reaction. With an equimolar loading of the two

catalysts, the domino product 2.3b was formed in 50% yield with full consumption of the

starting substrate 2.1b (Figure 2.8). It was apparent that lower loading of rhodium and BINAP

led to the formation of more Suzuki-Miyaura byproduct, while high loading inhibited the

amidation. The optimal loading was established at 2.5 mol % [Rh(cod)OH]2 (5 mol % Rh), 5.2

mol % BINAP, 2 mol % Pd(OAc)2, and 4 mol % XPhos. Keeping the metal catalyst loading at 5

mol % Rh and 2 mol % Pd, we varied the relative ligand loadings (Table 2.5, Figures 2.9, 2.10).

With increased BINAP loading (Table 2.5, entries 1-3) the reaction stalled at the intermediate

2.2b. In an attempt to reduce BINAP (10 mol %) inhibition, the loading of XPhos was increased,

but no improvement in yields was observed (entries 4-6). The increased XPhos loading may have

led to coordinative saturation of palladium, decreasing its catalytic activity.42

42 Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 12905-12906.

1Entry 432 5

79

Figure 2.8 Determination of optimal catalyst ratios for the domino reaction.43 Reactions conducted by J. Panteleev.

Table 2.5 Effect of relative ligand loading in the domino reactiona

Entry BINAP (mol %) XPhos (mol %) 2.2b (%) 2.3b (%) 2.2b:2.3b

1 5.2 4 6 69 1:11

2 5.5 4 22 47 1:2.1

3 7.5 4 38 33 1.2:1

4 10 4 55 27 2:1

5 10 2 47 36 1.3:1

6 10 6 61 21 2.9:1

7 10 8 75 6 12.5:1 a See Table 2.6 for reaction procedures. Reactions conducted by J. Panteleev.

43 Reactions were carried out after premixing the Rh/BINAP and the Pd/XPhos catalyst solutions separately for 15 min at 50 °C.

80

[Rh(cod)OH]2 (2.5 mol %), BINAPPd(OAc)2 (2 mol %), XPhos

PhB(OH)2 (2 equiv), K2CO3 (2.2 equiv)Dioxane, MeOH, 90 °C, 20 h

+2.1b 2.2b 2.3b

Figure 2.9 Effect of relative ligand loading on the formation of 2.2b in the domino reaction

[Rh(cod)OH]2 (2.5 mol %), BINAPPd(OAc)2 (2 mol %), XPhos

PhB(OH)2 (2 equiv), K2CO3 (2.2 equiv)Dioxane, MeOH, 90 °C, 20 h

+2.1b 2.2b 2.3b

Figure 2.10 Effect of relative ligand loading on the formation of 2.3b in the domino reaction

These metal-ligand interaction experiments suggest that the two catalytic cycles occur

independently and no cooperative interactions between the two catalytic cycles exist (Scheme

2.15). The reaction commences as the substrate 2.1 and arylboronic acid undergo rapid Rh-

catalyzed formal hydroarylation to yield 2.2. This intermediate then enters the second catalytic

81

cycle through a Pd-catalyzed C–N coupling to yield the product 2.3. Trace amounts of undesired

Suzuki-Miyaura cross-coupling of 2.1 with the arylboronic acid could be observed, along with

C-N coupling inhibition in the presence of excess BINAP. Through optimization of the catalyst

ratios however, these competing reaction pathways and inhibitory effects could be minimized.

Scheme 2.15 Proposed domino catalytic cycles

2.5 Scope of the Rh/Pd-catalyzed domino synthesis of dihydroquinolines

With the synthetic conditions optimized, we investigated the scope of the domino process with

respect to various substitution patterns on the alkyne substrate and the arylboronic acid. We also

investigated the role of the nitrogen protecting group on the substrate 2.1 (Table 2.6) and

82

observed the highest yields with mesyl and tosyl groups, though other sulfonyl groups were

tolerated.

Table 2.6 Scope of nitrogen protecting groupsa

a Stock catalyst solutions ([Rh(cod)OH]2 (0.005M) with BINAP (1.05 equiv to [Rh]) and Pd(OAc)2 (0.008M) with XPhos (2 equiv to

[Pd])), were mixed separately in dioxane at 50 oC for 15 min. 0.5 ml of each solution was added to a vial containing 2.1 (0.2 mmol),

ArB(OH)2 (2 equiv), K2CO3 (2.2 equiv) and 0.1 mL MeOH in 1 ml of dioxane. The mixture was stirred at 90 oC for 16 to 20 h. b

Reactions conducted by J. Panteleev.

83

Table 2.7 Scope of arylboronic acids in the domino reactiona

N

Ts

NO2

N

R

CN

N

R

S

N

R

N OEt

N

Ts

N F

N

R

OMe

N

R

O

49

47

3fa R = Ts, 403fb R = Ms, 49b

N

Ts

N

Ts

N

Ts

CF3

Ac

63

64

59

N

R

CF3

N

Ms

50OMe

OMe

N

Ar

RCl

NHR

1

2

3

4

5 3la R = Ts, 563lb R = Ms, 68b

3ra R = Ts, 463rb R = Ms, 78b

3sa R = Ts, 42b

3sb R = Ms, 64b

6

7

8

9

10

11

12


2.3i

2.3f

2.3e

2.3j

2.3k

2.3l

2.3nb

2.3s

2.3pb

3qa R = Ts, 473qb R = Ms, 65b

2.3r

N

Ts

39

2.3ob

F13

[Rh(cod)OH]2 (2.5 mol %)BINAP (5.2 mol %), ArB(OH)2 (1.5 - 2 equiv)

Pd(OAc)2 (2 mol %), XPhos (4 mol %)

K2CO3 (2.2 equiv), Dioxane (0.1M),MeOH, 90 °C, 16 - 20 h

2.1 2.3

3ma R = Ts, 633mb R = Ms, 55b

2.3m 2.3q

entry product yield (%)

a See Table 2.6 for reaction conditions. b Reaction conducted by J. Panteleev.

Using tosyl and mesyl protected substrates, we examined the scope with respect to the

arylboronic acid (Table 2.7). A variety of arylboronic acids were tolerated. Both electron rich to

poor boronic acids gave similar yields (entries 10-13). Excellent regioselectivity was observed

with respect to the alkyne for various boronic acids. Heteroarylboronic acids also exhibited

favorable reactivity. In particular, 3-thiophenyl boronic acid underwent the domino

transformation in a 78% yield (entry 12).

84

As we investigated the effects of substitution on the aryl alkyne (Table 2.8), we observed a

dependence of the isolated yield on the electronics of the aromatic system. In substrates bearing

electron deficient substituents, the products could be isolated in higher yields (60-81%, entries 2-

6). While electron-rich arenes were slightly lower yielding, the high regioselectivity of the

hydroarylation was retained. Various substitution patterns on the arene were well tolerated.

Table 2.8 Scope of substitutions on substrate

N

Ms

N

Ms

N

Ms

F

F

MeO

62

73

54

N

Ms

F61

S

N

Ms

78

81c

S

F3C

N

Ar

MsCl

NHMs

R'R'

1

2

3

4

5


2.4a

2.4b

2.4d

2.4eb

N

Ms

63

S

AcHN

2.4gb

N

N

Ms

S

2.4fb

63

6

7

[Rh(cod)OH]2 (2.5 mol %)BINAP (5.2 mol %), ArB(OH)2 (1.5 - 2 equiv)

Pd(OAc)2 (2 mol %), XPhos (4 mol %)

K2CO3 (2.2 equiv), Dioxane (0.1M),MeOH, 90 °C, 16 - 20 h

2.1 2.4

N

MsF

2.4cS

2.4hb

8

45

a See Table 6 for reaction conditions. b Reaction conducted by J. Panteleev. c Reaction conducted at 60 °C for 90 min and at 90 °C

for the rest of the reaction duration.

The ligand-dependent domino Rh/Pd catalysis strategy is versatile, as a Pd-catalyzed C-O cross

coupling could also be applied after hydroarylation to access aryl-2H-chromenes (Table 2.9).

Simply switching the palladium catalyst to [Pd(allyl)Cl]2 and the solvent to toluene resulted in an

85

effective domino hydroarylation/C-O cross coupling to afford the desired products in moderate

yields.

Table 2.9 Synthesis of chromenesa

a See Table 2.6 for reaction conditions.

The resulting dihydroquinoline products could be modified into the 3-substituted quinoline via

elimination of the sulfonyl group in the presence of KOtBu at room temperature (Eqn 2.14). The

chromene 2.4h could be dihydroxylated in high yield and ee (Eqn 2.15). In addition, the

hydrogenation of the stilbene double bond on the chromene could be achieved under mild

conditions.44

44 (a) Deschamps-Vallet, C.; Ilotse, J.-B.; Meyer-Dayan, M. Tetrahedron Lett. 1983, 24, 3993-3996. (b) Burali, C.; Desideri, N.; Stein, M. L.; Conti, C.; Orsi, N. Eur. J. Med. Chem. 1987, 22, 119-124.

86

2.6 Conclusion

We have developed a synthesis of dihydroquinolines and chromenes via a two-metal, two-ligand

domino process. This work demonstrated that in spite of the complexity of metal-ligand

interactions, applying multi-metal-ligand domino reactions could yield powerful one-step

transformations in high efficiency. Through our studies on the strength of the binding

interactions, we have gained valuable insight into the role of each individual component in this

domino reaction. Although inhibitory effects and side reactivity existed, modifications in the

reaction conditions could counter these problems. Our work provided an example of two

transition-metal complexes with different phosphine ligands capable of association and

dissociation whereby the active metal-ligand complexes function independently to catalyze the

desired reaction pathway.


Characterization data and experimental methods for 2.1j,45 2.1b, 2.1l, 2.1n, 2.1o, 2.2b, 2.2i,

2.5b, 2.3lb, 2.3qb, 2.3rb, 2.4c-f, 2.4h,25n and 2.746 were reported previously.

Substrate syntheses

N-(3-(2-chlorophenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide 2.1a

45 Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737-4739. 46 Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073-14075.

87

A round-bottom flask containing Pd(PPh3)2Cl2 (71 mg, 1 mol %) and CuI (38 mg, 2 mol %) was

purged with argon. N,N-dimethylformamide (50 mL, 0.2M) and triethylamine (10.1 g, 13.9 mL,

100 mmol, 10 equiv) were added, followed by the addition of 2-chloro-1-iodobenzene (2.62 g,

1.34 mL, 11 mmol, 1.1 equiv) and N-(prop-2-ynyl)toluenesulfonamide (2.09 g, 10 mmol, 1

equiv), and the flask was stirred at r.t. for 16 h. The reaction mixture was diluted with EtOAc and

partitioned with water. The organic phase was separated and washed with water 2x and brine,

dried over Na2SO4, filtered and concentrated under vacuum. Column chromatography

(pentane:EtOAc 7:3) yielded the titled compound as an off-white solid in 70% yield (2.24 g). 1H

NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.30 – 7.18 (m,

3H), 7.15 (d, J = 4.2 Hz, 2H), 4.72 (s, 1H), 4.14 (d, J = 6.1 Hz, 2H), 2.32 (s, 3H).; 13C NMR

(100 MHz, CDCl3) δ 143.9, 136.9, 135.9, 133.5, 129.9, 129.7, 129.3, 127.6, 126.4, 122.2, 88.6,

81.7, 34.0, 21.6; IR (NaCl, neat, cm-1): 3256, 2862, 1596, 1472, 1431, 1322, 1306, 1293, 1140,

1092, 1066, 963, 837, 819.; M.p.: 134-136 °C; HRMS (TOF, ESI+): calcd for C16H15ClNO2S

(M+H)+: 320.0506; Found: 320.0499.

N-(3-(2-Chlorophenyl)prop-2-ynyl)methanesulfonamide 2.1b

A round-bottom flask containing Pd(PPh3)2Cl2 (100 mg, 2 mol %) and CuI (60 mg, 4 mol %)

was purged with argon. Acetonitrile (30 mL, 0.2M) and triethylamine (30 mL, 0.2M) were

added, followed by the addition of 2-chloro-1-iodobenzene (1.81 g, 0.926 mL, 7.59 mmol, 1.1

equiv) and N-(prop-2-ynyl)methanesulfonamide (918 mg, 6.9 mmol, 1 equiv), and the flask was

stirred at 40 oC for 4 h when no starting material remained on TLC. The reaction crude was

filtered through a Celite plug and concentrated under vacuum. Column chromatography

(pentane:EtOAc 7:3) yielded the titled compound as an off-white solid in 75% yield (1.26 g). 1H

NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 7.5, 1.8 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.29

(td, J = 7.8, 1.8 Hz, 1H), 7.23 (td, J = 7.5, 1.4 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.27 (d, J = 6.2

Hz, 2H), 3.17 (s, 3H).; 13C NMR (100 MHz, CDCl3): δ136.1, 133. 130.1, 129.5, 126.8, 122.0,

89.3, 81.9, 41.8, 33.8.; IR (NaCl, neat): 3280, 3016, 2961, 2930, 2879, 1473, 1432, 1417, 1243,

88

1166, 1156, 1070, 1063, 1034, 996, 971, 827, 761, 739, 715, 667, 667, 589, 547, 522 cm-1; M.p.:

65-67 °C; HRMS (TOF, EI+): calcd for C10H10ClNO2S (M)+: 243.0121; Found: 243.0117.

tert-Butyl 3-(2-chlorophenyl)prop-2-ynylcarbamate 2.1d

A round-bottom flask containing Pd(PPh3)2Cl2 (354 mg, 1 mol %), CuI (192 mg, 2 mol %), and a

stirring bar was purged with argon. Triethylamine (170 mL, 0.3M) was added. Following this, 2-

chloro-1-iodobenzene (12.0 g, 6.15mL, 50.5 mmol, 1.01 equiv) was added, followed by tert-

butyl prop-2-yn-1-ylcarbamate (7.76 g, 50 mmol, 1 equiv), and the reaction was allowed to stir at

r.t.e for 4 h, at which point no starting material could be observed by TLC. The reaction crude

was filtered through a Celite plug and concentrated under vacuum. Column chromatography

(pentane:EtOAc 9:1) yielded the titled compound as a colorless solid in 95% yield (12.6 g). 1H

NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 7.4, 1.8 Hz, 1H), 7.35 (dd, J = 7.9, 1.2 Hz, 1H), 7.21

(td, J = 7.7, 1.9 Hz, 1H), 7.16 (td, J = 7.5, 1.4 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J = 3.3 Hz, 2H),

1.45 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 155.4, 136.0, 133.5, 129.4, 129.3, 126.5, 122.7,

90.9, 80.1, 79.9, 31.4, 28.4.; IR (NaCl, neat, cm-1): 3343, 2979, 2933, 1712, 1679, 1505, 1475,

1368, 1274, 1249, 1168, 1064, 1049, 1033, 859, 755.; M.p.: 58-60 °C; HRMS (TOF, DART+):

calcd for C14H17ClNO2 (M+H)+: 266.09478; Found: 266.09413.

General procedure A for protected propargyl amines:

A round bottom flask was charged with a stirring bar and tert-butyl 3-(2-chlorophenyl)prop-2-

ynylcarbamate (11.93 g, 45 mmol, 1 equiv) and cooled to 0 oC in an ice bath. A solution of

HCl(aq) in EtOAc (3M, 30 mL) was added to this flask. The reaction was allowed to stir at room

temperature, until no starting material was observed by TLC (2h). The liquids were removed

89

under reduced pressure, leaving an orange flaky solid (prop-2-yn-1-aminium chloride, 8.54g,

42.2 mmol), which was used without further purification. In order to synthesize the protected

propargyl amines, the prop-2-yn-1-aminium chloride was treated with triethylamine and the

appropriate electrophile in dichloromethane as described in each specific case.

N-(3-(2-Chlorophenyl)prop-2-ynyl)benzenesulfonamide 2.1c

According to the general procedure A, prop-2-yn-1-aminium chloride (500mg, 2.474 mmol, 1

equiv) was placed into an oven-dried round bottom flask with a stirring bar; dichloromethane (10

mL, 0.25M) and triethylamine (550 mg, 0.757 mL, 5.4 mmol, 2.2 equiv) were added. The

reaction was cooled to 0 oC in an ice bath. Benzenesulfonyl chloride (480 mg, 0.35 mL, 2.7

mmol, 1.1 equiv) was added dropwise over ~3 minutes, and the reaction was allowed to warm to

room temperature. When the reaction was complete, as observed by TLC (<1h), the mixture was

quenched with saturated NH4Cl(aq), extracted with dichloromethane, washed with brine, and

dried over MgSO4. Afterwards, the solvent was removed under reduced pressure, and the crude

was purified using column chromatography (pentane:EtOAc 9:1 to 8:2) yielding the title

compound in 74% yield (560 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.92

(m, 2H), 7.56 – 7.44 (m, 3H), 7.36 – 7.30 (m, 1H), 7.22 (ddd, J = 8.0, 6.6, 2.5 Hz, 1H), 7.18 –

7.11 (m, 2H), 4.87 (t, J = 5.8 Hz, 1H), 4.16 (d, J = 6.1 Hz, 2H).; 13C NMR (100 MHz, CDCl3) δ

139.9, 135.9, 133.5, 133.0, 129.8, 129.3, 129.3 (2), 127.5 (2), 126.4, 122.0, 88.4, 81.7, 34.0.; IR

(NaCl, neat, cm-1): 3282, 3059, 2931, 2854, 1475, 1448, 1334, 1266, 1164, 1091, 1072, 1032,

967, 947, 844, 730.; M.p.: 84-85 °C; HRMS (TOF, EI+): calcd for C15H12ClNO2S (M)+:

305.0277; Found: 305.0279.

90

N-(3-(2-Chlorophenyl)prop-2-ynyl)-4-methoxybenzenesulfonamide 2.1g

According to the general procedure A, prop-2-yn-1-aminium chloride (303 mg, 1.5 mmol, 1


mL, 0.3 M) and triethylamine (333.76 mg, 0.46 mL, 3.3 mmol, 2.2 equiv) were added. The

reaction was cooled to 0 oC in an ice bath. 4-Methoxybenzene-1-sulfonyl chloride (341 mg, 1.1

equiv) in dichloromethane (1mL) was added dropwise over ~3 minutes, and the reaction was

allowed to warm to room temperature. When the reaction was complete, as observed by TLC

(<1h), the mixture was quenched with saturated NH4Cl(aq), extracted with dichloromethane,

washed with brine, and dried over MgSO4. Afterwards, the solvent was removed under reduced

pressure, and the crude was purified using column chromatography (pentane:EtOAc 7:3 to 6:4)

yielding the title compound in 70% yield (352 mg) as a colorless solid. 1H NMR (400 MHz,

CDCl3): δ 7.85 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.20 (ddd,J = 2.4, 6.8, 8.0 Hz, 1H),

7.17 – 7.08 (m, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.05 (t, J = 6.0 Hz, 1H), 4.11 (d, J = 6.1 Hz, 2H),

3.73 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 163.1, 135.8, 133.5, 131.3, 129.7 (2), 129.6, 129.2,

126.4, 122.2, 114.3 (2), 88.8, 81.5, 55.6, 33.9.; IR (NaCl, neat, cm-1): 3268, 3094, 3023, 2981,

2854, 1595, 1575, 1472, 1432, 1326, 1310, 1302, 1265, 1152 1073, 1022, 832, 763.; M.p.: 105-

107 °C; HRMS (TOF, DART+): calcd for C16H15ClNO3S (M+H)+: 336.04612; Found:

336.04492.

N-(3-(2-Chlorophenyl)prop-2-ynyl)-4-nitrobenzenesulfonamide 2.1h

According to the general procedure A, prop-2-yn-1-aminium chloride (303 mg, 1.5 mmol, 1


91

mL, 0.3 M) and triethylamine (333.76 mg, 0.460 mL, 3.3 mmol, 2.2 equiv) were added. The

reaction was cooled to 0 oC in an ice bath. 4-Nitrobenzene-1-sulfonyl chloride (366 mg, 1.1

equiv) in dichloromethane (1mL) was added dropwise over ~3 minutes, and the reaction was

allowed to warm to room temperature. When the reaction was complete, as observed by TLC

(<1h), the mixture was quenched with saturated NH4Cl(aq), extracted with dichloromethane,

washed with brine, and dried over MgSO4. Afterwards, the solvent was removed under reduced

pressure, and the crude was purified using column chromatography (pentane:DCM:MeOH

47.5:47.5:5) yielding the title compound in 75% yield (385 mg) as a colorless solid. 1H NMR

(400 MHz, CDCl3): δ 8.24 (dt, J = 2, 9.2 Hz, 2H), 8.12 (dt, J = 2, 8.8 Hz, 2H), 7.31 (dd, J = 8.1,

0.8 Hz, 1H), 7.22 (ddd, J = 2, 7.2, 8 Hz 1H), 7.13 (td, J = 7.4, 1.2 Hz, 1H), 7.09 (dd, J = 2, 7.6

Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H).; 13C NMR (100 MHz, CDCl3): δ

150.2, 146.0, 135.7, 133.2, 130.3, 129.5, 128.9 (2), 126.7, 124.4 (2), 121.5, 87.8, 82.4, 34.1.; IR

(NaCl, neat, cm-1): 3285, 3101, 3076, 1520, 1471, 1432, 1344, 1159, 1053, 857, 766, 736, 622.;

M.p.: 128-129 °C; HRMS (TOF, DART+): calcd for C15H15ClN3O4S (M+NH4)+: 368.04718;

Found: 368.04750.

4-(2-chlorophenyl)but-3-yn-1-ol 2.1k

A round-bottom flask containing Pd(PPh3)2Cl2 (70 mg, 0.5 mol %), CuI (38 mg, 1 mol %), and a

stirring bar was purged with argon. Triethylamine (40 mL, 0.5M) was added. Following this, 2-

chloro-1-iodobenzene (5.25 g, 2.69mL, 22 mmol, 1.1 equiv) was added, followed by 3-butyn-1-

ol (1.40 g, 1.51 mL, 20 mmol, 1 equiv), and the reaction mixture was degassed with argon. The

mixture was stirred at room temperature for 16 hours. The reaction crude was filtered through a

celite plug and concentrated under vacuum. Column chromatography (pentane:EtOAc 9:1)

yielded the titled compound (2.85 g) as yellow oil in 79% yield. 1H NMR (300 MHz, CDCl3): δ

7.49 – 7.41 (m, 1H), 7.41 – 7.35 (m, 1H), 7.28 – 7.14 (m, 2H), 3.84 (t, J = 6.2 Hz, 2H), 2.74 (t, J

= 6.2 Hz, 2H).; 13C NMR (75 MHz, CDCl3): δ 135.9, 133.3, 129.2, 129.1, 126.5, 123.2, 92.3,

92

79.6, 61.1, 24.1.; IR (NaCl, CDCl3, cm-1): 3335, 2943, 2888, 2234, 1476, 1431, 1065, 1045,

1034, 75.; HRMS (TOF, ESI+): calcd for C10H10ClO:181.0420, Found: 181.0419.

N-(3-(2-Chloro-3-fluorophenyl)prop-2-ynyl)methanesulfonamide 2.1l

A round-bottom flask containing Pd(PPh3)4 (58 mg, 5 mol %), CuI (19 mg, 10 mol %), 1-bromo-

2-chloro-3-fluorobenzene (210 mg, 1 mmol) and N-(prop-2-ynyl)methanesulfonamide (160 mg,

1.2 mmol, 1.2 equiv) was purged with argon. Acetonitrile (5 mL, 0.2M) and diisopropylamine (5

mL, 0.2M) were added. The reaction was sealed and stirred at 90 oC for 16 hours. The reaction

crude was filtered through a Celite plug and concentrated under vacuum. Column

chromatography (hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a colorless solid in

63% yield (165 mg). 1H NMR (400MHz, CDCl3) δ 7.26 (d, J = 7.7 Hz, 1H), 7.20 (dt, J = 8.2,

5.1 Hz, 1H), 7.14 (dt, J = 8.6, 1.8 Hz, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H),

3.17 (s, 3H).; 13C NMR (100MHz, CDCl3) δ 158.5 (d, J = 250 Hz), 129.0 (d, J = 3 Hz), 127.8

(d, J = 8 Hz), 123.4 (d, J = 18 Hz), 124.2 (s), 117.3 (d, J = 21 Hz), 90.5 (s), 80.8 (d, J = 4 Hz),

41.8 (s), 33.7 (s).; 19F NMR (282 MHz, CDCl3) δ -112.99 (dd, J = 8.4, 5.2 Hz); IR (NaCl, neat,

cm-1) 3285, 1569, 1468, 1440, 1320, 1247, 1153, 1076, 1036, 787.; M.p.: 100-103 °C; HRMS

(TOF, ESI+): calcd for C10H10ClFNO2S (M+H)+: 262.0105; found 262.0106.

N-(3-(3-Chloropyridin-3-yl)prop-2-ynyl)methanesulfonamide 2.1m

A round-bottom flask containing Pd(PPh3)4 (347 mg, 3 mol %) was purged with argon.

Diisopropylamine (25 mL, 0.4M) and 2-bromo-3-chloropyridine (1.924 g, 10 mmol, 1 equiv)

were added, followed by tert-butyl prop-2-yn-1-ylcarbamate (1.86 g, 12 mmol, 1.2 equiv).The

93

flask was stirred at 100 oC for 16 hours. The reaction crude was filtered through a celite plug and

concentrated under vacuum. Column chromatography (pentane:EtOAc 7:3) yielded tert-butyl (3-

(2-chloropyridin-3-yl)prop-2-yn-1-yl)carbamate in 67% (1.79 g) yield as a brown solid. This

material was then placed in a round bottom flask, cooled to 0 oC in an ice bath, and was treated

with HCl(aq) in EtOAc (3M, 30 mL). The reaction was monitored by TLC. Upon completion, the

liquids were removed under vacuum to give a crystalline solid (3-(2-chloropyridin-3-yl)prop-2-

yn-1-aminium chloride). This material (500mg, 2.47 mmol, 1 equiv) was placed into a flame-

dried round bottom flask. Dichloromethane (12 mL, 0.2M) and triethylamine (860mg, 1.15 mL,

6.18 mmol, 2.5 equiv) were added. Upon cooling to 0 oC in an ice bath, methanesulfonyl

chloride (340 mg, 227 μl, 2.96 mmol, 1.2 equiv) was added dropwise over ~3 minutes. The

reaction was allowed to warm to room temperature and monitored by TLC. Upon completion,

the mixture was quenched with saturated NH4Cl(aq), extracted with dichloromethane, washed

with brine, and dried over MgSO4. Afterwards, the solvent was removed under reduced pressure,

and the crude was purified using column chromatography (pentane:EtOAc 1:1) yielding the title

compound in 58% yield (351 mg, 39% overall) as a colorless solid. 1H NMR (400 MHz, CDCl3)

δ 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 7.6, 4.9 Hz, 1H),

4.86 (t,J = 5.3 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H); 13C NMR(101 MHz, CDCl3) δ

152.4, 149.1, 141.9, 122.1, 119.4, 91.9, 80.0, 41.9, 33.7; IR (NaCl, neat, cm-1): 3269, 2918,

2850, 1395, 1318, 1152, 1092, 1070, 808.; M.p.: 113-114 °C; HRMS (TOF, DART+): calcd for

C9H10ClN2O2S (M+H)+: 245.01515; Found: 245.01471.

N-(3-(2-Chloro-5-fluorophenyl)prop-2-ynyl)methanesulfonamide 2.1n

A round-bottom flask containing Pd(PPh3)4 (58 mg, 5 mol %), CuI (19 mg, 10 mol %), 2-bromo-

1-chloro-4-fluorobenzene (210 mg, 1 mmol) and N-(prop-2-ynyl)methanesulfonamide (160 mg,

1.2 mmol, 1.2 equiv) was purged with argon. Acetonitrile (5 mL, 0.2M) and diisopropylamine (5

mL, 0.2M) were added. The reaction was sealed and stirred at 90 oC for 16 hours. The reaction

crude was filtered through a Celite plug and concentrated under vacuum. Column

94

chromatography (hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a colorless solid in

56% yield (146 mg). 1H NMR (300MHz, CDCl3) δ 7.36 (dd, J = 8.9, 5.1 Hz, 1H), 7.16 (dd, J =

8.5, 3.0 Hz, 1H), 7.02 (ddd, J = 8.9, 7.9, 3.0 Hz, 1H), 4.72 (s, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.16

(s, 3H).; 13C NMR (75MHz, CDCl3) δ 161.0 (d, J = 248 Hz), 131.5 (d, J = 4 Hz), 131.0 (d, J = 9

Hz), 123.6 (d, J = 10 Hz), 120.4 (d, J = 25 Hz), 117.8 (d, J = 23 Hz), 90.6 (s), 81.1 (d, J = 3 Hz),

42.0 (s), 33.8 (s).; 19F NMR (282 MHz, CDCl3) δ -115.33 (td, J = 8.1, 5.1 Hz).; IR (NaCl, neat):

3281, 1602, 1577, 1469, 1405, 1320, 1154, 1120, 1000, 874, 817, 649.; M.p.: 74-76 °C.; HRMS

(TOF, ESI+): calcd for C10H10ClFNO2S (M+H)+, 262.0104; found 262.0105.

N-(3-(2-Chloro-4-(trifluoromethyl)phenyl)prop-2-ynyl)methanesulfonamide 2.1o

A round-bottom flask containing Pd(PPh3)2Cl2 (72 mg, 2 mol %) and CuI (44 mg, 4 mol %) was

purged with argon. Acetonitrile (25 mL, 0.2M) and triethylamine (25 mL, 0.2M) were added,

followed by the addition of 2-chloro-1-iodo-4-(trifluoromethyl)benzene (1.53 g, 5 mmol, 1

equiv) and N-(prop-2-ynyl)methanesulfonamide (732 mg, 5.5 mmol, 1.1 equiv), and the flask

was stirred at 40 oC for 5 hours when no starting material remained on TLC. The reaction crude

was filtered through a Celite plug and concentrated under vacuum. Column chromatography

(hexane:EtOAc 9:1 to 8:2) yielded the titled compound as a pale yellow solid in 63% yield (0.98

g). 1H NMR (300MHz, CDCl3: δ 7.68 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H),

4.75 (br s, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.16 (s, 3H).; 13C NMR (75MHz, CDCl3) δ 136.6 (s),

133.9 (s), 131.8 (q, J = 34Hz), 126.5 (q, J = 4 Hz), 125.7 (s), 123.6 (q, J = 4 Hz), 123.0 (q, J =

273 Hz), 92.0 (s), 80.6 (s), 41.7 (s), 33.6 (s).; 19F NMR (282 MHz, CDCl3): δ -63.5.; IR (NaCl,

neat, cm-1): 3281, 1391, 1320, 1141, 1082, 834, 723.; M.p.: 73-75 °C.; HRMS (TOF, ESI+):

calcd for C11H10ClF3NO2S: 312.0073; Found: 312.0074.

N-(3-Chloro-4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)acetamide 2.1p

95

A round-bottom flask containing Pd(PPh3)2Cl2 (58 mg, 5 mol %) and CuI (19 mg, 10 mol %)

was purged with argon. Acetonitrile (5 mL, 0.2M) and diisopropylamine (5 mL, 0.2M) were

added, following this N-(4-bromo-3-chlorophenyl)acetamide (249 mg, 1 mmol, 1 equiv) was

added, followed by N-(prop-2-ynyl)methanesulfonamide (173 mg, 1.3 equiv). The reaction was

allowed to stir at 90 oC for 16 hours. The reaction crude was filtered through a Celite plug and

concentrated under vacuum. Column chromatography (pentane:EtOAc 1:1) yielded the titled

compound as a colorless solid in 50% yield (150mg). 1H NMR (400 MHz, DMSO) δ 10.26 (bs,

1H), 7.89 (s, 1H), 7.66 (t, J = 5.3 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H),

4.10 (d, J = 5.5 Hz, 2H), 3.03 (s, 3H), 2.06 (s, 3H).; 13C NMR (101 MHz, DMSO) δ 169.0,

140.7, 134.8, 134.0, 118.7, 117.4, 115.5, 90.0, 80.0, 40.7, 32.6, 24.1.; IR (NaCl, neat, cm-1):

3331, 3096, 3010, 2929, 2886, 1676, 1583, 1515, 1493, 1455, 1385, 1320, 1255, 1150, 1051,

1005, 964, 884, 843.; M.p.: 171-172 °C.; HRMS (TOF, DART+): calcd for C12H14ClN2O3S

(M+H)+: 301.04137; Found: 301.04054.

Rhodium-catalyzed hydroarylation

General Procedure B for Rh-catalyzed alkyne arylation: (Z)-N-(3-(2-Chlorophenyl)-2-

phenylallyl) methanesulfonamide 2.2b

[Rh(cod)OH]2 (11.4 mg, 2.5 mol % (5 mol % [Rh])) and BINAP (32.4 mg, 5.2 mol %) were

weighed into a 2-dram vial, which was fitted with a cap with a septum and purged with argon for

5 minutes. Dioxane (1 mL) was added to the vial and the solution was allowed to stir for 15

minutes at 50 oC (Note 1). Substrate 2.1b (244 mg, 1 mmol), phenylboronic acid (183mg, 1.5

mmol, 1.5 equiv), K2CO3 (166 mg, 1.2 mmol, 1.2 equiv) were weighed into a 25mL round-

bottom flask, which was fitted with a septum and purged with argon. 1,4-Dioxane (8 mL) and

MeOH (0.8 mL) were added to the reaction. The catalyst solution was added to this reaction

flask via syringe. The reaction was heated to 50 oC overnight (16 h), after which TLC showed

complete consumption of phenylboronic acid. The reaction mixture was cooled to room

96

temperature, filtered through a plug of silica (washing with EtOAc), and the solvent was

removed under vacuum. The crude was purified using column chromatography (loading with

toluene, pentane:EtOAc 8:2 to75:25) to yield a thick yellow oil which slowly solidified upon

standing (238 mg) in 74% yield (slightly higher yield (49.6 mg, 77%) was isolated on 0.2 mmol

scale). 1H NMR (400 MHz, CDCl3): δ 7.57 – 7.51 (m, 2H), 7.48 – 7.27 (m, 7H), 6.97 (s, 1H),

4.32 – 4.23 (m, 3H), 2.72 (s, 3H).; 13C NMR (100 MHz, CDCl3): δ 139.03, 138.39, 134.92,

134.02, 130.44, 129.86, 129.43, 129.38, 129.22 (2C), 128.77, 127.09, 126.99 (2C), 42.49, 40.53.;

IR (NaCl, neat, cm-1): 3282, 3058, 3023, 2963, 2932, 1496, 1471, 1445, 1428, 1409, 1318,

1264, 1153, 1067, 1052, 1034, 967, 883, 862, 836, 763, 699.; M.p.: 77-78 °C.; HRMS (TOF,

DART+): calcd for C16H20ClN2O2S (M+NH4)+: 339.09340; Found: 339.09383.

Note 1: Premixing [Rh(cod)OH]2 and BINAP was not crucial for the single step procedure and

similar yields (70-77%) were obtained if the catalyst and ligand were weighed as solids together

with base and substrates.

(Z)-N-(3-(2-chlorophenyl)-2-phenylallyl)-4-methylbenzenesulfonamide 2.2a

The product was synthesized according to general procedure B, using [Rh(cod)OH]2 (2.3 mg, 2.5

mol %), BINAP (6.23 mg, 5 mol %), substrate 2.1a (64 mg, 0.2 mmol, 1 equiv), phenylboronic

acid (49 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The crude product

was purified by flash chromatography with 0-10% EtOAc/hexanes to provide the title compound

(58.1 mg) as an off white solid 73%. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz, 2H),

7.31 (d, J = 7.7 Hz, 1H), 7.21 – 7.13 (m, 4H), 7.13 – 7.06 (m, 1H), 6.83 (s, 1H), 4.44 (s, 1H),

4.02 (d, J = 5.6 Hz, 2H), 2.38 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 143.5, 138.7, 137.3,

136.2, 134.8, 134.0, 130.2, 129.7, 129.6, 129.2, 129.0, 128.9, 128.5, 127.3, 126.8, 126.7, 42.4,

21.7.; IR (NaCl, CDCl3, cm-1): 3266, 3057, 1660, 1599, 1471, 1445, 1404, 1327, 1163, 1094,

1067, 1053, 887, 814, 760, 698, 667.; M.p.: 127-129 °C.; HRMS (TOF, ESI+): calc’d for

C22H21NO2SCl: 398.0976; Found: 398.0985.

97

(Z)-N-(3-(2-Chlorophenyl)-2-phenylallyl)benzenesulfonamide 2.2c

The titled compound was synthesized using procedure B using [Rh(cod)OH]2 (2.3 mg, 2.5 mol

%), BINAP (6.23 mg, 5 mol %), substrate 1c (61.2 mg, 0.2 mmol, 1 equiv), phenylboronic acid

(49 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The product was isolated

through column chromatography (pentane:EtOAc 9:1) as a pale yellow solid in 70% yield (48.6

mg). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J =

7.7 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.34 – 7.26 (m, 5H), 7.26 – 7.10 (m, 3H), 6.89 (s, 1H),

4.49 (t, J = 5.2 Hz, 1H), 4.10 (d, J = 5.6 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 139.2, 138.6,

137.2, 134.8, 134.0, 132.8, 130.2, 129.7, 129.3, 129.2(2), 129.0(2), 128.5, 127.3(2), 126.9,

126.7(2), 42.4.; IR (NaCl, neat, cm-1): 3260, 3061, 3023, 2917, 2849, 1471, 1447, 1321, 1166,

1095, 1066, 1049, 757, 721, 689.; M.p.: 131-134 °C.; HRMS (TOF, DART+): calcd for

C21H19ClNO2S (M+H)+: 384.08250; Found: 384.08289.

(Z)-tert-Butyl 3-(2-chlorophenyl)-2-phenylallylcarbamate 2.2d


%), BINAP (6.23 mg, 5 mol %), substrate 2.1d (53.2 mg, 0.2 mmol, 1 equiv), phenylboronic

acid (49 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The product was

isolated through column chromatography (pentane:EtOAc 95:5) as a colorless solid (33.7 mg) in

45% yield. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.4 Hz, 2H), 7.45 – 7.31 (m, 5H), 7.31 –

7.21 (m, 2H), 6.95 (s, 1H), 4.40 (s, 1H), 4.32 (d, J = 4.6 Hz, 2H), 1.37 (s, 9H).; 13C NMR (101

MHz, CDCl3) δ 155.6, 139.6, 139.4, 135.3, 134.0, 130.5, 129.5, 128.8, 128.7, 128.1, 128.0,

126.9, 126.7, 79.4, 39.7, 28.3 (3).; IR (NaCl, neat, cm-1): 3335, 3059, 3003, 2978, 2932, 1709,

98

1674, 1593, 1506, 1392, 1367, 1269, 1246, 1165, 1065, 1034, 860, 754.; M.p.: 84-88 °C.;

HRMS (TOF, DART+): calcd for C20H23ClNO2 (M+H)+: 344.14173; Found: 344.14281.

Cl NHTs

CF3

(Z)-N-(3-(2-chlorophenyl)-2-(4-(trifluoromethyl)phenyl)allyl)-4-methylbenzenesulfonamide

2.2e


mol %), BINAP (6.23 mg, 5 mol %), substrate 2.1a (64 mg, 0.2 mmol, 1 equiv), (4-

(trifluoromethyl)phenyl)boronic acid (76 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol,

1.1 equiv). The crude was purified by flash chromatography with 0-10% EtOAc/hexanes to

provide the title compound (64.3 mg) as an off white solid 69%. 1H NMR (400 MHz, CDCl3) δ

7.53 (d, J = 8.2 Hz, 3H), 7.43 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.28 – 7.13 (m, 5H),

6.93 (s, 1H), 4.61 (s, 1H), 4.07 (d, J = 5.8 Hz, 2H), 2.43 (s, 3H).; 13C NMR (75 MHz, CDCl3) δ

143.72 (s), 142.54 (s), 136.56 (s), 136.15 (s), 134.32 (s), 134.02 (s), 131.15 (s), 130.09 (s),

129.76 (s), 129.73 (s), 129.42 (s), 127.21 (s), 127.15 (s), 126.93 (s), 125.69 (q, J = 3.8 Hz), 42.37

(s), 21.60 (s).; 19F NMR (377 MHz, CDCl3) δ 63.0 (s).; IR (NaCl, CDCl3, cm-1): 3264, 1616,

1435, 1323, 1161, 1123, 1072, 748.; M.p.: 129-131°C.; HRMS (TOF, ESI+): calc’d for

C23H20NO2F3SCl: 466.0849; Found: 466.0835.

Cl NHTs

(Z)-N-(3-(2-chlorophenyl)-2-(p-tolyl)allyl)-4-methylbenzenesulfonamide 2.2f



(methyl)phenyl)boronic acid (54 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1

equiv). The crude was purified by flash chromatography with 0-10% EtOAc/hexanes to provide

99

the title compound (52.7 mg) as an off white solid 64%. 1H NMR (300 MHz, CDCl3) δ 7.57 (d,

J = 8.3 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.26 – 7.08 (m, 9H), 6.85 (s, 1H), 4.39 (s, 1H), 4.05 (d,

J = 5.6 Hz, 2H), 2.43 (s, 3H), 2.36 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 143.6, 138.5, 137.1,

136.2, 135.7, 134.9, 134.1, 130.2, 129.7, 129.7, 129.6, 129.0, 128.4, 127.4, 126.8, 126.6, 77.5,

77.2, 76.8, 42.4, 21.7, 21.3.; IR (NaCl, CDCl3, cm-1): 3244, 1435, 1316, 1165, 1096, 1065, 810,

748, 706.; M.p.: 122-125 °C.; HRMS (TOF, ESI+): calc’d for C23H23NO2SCl: 412.1132; Found:

412.1142.

Cl NHTs

OMe

(Z)-N-(3-(2-chlorophenyl)-2-(4-methoxyphenyl)allyl)-4-methylbenzenesulfonamide 2.2g



methoxyphenyl)boronic acid (61 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1

equiv). and purified by flash chromatography with 0-10% EtOAc/hexanes to provide the title

compound (59.9 mg) as an off white solid 70%. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.3

Hz, 2H), 7.36 (dd, J = 7.8, 1.0 Hz, 1H), 7.28 – 7.11 (m, 7H), 6.89 – 6.78 (m, 3H), 4.28 (t, J = 5.5

Hz, 1H), 4.04 (d, J = 5.6 Hz, 2H), 3.84 (s, 3H), 2.44 (s, 3H.; 13C NMR (101 MHz, CDCl3) δ

159.9, 143.5, 136.5, 136.1, 134.9, 134.0, 130.8, 130.1, 129.7, 129.5, 128.8, 127.8, 127.6, 127.3,

126.7, 114.3, 55.4, 42.3, 21.6.; IR (NaCl, CDCl3) 3264, 1616, 1435, 1323, 1161, 1123, 1072,

748.; M.p.: 129-131°C.; HRMS (TOF, ESI+): calc’d for C23H20NO2F3SCl: 466.0849; Found:

466.0835.

100

(Z)-N-(3-(2-Chlorophenyl)-2-(6-chloropyridin-3-yl)allyl)-4-methylbenzenesulfonamide 2.2h


%), BINAP (6.23 mg, 5 mol %), substrate 2.1a (64 mg, 0.2 mmol, 1 equiv), (6-chloropyridin-3-

yl)boronic acid (63 mg, 0.4 mmol, 2 equiv) and K2CO3 (61 mg, 0.44mmol, 2.2 equiv). The

product was isolated through column chromatography (pentane:EtOAc 8:2) as a yellow solid in

77% yield (67 mg). 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.3,

2.5 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.32 – 7.07 (m, 6H), 6.89 (s, 1H),

5.16 (t, J = 5.8 Hz, 1H), 4.02 (d, J = 5.8 Hz, 2H), 2.44 (s, 3H).; 13C NMR (75 MHz, CDCl3) δ

150.88, 147.89, 143.84, 137.02, 136.09, 133.98, 133.95, 133.87, 131.28, 130.07, 129.80 (2),

129.72, 129.51, 127.09 (2), 126.89, 124.03, 42.18, 21.67.; IR (NaCl, neat, cm-1) 3265, 3062,

2922, 2852, 1582, 1469, 1377, 1326, 1160, 1109, 1094, 1067, 756.; M.p.: 143-147 °C.; HRMS

(TOF, ESI+): calcd for C21H19Cl2N2O2S (M+H)+: 433.0538; Found: 433.0552.

(Z)-N-(3-(2-Chlorophenyl)-2-(thiophen-3-yl)allyl)methanesulfonamide 2.2i


%), BINAP (6.5 mg, 5.2 mol %), substrate 2.1i (48mg, 0.2mmol, 1 equiv), 3-thiophenylboronic

acid (51 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The product was

isolated as a colorless thick oil in 73% yield (48 mg). 1H NMR (399 MHz, CDCl3) δ 7.50 (dd, J

= 2.8, 1.4 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.41 – 7.25 (m, 5H), 7.10 (s, 1H), 4.53 (t, J = 5.6 Hz,

1H), 4.20 (d, J = 5.8 Hz, 2H), 2.79 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 140.3, 134.8, 134.0,

132.7, 130.4, 129.8, 129.4, 128.1, 127.1, 126.8, 125.8, 122.5, 42.8, 40.3.; IR (NaCl, neat, cm-1)

3286, 3108, 2959, 2917, 2850, 1468, 1428, 1403, 1321, 1152, 1066, 1053, 1033, 963, 912, 785,

101

759, 739.; HRMS (TOF, DART+): calcd for C14H15ClNO2S2: 328.02327 (M+H)+; Found:

328.02280.

(Z)-3-(2-chlorophenyl)-2-phenylprop-2-en-1-ol 2.2j


mol %), BINAP (6.5 mg, 5.2 mol %), substrate 2.1j (33.3 mg, 0.2mmol, 1 equiv), phenylboronic

acid (48.8 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The crude was

purified by flash chromatography with 0-10% EtOAc/hexanes to provide the title compound (25

mg) as an off white solid 51%. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.1 Hz, 2H), 7.47 (dd,

J = 7.3, 1.9 Hz, 1H), 7.41 (t, J = 7.3 Hz, 3H), 7.34 (t, J = 7.3 Hz, 1H), 7.26 (pd, J = 7.2, 1.7 Hz,

2H), 7.00 (s, 1H), 4.60 (s, 2H).; 13C NMR (101 MHz, CDCl3) δ 141.5, 140.0, 135.5, 134.2,

130.8, 129.6, 128.9, 128.9, 128.2, 128.1, 126.9, 126.8, 77.5, 77.2, 76.8, 60.5.; IR (NaCl, CDCl3,

cm-1): 3363, 3057, 2924, 1495, 1470, 1435, 1053, 1032, 1017, 758, 696.; M.p.: 69-70 °C.;

HRMS (TOF, ESI+): calc’d for C15H17ClNO (M+NH4+): 262.0999; Found: 262.0998.

(E)-4-(2-chlorophenyl)-3-phenylbut-3-en-1-ol 2.2k


mol %), BINAP (6.5 mg, 5.2 mol %), substrate 2.1k (36.1 mg, 0.2mmol, 1 equiv), phenylboronic

acid (49 mg, 0.4 mmol, 2 equiv) and K2CO3 (31 mg, 0.22 mmol, 1.1 equiv). The crude was

purified by flash chromatography with 0-10% EtOAc/hexanes to provide the title compound

(26.4 mg) as a white solid 51%. 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.19 (m, 10H), 6.86 (s,

1H), 3.63 (t, J = 6.7 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 141.6,

102

140.3, 136.3, 134.3, 130.7, 129.6, 128.7, 128.5, 128.4, 127.9, 126.9, 126.7, 77.5, 77.2, 76.8, 61.2,

33.6.; IR (NaCl, CDCl3, cm-1) 3354, 3057, 3023, 2961, 2883, 1495, 1468, 1442, 1035, 758, 698.;

M.p.: 75-76°C.; HRMS (TOF, ESI+): calc’d for C16H19ClNO (M+NH4+): 276.1155; Found:

276.1148.

Palladium-catalyzed Suzuki-Miyaura cross coupling of 2.2b

N-(3-(Biphenyl-2-yl)prop-2-ynyl)methanesulfonamide 2.5b

The substrate 2.1a was reacted under standard C-N coupling reactions. 2.1a (49 mg, 0.2 mmol),

phenylboronic acid (36.6 mg, 0.3 mmol, 1.5 equiv), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8

mg, 4 mol %) and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) were combined in a 2 dram vial

equipped with a stirring bar and a septum. After purging with argon, dioxane (2 mL, 0.1 M) and

methanol (0.05 mL) was added. The reaction was stirred at 90 oC for 1 hour, then was allowed to

cool, filtered through a silica plug and concentrated. Column chromatography (hexane:EtOAc

7:3) gave the titled compound in 76% yield (44 mg) as a pale yellow oil. 1H NMR (400 MHz,

CDCl3) δ 7.54 – 7.29 (m, 9H), 4.49 (t, J = 5.9 Hz, 1H), 4.07 (d, J = 6.2 Hz, 2H), 2.66 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 144.3, 140.6, 133.1, 129.8, 129.3, 129.2, 128.3, 127.9, 127.3,

120.5, 86.8, 84.8, 77.6, 77.2, 76.7, 40.9, 33.7.; IR (NaCl, neat, cm-1) 3287, 3061, 3024, 2931,

2853, 1589, 1476, 1432, 1415, 1322, 1153, 1071, 1009, 996, 960, 912, 831, 762, 738, 701.;

HRMS (TOF, DART+): calcd for C16H19N2O2S (M+NH4)+: 303.11672; Found: 303.11580.

Palladium-catalyzed C-N cross coupling of 2.2b

103

1-(Methylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.3b

(Z)-N-(3-(2-chlorophenyl)-2-phenylallyl)methanesulfonamide (2.2b) (64.4 mg, 0.2 mmol),

K2CO3 (39 mg, 0.28 mmol, 1.4 equiv), Pd(OAc)2 (0.9 mg, 2 mol %, Note 1) and XPhos (2.8 mg,

4 mol %, Note 1) were weighed into a 2 dram vial, which was fitted with a screw-cap with a

septum and purged with argon. Dioxane was added (2mL) and the septum was replaced with a

Teflon-lined screw-cap (Note 2). The reaction was heated to 90 oC for 16 h, upon which the

crude was filtered through a silica plug and concentrated. Column chromatography

(pentane:EtOAc 9:1) yielded the titled compound in 91% yield as a colorless solid (most of the

dihydropyridine compounds were highly fluorescent under UV light).

Note 1: Oftentimes Pd-XPhos was added as a stock solution prepared by stirring the Pd(OAc)2

and XPhos for 10-15 minutes (or until homogeneous) at room temperature or 50oC.

Note 2: Alternatively, the argon inlet was removed and the vial septum was wrapped with

parafilm.

Rh/Pd-catalyzed domino dihydroquinoline synthesis

General procedure C: Domino synthesis of 3-Aryl-1,2-dihydroquinolines 2.3 from

arylpropargyl alkynes 2.1.

Substrates 2.1 (0.2 mmol, 1 equiv), arylboronic acid (1.1-2 equiv) (Note 1) and K2CO3 (61 mg,

0.44 mmol, 2.2 equiv) were weighed into a 2-dram vial (Note 2) equipped with a stirring bar and

fitted with a septum. The reaction vial was purged with argon and then 1,4-dioxane (1 mL, 0.2

M) and MeOH (0.1 mL) were added. The catalyst solutions (0.5 mL of each, Note 3) were added

to this reaction vessel. The septum was exchanged with a Teflon-lined screw cap and the reaction

was heated at 90 oC for 16h. The crude was filtered though a plug of silica, concentrated under

reduced pressure and purified through column chromatography.

104

Note 1: 1.5 equiv of arylboronic acid was used for the majority of arylboronic acids (similar

results were seen with 1.1 equiv or 2 equiv). Two equivalents of heteroaromatic boronic acids

were used due to more facile protodemetallation reaction.

Note 2: Microwave vials could be used instead of screw-cap vials with similar results.

Note 3: The catalyst solutions were prepared as follows:

[Rh(cod)OH]2 (2.5 mol %; 5 mol % [Rh]) and BINAP (5.2 mol %) were weighed into a screw-

cap vial. Pd(OAc)2 (2 mol %) and XPhos (4 mol %) were weighed into a screw cap vial. Both

vials were equipped with a septum and purged with argon. Dioxane (0.5 mL, 0.01M for [Rh]2

(0.005M for [Rh]), 0.008M for [Pd]) was added to both vials and the catalyst solutions were

stirred at 50 oC for 15 minutes after which these solutions were added to the reaction flask. More

conveniently, for small scale reactions stock solutions of known concentration (usually: 0.01

mmol/mL for [Rh]2 and 0.008 mmol/mL for [Pd]) were prepared and used in several parallel

reactions. Sometimes a colorless precipitate (excess BINAP) was observed in the rhodium

catalyst mixture. In this case the precipitate was allowed to settle (~5min), and only the

supernatant was transferred to the reaction vessel.

3-phenyl-1-tosyl-1,2-dihydroquinoline 2.3a

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and phenylboronic acid

(37 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol %), BINAP

(6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and K2CO3 (61 mg,

0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated using column

chromatography (pentane:EtOAc 9:1) in 65% yield (47 mg) as a white solid. 1H NMR (400

MHz, CDCl3) δ 7.77 (d, J = 7.9 Hz), 7.43 – 7.18 (m), 7.16 (d, J = 8.4 Hz), 7.03 (dd, J = 7.5, 1.5

Hz), 6.91 (d, J = 8.5 Hz), 6.30 (s), 4.80 (d, J = 1.1 Hz), 2.28 (s).; 13C NMR (101 MHz, CDCl3) δ

143.49, 137.52, 135.73, 134.63, 134.34, 130.56, 128.97, 128.79, 128.35, 128.00, 127.19, 127.09,

105

127.07, 126.93, 125.25, 121.36, 77.48, 77.16, 76.84, 47.68, 21.60.; IR (NaCl, neat, cm-1) 2361,

1597,1481, 1346, 1165, 1088, 810, 760.; M.p.: 177-179 °C.; HRMS (TOF, ESI+): calcd for

C22H19NO2NaS (M+Na+): 384.1028; Found: 384.1031.

1-(Methylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.3b

According to the general procedure C, substrate 2.1b (49 mg, 0.2 mmol) and phenylboronic acid

(36.6 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol %), BINAP

(6.5 mg, 5.2 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and K2CO3 (61mg,

0.44 mmol, 2.2 equiv). The product was isolated using column chromatography (pentane:EtOAc

9:1) in 69% yield (39.5 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.63 (m,

1H), 7.59 – 7.53 (m, 2H), 7.47 – 7.40 (m, 2H), 7.40 – 7.33 (m, 1H), 7.34 – 7.26 (m, 3H), 6.94 (s,

1H), 4.78 (d, J = 1.0 Hz, 2H), 2.64 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ137.2, 135.9, 134.6,

123.0, 129.2 (2C), 128.8, 128.5, 127.5, 127.3, 126.5, 125.5 (2C), 122.0, 47.5, 37.7.; IR (NaCl,

neat, cm-1): 3070, 3031, 2930, 2891, 2853, 1589, 1496, 1484, 1455, 1344, 1321, 1203, 1154,

1083, 1037, 959, 912, 882, 845, 831, 761, 731, 693.; M.p.: 119-121 °C.; HRMS (TOF, EI):

calcd for C16H15NO2S: 285.0824; Found: 285.0816.

3-Phenyl-1-(phenylsulfonyl)-1,2-dihydroquinoline 2.3c

According to the general procedure C, substrate 2.1c (61.1 mg, 0.2 mmol) and phenylboronic

acid (37 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol %),

BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and K2CO3

(61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated

106

using column chromatography (pentane:EtOAc 8:2) in 54% yield (37.4 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ7.78 (d, J = 7.9 Hz, 1H), 7.42 – 7.18 (m, 10H), 7.13 (t, J = 7.9 Hz,

2H), 7.02 (dd, J = 7.5, 1.1 Hz, 1H), 6.27 (s, 1H), 4.81 (d, J = 0.5 Hz, 2H).; 13C NMR (101 MHz,

CDCl3) δ 138.55, 137.44, 134.66, 134.24, 132.75, 130.63, 128.83(2), 128.40, 128.34(2), 128.05,

127.21, 127.15(2), 127.10, 126.99, 125.22(2), 47.72.; IR (NaCl, neat, cm-1): 3062, 3035, 2919,

2850, 1484, 1447, 1350, 1168, 1091, 1072, 757.; M.p.: 135-138 °C.; HRMS (TOF, DART+):

calcd for C21H18NO2S (M+H)+: 348.10582; Found: 348.10636.

1-(4-Methoxyphenylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.3g

According to the general procedure C, substrate 2.1g (67.2 mg, 0.2 mmol) and phenylboronic



(61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated using

column chromatography (pentane:EtOAc 8:2) in 35% yield (26 mg) as a colorless oil. 1H NMR

(400 MHz, CDCl3): 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.43 – 7.27 (m,

6H), 7.22 (dt, J = 7.6, 1.2 Hz, 1H), 7.20 (d, J = 8.9 Hz, 2H), 7.03 (dd, J = 7.5, 1.3 Hz, 1H), 6.59

(d, J = 8.9 Hz, 2H), 6.34 (s, 1H), 4.80 (s, 2H), 3.74 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ

163.00, 137.52, 134.71, 134.48, 130.63, 130.56, 129.31 (2), 128.82 (2), 128.38, 128.02, 127.10,

127.09, 127.08, 125.29 (2), 121.34, 113.52 (2), 55.60, 47.69.; IR (NaCl, neat, cm-1): 3063, 2966,

2839, 1595, 1580, 1497, 1348, 1304, 1260, 1157, 1026.; HRMS (TOF, DART+): calcd for

C22H20NO3S (M+H)+: 378.11639; Found: 378.11693.

107

1-(4-Nitrophenylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.3h

According to the general procedure C, substrate 2.1h (70.2 mg, 0.2 mmol) and phenylboronic



(61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated using

column chromatography (pentane:EtOAc 9:1) in 36% yield (28 mg) as a yellow solid. 1H NMR

(400 MHz, CDCl3) δ 7.96 (dt, J = 8.9, 2.2 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.45 – 7.33 (m, 6H),

7.31 – 7.22 (m, 3H), 7.06 (dd, J = 7.5, 1.4 Hz, 1H), 6.31 (s, 1H), 4.83 (d, J = 0.5 Hz, 2H).; 13C

NMR (100 MHz, CDCl3) δ 150.1, 144.0, 136.9, 134.5, 133.5, 130.5, 129.2 (2), 128.9, 128.5,

128.4 (2), 127.9, 127.5, 127.0, 125.0 (2), 123.5 (2), 121.3, 47.8.; IR (NaCl, neat, cm-1): 3104,

3067, 2926, 2855, 1530, 1350, 1311, 1169, 1090.; M.p.: 190-192 °C.; HRMS (TOF, DART+):

calcd for C21H20N3O4S (M+NH4)+: 410.11745; Found: 410.11870.

3-(m-tolyl)-1-tosyl-1,2-dihydroquinoline 2.3i

The product was synthesized according to general procedure C, substrate 2.1a (64 mg, 0.2 mmol)

and m-tolylboronic acid (41 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg,

2.5 mol %), BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %)

and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The crude was

purified by flash chromatography with 0-5% EtOAc/hexanes to provide the title compound (44.3

mg) as an off white solid 59%. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 1H), 7.33 –

7.10 (m, 6H), 7.09 – 6.98 (m, 3H), 6.92 (d, J = 8.1 Hz, 2H), 6.29 (s, 1H), 4.79 (d, J = 0.8 Hz,

2H), 2.38 (s, 3H), 2.29 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 143.3, 138.3, 137.5, 135.7,

108

134.7, 134.3, 130.5, 129.0, 128.9, 128.6, 127.8, 127.1, 126.9, 126.8, 125.9, 122.3, 121.1, 47.7,

21.6, 21.5.; IR (NaCl, CDCl3, cm-1) 1348, 1200, 1163, 1090, 1074, 1032, 785, 762, 711, 694,

671, 650, 584, 557.; M.p.: 167-168 °C.; HRMS (TOF, ESI+): calc’d for C23H22NO2S (M+H)+:

376.1371; Found: 376.1381.

N

Ts

OMe

3-(4-methoxyphenyl)-1-tosyl-1,2-dihydroquinoline 2.3fa


and (4-methoxyphenyl)boronic acid (46 mg, 0.3 mmol, 1.5 equiv) were reacted using

[Rh(cod)OH]2 (2.3 mg, 2.5 mol %), BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %),

XPhos (3.8 mg, 4 mol %) and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1

mL:0.1 mL). The crude was purified by flash chromatography with 0-10% Et2O/hexanes to

provide the title compound (31.3 mg) as a white solid 40%. 1H NMR (400 MHz, CDCl3) δ 7.75

(d, J = 7.9 Hz, 1H), 7.30 – 7.16 (m, 4H), 7.15 (d, J = 8.3 Hz, 2H), 6.99 (dd, J = 7.5, 1.5 Hz, 1H),

6.94 – 6.85 (m, 4H), 6.21 (s, 1H), 4.75 (s, 2H), 3.84 (s, 3H), 2.27 (s, 3H).; 13C NMR (101 MHz,

CDCl3) δ 159.8, 143.4, 135.8, 134.2, 134.1, 130.8, 130.1, 128.9, 127.6, 127.2, 127.0, 126.9,

126.8, 126.5, 119.6, 114.2, 55.5, 47.6, 21.6.; IR (NaCl, CDCl3, cm-1) 1609, 1516, 1456, 1348,

1290, 1252, 1182, 1165, 1120, 1032, 1008, 831, 816, 756, 682, 667, 567.; M.p.: 109-110 °C.;

HRMS (TOF, ESI+): calc’d for C23H22NO3S (M+H)+: 392.1320; Found: 392.1331.

109

3-(4-methoxyphenyl)-1-(methylsulfonyl)-1,2-dihydroquinoline 2.3fb

The product was synthesized according to general procedure C, substrate 2.1b (48.8 mg, 0.2

mmol) and (4-methoxyphenyl)boronic acid (46 mg, 0.3 mmol, 1.5 equiv) were reacted using





– 7.59 (m, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.32 – 7.23 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.85 (d, J

= 0.6 Hz, 1H), 4.74 (d, J = 1.2 Hz, 2H), 3.85 (s, 3H), 2.62 (s, 3H).; 13C NMR (75 MHz, CDCl3)

δ 160.2, 135.4, 134.3, 130.3, 129.6, 128.0, 127.2, 127.2, 126.8, 126.5, 120.2, 114.6, 77.6, 77.2,

76.7, 6.56, 47.4, 37.7.; IR (NaCl, CDCl3, cm-1) 2359, 2342, 1684, 1653, 1607, 1562, 1516, 1506,

1481, 1456, 1344, 1249, 1182, 1155, 1080, 1034, 957, 827, 770.; M.p.: 127-130 °C.; HRMS

(TOF, ESI+): calc’d for C17H21N2O3S (M+NH4)+: 333.1273; Found: 333.1278.

1-(4-(1-tosyl-1,2-dihydroquinolin-3-yl)phenyl)ethanone 2.3j


and (4-acetylphenyl)boronic acid (49 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2

(2.3 mg, 2.5 mol %), BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg,

4 mol %) and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The

crude was purified by flash chromatography with 0-20% Et2O/hexanes to provide the title

compound (50.8 mg) as a white solid 63%. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz,

110

2H), 7.78 (d, J = 7.9 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.24 (td, J = 7.5, 1.1 Hz, 1H), 7.13 (d, J = 8.3

Hz, 2H), 7.07 (dd, J = 7.5, 1.3 Hz, 1H), 6.91 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H), 4.82 (s, 2H), 2.63

(s, J = 6.7 Hz, 3H), 2.29 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 197.4, 143.5, 141.7, 136.4,

135.6, 134.6, 133.1, 129.9, 128.9, 128.8, 128.6, 127.4, 127.1, 127.0, 126.9, 125.1, 123.3, 47.3,

26.6, 21.5.; IR (NaCl, CDCl3, cm-1) 1680, 1599, 1483, 1450, 1412, 1349, 1269, 1165, 1090,

1074, 810, 762, 716.; M.p.: 179-180 °C.; HRMS (TOF, ESI+): calc’d for C24H22NO3S (M+H)+:

404.1320; Found: 404.1336.

3-(3-Nitrophenyl)-1-tosyl-1,2-dihydroquinoline 2.3k

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and 3-

nitrophenylboronic acid (50 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg,


and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was

purified by flash chromatography with 0-10% Et2O/hexanes to provide the title compound as a

yellow solid 49%. 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.12 (m, 1H), 7.95 (s, 1H), 7.79 (d, J =

8.0 Hz, 1H), 7.61 – 7.53 (m, 2H), 7.37 (td, J = 7.8, 1.5 Hz, 1H), 7.28 (td, J = 7.4, 1.7 Hz, 1H),

7.16 – 7.03 (m, 3H), 6.95 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H), 4.80 (s, 2H), 2.32 (s, 3H).; 13C NMR

(101 MHz, CDCl3) δ 148.6, 143.9, 139.3, 135.6, 134.6, 131.9, 130.7, 129.8, 129.6, 129.1, 128.9,

127.5, 127.2, 127.1, 127.0, 123.9, 122.7, 120.1, 77.4, 77.0, 76.7, 47.3, 21.5.; IR (NaCl, CDCl3,

cm-1): 1597, 1526, 1483, 1348, 1163, 1090, 880, 808, 762, 735.; M.p.: 196-197 °C.; HRMS

(TOF, ESI+): calc’d for C22H22N3O4S (M+H)+: 424.1331; Found: 424.1327.

111

4-(1-Tosyl-1,2-dihydroquinolin-3-yl)benzonitrile 2.3la


(cyano)phenylboronic acid (44 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3

mg, 2.5 mol %), BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4

mol %) and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The

product was isolated using column chromatography (pentane:EtOAc 95:5 to 9:1) in 56% yield

(41 mg) as a colorless solid.1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.66 (d, J =

8.4 Hz, 2H), 7.40 – 7.30 (m, 3H), 7.25 (dt, J = 1.2, 7.2 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 7.07

(dd, J = 7.5, 1.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H), 4.79 (s, 2H), 2.30 (s, 3H).; 13C

NMR (100 MHz, CDCl3) δ 143.80, 141.76, 135.75, 134.79, 132.66 (2), 132.50, 129.71, 129.12,

129.09 (2), 127.66, 127.29, 127.13 (2), 127.03, 125.66 (2), 124.34, 118.72, 111.66, 47.19, 21.62;

IR (NaCl, neat, cm-1) 3040, 2960, 2918, 2850, 2227, 1600, 1345, 1166, 1091, 840, 811, 759,

710.; M.p.: 220-222 °C.; HRMS (TOF, ESI+): calcd for C23H19N2O2S (M+H)+: 387.11672;

Found: 387.11675.

4-(1-(Methylsulfonyl)-1,2-dihydroquinolin-3-yl)benzonitrile 2.3lb

According to the general procedure C, substrate 2.1b (48.7 mg, 0.2 mmol) and (4-

cyanophenyl)boronic acid (44 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3



product was isolated using column chromatography (pentane:EtOAc 7:3) in 68% yield (42.3 mg)

as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.69 – 7.63 (m, 3H),

112

7.40 – 7.28 (m, 3H), 7.06 (s, 1H), 4.78 (s, 2H), 2.65 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ

141.4, 134.8, 133.6, 132.9 (2), 129.5, 129.1, 128.1, 127.3, 126.2, 125.9 (2), 124.9, 118.6, 112.0,

47.0, 37.9.; IR (NaCl, neat, cm-1) 3060, 3015, 2931, 2855, 2230, 1603, 1506, 1480, 1456, 1340,

1234, 1154, 1082, 1036, 960, 842, 773, 763, 734.; M.p.: 105-110 °C.; HRMS (TOF, DART+):

calcd for C17H18N3O2S (M+NH4)+: 328.11197; Found: 328.11138.

1-tosyl-3-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline 2.3e


and (3-(trifluoromethyl)phenyl)boronic acid (57 mg, 0.3 mmol, 1.5 equiv) were reacted using





(d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.6 Hz, 2H), 7.41 – 7.29 (m, 3H), 7.24 (td, J = 7.5, 1.1 Hz, 1H),

7.14 (d, J = 8.3 Hz, 2H), 7.06 (dd, J = 7.5, 1.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.39 (s, 1H),

4.80 (s, 2H), 2.29 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 143.71 (s), 140.94 (s), 135.75 (s),

134.64 (s), 133.07 (s), 129.99 (s), 129.06 (s), 128.73 (s), 127.46 (s), 127.22 (s), 127.16 (s),

127.01 (s), 125.80 (q, J = 3.8 Hz), 125.44 (s), 123.39 (s), 47.45 (s), 21.60 (s); 19F NMR (377

MHz, CDCl3): δ 63.6 (s).; IR (NaCl, CDCl3, cm-1) 1614, 1599, 1483, 1450, 1412, 1325, 1165,

1117, 1090, 1071, 831, 810, 762, 716, 679, 654.; M.p.: 152-155 °C.; HRMS (TOF, ESI+):

calc’d for C23H19F3NO2S (M+H)+: 430.1089; Found: 430.1084.

113

1-Tosyl-3-(3-(trifluoromethyl)phenyl)-1,2-dihydroquinoline 2.3ma


(trifluoromethyl)phenyl)boronic acid (57 mg, 0.3 mmol, 1.5 equiv) were reacted using



mL:0.1 mL). The product was isolated using column chromatography (pentane:EtOAc 9:1) in

63% yield (54 mg) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz,

1H), 7.57 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.35 (td, J = 7.8,

1.5 Hz, 1H), 7.31 (s, 1H), 7.26 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 7.08 (dd, J =

7.5, 1.3 Hz, 1H), 6.94 (d, J = 8.1 Hz, 2H), 4.79 (d, J = 0.7 Hz, 2H), 2.31 (s, 3H).; 13C NMR (101

MHz, CDCl3) δ 143.8 (s), 138.5 (s), 135.8 (s), 134.6 (s), 132.9 (s), 131.2 (q, J = 32.3 Hz), 130.0

(s), 129.4 (s), 129.1 (2), 128.6 (s), 128.3 (q, J = 1.2 Hz), 127.4 (s), 127.3 (s), 127.2 (s), 127.1 (2),

124.8 (q, J = 3.8 Hz), 124.1 (q, J = 273.7 Hz) 123.0 (s), 122.1 (q, J = 3.8 Hz), 47.5 (s), 21.5 (s).; 19F NMR (377 MHz, CDCl3): δ -61.82.; IR (NaCl, neat, cm-1) 3066, 2960, 2922, 2850, 1647,

1598, 1489, 1453, 1336, 1241, 1160, 1122, 1032, 1009, 895, 815, 738, 701, 682.; M.p.: 97-100

°C.; HRMS (TOF, EI+): calcd for C23H18F3NO2S (M)+: 429.1010; Found: 429.1017.

1-(Methylsulfonyl)-3-(3-(trifluoromethyl)phenyl)-1,2-dihydroquinoline 2.3mb

According to the general procedure C, substrate 2.1b (48.7 mg, 0.2 mmol) and (3-

(trifluoromethyl)phenyl)boronic acid (57 mg, 0.3 mmol, 1.5 equiv) were reacted using



114

mL:0.1 mL). The product was isolated using column chromatography (pentane:EtOAc 85:15) in

55% yield (39 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.72 (d, J =

7.6 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.37 –

7.27 (m, 3H), 7.01 (s, 1H), 4.79 (s, 2H), 2.65 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 138.0 (s),

134.7 (s), 134.2 (s), 131.7 (q, J = 32.4 Hz), 129.8 (s), 129.4 (s), 129.1 (s), 128.6 (q, J = 1.1 Hz),

127.8 (s), 127.3 (s), 126.3 (s), 125.3 (q, J = 3.7 Hz), 124.2 (q, J = 310 Hz) 123.6, 122.1 (q, J =

3.8 Hz), 47.3 (s), 37.8 (s).; 19F NMR (377 MHz, CDCl3) δ -63.73.; IR (NaCl, neat, cm-1) 3070,

3037, 2930, 2854, 1593, 1484, 1451, 1432, 1343, 1332, 1278, 1268, 1156, 1126, 1076, 959.;

HRMS (TOF, DART+): calcd for C17H18F3N2O2S (M+NH4)+: 371.10411; Found: 371.10396.

3-(3,4-Dimethoxyphenyl)-1-(methylsulfonyl)-1,2-dihydroquinoline 2.3n

According to the general procedure C, substrate 2.1b (48.7 mg, 0.2 mmol) and (3,4-

dimethoxyphenyl)boronic acid (55 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2



product was isolated using column chromatography (pentane:EtOAc 8:2) in 50% yield (34.7 mg)

as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 1H), 7.31 – 7.23 (m, 3H), 7.13

(dd, J = 8.3, 2.2 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 4.74 (d,

J = 0.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 2.63 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 150.0,

149.6, 135.6, 134.4, 130.2, 129.9, 128.2, 127.3, 127.2, 126.5, 120.4, 118.4, 111.5, 108.5, 56.20,

56.18, 47.5, 37.7.; IR (NaCl, neat, cm-1) 3061, 3003, 2957, 2928, 2852, 1601, 1516, 1456, 1342,

1252, 1155, 1080, 1024, 959, 763.; HRMS (TOF, DART+): calcd for C18H23N2O4S (M+NH4)+:

363.13785; Found: 363.13923.

115

3-(2-Fluorophenyl)-1-tosyl-1,2-dihydroquinoline 2.3o


fluorophenylboronic acid (40 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2 (2.3



product was isolated using column chromatography (pentane:EtOAc 95:5 to 9:1) in 39% yield

(27.8 mg) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.37 – 7.20

(m, 3H), 7.18 (d, J = 8.2 Hz, 2H), 7.14 – 7.01 (m, 3H), 6.98 (d, J = 8.1 Hz, 2H), 6.92 (td, J = 7.7,

1.6 Hz, 1H), 6.31 (s, 1H), 4.78 (s, 2H), 2.34 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 160.33 (d, J

= 249.6 Hz), 143.50 (s), 136.05 (s), 134.49 (s), 130.73 (d, J = 2.5 Hz), 130.09 (s), 129.79 (d, J =

8.4 Hz), 129.10 (2), 128.39 (s), 128.34 (d, J = 4.2 Hz), 127.25 (2), 127.23 (s), 127.04 (s), 127.02

(s), 126.03 (d, J = 13.6 Hz), 124.85 (d, J = 4.3 Hz), 124.33 (d, J = 3.4 Hz), 116.24 (d, J = 22.4

Hz), 48.24 (d, J = 7.2 Hz), 21.62 (s).; 19F NMR (377 MHz, CDCl3) δ -111.28 – -111.38 (m).; IR

(NaCl, neat, cm-1) 3063, 2957, 2921, 2850, 1598, 1580, 1496, 1451, 1348, 1220, 1165, 1122,

1032, 1008, 815, 761, 679, 614.; HRMS (TOF, EI+): calcd for C22H18NO2FS (M)+: 379.1042;

Found: 379.1040.

N

Ts

N F

3-(6-Fluoropyridin-3-yl)-1-tosyl-1,2-dihydroquinoline 2.3p

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and (6-fluoropyridin-3-

yl)boronic acid (56 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol

%), BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and

K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was

116

isolated using column chromatography (pentane:EtOAc 9:1) as an yellow solid in 47% yield. 1H

NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.27

(t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.3 Hz, 1H),

6.88 (d, J = 8.1 Hz, 3H), 6.24 (s, 1H), 4.67 (s, 2H), 2.23 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ

163.3 (d, J = 241.2 Hz), 144.6 (s), 144.5 (s), 143.9 (s), 137.7 (d, J = 8.0 Hz), 135.7 (s), 134.5 (s),

131.5 (d, J = 4.9 Hz), 130.2 (s), 129.7 (s), 129.1 (s), 128.8 (s), 127.3 (d, J = 6.3 Hz), 127.1 (s),

122.9 (d, J = 1.4 Hz), 109.7 (d, J = 37.6 Hz), 47.2 (s), 21.6 (s).; 19F NMR (377 MHz, CDCl3) δ -

67.32, -67.33.; IR (NaCl, CDCl3, cm-1) 1582, 1485, 1472, 1346, 1258, 1167, 1020, 833, 762,

712, 664.; M.p.: 114-115 °C.; HRMS (TOF, ESI+): calcd for C21H18N2O2FS (M)+: 381.1073;

Found: 381.1074.

3-(6-Ethoxypyridin-3-yl)-1-tosyl-1,2-dihydroquinoline 2.3qa

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and (6-ethoxypyridin-3-

yl)boronic acid (67 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol



isolated using column chromatography (pentane:EtOAc 9:1) in 47% yield (38.5 mg) as an orange

solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.45 (dd,

J = 8.7, 2.6 Hz, 1H), 7.29 (td, J = 7.8, 1.4 Hz, 1H), 7.21 (td, J = 7.5, 1.0 Hz, 1H), 7.15 (d, J = 8.2

Hz, 2H), 7.01 (dd, J = 7.4, 1.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.7 Hz, 1H), 6.21

(s, 1H), 4.73 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).; 13C NMR

(101 MHz, CDCl3) δ 163.8, 143.8, 143.6, 135.7, 135.4, 134.2, 131.6, 130.4, 129.0 (2), 128.0,

127.1 (3), 126.99, 126.98, 126.5, 120.5, 111.1, 62.2, 47.3, 21.6, 14.8.; IR (NaCl, neat, cm-1)

3059, 2981, 2926, 2870, 1605, 1498, 1475, 1383, 1346, 1293, 1245, 1164, 1122, 1091, 1033,

1009, 925, 816, 735, 681.; M.p.: 92-95 °C.; HRMS (TOF, DART+): calcd for C23H23N2O3S

(M+H)+: 407.14294; Found: 407.14393.

117

3-(6-Ethoxypyridin-3-yl)-1-(methylsulfonyl)-1,2-dihydroquinoline 2.3qb

According to the general procedure C, substrate 2.1b (49 mg, 0.2 mmol) and 6-ethoxypyridin-3-

ylboronic acid (67 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol

%), BINAP (6.5 mg, 5.2 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and

K2CO3 (61mg, 0.44 mmol, 2.2 equiv). The product was isolated using column chromatography

(pentane:EtOAc 7:3) in 66% yield (44 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ

8.36 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.7, 2.6 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.33 – 7.23 (m, 3H),

6.86 (s, 1H), 6.79 (dd, J = 8.53, 0.34 Hz, 1H), 4.73 (d, J = 1.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H),

2.64 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ164.1, 144.1, 135.6, 134.4,

132.82, 129.8, 128.4, 127.34, 127.26, 126.4, 126.0, 121.0, 111.5 , 62.2, 47.1, 37.7, 14.7.; IR

(NaCl, neat, cm-1) 3070, 3053, 3025, 2975, 2932, 2896, 2861, 1602, 1569, 1501, 1481, 1454,

1401, 1380, 1342, 1292, 1268, 1155, 1083, 1040, 956, 925, 842, 816, 771.; M.p.: 137-140 °C.;

HRMS (TOF, DART+): calcd for C17H19N2O3S (M+H)+: 331.11164; Found: 331.11134.

3-(Thiophen-3-yl)-1-tosyl-1,2-dihydroquinoline 2.3ra

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and thiophen-3-

ylboronic acid (51 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol



isolated using column chromatography (pentane:EtOAc 9:1) in 46% yield (33.7 mg) as a pale

118

yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 7.8 Hz, 1H), 7.35 – 7.12 (m, 6H), 7.07

(dd, J = 5.0, 1.4 Hz, 1H), 7.01 (dd, J = 7.4, 1.5 Hz, 1H), 6.89 (d, J = 8.1 Hz, 2H), 6.27 (s, 1H),

4.74 (d, J = 0.9 Hz, 2H), 2.27 (s, 3H).; 13C NMR (75 MHz, CDCl3) δ 143.5, 139.2, 135.6, 134.3,

130.4, 129.8, 128.9 (2), 127.8, 127.13 (2), 127.05, 126.94, 126.92, 126.5, 124.6, 121.1, 120.0,

47.5, 21.6.; IR (NaCl, neat, cm-1) 3110, 3070, 3037, 2921, 2851, 1596, 1480, 1456, 1343, 1162,

1090, 1078, 811, 769, 707, 694.; M.p.: 175-177 °C.; HRMS (TOF, ESI+): calcd for

C20H17NO2NaS2 (M+Na)+: 390.0592; Found: 390.0603.

1-(Methylsulfonyl)-3-(thiophen-3-yl)-1,2-dihydroquinoline 2.3rb

According to the general procedure C, substrate 2.1b (49 mg, 0.2 mmol) and 3-

thiophenylboronic acid (51 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg,

2.5 mol %), BINAP (6.5 mg, 5.2 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol

%) and K2CO3 (61mg, 0.44 mmol, 2.2 equiv). The product was isolated using column

chromatography (pentane:EtOAc 85:15) in 78% yield (45.5 mg) as a colorless solid. 1H NMR

(400 MHz, CDCl3) δ7.67 – 7.61 (m, 1H), 7.44 – 7.36 (m, 3H), 7.30 – 7.22 (m, 3H), 6.90 (s, 1H),

4.71 (s, 2H), 2.62 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ138.7, 134.4, 130.9, 129.8, 128.2,

127.3, 127.23, 127.19, 126.5, 124.6, 121.8, 120.6, 47.3, 37.6.; IR (NaCl, neat, cm-1) 3105, 3066,

3018, 2929, 2853, 1625, 1599, 1482, 1455, 1409, 1342, 1322, 1203, 1155, 1118, 1078, 1036,

959, 909, 877, 819, 773, 760, 731.; M.p.: 101-103 °C.; HRMS (TOF, DART+): calcd for

C14H17N2O2S2 (M+NH4)+: 309.07314; Found: 309.07257.

119

3-(Furan-3-yl)-1-tosyl-1,2-dihydroquinoline 2.3sa

According to the general procedure C, substrate 2.1a (64 mg, 0.2 mmol) and fur-3-ylboronic acid

(45 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol %), BINAP (6.23

mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and K2CO3 (61 mg, 0.44

mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated using column

chromatography (pentane:EtOAc 9:1) in 42% yield (29.4 mg) as a pale yellow solid. 1H NMR

(400 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.42 (t, J = 1.6 Hz, 1H),7.27 (td, J =

7.7, 1.6 Hz, 1H), 7.21 (dd, J = 7.5, 1.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 6.98 (dd, J = 7.5, 1.4

Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.38 (dd, J = 1.8, 0.7 Hz, 1H), 6.12 (s, 1H), 4.59 (d, J = 0.9

Hz, 2H), 2.28 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 144.2, 143.5, 139.5, 135.5, 134.3, 130.3,

128.9 (2), 127.6, 127.1 (2), 127.1, 127.0, 126.7, 126.7, 124.3, 119.3, 107.1, 47.2, 21.6.; IR

(NaCl, neat, cm-1) 3067, 2921, 2850, 1761, 1597, 1492, 1451, 1348, 1224, 1164, 1122, 1033,

1010, 815, 735, 682.; M.p. (decomp): 138-148 °C.; HRMS (TOF, EI+): calcd for C20H17NO3S

(M)+: 351.0929; Found: 351.0931.

3-(Furan-3-yl)-1-(methylsulfonyl)-1,2-dihydroquinoline 2.3sb

According to the general procedure C, substrate 2.1b (48.7 mg, 0.2 mmol) and furan-3-ylboronic

acid (45 mg, 0.4 mmol, 2 equiv) were reacted using [Rh(cod)OH]2 (2.3 mg, 2.5 mol %), BINAP

(6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %) and K2CO3 (61 mg,

0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was isolated using column

chromatography (pentane:EtOAc 85:15) in 51% yield (28.3 mg) as a pale yellow solid. 1H NMR

(399 MHz, CDCl3) δ 7.68 (s, 1H), 7.66 – 7.60 (m, 1H), 7.49 (t, J = 2 Hz, 1H), 7.30 – 7.19 (m,

120

3H), 6.76 (s, 1H), 6.67 (dd, J = 1.8, 0.8 Hz, 1H), 4.57 (d, J = 1.0 Hz, 2H), 2.63 (s, 3H).; 13C

NMR (100 MHz, CDCl3) δ 144.6, 139.9, 134.4, 129.7, 128.1, 127.7, 127.3, 127.1, 126.6, 123.9,

119.8, 107.2, 47.0, 37.6.; IR (NaCl, neat, cm-1) 3160, 3057, 3018, 3009, 2928, 2855, 1484, 1336,

1323, 1151, 1079, 1035, 967, 958, 872, 889, 820, 786, 767.; M.p.: 163-167 °C.; HRMS (TOF,

DART+): calcd for C14H14NO3S (M+H)+: 276.06944; Found: 276.06845.

7-methoxy-1-(methylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.4a

The product was synthesized according to general procedure C, substrate 2.1g (54.7 mg, 0.2

mmol) and phenylboronic acid (37 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2



product was purified by flash chromatography with 0-10% Et2O/hexanes to provide the title

compound in 54% yield (34.1 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J =

7.3 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.19 (d, J

= 8.5 Hz, 1H), 6.89 (s, 1H), 6.84 (dd, J = 8.4, 2.6 Hz, 1H), 4.75 (d, J = 0.8 Hz, 2H), 3.86 (s, 3H),

2.64 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 159.7, 137.4, 136.0 132.6, 129.2, 128.4, 128.4,

125.3, 123.1, 121.7, 113.9, 111.5, 77.5, 77.2, 76.8, 55.8, 47.5, 37.8.; IR (NaCl, CDCl3, cm-1)

3011, 2362, 1616, 1600, 1496, 1328, 1270, 1213, 1155, 1039, 761, 698, 554.; M.p.: 119-187 °C.;

HRMS (TOF, ESI+): calc’d for C17H17NO3SNa (M+Na)+: 338.0821; Found: 338.0823.

121

N

MsF

8-fluoro-1-(methylsulfonyl)-3-phenyl-1,2-dihydroquinoline 2.4b

The product was synthesized according to general procedure C, substrate 2.1l (52.4 mg, 0.2

mmol) and phenylboronic acid (37 mg, 0.3 mmol, 1.5 equiv) were reacted using [Rh(cod)OH]2



product was purified by flash chromatography with 0-5% Et2O/hexanes to provide the title

compound in 62% (37.6 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.2 Hz,

2H), 7.44 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.29 – 7.21 (m, 1H), 7.11 – 7.04 (m, 2H),

6.93 (s, 1H), 4.69 (s, 2H), 2.94 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 158.3 (s), 155.8 (s),

138.5 (s), 136.9 (s), 132.8 (d, J = 1.6 Hz), 129.1 (s), 128.9 (s), 128.1 (d, J = 8.5 Hz), 125.6 (s),

122.7 (d, J = 3.2 Hz), 122.5 (d, J = 12.3 Hz), 121.6 (d, J = 3.4 Hz), 116.0 (d, J = 21.1 Hz), 47.7

(s), 39.6 (d, J = 3.7 Hz).; 19F NMR (377 MHz, CDCl3) δ -118.85 (dd, J = 10.1, 4.8 Hz).; IR

(NaCl, CDCl3, cm-1) 3063, 3030, 2934, 1615. 1574, 1476, 1343, 1155, 1080, 1042, 968, 872,

835, 746, 696.; M.p.: 58-60 °C.; HRMS (TOF, EI+): calc’d for C16H14FNO2S (M+H)+:

303.0729; Found: 303.0728.

8-Fluoro-1-(methylsulfonyl)-3-(thiophen-3-yl)-1,2-dihydroquinoline 2.4c

According to the general procedure C, substrate 2.1l (52.4 mg, 0.2 mmol) and 3-


2.5 mol %), BINAP (6.5 mg, 5.2 mol %), Pd(OAc)2(0.9 mg, 2 mol %), XPhos (3.8 mg, 4 mol %)

and K2CO3 (61mg, 0.44 mmol, 2.2 equiv). The product was isolated using column

chromatography (pentane:EtOAc 8:2) in 73% yield (45.2 mg) as a colorless oil. 1H NMR (399

122

MHz, CDCl3) δ 7.44 (dd, J = 2.7, 1.3 Hz, 1H), 7.40 (dd, J = 5.1, 2.8 Hz, 1H), 7.37 (dd, J = 5.1,

1.4 Hz, 1H), 7.23 (ddd, J = 12.7, 7.2, 3.2 Hz, 1H), 7.09 – 7.00 (m, 2H), 6.91 (d, J = 1.0 Hz, 1H),

4.63 (d, J = 1.0 Hz, 2H), 2.91 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 157.2 (d, J = 252.4 Hz),

138.4 (s), 133.4 (s), 132.8 (d, J = 1.7 Hz), 128.2 (d, J = 8.5 Hz), 127.2 (s), 124.8 (s), 122.6 (d, J =

3.2 Hz), 122.3 (d, J = 12.5 Hz), 122.2 (s), 120.2 (d, J = 3.4 Hz), 115.9 (d, J = 21.1 Hz), 47.6 (s),

39.5 (d, J = 3.7 Hz).; 19F NMR (282 MHz, CDCl3) δ -118.17 (dd, J = 10.0, 4.7 Hz).; IR (NaCl,

neat, cm-1) 3104, 3025, 2930, 2896, 2850, 1611, 1572, 1471, 1342, 1296, 1271, 1220, 1156,

1079, 1006, 961, 909, 863, 836, 794, 730.; HRMS (TOF, EI+): calcd for C14H12NO2S2F

(M+H)+: 309.0294; Found: 309.0291.

1-(Methylsulfonyl)-3-(thiophen-3-yl)-1,2-dihydro-1,5-naphthyridine 2.4d

According to the general procedure C, substrate 2.1m (49 mg, 0.2 mmol) and 3-



%) and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv). The product was isolated using column

chromatography (pentane:EtOAc 1:1) in 45% yield (26.3 mg) as a colorless solid which turned

dark green upon standing. 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 4.8, 1.5 Hz, 1H), 7.91

(ddd, J = 8.1, 1.5, 0.7 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.45 – 7.41 (m, 2H), 7.19 (dd, J = 8.1, 4.8

Hz, 1H), 7.10 (s, 1H), 4.78 (d, J = 1.2 Hz, 2H), 2.68 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ

148.9, 148.1, 138.0, 135.3, 133.4, 131.3, 127.6, 124.9, 123.1, 122.5, 121.7, 47.0, 38.0.; IR

(NaCl, neat, cm-1) 3105, 3007, 2927, 2850, 1620, 1580, 1435, 1188, 1157, 960, 910, 875, 820,

776, 730.; M.p.: 128-130°C.; HRMS (TOF, EI+): calcd for C13H12N2O2S2 (M+H)+: 292.0340;

Found: 292.0347.

123

6-Fluoro-1-(methylsulfonyl)-3-(thiophen-3-yl)-1,2-dihydroquinoline 2.4e

According to the general procedure C, substrate 2.1n (52.4 mg, 0.2 mmol) and 3-




chromatography (pentane:EtOAc 9:1) in 70% yield (43.3 mg) as an off-white solid. 1H NMR

(300 MHz, CDCl3) δ 7.60 (dd, J = 9.9, 5.1 Hz), 7.50 – 7.34 (m), 7.03 – 6.91 (m), 6.85 (s), 4.71

(d, J = 1.1 Hz), 2.61 (s).; 13C NMR (75 MHz, CDCl3) δ 161.5 (d, J = 246 Hz), 138.3 (s), 132.3

(s), 131.6 (d, J = 9 Hz), 130.2 (d, J = 3 Hz), 128.5 (d, J = 9 Hz), 127.5 (s), 124.6 (s), 122.5 (s),

119.8 (d, J = 2 Hz), 114.9 (d, J = 23 Hz), 113.4 (d, J = 23 Hz), 47.5 (s), 37.6 (s).; 19F NMR (282

MHz, CDCl3) δ -115.05 (td, J = 8.4, 5.1 Hz).; IR (NaCl, CDCl3, cm-1) 3091, 1485, 1338, 1156,

1076, 964, 827, 806, 769.; M.p.: 185-187 °C.; HRMS (TOF, ESI+): calc’d for C14H13FNO2S2

(M+H)+: 310.0360; Found: 310.0372.

1-(Methylsulfonyl)-3-(thiophen-3-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline 2.4f

According to the general procedure C, substrate 2.1o (62.3 mg, 0.2 mmol) and 3-




chromatography (pentane:EtOAc 8:2) in 78% yield (56.1 mg) as a pale yellow solid.

Alternatively, this compound was synthesized by the above procedure, heating at 60 oC for 1.5h

then to 90 oC for 15 h to give 81% yield (58.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.86

124

(m, 1H), 7.53 – 7.47 (m, 2H), 7.44 (dd, J = 5.1, 2.8 Hz, 1H), 7.41 (dd, J = 5.1, 1.4 Hz, 1H), 7.36

(d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 4.75 (d, J = 0.9 Hz, 2H), 2.66 (s, 3H).; 13C NMR (100 MHz,

CDCl3) δ 138.1 (s), 134.6 (s), 133.3 (s), 132.9 (s), 129.9 (q, J = 32.8 Hz), 127.6 (s), 127.5 (s),

124.6 (s), 123.9 (q, J = 3.8 Hz), 123.8 (q, J = 272.2 Hz), 123.5 (q, J = 4.0 Hz), 122.9 (s), 119.3

(s), 47.2 (s), 38.0 (d, J = 2.0 Hz).; 19F NMR (282 MHz, CDCl3) δ -62.84 (s).; IR (NaCl, neat,

cm-1) 3106, 3051, 3014, 2932, 2896, 2852, 1614, 1569, 1502, 1346, 1330, 1297, 1270, 1253,

1225, 1158, 1125, 1071, 1032, 960, 916, 875, 847, 828, 778.763, 740.; M.p.: 122-123 °C;

HRMS (TOF, ESI+): calcd for C15H16F3N2O2S2 (M+NH4)+: 377.06053; Found: 377.05937.

N-(1-(Methylsulfonyl)-3-(thiophen-3-yl)-1,2-dihydroquinolin-7-yl)acetamide 2.4g

According to the general procedure C, substrate 2.1p (60.2 mg, 0.2 mmol) and 3-



and K2CO3 (61 mg, 0.44 mmol, 2.2 equiv) in dioxane:MeOH (1 mL:0.1 mL). The product was

isolated using column chromatography (pentane:EtOAc 7:3) in 63% yield (43.9 mg) as a

colorless solid. 1H NMR (399 MHz, DMSO): δ 10.11 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.64

(dd, J = 5.0, 2.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 8.3 Hz,

1H), 7.10 (s, 1H), 4.63 (s, 2H), 2.72 (s, 3H), 2.05 (s, 3H).; 13C NMR (100 MHz, DMSO) δ

168.4, 138.7, 138.6, 134.5, 128.5, 127.5, 127.4, 124.9, 124.5, 121.7, 119.9, 117.0, 115.6, 46.5,

37.8, 24.0.; IR (NaCl, neat, cm-1) 3341, 2956, 2922, 2850, 1665, 1585, 1532, 1322, 1155, 1075,

1024, 875, 723.; M.p.: 218-220 °C.; HRMS (TOF, DART+): calcd for C16H17N2O3S2 (M+H)+:

349.06806; Found: 349.06860.

125

General procedure D: Domino synthesis of chromenes from arylpropargyl alkynes 2.1j.

Substrate 2.1j (33.3 mg, 0.2 mmol, 1 equiv), arylboronic acid (0.3 mmol, 1.5 equiv) and K2CO3

(61 mg, 0.44 mmol, 2.2 equiv) were weighed into a 2-dram vial (Note 2) equipped with a stirring

bar and fitted with a septum. The reaction vial was purged with argon and then toluene (1 mL,

0.2 M) and MeOH (0.1 mL) were added. The catalyst solutions (0.5 mL of each) containing

[Rh(cod)OH]2 (2.3 mg, 2.5 mol %) and BINAP (6.23 mg, 5 mol %), Pd(OAc)2 (0.9 mg, 2 mol

%) and XPhos (3.8 mg, 4 mol %) were added to this reaction vessel. The septum was exchanged

with a Teflon-lined screw cap and the reaction was heated at 90oC for 16h. The crude mixture

was filtered though at plug of silica, concentrated under reduced pressure and purified through

column chromatography.

3-phenyl-2H-chromene 2.4h

The product was synthesized according to general procedure D, using phenylboronic acid (36.6

mg, 0.3 mmol, 1.5 equiv) and purified by flash chromatography with 0-3% Et2O/hexanes to

provide the title compound in 59% (24.6 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ

7.46 – 7.26 (m, 5H), 7.17 – 7.04 (m, 2H), 6.95 – 6.82 (m, 2H), 6.80 (s, 1H), 5.16 (d, J = 1.4 Hz,

2H).; 13C NMR (75 MHz, CDCl3) δ 153.4, 136.9, 131.9, 129.2, 128.9, 128.2, 127.2, 124.9,

123.1, 121.7, 120.3, 115.6, 77.6, 77.2, 76.7, 67.3.; Spectral data is in accord with the literature.44

126

4-(2H-chromen-3-yl)benzonitrile 2.4i

The product was synthesized according to general procedure D, using (4-cyanophenyl)boronic

acid (44 mg, 0.3 mmol, 1.5 equiv) and purified by flash chromatography with 0-3%

Et2O/hexanes to provide the title compound in 27% yield (12.6 mg) as a yellow solid. 1H NMR

(400 MHz, CDCl3) δ 7.73 – 7.63 (m, 2H), 7.55 – 7.48 (m, 2H), 7.19 (td, J = 7.9, 1.6 Hz, 1H),

7.13 (dd, J = 7.5, 1.5 Hz, 1H), 6.98 – 6.91 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 5.15 (d, J = 1.3 Hz,

2H).; 13C NMR (101 MHz, CDCl3) δ 153.7, 141.2, 132.7, 130.3, 129.8, 127.8, 125.3, 123.5,

122.4, 122.1, 118.9, 115.9, 111.3, 77.5, 77.2, 76.8, 66.7.; IR (NaCl, CDCl3, cm-1) 2224, 1614,

1599, 1483, 1451, 1412, 1348, 1215, 1090, 1074, 831, 762, 716, 660.; M.p.: 104-105 °C.;

HRMS (TOF, EI+): calc’d for C16H10NO (M+H)+: 232.0762; Found: 232.0760.

methyl 4-(2H-chromen-3-yl)benzoate 2.4j

The product was synthesized according to general procedure D, using (4-

(methoxycarbonyl)phenyl)boronic acid (54 mg, 0.3 mmol, 1.5 equiv) and purified by flash

chromatography with 0-3% Et2O/hexanes to provide the title compound in 50% yield (26.6 mg)

as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz,

2H), 7.19 – 7.13 (m, 1H), 7.11 (dd, J = 7.5, 1.6 Hz, 1H), 6.93 (ddd, J = 7.4, 6.7, 1.1 Hz, 2H),

6.87 (d, J = 8.0 Hz, 1H), 5.18 (s, 2H), 3.93 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 166.8,

153.6, 141.4, 130.7, 130.2, 129.9, 129.5, 127.6, 124.75, 122.7, 122.4, 121.9, 115.8, 67.0, 52.3.;

IR (NaCl, CDCl3, cm-1) 2359, 2340, 1724, 1487, 1456, 1431, 1415, 1321, 1279, 1211, 1192,

1107, 1015, 934, 853, 769, 746, 737, 696, 667.; M.p.: 129-132 °C.; HRMS (TOF, ESI+): calc’d

for C17H15O3 (M+H)+: 267.1021; Found: 267.1018.

127

Product derivatizations

3-(thiophen-3-yl)quinoline 2.7

To the substrate 2.3rb (58 mg, 0.2 mmol) in a dry round bottom flask under N2 atmosphere was

added anhydrous THF (3.5 mL) and t-BuOH (73 mg, 0.6 mmol, 3 equiv), followed by KOt-Bu

(45 mg, 0.4 mmol, 2 equiv) at r.t. The mixture was stirred at r.t. for 16 h. Upon reaction

completion, 10% NaOH (10 mL) was added and the mixture was extracted with EtOAc (2x),

washed with water, brine, dried over Na2SO4, filtered, and concentrated to afford the crude

product. The product was purified by flash chromatography with 0-10% Et2O/hexanes to provide

the title compound in 93% yield (39.3 mg) as a white solid 93%. 1H NMR (400 MHz, CDCl3) δ

9.21 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 8.1, 1.4

Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.67 (dd, J = 2.9, 1.4 Hz, 1H), 7.57 (ddd, J = 8.1,

6.9, 1.2 Hz, 1H), 7.54 (dd, J = 5.0, 1.4 Hz, 1H), 7.50 (dd, J = 5.0, 2.9 Hz, 1H).; Spectral data is

in accord with the literature.46

(3S,4R)-3-phenylchroman-3,4-diol 2.8

To a round bottom flask equipped with a magnetic stir bar was added AD-mix α (282 mg),

followed by 4 mL of 1:1 mixture of H2O:t-BuOH. With vigorous stirring, the flask was cooled to

0 °C in an ice bath and the substrate 2.4a (42 mg, 0.2 mmol) was added at once. The flask was

gradually warmed to r.t. and stirred vigorously for 3 d. To the mixture was partitioned with

EtOAc and water. The organic phase was washed with water then brine, dried over Na2SO4,

filtered, and concentrated to afford the crude product. The product was purified by flash

128

chromatography with 0-10% EtOAc/hexanes to provide the title compound as a white solid (38

mg, 78%). The opposite enantiomer was synthesized using the same procedure employing AD-

mix β. The enantiomers were separated on HPLC with Chiracel ODH column. 90:10 (hexanes:2-

propanol). 0.8 mL/min flow rate. 210 nm. Retention times:13.5 (2.8) and 14.9 min. >99% ee was

obtained. [α]D20 = 28.8 ° cm2/g (c = 1.0, >99% ee, CHCl3).

1H NMR (400 MHz, CDCl3) δ 7.57 –

7.47 (m, J = 8.9, 3.7 Hz, 3H), 7.40 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.24 (t, J = 7.8

Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.08 (s, J = 5.4 Hz, 1H), 4.22 (d, J =

11.9 Hz, 1H), 4.14 (d, J = 11.9 Hz, 1H), 2.99 (s, 1H), 2.48 (s, 1H).; 13C NMR (100 MHz,

CDCl3) δ 153.3, 140.6, 129.5, 129.3, 128.8, 128.2, 125.8, 123.8, 121.7, 116.6, 71.7, 71.0, 70.3.;

IR (NaCl, CDCl3, cm-1) 3408, 1611, 1586, 1489, 1460, 1447, 1229, 1200, 1045, 1026, 964, 910,

787, 756, 733, 700, 607.; M.p.: 76-77 °C; HRMS (TOF, ESI+): calc’d for C15H18NO3 (M+H)+:

260.1288; Found: 260.1287.

129

Chapter 3 Enantioselective Sequential Multi-Metal Catalysis in the Presence

of Achiral Ligands: Time Resolution and Orthogonal Ligand Affinity Enabled Synthesis of Heterocycles

130

3 Enantioselective Sequential Multi-Metal Catalysis in the Presence of Achiral Ligands: Time Resolution and Orthogonal Ligand Affinity Enabled Synthesis of Heterocycles

The work described in this chapter was performed in collaboration with fellow graduate students

Zafar Qureshi (PhD student), Alvin Jang (MSc Student), and Dr. Lorenzo Sonaglia. The majority

of the work described was carried out by the author and contributions by others are labelled as

such.

3.1 Introduction

The development of Rh/Pd-based multi-metal catalysis described in Chapter 2 became an

impetus for us to demonstrate the ability of ligands to enable a wide scope of reactivity. By

simply using compatible combinations of ligands, the same Rh/Pd metal system can potentially

achieve a multitude of different transformations. Described in this chapter are our efforts in

applying this concept in the development of a Rh/Pd system that could achieve domino

enantioselective catalysis even in the presence of achiral ligands.

3.1.1 Time resolution

A successful asymmetric catalytic system would require independent catalytic cycles that operate

with differing rates such that undesired catalytic pathways would be suppressed to afford a

controlled reaction sequence, conferring time resolution. Two common strategies employed to

achieve time-resolved processes are: taking advantage of entropic effects to confer selectivity

and taking advantage of chemoselectivity in terms of relative reactivity of functional groups.

Relying on entropic effects by pairing an intramolecular reaction followed by an intermolecular

reaction provides time resolution. As the intramolecular reaction usually involves cyclization,

domino methods developed using this strategy are suitable for the construction of rings. The

Lambert group disclosed a Pd/In-catalyzed domino synthesis of pyrrolidines.47 The

47 Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124-3125.

131

aminocarbonylation afforded the cyclized intermediate, which subsequently participated in the

Friedel Crafts acylation (Eqn 3.1).

Time resolution can also be achieved by tuning the reactivity of functional groups such that the

reaction sequence can occur in a fixed chronological order. This strategy can be important to the

success of domino methods that have steps that follow independent mechanisms. Tietze and

coworkers reported a Pd-catalyzed domino Tsuji-Trost-Heck process that illustrated the effect of

chemoselectivity on time resolution (Eqn 3.2).48 In the domino synthesis of

tetrahydroanthracenes, two competitive processes could occur: either the Pd could oxidatively

insert into the aryl iodide or displace the OAc to form a π-allyl complex. Increasing the electron

density of the arene (R = OMe) slowed down the oxidative insertion into the aryl iodide bond,

leading to the desired Tsuji-Trost-Heck sequence, affording the product in 83% yield. However,

in the case (R = H) that aryl halide oxidative insertion became competitive, the lack of time

resolution resulted in significantly decreased yields.

Similar in multi-metal-catalyzed processes where two independent catalytic cycles are operating,

the chronological sequence of events can be important. Cossy and coworkers reported a Ru/Pt-

catalyzed cross metathesis/hydrogenation domino sequence that illustrated the effect of relative

rates of catalysis (Scheme 3.1).49 In the sequence, cross metathesis of an allylic alcohol with an

48 Tietze, L. F.; Nordmann, G. Eur. J. Org. Chem. 2001, 3247-3253. 49 Cossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459-462.

132

α,β-unsaturated enone had to occur first, forming trans-alkene intermediates. The internal

alkenes were subsequently hydrogenated, allowing cyclization to access the desired lactones or

lactols (Scheme 3.1). However, the use of bulky allylic alcohols was unfavorable, as the cross

metathesis became slow and the competitive hydrogenation pathway led to significant amounts

of saturated alcohols.

Scheme 3.1 Ru/Pt-catalyzed cross metathesis/hydrogenation sequence for the synthesis of lactones

Time resolution was also crucial to the success of the Rh/Pd-catalyzed domino reaction

described in Chapter 2 (Scheme 3.2). The fast rate of reaction of the Rh-catalyzed step over Pd-

catalyzed C-N coupling suppressed undesired reaction pathways.

Scheme 3.2 Time-resolved domino Rh/Pd-catalyzed hydroarylation/C-N cross coupling

133

Jennifer Tsoung in our group recently reported a multi-metal-catalyzed multicomponent reaction

(MC)2R with a remarkable control in the reaction pathway.50 Using a combination of Rh and Pd,

a vinyl pyridine, o-chloroaryl boronic acid, and an amine could successfully be stitched together

to access benzodiazapines (Eqn 3.3). Given the number of reactive functional groups present that

could lead to various undesired pathways, the time resolution conferred by Rh-catalysis was

crucial in the success of this reaction.

3.1.2 Ligand interference

Another necessary element for the development of enantioselective domino catalysis in the

presence of achiral ligands was our observation of the preferential ligand binding behaviour of

the [Rh(cod)OH]2 catalyst (Scheme 3.3). As Rh had a weak affinity for XPhos, the ability for Rh

to preferentially associate with a chiral bisphosphine or diene based ligand was important for the

development of enantioselective catalysis.

Scheme 3.3 Preferential Rh-BINAP association over XPhos

In the reaction, the ligands may bind selectively or non-selectively to the metal catalysts.

Equilibrium between the ligands and metals may exist. However simple or complex this

interaction may be, if a specific binding combination creates a highly active catalyst while the

other species remain inactive, then a ligand-dependent transformation can still occur in the

presence of multiple ligands. This allows similar ligands (two or more phosphines) or different

ligands (diene and phosphine) to be mixed in the same vessel. Particularly, under these

50 Tsoung, J.; Panteleev, J.; Tesch, M. Lautens, M. Org. Lett. 2014, 16, 110-113.

134

conditions, chiral and achiral ligands can be used and still confer enantioselective catalysis.

However, if a competing active catalyst could be created with another ligand-metal species, then

interference in the reactivity could occur. A number of important studies on ligand interference

by fellow colleagues, Jane Panteleev, Gavin C. Tsui, and Jennifer Tsoung have been made that

uncovered the necessary requirements for the enantioselective catalysis in presence of achiral

ligands.

Following our work described in Chapter 2, Tsui and Tsoung studied the feasibility of Rh/Pd

catalysis for the enantioselective construction of dihydrobenzofurans.51 The method utilized a

Rh-catalyzed asymmetric ring opening (ARO) of oxanorbornadienes and Pd-catalyzed C-O

coupling in a one pot process, affording products with high enantioselectivity (Eqn 3.4).

However, attempts to combine the two catalysts into an “all-in-one” domino process proved to

be difficult (Eqn 3.5). Among other byproducts and intermediates, the desired product was

isolated with significantly decreased ee. Detailed examination of the effects of the catalytic

components on the ARO step revealed that ligand combinations with Pd formed competent

catalysts for the ring opening. Pd(OAc)2 and Josiphos could catalyze the ring opening with 61%

yield and 28% ee.52 Pd(OAc)2 and XPhos could also catalyze the ring opening yielding racemic

product.52 Thus, the effect of combining two steps together was not straightforward in this case.

Since two different metals catalyzed the same reaction but with very different

enantioselectivities, a deterioration of enantioselectivity was observed.

51 Tsui, G. C.; Tsoung, J.; Dougan, P.; Lautens, M. Org. Lett. 2012, 14, 5542–5545.

135

The strong influence imparted by added ligands in catalysis prompted our group to examine the

extent of this effect and generate possible guidelines toward developing multi-ligand based

catalyst systems. Using the Rh-catalyzed ARO of oxanorbornadienes with methanol as a model

study, Tsui and coworkers tested the effect of added achiral ligands.52 Employing [Rh(cod)Cl]2

and Josiphos, the ARO of oxabicylic alkene with MeOH afforded the product with 85% yield

and 94% ee (Table 3.1, entry 1). By adding achiral ligands to this system and observing the ee of

the product, a correlation can be drawn between the affinity of the achiral ligand for the Rh

catalyst and the catalytic competency of resulting complex, thus the concept of “ligand

interference”. Various combinations of added ligands and metals were examined. While the

majority of the achiral ligand combinations used shown competitive binding to the catalyst, a

select number of achiral ligands were tolerated, causing slight deterioration in enantioselectivity.

This select set of ligands included DPPM, DPPE, and XPhos (entries 2-7). Thus, choosing a

compatible ligand combination where the achiral ligand has low affinity for the metal

responsible for enantioselective catalysis or that the achiral ligand-metal complex does not

exhibit catalytic activity would be important.

52 Tsui, G. C.; Dougan, P.; Lautens, M. Org. Lett., 2013, 15, 2652–2655

136

Table 3.1 Catalyst competition studies in Rh-catalyzed ARO with exogenous metal and ligand additives.

Entry L M Rh:L*:L:M % Yield Ee

1 4:4:0:0 85 94

2 Dppm 4:2:2:0 81 90

3 Dppm 4:4:4:0 82 89

4 Dppe 4:2:2:0 85 94

5 Dppp 4:2:2:0 70 90

6 Dppf 4:2:2:0 55 92

7 XPhos 4:2:4:0 83 94

8 (±)-binap 4:2:2:0 77 84

9 Dppp Pd(OAc)2 4:4:4:4 57 92

10 Dppp Pd(OAc)2 8:4:4:8 37 96

Taking the lessons learned in the studies on ligand interference, our group found a compatible

combination of rhodium with a chiral diene ligand and palladium with a Buchwald ligand. While

reports on Pd catalysis with diene ligands do exist, the development of Pd-phosphine catalysis

has received far more attention. As rhodium has weak affinity for XPhos, pairing a diene ligand

and a Buchwald ligand in a Rh/Pd system would confer orthogonal binding affinity, where

rhodium would preferentially bind the diene while palladium would bind the phosphine. Using

this ligand combination in Rh/Pd catalysis, J. Tsoung successfully demonstrated an

enantioselective arylation of vinyl pyridines followed by C-O coupling to access chiral

dihydrodibenzoxepines with high enantioselectivity (Eqn 3.6).53

53 Friedman, A. A.; Panteleev, J.; Tsoung, J.; Huynh, V.; Lautens, M. Angew. Chem. Int. Ed. 2013, 52, 9755-9758.

137

Though the potential for further improvements in catalyst loading, yields, and scope existed, this

was the first example that demonstrated the enantioselective domino catalysis in the presence of

achiral ligands. Judicious choice of a compatible combination of ligands with minimal ligand

interference and a domino sequence that confers time resolution would be key in the

development of future multi-metal-catalyzed domino reactions.

3.2 Research plan

Our group’s report on enantioselective synthesis of dihydrodibenzoxepines provided an excellent

Rh/Pd platform for method development and reaction discovery. As the Rh/Pd system is ligand-

dependent, the choice of ligands can provide new reactivity and demonstrate the versatility of

multi-metal catalysis. Herein, we describe the use of a Rh/Pd catalyst system with a different

ligand combination that effected another enantioselective domino sequence, involving a Rh-

catalyzed asymmetric conjugate arylation to an acrylamide followed by a Pd-catalyzed amidation

to access enantioenriched C4-substituted dihydroquinolinones (Eqn 3.7).

3.2.1 Synthetic access to C4-substituted dihydroquinolinones

Molecules of this class of heterocycles exhibit important and diverse biological activities. 54

Furthermore, these chiral heterocyclic products can be derivatized into various

tetrahydroquinolines. Several methods exist for the synthesis of C4-substituted

dihydroquinolinones. However, asymmetric variants are less common.55 Important bioactive

54 For a review, see: (a) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem. Rev. 2011, 111, 7157-7259. For selected examples, see: (b) Comesse, S.; Sanselme, M.; Daïch, A. J. Org. Chem. 2008, 73, 5566-5569. (c) Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009, 9, 1959-1962. (d) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598-4599. (e) Xie, M.; Chen, X.; Zhu, Y.; Gao, B.; Lin, L.; Liu, X.; Feng, X. Angew. Chem. Int. Ed. 2010, 49, 3799-3802. (f) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 661-665. (g) Lu, H.-H.; Liu, H.; Wu, W.; Wang, X.-F.; Lu, L.-Q.; Xiao, W.-J. Chem. Eur. J. 2009, 15, 2742-2746. (h) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498-10499. (i) Kim, Y.; Shin, E.-K.; Beak, P.; Park, Y. S. Synthesis 2006, 22, 3805-3808. (j) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 17, 3821-3824.

138

members of this family that bears this C4-substituted motif include Martinellic acid, antibacterial

agents, and azapodophylotoxins (Figure 3.1).

NH

Ph

R

N

H

H

NH

Ph

N

H

HHN

Ph

NH

H

NH

OO

O

R = H, OMeAntibacterial (DNA gyrase)

O

OMe

OMe

MeO

aza-podophyllotoxin

NH

N

HO2C

HN

HN

HN

HN

NHMartinellic acid

Figure 3.1 Bioactive C4-substituted tetrahydroquinolines.

An approach toward C4 substitution utilized enantioselective Lewis acid catalysis in the Povarov

reaction. For example, using scandium and a chiral N,N-dioxide ligand, Feng and coworkers

could successfully assemble an aniline, aldehyde, and cyclopentadiene in a multicomponent

reaction to access the C4 substituted tetrahydroquinoline in high yield, d.r., and ee (Eqn 3.8).55e

Organocatalysis was shown to be a very effective strategy for the asymmetric synthesis of

functionalized tetrahydroquinolines. Jörgensen and coworkers demonstrated the use of a chiral

imidazoline catalyst in the Michael addition of malonate to an enone (Eqn 3.9).

Transesterification of the benzyl groups occurred prior to the Pd/C catalyzed hydrogenation of

the nitro group, affording the desired tetrahydroquinoline in a three step sequence with good

139

ee.55f The use of Jörgensen’s catalyst was subsequently discovered to be effective in the

intramolecular Friedel-Crafts addition onto a tethered enal (Eqn 3.10).55g

NO2

O

NO2

OBnO2C CO2Bn

CO2BnBnO2C NH

MeO2C CO2Me

N

NH

Bn CO2H

(10 mol %)

87% yield86% ee

1)HCl, MeOH, 77%

2) Pd/C, H2, 78%

(3.9)

The ruthenium thiolate complex used by Nishibiyashi described in Chapter 2 was also effective

in the enantioselective synthesis of tetrahydroquinolines (Eqn 3.11).55h A chiral thiol ligand-

bound catalyst afforded products with high ee.

Another asymmetric non-catalytic method to access C4-substituted dihydroquinolinones was

reported by Beak and coworkers (Eqn 3.12).55i The use of stoichiometric sparteine in the

benzylic deprotonation of 2-alkyl-N-pivaloylaniline promoted the formation of a chiral alkyl

lithium through equilibration. Trapping the alkyl lithium with an α-bromoacetate established the

chiral center in the alkylated adduct. Treatment with HCl promoted deprotection of the tert-butyl

group and lactamization to furnish the dihydroquinolinone in two steps with a good yield and

excellent ee.

140

Another variant of the catalytic enantioselective conjugate addition/hydrogenation approach to

access these quinolinones was reported by Carreira and coworkers. Through a Rh-catalyzed

asymmetric conjugate arylation of a nitrocinnamate followed by hydrogenation in the presence

of acetic acid, a good overall yield and excellent ee were achieved (Eqn 3.13).55j

Using Rh/Pd catalysis, the development of our “all-in-one” method would provide a direct and

expedient access to dihydroquinolinones in an enantioselective manner. Furthermore, the

reaction conditions would be mild, practical, and functional group tolerant, without the use of

stoichiometric amounts of chiral reagents and cryogenic conditions. Additionally, the starting

acrylamides employed in could be readily accessed in a reliable and straightforward manner,

thereby providing a broad reaction scope (Scheme 3.4).

Cl

O

NHR

I

Cl NHR

O+

+ PEtO

O

OEtNHR

O

Cl

O

+

Cl

NH2RCl

O

Heck

Horner-WadsworthEmmons

Acylation

Scheme 3.4 Access to aryl acrylamides for the Rh/Pd enantioselective catalysis

3.3 Reaction optimization

Prior to achieving a successful strategy, numerous attempts were made to realize a Rh-catalyzed

1,4-conjugate arylation to afford adducts that contain an aryl halide group that could participate

141

in a subsequent Pd-catalyzed coupling. Various attempts to add o-chlorophenyl boronic acid to

Michael acceptors were unsuccessful. Rh precursors, ligand or ligand-less conditions were

investigated. We found that acceptors with β-substituents did not yield addition products (Eqn

3.14). However, substituting the o-chlorophenylboronic acid with phenylboronic acid afforded

products with smooth conversion. Thus, the “ortho-halogen” substituent was an enduring

problem in the development of Rh-catalyzed addition reactions. Switching the substrate to α-

substituted acrylamides became problematic as the substrates were highly prone to

polymerization, posing difficulty for synthesis and isolation (Eqn 3.15). Although α-amino

acrylates could be synthesized, the addition to the alkene did not occur as well (Eqn 3.16).

Preliminary efforts were also made toward extending the tether such that the aryl halide group

would be remote from the reactive site for the Rh catalysis without success. However, the

concept of Rh-catalyzed conjugate arylation/Pd-catalyzed α-arylation would access the dual

metal cooperative mode of catalysis (Eqn 3.17).

The ortho-chloride problem was not solved until Jane Panteleev demonstrated that the addition

of o-chlorophenyl boronic acid to vinyl pyridines was feasible.51 The key was the omission of

phosphine ligands. Indeed, our initial study using Rh and binap on the conjugate addition of

phenylboronic acid to acrylamide 3.1a did not afford conversion (Table 3.2, entry 1). However,

142

the desired reactivity resumed once binap was removed and full conversion was observed within

30 min (entry 2). The conjugate addition delivered 3.2a that contained an aryl chloride that could

participate in a C-N coupling with the amide, which was readily achieved with a Pd catalyst and

XPhos (L6) over 16 h, accessing the dihydroquinolinone 3.3a.

Table 3.2 Reaction optimization of the domino Rh/Pd-catalyzed dihydroquinolinone synthesisa

Entry Rh/L Pd Base % Yield (3.2a/3.3a) % Ee (3.3a)

1 [Rh(cod)Cl]2/binap - K3PO4 0/- -

2 [Rh(cod)Cl]2 - K3PO4 99/- -

3 [Rh(cod)Cl]2 [Pd(allyl)Cl]2/L6 K3PO4 0/99 -

4 [Rh(C2H4)2Cl]2/L1 [Pd(allyl)Cl]2/L6 K3PO4 0/76 0

5 [Rh(C2H4)2Cl]2/L2 [Pd(allyl)Cl]2/L6 K3PO4 22/0 -



8b,c [Rh(L4)2Cl]2 L6-Pd-G1 KOH 0/63 95

9c [Rh(L5)2Cl]2 L6-Pd-G1 KOH 0/68 95

10d [Rh(L5)2Cl]2 L6-Pd-G1 KOH 0/89 95 a Representative reaction conditions: [Rh], [Pd], and respective ligands were added to a 2 dram vial under Ar atmosphere and

subsequently 3.1a, phenylboronic acid, and base (2.2 equiv) were added. To the vial was added the solvent, and the mixture was

stirred for 5 min at r.t. prior to heating at 110 °C for 18 h. t-am-OH = tert-amyl alcohol (2-methyl-2-butanol). Yields were determined

by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard. b 8 mol % [Rh] was used. c 3.5 equiv KOH used. d

2.5 equiv phenylboronic acid was used. Isolated yield.

As XPhos demonstrated compatibility in a number of Rh-catalyzed arylation reactions, the

concurrent use of XPhos, Pd, and Rh was tolerated, accessing the dihydroquinolinone directly

from the acrylamide in a single operation (entry 3). The time resolution of the reaction sequence

143

was crucial in rendering high control over undesired reaction pathways. In particular, the faster

Rh-catalyzed conjugate addition consumed the phenylboronic acid and prevented the Pd-

catalyzed Suzuki-Miyaura cross coupling of 3.1a. Control study of the reaction without Rh under

the same reaction conditions indeed provided the Suzuki-Miyaura coupling product 3.4a in a

high yield (Eqn 3.18).

The time-resolved process also provided a defined sequence of reactions. Thus an alkene

isomerization of the acrylamide 3.1a from E to Z, subsequent Pd-catalyzed C-N coupling to

afford 3.5a, followed by Rh-catalyzed conjugate addition would not have been an operative

reaction pathway. This prediction was verified when 3.5a was subjected to the Rh-catalyzed

conjugate addition (Eqn 3.19). No product formation was observed and byproducts were noted.

In addition, as the direct conjugate addition to 3.5a was not achieved, our Rh/Pd catalysis

sequence proved to be a superior alternative.

As cyclooctadiene (cod) was a native ligand for Rh in the domino catalysis, we sought to

develop the Rh-catalyzed enantioselective conjugate addition using chiral diene ligands. From

our initial observation of Rh-ligand binding behaviour, we postulated that pairing a chiral diene

ligand with XPhos could achieve enantioselective Rh catalysis. In addition, the abundance of

diene ligands in Rh catalysis and the use of XPhos in Pd0 catalysis offer orthogonality in ligand

association, opportunities for ligand screening, and possible minimization of ligand interference.

Consequently, we screened a number of diene ligands in the one step operation. Unfavorable

144

reactivity was observed with use of diene ligands developed by Genet,55 Carreira,55j and Lam56

(Table 3.2, entries 4-6). No enantioselectivity was observed with the use of L1 and L3. Only

conversion to the intermediate 3.2a was achieved with the use of L2. However, the use of ligand

L4 developed by Hayashi57 afforded the desired product in 24% yield with an excellent 95% ee

(entry 7). A significant improvement in yield was observed as the Rh/L4 loading was increased

to 8 mol % and KOH was used as base (entry 8). The use of the Buchwald palladacycle L6-Pd-

G1 as the amidation catalyst further simplified the reaction protocol. We realized that the use of

KOH and MeOH in the reaction conditions may hydrolyze the naphthyl ester on the diene ligand

L4, thereby stifling the conjugate arylation. Substitution of naphthyl to a bulkier group would

withstand the hydrolytic conditions. Consequently, the use of Rh/L5 in lowered catalytic

loadings (5 mol %) still gave a suitable yield and excellent ee (entry 9). Increasing the

equivalents of the arylboronic acid gave an excellent yield of 89% with 95% ee, exemplifying

the efficiency of the time-resolved domino catalysis sequence. To verify that the catalysts in the

domino sequence indeed operate in an independent manner, we performed the individual steps

separately (Eqn 3.20). The Rh-catalyzed conjugate addition was highly enantioselective, and no

erosion of optical purity was observed in the subsequent Pd-catalyzed amidation. Comparing the

optical rotation of the product to the literature,55i,j we were able to assign the absolute

configuration of the carbon bearing the phenyl group as (S).

55 Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem. Int. Ed. 2008, 47, 7669-7672. 56 Saxena, A.; Lam, H. W. Chem. Sci. 2011, 2, 2326-2331. 57 Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009, 4815-4817. (b) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 13168-13169. (c) Shintani, R.; Hayashi, T. Org. Lett. 2011, 13, 350-352.

145

3.4 Scope of the enantioselective Rh/Pd-catalyzed sequential synthesis of dihydroquinolinones

To explore the reaction scope of the developed Rh/Pd domino catalysis, we examined a variety

of arylboronic acids (Table 3.3). In general, three equivalents of the substituted arylboronic acids

were used to achieve consistent and improved yields. The reaction exhibited good to high yields

and enantioselectivity. While electron rich (entries 3-8) and poor (entries 12-14) arylboronic

acids were tolerated in the reaction, substitution at the 3 position gave poorer reactivity (entries

4, 13). Functionalized nucleophiles such as thioether and fluorine-containing arylboronic acids

(entries 6, 11, 12, 14-16) could be readily employed.

Table 3.3 Reaction scope with respect to arylboronic acidsa

Entry R Product % Yield % Ee

1b 3-Me 3.3ab 89 94

2b 4-Me 3.3ac 88 98

3b 4-tBu 3.3ad 76 96

4b 3-OMe 3.3ae 56 92

5b 4-OMe 3.3af 80 96

6 3,4-(OMe)2 3.3ag 80 95

7 3,4,5-(OMe)3 3.3ah 78 94

8b 4-Ph 3.3ai 70 92

9 2-naphthyl 3.3aj 75 95

10 4-SMe 3.3ak 72 96

11 4-Ac 3.3al 48 92

12 4-F 3.3am 61 94

13b 3-CF3 3.3an 46 82

14b 4-CF3 3.3ao 82 75 a Reaction conducted on 0.2 mmol scale; see Experimental section for reaction details. b Reactions conducted by Z. Qureshi.

The reaction also tolerated substitutions on the acrylamides (Scheme 3.5). A variety of these

acrylamides could be accessed reliably in a straightforward manner (see Experimental section).

Both electron donating (3.3b-3.3d) and withdrawing groups (R1) (3.3e-3.3g) on the aryl

acrylamide reacted favorably and high yields and enantioselectivities were achieved. Other

heterocyclic derivatives could also be accessed with thiophenyl and indolyl acrylamides with an

increased Rh loading (3.3g-3.3i). While the observed deterioration in the enantioselectivity of the

146

conjugate addition for the thiophenyl acrylamide 3.3ha may be an effect of the proximal sulfur

atom, the use of an electron rich arylboronic acid resulted in good yield and enantioselectivity

(3.3hb). The indolyl acrylamide (3.3i) also exhibited poorer reactivity at the conjugate addition

step, and byproduct formation was noted. Nevertheless the “all-in-one” process can achieve a

modest yield with a high enantioselectivity.

Scheme 3.5 Reaction scope of aryl acrylamides. Reaction conducted on 0.2 mmol scale. a [Rh(L5)Cl]2 (4 mol %, 8 mol % [Rh]) and 3 equiv of arylboronic acid was used. b [Pd(allyl)Cl]2 (3 mol %) and L7 (6 mol %) was used instead of L6-Pd-GI. c Reaction conducted by Z. Qureshi.

147

N-Substituted acrylamides also could participate in the reaction (3.3k-3.3m). While N-phenyl

substitution (3.3m) can be accessed with L6, other substituents including N-alkyl (3.3j-l) react

less readily. Switching the Pd catalyst and the ligand to [Pd(allyl)Cl]2 and L7 (Brettphos),

modest yields were achieved while retaining the high enantioselectivity. The ability to pair the

Rh-catalyzed conjugate addition with a number of Buchwald ligands to tailor specific reactivity

demonstrates the flexibility of the two catalyst strategy.

While the reaction scope exhibited good generality, the use of heteroarylboronic acids did not

afford any conversion. The corresponding boronates were as unreactive. However, to the best of

our knowledge, no reports exist on the enantioselective conjugate addition of heteroarylboron

nucleophiles onto Michael acceptors. A number of hetercyclic substrates were also investigated

and proved to be unsuccessful (Figure 3.2). For example, the 2-substituted indolyl acrylamides,

both 1- and 2-substituted benzofuran acrylamides were sluggish to react under Rh catalysis.

Again, it seemed that the ortho-chloride was responsible as the non-chlorinated substrates were

known to react.55j

Figure 3.2 Unsuccessful substrates in the Rh/Pd catalysis

Unfortunately, the pyridyl acrylamides were unsuccessful partners in the method. Under Rh

catalysis without the chiral ligand, low amounts of the conjugate addition product were obtained.

Sluggish catalysis by Rh was problematic as time resolution was not possible. Subjecting the

acrylamide under Rh/Pd catalysis (with excess phenylboronic acid), we observed substantial

formation of the Suzuki-Miyaura coupling product and conjugate addition. Though the reaction

was not productive, it did stress the importance of the relative rates of each step (Scheme 3.6).

The reversal in sequence of catalysis probably arose from the sluggish Rh-catalyzed addition

onto the chlorinated substrate, leading to a bottleneck. Thus, competitive Pd catalysis took

priority. Once the Suzuki-Miyaura coupling occurred, the substrate lacking the halide then

underwent the Rh-catalyzed conjugate addition of a second equivalent of phenylboronic acid.

148

Scheme 3.6 Lack of time resolution on the Rh/Pd catalysis for pyridine containing substrates

The quinolone scaffolds accessed from the Rh/Pd catalysis have the potential for further

manipulation. A number of reports have demonstrated subsequent transformations, including

Friedel-Crafts, amination, and reductive alkylation (Scheme 3.7). 58

N

Ph

O

Boc

1) Boc2ODMAP

MeCNquant

3.3a

1) LiBEt3H, THF, -78 C2) NaH, (EtO)2P(O)CH2CO2Et,

0 C - r.t., 85% (2 steps)

3) CF3CO2H, CH2Cl20 C, 96 %

NH

Ph

OEt

O

3.3a

N

Ph

NH2NH

Ph

O

O

HOPPA, 140 C50%

O

HO

Cl1) Lawesson's reagent

PhMe, 67%

2) NH4OH, HgCl2THF, 45%

Scheme 3.7 Derivatization of dihydroquinolinones

Beak and coworkers also established an efficient synthesis of 3,4-disubstituted

tetrahydroquinolines in a stereoselective manner in two steps (Eqn 3.21).55h

58 (a) Venet, M. G.; Angibaud, P. R.; Sanz, G. C.; End D. W. (Janssen Pharmaceutica, N.V.) US 5968952, 1999. (b) Thorsett, E. D.; Porter, W. J.; Nissen, J. S.; Latimer, L. H.; Audia, J. E.; Droste J. (Athena Neurosciences, Inc), US 6506782, 2003. (c) Lee, E.; Han, S.; Jin, G. H.; Lee, H. J.; Kim, W.-Y.; Ryu, J.-H.; Jeon, R. Bioorg. Med. Chem. Lett. 2013, 23, 3976-3978.

149

3.5 Future work: multi-metal-catalyzed multicomponent reactions (MC)2R: enantioselective Rh/Pd-catalyzed bidirectional functionalization and Rh-catalyzed domino conjugate addition/α-arylation

The substrates that failed to participate in the Rh/Pd catalysis were ultimately attributed to the

ortho-halogen substituent. The attenuated reactivity of these substrates in the Rh-catalysis caused

a breakdown of the domino sequence. Thus, from these substrates, we envisioned a number of

resolutions to address the ortho-halogen problem. For instance, a multicomponent approach

using a cinnamate, arylboronic acid, and primary amine could access the same

dihydroquinolinones with Rh/Pd catalysis (Eqn 3.22). The cinnamate would be more

electrophilic than the acrylamides, thereby facilitating the Rh-catalyzed addition and maintaining

time resolution.

Cl

O

ORRh/L*

PhB(OH)2Cl

O

OR

ArPd

RNH2NHR

O

OR

Ar

NR

Ar

O

(3.22)

Despite concerns of the competitive addition of the amine to the Michael acceptor, a preliminary

examination of this multicomponent approach yielded a promising product distribution (Eqn

3.23). The use of tert-butyl cinnamate 3.6, phenylboronic acid, and an aniline afforded the

desired product 3.8 in 40% yield. Also, the only other observed product came from the Suzuki-

Miyaura/conjugate addition pathway (3.7). Importantly, products that arose from aza-Michael

addition were absent.

150

Cl

OtBu

O [Rh(cod)Cl]2 (2.5 mol %)L6-Pd-GI (2 mol %)

KOH (3.5 equiv)dioxane/H2O, 110 C

PhB(OH)2

+

Ph

OtBu

OPh

NHPMP

OtBu

OPh

+

35% 40%

Cl

OtBu

ONHPMP

+

NHPMP

OtBu

ONHPMP

not observed

(3.23)

3.6 3.7 3.8O

H2N

2.5 equiv

2 equiv

In fact, the Pd-catalyzed C-N coupling was favoured over the aza-Michael addition (Eqn 3.24).

Subjecting 3.6 to the Pd-catalysis with the amine yielded exclusively the coupling product 3.9.

Alvin Jang subsequently studied this reaction under my guidance. Interestingly, taking the C-N

coupling product 3.9 forward in the Rh-catalyzed enantioselective conjugate addition afforded

the desired product with high enantioselectivity and yield (Eqn 3.25). The (MC)2R was further

investigated by A. Jang with the aim of minimizing the Suzuki-Miyaura coupling and ligand

screening for enantioselective catalysis. The use of the chiral diene ligand played a significant

role in the product distribution. L5, the optimal diene ligand used in the synthesis of

dihydroquinolinones, was switched to L4. As no methanol was used in this reaction, the bulkier

ester on L5 that was postulated to withstand hydrolysis and ensure catalyst stability was no

longer needed. More importantly, the switch to L4 with a naphthyl ester probably also removed

steric bulk on the catalyst and promoted a faster Rh-catalyzed addition. An increased rate in Rh

catalysis meant a faster consumption of excess arylboronic acids and minimized Suzuki-Miyaura

151

coupling. As a result, the ligand L4 enabled the (MC)2R to access the desired conjugate

addition/C-N coupling product with high yield and excellent ee (Eqn 3.26).

While time resolution was still an important aspect in the multicomponent reaction, the

alternative reaction pathway with a reversal of reaction sequence could still be operative as the

C-N coupling product 3.9 also underwent Rh-catalyzed addition to afford the product with high

ee (Eqn 3.25). Thus the idea of a tandem (MC)2R came to our attention. As the ortho-halogen

was a problem in the various systems investigated, moving the halide to other positions on the

arene could provide a chemoselective bidirectional functionalization process (Eqn 3.27). Halide

substitutions at positions other than the proximal ortho position also could facilitate the Rh-

catalyzed addition and tackle more challenging heteroaryl substrates.

The reactivity issues of substrates with ortho-halogen groups were a persistent problem during

the development of Rh/Pd catalysis. Thus the strategy of removing the proximal halide from the

Rh-catalyzed reaction site was considered. One approach was combining the conjugate addition

with a Pd-catalyzed α-arylation. While the system described in equation 3.17 was briefly

attempted, we modified our strategy to a different substrate class (Eqn 3.28). The substrate

would be an acrylamide where the aryl halide is tethered to the amide. Conjugate addition would

afford an enolate and subsequent Pd-catalyzed α-arylation would couple the enolate with the aryl

halide. The in situ generation of an enolate via conjugate addition would mitigate the use of

strong bases. The advantages of this domino sequence would be mild reaction conditions and

functional group tolerance.

152

To our surprise, A. Jang observed that the Rh-catalyzed conjugate addition of phenylboronic acid

onto the β-unsubstituted acrylamide 3.10 subsequently underwent an α-arylation to afford the

final product directly, without the need of Pd catalysis (Eqn 3.29). The Rh-catalyzed α-arylation

to our best knowledge has not been reported in literature. However, the oxidative insertion of Rh

into an aryl halide bond is a known process, as described in Chapter 2.

O

N

Me Br

[Rh(cod)Cl]2 (2.5 mol %)PhB(OH)2 (1.5 equiv)

K2CO3 (3 equiv)dioxane/H2O, 110 C

O-

N

Me Br

PhN

O

Ph

Me66%

(3.29)

3.10 3.11

A number of questions need to be addressed. For example, did the enolate addition occur via a

benzyne intermediate? It seemed unlikely due to the mild reaction conditions and presence of

water, but it could be verified by subjecting the substrate bearing the bromide meta to the

nitrogen (Eqn 3.30). Also, the use chiral ligands in the domino process did not afford oxindole

3.11 with any observable enantioselectivity, presumably not due to catalyst control, but due to

the acidity of the C3 proton on the oxindole. Potentially, the use of β-substituted substrates would

be able to induce enantioselectivity in the conjugate addition and also control the C3 stereocenter

on the oxindole (Eqn 3.31). Another possible solution would be extending the tether length to

access isoquinolines (Eqn 3.32). The C4 stereocenter would be less prone to epimerization.

153

O

N

Me

Br

O

N

PG Br

R

O

N

PG

Br

NO

ArR

PG

N

Ar

O

PG

NO

Ph

Me

(3.30)

(3.31)

(3.32)

An alternative strategy could also be investigated. As the C3 of the oxindole is prone to

epimerization, an enantioselective Rh-catalyzed allylation of the oxindole can be attempted in

either a domino or one pot manner (Eqn 3.33).59 Preliminary work by Jang has demonstrated the

viability of a domino sequence.

3.6 Conclusions

We have developed a versatile two catalyst-two ligand system, where one ligand is chiral and the

other is achiral, that enables the direct and efficient access to chiral dihydroquinolinone cores in

a single step. Selecting ligands that confer time resolution and minimize effects of ligand

interference was pivotal in controlling the domino sequence. The “all-in-one” 1,4-conjugate

arylation and C-N cross coupling Rh/Pd catalysis sequence provided access to enantioenriched

dihydroquinolinone building blocks. Further investigation into the ortho-halide problem led to

59 For selected examples of Rh-catalyzed enantioselective allylation, see: Menard, F.; Chapman, T.M.; Dockendorff, C.; Lautens, M. Org. Lett. 2006, 8, 4569-4572. (b) Yu, B.; Menard, F.; Isono, N.; Lautens, M. Synthesis 2009, 853-859.

154

our current endeavours to develop enantioselective multi-metal-catalyzed multicomponent

reactions (MC)2R and the Rh-catalyzed conjugate addition/α-arylation.


(E)-3-([1,1'-biphenyl]-2-yl)acrylamide 3.4a

To a dry 2 dram vial under an argon atmosphere was introduced powdered KOH (39 mg, 3.5

equiv) followed by Pd-XPhos-GI (3.0 mg, 2 mol %), aryl acrylamide (36.3 mg, 0.2 mmol), and

the phenylboronic acid (61 mg, 2.5 equiv). To the mixture was added t-am-OH (tert-amyl

alcohol, 2-methyl-2-butanol) (2 mL) and MeOH (0.2 mL). The vial was sealed with a Teflon

coated cap and the mixture was vigorously stirred for 5 min at r.t. prior to heating at 110 °C for

18 h. Subsequently, the mixture was cooled to r.t., filtered through a silica gel pad, and washed

with EtOAc. The filtrate was concentrated and purified using flash-column chromatography (20

– 60% EtOAc in Hex) to afford the product as white solids (43.2 mg, 97%). 1H NMR (500 MHz,

CDCl3) δ 7.68 – 7.65 (m, 1H), 7.61 (d, J = 15.7 Hz, 1H), 7.43 (ddt, J = 7.0, 2.0, 1.3 Hz, 3H),

7.40 – 7.35 (m, 3H), 7.33 – 7.29 (m, 2H), 6.37 (d, J = 15.7 Hz, 1H).; 13C NMR (126 MHz,

CDCl3) δ 142.9, 141.4, 140.1, 132.9, 130.7, 129.9, 129.7, 128.5, 127.73, 127.72, 126.9, 121.1.;

IR (powder, cm-1) 3342, 3331, 3180, 3061, 1664, 1651, 1604, 1473, 1437, 1396, 1238, 1199,

1157, 1126, 1074, 1008, 981, 912, 744, 702.; M.p. 158-160 °C.; HRMS (DART+): 224.1081

[M+H]+ (calc’d 224.1070 for C15H14NO).

155

Stepwise conjugate addition and amidation sequence

(S)-3-(2-chlorophenyl)-3-(4-methoxyphenyl)propanamide 3.2af


equiv) followed by [Rh(L5)Cl]2 (4.5 mg, 5 mol % [Rh]), aryl acrylamide (36.3 mg, 0.2 mmol),

and the arylboronic acid (91 mg, 3 equiv). To the mixture was added t-am-OH (2 mL) and

MeOH (0.200 mL). The vial was sealed with a Teflon coated cap and the mixture was vigorously

stirred for 5 min at r.t. prior to heating at 110 °C for 1 h. Subsequently, the mixture was cooled to

r.t., filtered through a silica gel pad, and washed with EtOAc. The filtrate was concentrated and

purified using flash-column chromatography (20 – 75% EtOAc in Hex) to afford the product as

white solids (50.0 mg, 86%). 1H NMR (500 MHz, CDCl3) δ 7.34 (dd, J = 7.9, 1.2 Hz, 1H), 7.26

– 7.19 (m, 2H), 7.19 – 7.12 (m, 3H), 6.85 – 6.79 (m, 2H), 5.59 (s, 1H), 5.43 (s, 1H), 4.96 (dd, J =

8.6, 7.1 Hz, 1H), 3.76 (s, 3H), 3.00 – 2.84 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 173.2,

158.4, 141.2, 134.06, 134.05, 130.2, 129.1, 128.3, 127.9, 127.1, 114.1, 55.3, 42.9, 41.9.; IR

(NaCl, CHCl3, cm-1) 3462, 3331, 3188, 3007, 2933, 2835, 1662, 1651, 1608, 1512, 1471, 1440,

1303, 1249, 1178, 1112, 1035, 960, 827, 767, 750.; M.p. 118-120 °C.; HRMS (DART+):

290.09429 [M+H]+ (calc’d 290.09478 for C16H17ClNO2). The ee was measured by HPLC:

Chiralpak AD-H column, flow 0.5 mL/min, hexane/2-propanol = 90/10, tR = 24.2 min (major)

and 26.2 min (minor).; For (S)-enantiomer: [α]D20 = -1.9° (c = 0.205, CHCl3) ) for 96% ee; The

absolute configuration was assigned by analogy with compound 3.3a.

I. General procedure A for the enantioselective domino Rh/Pd catalysis


equiv) followed by [Rh(L5)Cl]2 (4.5 mg, 5 mol % [Rh]), Pd-XPhos-GI (3.0 mg, 2 mol %), aryl

acrylamide (0.2 mmol, 1 equiv), and the arylboronic acid (2.5 or 3 equiv). To the mixture was

156

added t-am-OH (2 mL) and MeOH (0.2 mL). The vial was sealed with a Teflon coated cap and

the mixture was vigorously stirred for 5 min at r.t. prior to heating at 110 °C for 18 h.

Subsequently, the mixture was cooled to r.t., filtered through a silica gel pad, and washed with

EtOAc. The filtrate was concentrated and purified using flash-column chromatography to afford

the dihydroquinolinone.

Products from the enantioselective domino Rh/Pd catalysis:

(S)-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3a

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using

phenylboronic acid (61 mg, 2.5 equiv): Purified by silica gel chromatography (0 to 30%

EtOAc:Hex) and isolated as white solids (39.7 mg, 89%). 1H NMR (500 MHz, CDCl3) δ 8.01 (s,

2H), 7.34 (t, J = 7.4 Hz, 4H), 7.30 – 7.25 (m, 5H), 7.21 (dd, J = 9.0, 7.6 Hz, 6H), 7.00 – 6.89 (m,

4H), 6.82 (d, J = 7.8 Hz, 2H), 4.30 (t, J = 7.5 Hz, 2H), 3.00 – 2.87 (m, 4H).; 13C NMR (126

MHz, CDCl3) δ 170.4, 141.5, 137.1, 129.1, 128.6, 128.2, 128.0, 127.4, 126.9, 123.5, 115.6, 42.2,

38.6.; The ee was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-

propanol = 90/10/, tR = 12.8 min (minor), 14.2 min (major); For (S)-enantiomer: [α]D20 = 60.4°

(c = 0.89, CHCl3) for 95% ee; Spectral data are in accordance with literature.55g The absolute

configuration was assigned by reference to literature.55g

(S)-4-(m-tolyl)-3,4-dihydroquinolin-2(1H)-one 3.3ab

157

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using m-

tolylboronic acid (82 mg, 3 equiv): Purified by silica gel chromatography (10% EtOAc:Hex) and

isolated as a white solid (42.2 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.31 – 7.23

(m, 1H), 7.23 – 7.17 (m, 1H), 7.01 – 6.91 (m, 2H), 6.87 (dd, J = 7.8, 1.1 Hz, 1H), 6.85 – 6.77 (m,

2H), 6.76 – 6.70 (m, 1H), 4.27 (dd, J = 8.3, 6.8 Hz, 1H), 3.78 (s, 2H), 2.93 (dd, J = 7.4, 2.8 Hz,

2H).; 13C NMR (101 MHz, CDCl3) δ 170.9, 160.1, 143.2, 137.2, 130.1, 128.5, 128.2, 126.7,

123.5, 120.3, 115.8, 114.1, 112.4, 55.3, 42.2, 38.5.; IR (NaCl, CHCl3, cm-1) 3206, 3060, 2979,

2862, 1679, 1674, 1593, 1486, 1377, 752.; M.p. 122.1-123.1 oC.; HRMS (DART+): 238.12294

[M+H]+ (calc’d 238.12319 for C16H16NO). The ee was measured by HPLC: Chiralpak AD-H

column, flow 1.0 mL/min, hexane/2-propanol = 90/10, tR = 8.4 min (minor), 9.1 min (major);

For (S)-enantiomer: [α]D20 = 34.0° (c = 1.2, CHCl3) for 94% ee; The absolute configuration was

assigned by analogy with compound 3.3a.

(S)-4-(p-tolyl)-3,4-dihydroquinolin-2(1H)-one 3.3ac

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using p-

tolylboronic acid (82 mg, 3 equiv): Purified by silica gel chromatography (10% EtOAc:Hex) and

isolated as a white solid (41.7 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 7.26 – 7.13

(m, 4H), 7.02 (dd, J = 7.1, 2.0 Hz, 1H), 6.97 – 6.88 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 4.62 – 4.53

(m, 1H), 2.90 (d, J = 2.7 Hz, 1H), 2.89 – 2.87 (m, 1H), 2.39 (s, 3H).; 13C NMR (101 MHz,

CDCl3) δ 171.4, 139.3, 137.6, 136.2, 130.9, 128.1, 128.0, 127.5, 127.2, 126.83, 126.79, 123.6,

115.8, 38.0, 37.6, 19.7.; IR (NaCl, CHCl3, cm-1)3102, 2354, 1680, 1592, 1486, 1379, 1220, 772.;

M.p. 178.8-179.7 oC.; HRMS (DART+): 238.12333 [M+H]+ (calc’d 238.12319 for C16H16NO).;

The ee was measured by HPLC: Chiralpak AD-H column, flow 1.0 mL/min, hexane/2-propanol

= 95/5, tR = 13.8 min (minor), 15.3 min (major).; For (S)-enantiomer: [α]D20 = 52.5° (c = 0.9,

CHCl3) for 98% ee; The absolute configuration was assigned by analogy with compound 3.3a.

158

(S)-4-(4-(tert-butyl)phenyl)-3,4-dihydroquinolin-2(1H)-one 3.3ad

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using (4-(tert-

butyl)phenyl)boronic acid (107 mg, 3 equiv): Purified by silica gel chromatography (10%

EtOAc:Hex) and isolated as a white solid (42.4 mg, 76%). 1H NMR (500 MHz, CDCl3) δ 8.58

(s, 1H), 7.38 – 7.29 (m, 2H), 7.23 – 7.14 (m, 1H), 7.14 – 7.09 (m, 2H), 7.00 – 6.93 (m, 2H), 6.88

– 6.83 (m, 1H), 4.28 (dd, J = 8.1, 6.5 Hz, 1H), 3.02 – 2.83 (m, 2H), 1.31 (s, 9H).; 13C NMR (126

MHz, CDCl3) δ 171.0, 150.2, 138.4, 137.1, 128.6, 128.1, 127.5, 127.1, 125.9, 123.5, 115.7, 41.7,

38.5, 34.6, 31.5.; IR (NaCl, CHCl3, cm-1) 3207, 3058, 2963, 2927, 2903, 2867, 1680, 1593,

1486, 1380, 1364, 772, 753.; M.p. 174.4-175.3 oC.; HRMS (DART+): 280.16910 [M+H]+

(calc’d 280.17014 for C19H22NO).; The ee was measured by HPLC: Chiralpak AD-H column,

flow 1.0 mL/min, hexane/2-propanol = 90/10, tR = 6.5 min (minor), 7.1 min (major); For (S)-

enantiomer: [α]D20 = 43.5° (c = 2.1 CHCl3) for 96% ee; The absolute configuration was assigned

by analogy with compound 3.3a.

(S)-4-(3-methoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 3ae

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using (3-

methoxyphenyl)boronic acid (91 mg, 3 equiv): Purified by silica gel chromatography (10%


159

(s, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.20 (dddd, J = 7.6, 7.0, 2.0, 0.6 Hz, 1H), 7.00 – 6.90 (m, 2H),

6.83 – 6.76 (m, 3H), 4.29 – 4.24 (m, 1H), 3.77 (s, 3H), 2.98 – 2.86 (m, 2H).; 13C NMR (126

MHz, CDCl3) δ 170.2, 160.1, 143.1, 137.0, 130.1, 128.6, 128.2, 126.8, 123.5, 120.3, 115.6,

114.1, 112.4, 55.3, 42.2, 31.7.; IR (NaCl, CHCl3, cm-1) 2956, 2923, 2853, 1678, 1674, 1593,

1485, 1377, 1359, 1264, 1219, 1151, 771, 754.; M.p. 159.2-159.9 oC.; HRMS (DART+):

254.11852 [M+H]+ (calc’d 254.11810 for C16H16NO2).; The ee was measured by HPLC:

Chiralpak AD-H column, flow 1.0 mL/min, hexane/2-propanol = 95/5, tR = 25.1 min (minor),

28.3 min (major).; For (S)-enantiomer: [α]D20 = 21.2° (c = 1.4, CHCl3) for 92% ee; The absolute

configuration was assigned by analogy with compound 3.3a

(S)-4-(4-methoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 3af


methoxyphenyl)boronic acid (91 mg, 3 equiv): Purified by silica gel chromatography (10%


(s, 1H), 7.20 (td, J = 7.5, 1.8 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.01 – 6.90 (m, 2H), 6.88 – 6.84

(m, 3H), 4.25 (dd, J = 8.4, 6.5 Hz, 1H), 3.79 (s, 3H), 2.91 (dd, J = 7.5, 3.9 Hz, 2H).; 13C NMR

(101 MHz, CDCl3) δ 171.0, 158.8, 137.13, 137.11, 133.6, 133.5, 128.9, 128.46, 128.45, 128.1,

127.3, 127.2, 123.5, 115.81, 115.76, 114.4, 55.4, 41.4, 38.7.; IR (NaCl, CHCl3, cm-1) 3208,

3033, 2975, 2908 1679, 1610, 1593, 1511, 1486, 1377, 1304, 1249, 1177, 1034, 770, 754.; M.p.:

134.9-135.6 oC.; HRMS (DART+): 254.11911 [M+H]+ (calc’d 254.11810 for C16H16NO2).; The

ee was measured by HPLC: Chiralpak AD-H column, flow 1.0 mL/min, hexane/2-propanol =

95/5, tR = 23.4 min (minor), 30.9 min (major).; For (S)-enantiomer: [α]D20 = 31.9° (c = 0.97,

CHCl3) for 96% ee; The absolute configuration was assigned by analogy with compound 3.3a

160

(S)-4-(3,4-dimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 3ag

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using (3,4-

dimethoxyphenyl)boronic acid (109 mg, 3 equiv): Purified by silica gel chromatography (30 to

50% EtOAc:Hex) and isolated as white solids (45.5 mg, 80%). 1H NMR (400 MHz, CDCl3) δ

7.81 (s, 1H), 7.24 – 7.14 (m, 1H), 7.03 – 6.89 (m, 2H), 6.82 (dd, J = 11.3, 8.3 Hz, 2H), 6.73 (dd,

J = 6.0, 2.0 Hz, 2H), 4.25 (dd, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.98 – 2.82 (m, 2H).;

M.p. 155-156 °C.; 13C NMR (100 MHz, CDCl3) δ 171.2, 149.4, 148.3, 137.11, 134.0, 128.4,

128.1, 127.1, 123.5, 120.1, 115.8, 111.6, 111.1, 56.04, 56.01, 41.8, 38.7.; IR (powder, cm-1)

2939, 1674, 1613, 1467, 1385, 1347, 1293, 1254, 1163, 1058, 1030, 1011, 814, 755, 698.;

HRMS (DART+): 284.12881 [M+H]+ (calc’d 284.12867 for C17H18NO3). The ee was measured

by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 60/40/, tR = 7.4 min

(minor), 8.1 min (major); For (S)-enantiomer: [α]D20 = 40.0° (c = 0.24, CHCl3) for 95% ee; The

absolute configuration was assigned by analogy with compound 3.3a

(S)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 3ah

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using (3,4,5-

trimethoxyphenyl)boronic acid (127 mg, 3 equiv): Purified by silica gel chromatography (30 to

60% EtOAc:Hex) and isolated as white solids (48.9 mg, 78%). 1H NMR (500 MHz, CD3OD) δ

7.25 – 7.19 (m, 1H), 7.04 – 6.97 (m, 2H), 6.95 (d, J = 7.5 Hz, 1H), 6.50 (s, 2H), 4.29 (t, J = 6.8

161

Hz, 1H), 3.76 (s, 6H), 3.74 (s, 3H), 2.94 – 2.79 (m, 2H).; 13C NMR (126 MHz, CD3OD) δ 172.9,

154.7, 139.7, 138.8, 138.1, 129.5, 129.1, 128.1, 124.4, 116.9, 106.1, 61.1, 56.5, 43.3, 39.4.; IR

(powder, cm-1) 2973, 1678, 1587, 1509, 1486, 1461, 1431, 1392, 1369, 1325, 1247, 1182, 1123,

1055, 1033, 1004, 933, 827, 755, 695.; M.p. 194-196 °C.; HRMS (DART+): 314.13909 [M+H]+

(calc’d 314.13923 for C18H20NO4).; The ee was measured by HPLC: Chiralpak AD-H column,

flow 0.5 mL/min, hexane/2-propanol = 90/10, tR = 45.2 min (major), 48.2 min (minor).; For (S)-

enantiomer: [α]D20 = 28.0° (c = 0.25, CHCl3) ) for 94% ee; The absolute configuration was

assigned by analogy with compound 3.3a

(S)-4-([1,1'-biphenyl]-4-yl)-3,4-dihydroquinolin-2(1H)-one 3ai

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using [1,1'-

biphenyl]-4-ylboronic acid (119 mg, 3 equiv): Purified by silica gel chromatography (10%


(s, 1H), 7.59 – 7.52 (m, 2H), 7.45 – 7.40 (m, 2H), 7.36 – 7.32 (m, 1H), 7.28 – 7.25 (m, 2H), 7.24

– 7.19 (m, 1H), 7.01 – 6.96 (m, 3H), 6.91 – 6.87 (m, 1H), 4.35 (dd, J = 8.3, 6.4 Hz, 1H), 2.98

(dd, J = 7.4, 4.9 Hz, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.4, 140.8, 140.6, 140.4, 137.1,

128.9, 128.7, 128.3, 128.2, 127.8, 127.5, 127.2, 126.8, 123.6, 115.7, 41.9, 38.6.; IR (NaCl,

CHCl3, cm-1) 3196, 3177, 3056, 3030, 2970, 2919, 2856, 2358, 1673, 1593, 1486, 1375, 839,

756, 696.; M.p.: 225.2-226.6 oC.; HRMS (DART+): 300.13815 [M+H]+ (calc’d 300.13884 for

C21H18NO).; The ee was measured by HPLC: Chiralpak AD-H column, flow 1.0 mL/min,

hexane/2-propanol = 90/10, tR = 10.9 min (minor), 14.1 min (major); For (S)-enantiomer: [α]D20

= 51.5° (c = 2.1, CHCl3) for 96% ee; The absolute configuration was assigned by analogy with

compound 3.3a

162

(S)-4-(naphthalen-2-yl)-3,4-dihydroquinolin-2(1H)-one 3aj

Prepared according to General Procedure A (0.2 mmol scale of 3.1a, 36.3 mg) using 2-

naphthylboronic acid (103 mg, 3 equiv): Purified by silica gel chromatography (0 to 20%

EtOAc:Hex) and isolated as white solids (40.2 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.88 –

7.80 (m, 2H), 7.80 – 7.75 (m, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.51 – 7.44 (m, 2H), 7.35 (dd, J =

8.6, 1.7 Hz, 1H), 7.25 – 7.20 (m, 1H), 7.00 – 6.92 (m, 2H), 6.83 (d, J = 7.9 Hz, 1H), 4.53 – 4.42

(m, 1H), 3.12 – 2.92 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.5, 138.8, 137.2, 133.7, 132.8,

128.9, 128.7, 128.2, 127.9, 127.8, 126.84, 126.76, 126.5, 126.1, 125.9, 123.6, 115.7, 42.4, 38.5.;

IR (powder, cm-1) 3206, 3070, 2981, 2922, 1672, 1589, 1486, 1366, 1250, 1154, 953, 905, 869,

825, 766, 748, 658.; M.p. 174-176 °C.; HRMS (DART+): 274.12351 [M+H]+ (calc’d 274.12319

for C19H16NO).; The ee was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min,

hexane/2-propanol = 80/20, tR = 10.2 min (minor), 14.2 min (major).; For (S)-enantiomer: [α]D20


compound 3.3a

(S)-4-(4-(methylthio)phenyl)-3,4-dihydroquinolin-2(1H)-one 3ak


(methylthio)phenyl boronic acid (101 mg, 3 equiv): Purified by silica gel chromatography (0 to

20% EtOAc:Hex) and isolated as white solids (38.8 mg, 72%). 1H NMR (500 MHz, CDCl3) δ

163

8.24 (s, 1H), 7.24 – 7.19 (m, 3H), 7.13 – 7.10 (m, 2H), 6.97 (td, J = 7.4, 1.2 Hz, 1H), 6.93 (dd, J

= 7.6, 0.6 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 4.26 (dd, J = 8.3, 6.5 Hz, 1H), 2.91 (qd, J = 16.2, 7.4


128.2, 127.3, 126.7, 123.5, 115.8, 41.7, 38.5, 16.03, 16.01.; IR (powder, cm-1) 3014, 2922, 1667,

1586, 1508, 1486, 1369, 1277, 1248, 1168, 1089, 1034, 941, 900, 820, 767, 753, 713.; M.p. 142-

144 °C.; HRMS (DART+): 270.09605 [M+H]+ (calc’d 270.09526 for C16H16NOS).; The ee was


= 17.3 min (minor) 23.2 min (major).; For (S)-enantiomer: [α]D20 = 62.6° (c = 0.335, CHCl3) for

96% ee; The absolute configuration was assigned by analogy with compound 3.3a

(S)-4-(4-acetylphenyl)-3,4-dihydroquinolin-2(1H)-one 3al


acetylphenyl boronic acid (98 mg, 3 equiv): Purified by silica gel chromatography (30 to 50%


1H), 7.92 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.2

Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 4.37 (dd, J = 7.2 Hz, 1H), 2.95 (qd, J

= 16.2, 7.2 Hz, 2H), 2.59 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 197.7, 170.3, 147.1, 137.2,

136.4, 129.2, 128.53, 128.49, 128.2, 125.8, 123.7, 116.0, 42.1, 38.3, 26.8.; IR (powder, cm-1)

2967, 2934, 2857, 1675, 1587, 1482, 1361, 1267, 1052, 1035, 1002, 842, 759.; M.p. 177-178

°C.; HRMS (DART+): 266.11813 [M+H]+ (calc’d 266.11810 for C17H16NO2).; The ee was


= 8.8 min (minor), 10.4 min (major).; For (S)-enantiomer: [α]D20 = 67.6° (c = 0.275, CHCl3) for

92% ee; The absolute configuration was assigned by analogy with compound 3.3a

164

(S)-4-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one 3am


fluorophenyl boronic acid (84 mg, 3 equiv): Purified by silica gel chromatography (0 to 25%


1H), 7.22 (td, J = 7.7, 1.5 Hz, 1H), 7.18 – 7.12 (m, 2H), 7.05 – 6.96 (m, 3H), 6.92 (dd, J = 7.6,

0.6 Hz, 1H), 6.83 (dd, J = 7.9, 1.2 Hz, 1H), 4.29 (dd, J = 8.2, 6.4 Hz, 1H), 2.91 (qd, J = 16.2, 7.3

Hz, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.2 (s), 162.1 (d, J = 245.9 Hz), 137.2 (d, J = 3.4

Hz), 137.0 (s), 129.5 (s), 129.4 (s), 128.4 (d, J = 21.9 Hz), 126.7 (s), 123.6 (s), 115.9 (d, J = 21.4

Hz), 115.8 (s), 41.5 (s), 38.7 (s).; 19F NMR (376 MHz, CDCl3) δ -115.45.; IR (powder, cm-1)

3195, 3055, 2981, 2895, 1669, 1593, 1505, 1488, 1384, 1322, 1216, 1154, 1096, 1055, 1013,

979, 824, 758, 734, 700, 637.; M.p. 191-192 °C.; HRMS (DART+): 242.09798 [M+H]+ (calc’d

242.09812 for C15H13FNO).; The ee was measured by HPLC: Chiralpak AD-H column, flow 0.8

mL/min, hexane/2-propanol = 90/10, tR = 13.0 min (minor), 15.7 min (major).; For (S)-

enantiomer: [α]D20 = 39.1° (c = 0.245, CHCl3) for 94% ee; The absolute configuration was

assigned by analogy with compound 3.3a

(S)-4-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one 3an


(trifluoromethyl)phenyl)boronic acid (114 mg, 3 equiv): Purified by silica gel chromatography

(10% EtOAc:Hex) and isolated as a white solid (26.8 mg, 46%). 1H NMR (400 MHz, CDCl3) δ

165

8.96 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.50 – 7.40 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.27 – 7.20

(m, 1H), 6.99 (td, J = 7.5, 1.2 Hz, 1H), 6.94 – 6.85 (m, 2H), 4.48 – 4.21 (m, 1H), 2.95 (qd, J =

16.2, 7.3 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.4, 142.7, 137.2, 131.6, 131.3, 129.6,

128.6, 128.4, 125.7, 124.8 (q, J = 3.8 Hz), 124.4 (q, J = 3.8 Hz), 123.7, 122.8, 116.1, 42.1, 38.5.;

19F NMR (377 MHz, CDCl3) δ -62.58.; M.p.: 125-126 oC.; IR (NaCl, CHCl3, cm-1) 3211, 3077,

3063, 2978, 2921, 2856, 1680, 1593, 1486, 1377 1330, 1166, 1024, 1075, 755, 702.; HRMS

(DART+): 292.09451 [M+H]+ (calc’d 292.09492 for C16H13F3NO). The ee was measured by


(minor), 16.5 min (major). For (S)-enantiomer: [α]D20 = 26.4° (c = 1.3, CHCl3) for 82% ee; The

absolute configuration was assigned by analogy with compound 3.3a

(S)-4-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one 3ao


(trifluoromethyl)phenyl)boronic acid (114 mg, 3 equiv): Purified by silica gel chromatography

(10% EtOAc:Hex) and isolated as a white solid (47.7 mg, 82%). 1H NMR (400 MHz, CDCl3) δ

8.82 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 – 7.17 (m, 1H), 6.99 (td, J =

7.5, 1.3 Hz, 1H), 6.95 – 6.87 (m, 2H), 4.37 (t, J = 7.1 Hz, 1H), 2.95 (qd, J = 16.2, 7.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.3, 145.8, 137.2, 129.6, 128.6, 128.5, 128.3, 126.1 (q, J = 3.7

Hz), 125.7, 123.7, 116.1, 42.0, 38.4.; 19F NMR (377 MHz, CDCl3) δ -62.55.; IR (NaCl, CHCl3,

cm-1) 3207, 306, 2964, 2924, 2854, 1681, 1593, 1489, 1419, 1379, 1246, 1165, 1122, 1068,

1018, 840, 754.; M.p.: 150-151 oC.; HRMS (DART+): 292.09443 [M+H]+ (calc’d 292.09492 for

C16H13F3NO). The ee was measured by HPLC: Chiralpak AD-H column, flow 0.5 mL/min,

hexane/2-propanol = 90/10, tR = 48.4 min (minor), 51.1 min (major); For (S)-enantiomer: [α]D20


compound 3.3a

166

(S)-7-(tert-butyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3b

Prepared according to General Procedure A (0.2 mmol scale of 3.1b, 47.4 mg) using



1H), 7.34 (t, J = 7.3 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.23 – 7.16 (m, 2H), 6.98 (dd, J = 8.0, 1.8

Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 4.26 (dd, J = 7.6 Hz, 1H), 3.06 – 2.75

(m, 2H), 1.30 (s, 9H).; 13C NMR (100 MHz, CDCl3) δ 171.0, 151.6, 141.8, 136.9, 129.0, 128.1,

8.0, 127.3, 124.0, 120.5, 112.9, 41.9, 38.7, 34.7, 31.4.; IR (powder, cm-1) 2967, 2901, 1675,

1621, 1579, 1491, 1376, 1233 1171, 1078, 1033, 975, 883, 814, 757, 698.; M.p. 167-169 °C.;

HRMS (DART+): 280.17051 [M+H]+ (calc’d 280.17014 for C19H22NO).; The ee was measured

by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 90/10, tR = 10.6 min

(minor), 12.4 min (major).; For (S)-enantiomer: [α]D20 = 41.6° (c = 0.37, CHCl3) for 96% ee; The


(S)-8-phenyl-7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one 3.3c

Prepared according to General Procedure A (0.2 mmol scale of 3.1c, 45.1 mg) using



1H), 7.34 (t, J = 7.3 Hz, 2H), 7.27 (t, J = 7.2 Hz, 2H), 7.18 (d, J = 7.0 Hz, 2H), 6.38 (d, J = 11.8

Hz, 2H), 5.91 (d, J = 0.6 Hz, 2H), 4.24 – 4.12 (m, 1H), 2.96 – 2.80 (m, 2H), 1.56 (s, 6H).; 13C

NMR (100 MHz, CDCl3) δ 170.9, 147.3, 143.8, 141.8, 131.5, 129.1, 127.9, 127.4, 119.3, 108.6,

167

101.4, 98.0, 42.1, 38.6.; IR (powder, cm-1) 2976, 1667, 1634, 1499, 1483, 1380, 1229, 1207,

1160, 1033, 944, 836, 821, 770, 725, 703.; M.p.: 196-197 °C.; HRMS (DART+): 268.09714

[M+H]+ (calc’d 268.09737 for C16H14NO3).; The ee was measured by HPLC: Chiralpak AD-H

column, flow 0.8 mL/min, hexane/2-propanol = 60/40, tR = 9.1 min (minor), 9.6 min (major).;



(S)-7,8-dimethoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3d

Prepared according to General Procedure A (0.2 mmol scale of 3.1d, 48.3 mg) using


EtOAc:Hex) and isolated as white solids (42.6 mg, 75%). 1H NMR (500 MHz, CD3OD) δ 7.33 –

7.26 (m, 2H), 7.25 – 7.20 (m, 1H), 7.18 – 7.13 (m, 2H), 6.64 (s, 2H), 4.27 (t, J = 6.8 Hz, 1H),

3.86 (s, 3H), 3.83 (s, 3H), 2.85 (qd, J = 16.1, 6.8 Hz, 2H).; 13C NMR (126 MHz, CD3OD) δ

172.5, 153.2, 143.7, 137.1, 132.1, 129.8, 128.7, 128.1, 124.2, 121.4, 108.0, 61.2, 56.4, 42.7,

39.7.; M.p. 134-135 °C.; IR (powder, cm-1) 2939, 1674, 1613, 1467, 1385, 1347, 1293, 1254,

1163, 1057, 1031, 1011, 814, 775, 755, 698.; HRMS (DART+): 284.12895 [M+H]+ (calc’d

284.12867 for C17H18NO3).; The ee was measured by HPLC: Chiralpak AS column, flow 0.8

mL/min, hexane/2-propanol = 60/40, tR = 28.7 min (minor), 37.2 min (major).; For (S)-

enantiomer: [α]D20 = 24.0° (c = 0.25, CHCl3) for 92% ee; The absolute configuration was


168

(S)-7-fluoro-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3e

Prepared according to General Procedure A (0.2 mmol scale of 3.1e, 39.9 mg) using



1H), 7.38 – 7.32 (m, 2H), 7.31 – 7.26 (m, 1H), 7.20 (dd, J = 5.1, 3.4 Hz, 2H), 6.86 (dd, J = 8.4,

5.9 Hz, 1H), 6.69 (dd, J = 9.3, 2.5 Hz, 1H), 6.65 (td, J = 8.4, 2.5 Hz, 1H), 4.27 (t, J = 7.5 Hz,

1H), 3.09 – 2.81 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 171.7 (s), 162.4 (d, J = 245.5 Hz),

141.4 (s), 138.6 (d, J = 10.6 Hz), 129.7 (d, J = 9.3 Hz), 129.1 (s), 127.8 (s), 127.5 (s), 122.4 (d, J

= 3.2 Hz), 109.9 (d, J = 21.4 Hz), 103.4 (d, J = 25.5 Hz), 41.5 (s), 38.5 (s).; 19F NMR (564 MHz,

CDCl3) δ -113.93 (dd, J = 15.1, 8.4 Hz).; IR (powder, cm-1) 3185, 3069, 2973, 1683, 1617, 1603,

1508, 1497, 1265, 1351, 1324, 1261, 1182, 1156, 1107, 1072, 977, 909, 898, 831, 768, 745,

698.; M.p. 174-175 °C.; HRMS (DART+): 242.09852 [M+H]+ (calc’d 242.09812 for

C15H13FNO).; ).; The ee was measured by HPLC: Chiralpak OD-H column, flow 0.8 mL/min,

hexane/2-propanol = 90/10, tR = 17.9 min (major), 24.4 min (minor).; For (S)-enantiomer: [α]D20


compound 3.3a.

(S)-6-fluoro-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3f

Prepared according to General Procedure A (0.2 mmol scale of 3.1f, 39.9 mg) using



1H), 7.36 (tt, J = 8.3, 1.6 Hz, 2H), 7.32 – 7.28 (m, 1H), 7.22 – 7.18 (m, 2H), 6.61 (dd, J = 9.0,

169

2.6 Hz, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.00 – 2.81 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.9

(s), 159.0 (d, J = 242.3 Hz), 140.8 (s), 133.4 (s), 129.2 (s), 128.8 (d, J = 7.2 Hz), 127.9 (s), 127.7

(s), 116.9 (s), 115.4 (d, J = 23.8 Hz), 114.8 (d, J = 23.0 Hz), 42.3 (s), 38.1 (s).; 19F NMR (376

MHz, CDCl3) δ -119.35.; IR (powder, cm-1) 2972, 1686, 1492, 1371, 1253, 1209, 1143, 1110,

1055, 1033, 981, 915, 869, 830, 762, 707, 696.; M.p. 155-157 °C.; HRMS (DART+): 242.09878

[M+H]+ (calc’d 242.09812 for C15H13FNO).; The ee was measured by HPLC: Chiralpak AD-H

column, flow 0.8 mL/min, hexane/2-propanol = 95/5, tR = 20. 5min (minor), 22.3 min (major).;



(S)-4-phenyl-7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one 3.3g

Prepared according to General Procedure A (0.2 mmol scale of 3.1g, 49.9 mg) using


EtOAc:Hex) and isolated as off white solids (54.3 mg, 93%). 1H NMR (500 MHz, CDCl3) δ

9.45 (s, 1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.28 (m, 1H), 7.23 – 7.17 (m, 3H), 7.14 (s, 1H), 7.03 (d,

J = 8.0 Hz, 1H), 4.35 (t, J = 7.6 Hz, 1H), 3.06 – 2.90 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ

170.9 (s), 140.4 (s), 137.6 (s), 130.50 (q, J = 32.8 Hz), 130.48 (d, J = 1.2 Hz), 129.1 (s), 128.9

(s), 127.7 (s), 127.6 (s), 123.7 (q, J = 272.3 Hz), 120.0 (q, J = 3.8 Hz), 112.6 (q, J = 3.6 Hz), 41.9

(s), 37.9 (s).; 19F NMR (282 MHz, CDCl3) δ -62.72.; IR (powder, cm-1) 3101, 3047, 2993, 2883,

1685, 1626, 1590, 1485, 1404, 1370, 1334, 1236, 1168, 1101, 1076, 889, 819, 769, 699.; M.p.

152-153 °C.; HRMS (DART+): 292.09527 [M+H]+ (calc’d 292.09492 for C16H13F3NO).; The ee

was measured by HPLC: Chiralpak AS column, flow 0.8 mL/min, hexane/2-propanol = 70/30, tR

= 19.8 min (minor), 25.2 min (major).; For (S)-enantiomer: [α]D20 = 66.9° (c = 0.245, CHCl3) for

95% ee; The absolute configuration was assigned by analogy with compound 3.3a.

170

(S)-7-phenyl-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one 3.3ha

Prepared according to General Procedure A (0.2 mmol scale of 3.1h, 37.5 mg) using

phenylboronic acid (73 mg, 3 equiv) and [Rh(L5)Cl]2 (7.2 mg, 8 mol % [Rh]): Purified by silica

gel chromatography (0 to 25% EtOAc:Hex) and isolated as white solids (30.9 mg, 67%). 1H

NMR (500 MHz, CDCl3) δ 8.62 (s, 2H), 7.37 – 7.32 (m, 4H), 7.29 (dt, J = 4.6, 1.9 Hz, 2H), 7.27

– 7.24 (m, 5H), 7.14 (dd, J = 5.3, 0.5 Hz, 2H), 6.70 (d, J = 5.3 Hz, 2H), 4.39 (dd, J = 9.0, 6.8 Hz,

2H), 3.03 (dd, J = 16.2, 6.7 Hz, 2H), 2.91 (dd, J = 16.2, 9.0 Hz, 2H).; 13C NMR (126 MHz,

CDCl3) δ 170.4, 142.2, 136.0, 129.1, 127.7, 127.4, 124.7, 120.3, 117.8, 40.2, 39.3.; IR (NaCl,

CDCl3, cm-1) 3238, 3109, 1678, 1674, 1651, 1573, 1494, 1454, 1433, 1361, 1232, 1174, 1159,

1109, 1076, 1051, 1030, 949, 902, 858, 819, 763, 700.; M.p. 170-172 °C.; HRMS (DART+):

230.06417 [M+H]+ (calc’d 230.06396 for C13H12NOS).; The ee was measured by HPLC:

Chiralpak OD-H column, flow 0.8 mL/min, hexane/2-propanol = 90/10, tR = 16.6 min (major),

18.3 min (minor).; For (S)-enantiomer: [α]D20 = 3.7° (c = 0.265, CHCl3) for 72% ee; The absolute

configuration was assigned by analogy with compound 3.3a.

(S)-7-(4-methoxyphenyl)-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one 3.3hb

Prepared according to General Procedure A (0.2 mmol scale of 3.1h, 37.5 mg) using 4-

methoxyphenylboronic acid (91 mg, 3 equiv) and [Rh(L5)Cl]2 (7.2 mg, 8 mol % [Rh]): Purified

by silica gel chromatography (0 to 30% EtOAc:Hex) and isolated as white solids (42.3 mg,

82%). 1H NMR (500 MHz, CD3OD) δ 7.23 (dd, J = 5.3, 0.7 Hz, 1H), 7.17 – 7.13 (m, 2H), 6.90

– 6.83 (m, 2H), 6.74 (d, J = 5.3 Hz, 1H), 4.40 – 4.27 (m, 1H), 3.77 (s, 3H), 2.93 (dd, J = 16.1,

171

6.8 Hz, 1H), 2.78 (dd, J = 16.1, 8.5 Hz, 1H).; 13C NMR (126 MHz, CD3OD) δ 160.4, 137.4,

135.9, 129.3, 125.5, 122.0, 118.9, 115.2, 55.7, 39.3.; IR (powder, cm-1) 2398, 1675, 1635, 1508,

1457, 1424, 1352, 1304, 1256, 1174, 1109, 1032, 946, 882, 834, 813, 773, 735, 725, 709.; M.p.

145-147 °C.; HRMS (DART+): 260.07467 [M+H]+ (calc’d 260.07452 for C14H14NO2S).; The ee

was measured by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol =

85/15, tR = 12.2 min (major), 13.0 min (major).; For (S)-enantiomer: [α]D20 = 10.1° (c = 0.275,


(S)-5-methyl-4-phenyl-3,4-dihydro-1H-pyrido[3,2-b]indol-2(5H)-one 3.3i

Prepared according to General Procedure A (0.2 mmol scale of 3.1i, 46.9 mg) using

phenylboronic acid (61 mg, 2.5 equiv) and [Rh(L5)Cl]2 (7.2 mg, 8 mol % [Rh]): Purified by

silica gel chromatography (0 to 20% EtOAc:Hex) and isolated as light yellow solids (21.9 mg,

40%). 1H NMR (500 MHz, CD3OD) δ 7.64 – 7.59 (m, 1H), 7.33 – 7.26 (m, 3H), 7.24 – 7.20 (m,

1H), 7.17 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.12 – 7.09 (m, 2H), 7.07 (ddd, J = 8.0, 7.1, 1.0 Hz,

1H), 4.58 (dd, J = 8.5, 2.0 Hz, 1H), 3.51 (s, J = 19.7 Hz, 3H), 3.35 (dd, J = 16.3, 8.5 Hz, 1H),

2.75 (dd, J = 16.3, 2.0 Hz, 1H).; 13C NMR (126 MHz, CD3OD) δ 169.5, 141.9, 136.0, 128.7,

126.9, 126.6, 123.0, 121.4, 118.8, 117.7, 116.5, 114.9, 108.9, 40.2, 36.0, 28.3.; IR (powder, cm-

1) 3197, 3138, 3019, 2925, 1661, 1508, 1490, 1469, 1368, 1332, 1252, 1205, 1169, 1152, 1057,

1032, 1015, 991, 941, 831, 770 754, 717, 698, 672.; M.p. 250 °C (decomposition).; HRMS

(DART+): 277.13420 [M+H]+ (calc’d 277.13409 for C18H17N2O).; The ee was measured by


(minor), 19.5 min (major).; For (S)-enantiomer: [α]D20 = 192.7° (c = 0.22, CHCl3) for 95% ee;

The absolute configuration was assigned by analogy with compound 3.3a.

172

(S)-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3j

Prepared according to General Procedure A (0.2 mmol scale of 3.1j, 39.1 mg) using

phenylboronic acid (62 mg, 2.5 equiv), [Pd(allyl)Cl]2 (1.1 mg, 3 mol %), and L7 (6.4 mg, 6 mol

%) was used instead of Pd-XPhos-GI: Purified by silica gel chromatography (0 to 10%

EtOAc:Hex) and isolated as white solids (24.3 mg, 51%). 1H NMR (500 MHz, CDCl3) δ 7.35 –

7.30 (m, 2H), 7.30 – 7.23 (m, 2H), 7.18 – 7.14 (m, 2H), 7.06 (dd, J = 8.1, 0.8 Hz, 1H), 7.00 (td, J

= 7.5, 1.1 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.31 – 4.17 (m, 1H), 3.40 (s, 3H), 3.06 – 2.87 (m,

2H).; 13C NMR (126 MHz, CDCl3) δ 169.4, 141.1, 140.4, 129.2, 128.9, 128.1, 127.93, 127.85,

127.2, 123.1, 115.0, 41.5, 38.9, 29.6.; IR (powder, cm-1) 3014, 2882, 1662, 1596, 1508, 1468,

1369, 1303, 1275, 1245, 1174, 1136, 1109, 1036, 927, 828, 759, 706, 679, 660.; M.p. 112-114

°C.; HRMS (DART+): 238.12321 [M+H]+ (calc’d 238.12319 for C16H16NO).; The ee was

measured by HPLC: Chiralpak OD-H column, flow 0.8 mL/min, hexane/2-propanol = 95/5, tR =

18.3 min (minor), 20.4 min (major).; For (S)-enantiomer: [α]D20 = 37.4° (c = 0.235, CHCl3) for

95% ee; The absolute configuration was assigned by analogy with compound 3.3a.

(S)-1-isopropyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3k

Prepared according to General Procedure A (0.2 mmol scale of 3.1k, 44.7 mg) using


%) was used instead of Pd-XPhos-GI: Purified by silica gel chromatography (10% EtOAc:Hex)

and isolated as a white solid (27.5 mg, 52%). 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.30 (m, 2H),

7.29 – 7.23 (m, 2H), 7.21 – 7.14 (m, 3H), 6.99 (td, J = 7.4, 1.2 Hz, 1H), 6.97 – 6.93 (m, 1H),

4.65 (p, J = 7.0 Hz, 1H), 4.15 (dd, J = 8.0, 5.4 Hz, 1H), 2.98 – 2.83 (m, 2H), 1.54 (d, J = 7.0 Hz,

173

3H), 1.48 (d, J = 7.0 Hz, 3H).; 13C NMR (126 MHz, CDCl3) δ 170.0, 140.7, 140.5, 131.2, 128.8,

128.2, 128.0, 127.6, 127.18, 123.2, 116.8, 48.9, 41.6, 40.3, 20.32, 20.30.; IR (NaCl, CHCl3, cm-

1) 2967, 2928, 1672, 1599, 1490, 1459, 1405, 1354, 1308, 1286, 1260, 1219, 1159, 772.; M.p.:

225.2-226.6 oC.; HRMS (DART+): 266.15413 [M+H]+ (calc’d 266.15449 for C18H20NO). The

ee was measured by HPLC: Chiralpak AD-H column, flow 0.5 mL/min, hexane/2-propanol =

95/5, tR = 14.4 min (minor), 15.2 min (major); For (S)-enantiomer: [α]D20 = 10.0° (c = 1.3,


(S)-1-benzyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one 3.3l

Prepared according to General Procedure A (0.2 mmol scale of 3.1l, 54.3 mg) using


%) was used instead of Pd-XPhos-GI: Purified by silica gel chromatography (0 to 10%

EtOAc:Hex) and isolated as white solids (27.5 mg, 44%). 1H NMR (500 MHz, CDCl3) δ 7.33 (t,

J = 7.5 Hz, 2H), 7.30 – 7.26 (m, 3H), 7.23 (t, J = 7.3 Hz, 1H), 7.20 – 7.11 (m, 5H), 7.00 – 6.93

(m, 3H), 5.31 (d, J = 16.1 Hz, 1H), 5.10 (d, J = 16.1 Hz, 1H), 4.35 – 4.23 (m, 1H), 3.12 (qd, J =

15.7, 6.9 Hz, 2H).; 13C NMR (126 MHz, CDCl3) δ 169.6, 141.1, 139.7, 137.0, 129.3, 129.0,

128.8, 128.5, 127.99, 127.97, 127.3, 127.2, 126.8, 123.3, 116.0, 46.1, 41.6, 39.0.; IR (powder,

cm-1) 2984, 2886, 1668, 1599, 1507, 1492, 1463, 1450, 1374, 1331, 1304, 1245, 1197, 1155,

1035, 992, 874, 829, 804, 754, 734, 697.; M.p. 97-99 °C.; HRMS (DART+): 314.15403 [M+H]+

(calc’d 314.15449 for C22H20NO).; The ee was measured by HPLC: Chiralpak AD-H column,

flow 0.8 mL/min, hexane/2-propanol = 85/15, tR = 10.8 min (major), 13.7 min (minor).; For (S)-

enantiomer: [α]D20 = -5.7° (c = 0.385, CHCl3) for 94% ee; The absolute configuration was


174

(S)-1,4-diphenyl-3,4-dihydroquinolin-2(1H)-one 3.3m

Prepared according to General Procedure A (0.2 mmol scale of 3.1m, 51.5 mg) using


EtOAc:Hex) and isolated as white solids (35.9 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.51 (t,

J = 7.5 Hz, 2H), 7.45 – 7.33 (m, 3H), 7.32 – 7.18 (m, 7H), 7.12 – 7.03 (m, 1H), 7.03 – 6.91 (m,

2H), 6.45 (d, J = 8.0 Hz, 1H), 4.40 (t, J = 6.9 Hz, 1H), 3.23 – 3.09 (m, 2H).; 13C NMR (100

MHz, CDCl3) δ 169.2, 141.6, 141.3, 138.5, 130.0, 129.10, 129.06, 128.7, 128.4, 128.3, 127.9,

127.7, 127.4, 123.4, 117.5, 41.9, 39.5.; IR (powder, cm-1) 3020, 2883, 1683, 1660, 1597, 1584,

1507, 1495, 1451, 1333, 1298, 1265, 1212, 1157, 1034, 926, 791, 746, 693.; M.p. 126-128 °C.;

HRMS (DART+): 300.13933 [M+H]+ (calc’d 300.13884 for C21H18NO).; The ee was measured

by HPLC: Chiralpak AD-H column, flow 0.8 mL/min, hexane/2-propanol = 80/20, tR = 9.6 min

(major), 12.4 min (minor).; For (S)-enantiomer: [α]D20 = 9.9° (c = 0.22, CHCl3) for 92% ee; The


III. Synthesis of arylacrylamides:

General procedure B: Horner-Wadsworth-Emmons olefination

To diethyl (2-amino-2-oxoethyl)phosphonate60 (1.17g, 6 mmol, 1.2 equiv) in a dry roundbottom

flask equipped with a stir bar was added THF (15 mL). The suspension was cooled to 0 °C and

KOtBu (673 mg, 1.2 equiv) was added at once. The mixture was stirred at 0 °C for 15 min

60 (a) Zhang, Z.; Yi, P.; Hongwen, H.; Tsi-yu, K. Synth. Commun. 1990, 20, 3563-3574. (b) Zhang, Z.; Yi, P.; Hongwen, H.; Tsi-yu, K. Synthesis 1991, 7, 539-542.

175

followed by the slow addition of the arylaldehyde (5 mmol, 1 equiv) in 10 mL of THF. The

mixture was allowed to warm to r.t. and stirred for 5 h. Upon reaction completion, the mixture

was quenched with water and concentrated. The residue was triturated in Et2O, the solids were

filtered, washed with water and dried in high vac to afford the acrylamide. Or, the residue was

extracted with EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated to

afford the acrylamide.

General procedure C: Amide acylation

To the acylchloride (5 mmol, 1 equiv) in a dry roundbottom flask equipped with a stir bar was

added CH2Cl2 (25 mL) and the mixture was cooled to 0 °C. Triethylamine (606 mg, 0.835 mL, 6

mmol, 1.2 equiv) was added dropwise followed by dropwise addition of the primary amine (1.2

equiv) at 0 °C. The mixture was allowed to warm to r.t. and stirred for 30 min. The reaction was

quenched with water and extracted with DCM, washed with water, brine, dried over MgSO4,

filtered, and concentrated. The crude residue was purified using flash column chromatography to

afford the acrylamide.

General procedure D: Heck coupling

To a dry roundbottom flask equipped with a stir bar was added the aryl iodide (5 mmol, 1 equiv)

and acrylamide (420 mg, 6 mmol, 1.2 equiv). The content was dissolved in MeCN (25 mL)

followed by Et3N (2.53 g, 3.48 mL, 25 mmol, 5 equiv). A stream of argon was bubbled through

the mixture for 15 min and Pd(OAc)2 (22 mg, 2 mol %) and phosphine (61 mg, 4 mol %) was

subsequently added. The flask was equipped with a reflux condenser and the mixture was heated

at 100 °C for 18 h. Upon completion, the mixture was cooled to r.t. and concentrated. The

176

residue was taken up in EtOAc and washed with water, brine, dried over MgSO4, filtered, and

concentrated. The crude residue was purified using flash column chromatography to afford the

acrylamide.

(E)-3-(2-chlorophenyl)acrylamide 3.1a

Prepared according to General Procedure C using NH3aq (5 equiv), no Et3N was used: Isolated as

white solids (835 mg, 92%). Spectroscopic data are in accordance with literature.61 1H NMR

(500 MHz, CDCl3) δ 8.00 (dd, J = 15.8, 0.4 Hz, 1H), 7.63 – 7.54 (m, 1H), 7.43 – 7.39 (m, 1H),

7.33 – 7.24 (m, 2H), 6.46 (d, J = 15.8 Hz, 1H), 5.66 (s, 2H).; 13C NMR (126 MHz, CDCl3) δ

167.3, 138.4, 135.0, 133.0, 130.9, 130.4, 127.8, 127.2, 122.6.; IR (powder, cm-1) 3342, 3158,

1665, 1607, 1469, 1438, 1396, 1277, 1243, 1136, 1047, 1033, 964, 950, 872, 853, 789, 750, 723,

675.;

(E)-3-(6-chlorobenzo[d][1,3]dioxol-5-yl)acrylamide 3.1c

Prepared according to General Procedure C using NH3aq (5 equiv), no Et3N was used: Isolated as

brown solids (1.13 g, quant). 1H NMR (400 MHz, CD3OD) δ 7.93 (d, J = 15.7 Hz, 1H), 7.22 (s,

1H), 6.96 (s, 1H), 6.53 (d, J = 15.7 Hz, 1H), 6.06 (s, 2H).; 13C NMR (101 MHz, CD3OD) δ

170.6, 151.3, 149.0, 138.1, 129.1, 127.4, 122.1, 110.9, 106.9, 103.9.; IR (powder, cm-1) 3381,

3205, 2978, 2864, 1659, 1598, 1504, 1477, 1410, 1339, 12295, 1256, 1239, 1123, 1035, 967,

61 Zhang, J.; Polishchuk, E. A.; Chen, J.; Ciufolini, M. A. J. Org. Chem. 2009, 74, 9140-9151.

177

931, 879. 849, 721, 707, 650, 629.; M.p. 208-210 °C.; HRMS (DART+): 226.02674 [M+H]+

(calc’d 226.02710 for C10H9ClNO3).

NH2

O

ClO

O

(E)-3-(2-chloro-3,4-dimethoxyphenyl)acrylamide 3.1d

Prepared according to General Procedure B: Isolated as white solids (1.21 g, quant). 1H NMR

(500 MHz, CD3OD) δ 7.91 (dt, J = 15.7, 0.5 Hz, 1H), 7.49 (dd, J = 8.8, 0.4 Hz, 1H), 7.03 (d, J =

8.7 Hz, 1H), 6.55 (d, J = 15.7 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H).; 13C NMR (126 MHz,

CD3OD) δ 170.7, 156.3, 146.9, 138.4, 130.2, 127.5, 124.0, 122.1, 112.3, 60.9, 56.7.; IR (powder,

cm-1) 2977, 2931, 2856, 1670, 1609, 1466, 1377, 1344, 1289, 1256, 1156, 1052, 1030, 1013,

809, 803, 777, 758, 698.; M.p. 194-195 °C.; HRMS (DART+): 242.05889 [M+H]+ (calc’d

242.05840 for C11H13ClNO3).

(E)-3-(2-chloro-4-fluorophenyl)acrylamide 3.1e

Prepared according to General Procedure D: 7.5 mmol reaction scale. Isolated as white solids

(1.31 g, 87%). 1H NMR (500 MHz, CD3OD) δ 7.90 (d, J = 15.8 Hz, 1H), 7.76 (dd, J = 8.8, 6.0

Hz, 1H), 7.28 (dd, J = 8.6, 2.6 Hz, 1H), 7.13 (tdd, J = 8.7, 2.6, 0.5 Hz, 1H), 6.62 (dd, J = 15.8,

0.5 Hz, 1H).; 13C NMR (126 MHz, CD3OD) δ 170.1 (s), 164.5 (d, J = 252.1 Hz), 137.1 (d, J =

1.2 Hz), 136.6 (d, J = 10.4 Hz), 130.8 (d, J = 3.7 Hz), 124.3 (s), 124.3 (s), 118.2 (d, J = 25.3 Hz),

115.9 (d, J = 21.9 Hz).; IR (powder, cm-1) 3345, 3161, 1662, 1637, 1590, 1573, 1480, 1394,

1286, 1230, 1178, 1138,1040, 1033, 966, 909, 869, 812, 727, 675.; 19F NMR (564 MHz, CDCl3)

δ -111.17 (dd, J = 14.7, 8.3 Hz).; M.p. 177-179 °C.; HRMS (ESI+): 200.02799 [M+H]+ (calc’d

200.02784 for C9H8ClFNO).

178

(E)-3-(2-chloro-5-fluorophenyl)acrylamide 3.1f

Prepared according to General Procedure B: 2.5 mmol reaction scale. Isolated as white solids

(476mg, 95%). 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J = 15.7, 1.5 Hz, 1H), 7.38 (dd, J = 8.8,

5.2 Hz, 1H), 7.29 (dd, J = 9.2, 3.0 Hz, 1H), 7.02 (ddd, J = 8.8, 7.6, 3.0 Hz, 1H), 6.43 (d, J = 15.7

Hz, 1H), 5.71 (s, 2H).; 13C NMR (126 MHz, CDCl3) δ 166.9 (s), 161.4 (d, J = 247.0 Hz), 137.6

(d, J = 2.2 Hz), 134.6 (d, J = 7.8 Hz), 131.6 (d, J = 8.2 Hz), 130.0 (d, J = 3.3 Hz), 123.6 (s),

118.0 (d, J = 23.1 Hz), 114.2 (d, J = 23.8 Hz).; IR (powder, cm-1) 3475, 3128, 1696, 1636, 1608,

1469, 1416, 1388, 1285, 1268, 1209, 1159, 1048, 1033, 963, 851, 807, 665.; 19F NMR (564

MHz, CDCl3) δ -114.74 (dd, J = 13.6, 8.3 Hz).; M.p. 158-159 °C.; HRMS (ESI+): 200.02840

[M+H]+ (calc’d 200.02784 for C9H8ClFNO).

(E)-3-(2-chloro-4-(trifluoromethyl)phenyl)acrylamide 3.1g

Prepared according to General Procedure D: Isolated as white solids (1.21 g, 96%). 1H NMR

(400 MHz, CDCl3) δ 7.99 (d, J = 15.8 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.2 Hz,

1H), 6.53 (d, J = 15.7 Hz, 1H), 5.99 – 5.67 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 166.7 (s),

137.1 (s), 136.6 (s), 135.3 (s), 128.2 (s), 127.4 (q, J = 3.9 Hz), 124.9 (s), 124.0 (q, J = 3.7 Hz),

123.2 (q, J = 272.6 Hz).; IR (powder, cm-1) 3381, 3184, 2973, 1655, 1605, 1393, 1320, 1172,

1129, 1080, 1057, 971, 899, 866, 829, 785, 716.; 19F NMR (377 MHz, CDCl3) δ -63.04.; M.p.

142-144 °C.; HRMS (DART+): 250.02448 [M+H]+ (calc’d 250.02465 for C10H8ClF3NO).

179

(E)-3-(3-chlorothiophen-2-yl)acrylamide 3.1h

Prepared according to General Procedure B: Isolated as yellow solids (895 mg, 95%). 1H NMR

(400 MHz, CDCl3) δ 7.82 (d, J = 15.5 Hz, 1H), 7.29 (d, J = 5.3 Hz, 1H), 6.95 (d, J = 5.4 Hz,

1H), 6.32 (d, J = 15.5 Hz, 1H), 5.96 – 5.58 (m, 2H).; 13C NMR (101 MHz, CDCl3) δ 167.3,

132.5, 131.8, 129.2, 128.8, 126.5, 120.0.; IR (powder, cm-1) 3355, 3161, 1658, 1609, 1598,

1431, 1379, 1347, 1284, 1218, 1160, 958, 948, 877, 860, 711.; M.p. 132-134 °C.; HRMS

(DART+): 187.99327 [M+H]+ (calc’d 187.99369 for C7H7ClNOS).

(E)-3-(3-chloro-1-methyl-1H-indol-2-yl)acrylamide 3.1i

Prepared according to General Procedure B: Isolated as yellow solids (1.06 g, 90%). 1H NMR

(500 MHz, CDCl3) δ 7.80 (d, J = 15.6 Hz, 1H), 7.62 (dt, J = 8.0, 0.8 Hz, 1H), 7.33 – 7.30 (m,

2H), 7.19 (ddd, J = 7.9, 5.0, 2.9 Hz, 1H), 7.03 (d, J = 15.6 Hz, 1H), 5.68 (s, 2H), 3.83 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ 167.7, 137.0, 129.4, 128.7, 125.8, 124.8, 121.7, 121.0, 119.0,

109.9, 108.1, 30.7.; IR (powder, cm-1) 3399, 3338, 3213, 3162, 1698, 1656, 1594, 1518, 1463,

1360, 1330, 1345, 1298, 1230, 1167, 966, 846, 789, 753 709.; M.p. 161-163 °C.; HRMS

(DART+): 235.06299 [M+H]+ (calc’d 235.06247 for C12H12ClN2O).

180

(E)-3-(2-chlorophenyl)-N-methylacrylamide 3.1j

Prepared according to General Procedure C using aqueous methylamine: Isolated as white solids

(929 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 15.7 Hz, 1H), 7.55 (dd, J = 7.4, 1.7

Hz, 1H), 7.39 (dd, J = 7.5, 1.4 Hz, 1H), 7.30 – 7.20 (m, 2H), 6.42 (d, J = 15.7 Hz, 1H), 5.90 (s,


130.3, 127.7, 127.1, 123.8, 26.7.; IR (powder, cm-1) 3280, 1650, 1617, 1563, 1470, 1439, 1408,

1350, 1275, 1350, 1275, 1231, 1163, 1073, 1037, 973, 737, 704, 678.; M.p. 127-129 °C.; HRMS

(DART+): 196.05247 [M+H]+ (calc’d 196.05292 for C10H11ClNO).

(E)-N-benzyl-3-(2-chlorophenyl)acrylamide 3.1l

Prepared according to General Procedure C using benzylamine: Isolated as white solids (1.20g,

89%). 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 15.7 Hz, 1H), 7.54 (dd, J = 7.6, 1.8 Hz, 1H),

7.42 – 7.37 (m, 1H), 7.37 – 7.31 (m, 4H), 7.31 – 7.20 (m, 3H), 6.43 (d, J = 15.7 Hz, 1H), 6.11 (s,


130.6, 130.3, 128.9, 128.1, 127.8, 127.7, 127.1, 123.5, 44.1.; IR (powder, cm-1) 3268, 3027,

1650, 1614, 1532, 1456, 1365, 1313, 1268, 1215, 1156, 1050, 1033, 1015, 971, 752, 738, 685.;

M.p. 150-155 °C.; HRMS (DART+): 272.08391 [M+H]+ (calc’d 272.08422 for C16H15ClNO).

181

(E)-3-(2-chlorophenyl)-N-phenylacrylamide 3.1m

Prepared according to General Procedure C using aniline: Isolated as white solids (1.22 g, 95%). 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 15.6 Hz, 1H), 7.68 – 7.57 (m, 3H), 7.49 (s, 1H), 7.42

(dd, J = 7.8, 1.5 Hz, 1H), 7.36 (dd, J = 10.8, 5.1 Hz, 2H), 7.30 (td, J = 7.6, 1.9 Hz, 1H), 7.26 (t, J

= 7.3 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 15.6 Hz, 1H).; 13C NMR (126 MHz, CDCl3)

δ 163.6, 138.4, 138.0, 135.1, 133.1, 130.8, 130.4, 129.2, 127.8, 127.1, 124.7, 123.9, 120.1.; IR

(powder, cm-1) 3082, 1657, 1621, 1594, 1544, 1486, 1441, 1346, 1244, 1155, 1033, 973, 860,

768, 737, 682.; M.p. 167-169 °C.; HRMS (DART+): 258.06801 [M+H]+ (calc’d 258.06857 for

C15H13ClNO).

182

Chapter 4 The Development of Multi-Metal-Catalyzed Multicomponent

Reactions: (MC)2R

183

4 The Development of Multi-Metal-Catalyzed Multicomponent Reactions: (MC)2R

The work described in this chapter was performed in collaboration with Dr. Lorenzo Sonaglia,

Jung Yun (Davie) Kim (MSc student), and undergraduate students Jason Stacey and Theodora

Bruun. The majority of the work was carried out by the author and contributions by others are

noted as such.

4.1 Introduction

Multicomponent reactions (MCR) assemble three or more reactants in a controlled and

convergent manner to afford a single product that retains the majority of atoms in the reactants.

Due to the broad scope that MCRs can achieve, these reactions are highly useful in combinatorial

chemistry. Libraries generated from MCRs can be assayed in high throughput screening to look

for desired biological properties. Thus, MCR remains a common and important tool used in drug

discovery, often employed to develop new leads. Notable examples include the Hanzsch pyridine

synthesis (Eqn 4.1), Biginelli reaction (Eqn 4.2), Strecker amino acid synthesis (Eqn 4.3), and

the Ugi reaction (Eqn 4.4).

O

EtO2C R OH2N NH2

ONH

R

NH

O

EtO2C+ + (4.2)

O

EtO2C+

O

HH

NH4OAc2

NH

EtO2C CO2Et [O]

N

EtO2C CO2Et(4.1)

R

O KCN

NH4Cl R CN

NH2

R CO2H

NH2H+

(4.3)

R3 NH2

R1 R2

O

R5 NC

R4 OH

ON

NHR1 R2

O

R5R4

O

R3

++++ (4.4)

Due to the sheer diversity of the products, the Ugi 4-component reaction has seen application in

total synthesis. Coupling the Ugi sequence with additional transformations has also been widely

184

studied. Examples include the Ugi/Smiles, Diels Alder, Heck, or Buchwald-Hartwig.62 A number

of MCRs were initially discovered over 150 years ago due to their simplicity of operation. More

recent advances include the boron mediated MCR such as the Petasis reaction.63 Particularly, the

advent of metal catalysis has created new chemical space for the development of MCRs.64

For example, Buchwald and coworkers developed a cross coupling of aryl halides with sodium

cyanate to access aryl cyanates, which formed carbamates in the presence of alcohols (Eqn

4.5).65 Senanakaye and coworkers also developed a Sonogashira/carboamination MCR based on

palladium catalysis (Eqn 4.6).66 The cross coupling between a bromoanilide and acetylene

occurred first, and the subsequent addition of an aryl halide promoted the carboamination to

furnish an indole.

Gold catalysis has also been reported for the multicomponent synthesis of furans from an

acetaldehyde, amine, and acetylene (Eqn 4.7).67 After the amine-acetaldehyde condensation,

gold catalyzed the alkyne addition to form a propargylamine. The subsequent gold-catalyzed

endo-dig cyclization of the carbonyl onto the alkyne furnished the furan.

62 For a review, see: Scheffelaar, R.; Ruijter, E.; Orru, R. V. A. Multicomponent Reaction Design Strategies: Towards Scaffold and Stereochemical Diversity. In Synthesis of Heterocycles via Multicomponent Reactions II; Orru, R. V. A.; Ruijter, E., Ed.; Springer-Verlag: Berlin Heidelberg, 2010; pp 95-126. 63 For a review, see: Petasis, N. Multicomponent Reactions with Organoboron Compounds. In Multicomponent Reactions; Zhu, J.; Bienaymé, H., Ed.; Wiley VCH-Verlag GmbH: Germany, 2005; pp 199-223. 64 For a review, see: Balme, G.; Bouyssi, D.; Monteiro, N. Metal-Catalyzed Multicomponent Reactions. In Multicomponent Reactions; Zhu, J.; Bienaymé, H., Ed.; Wiley VCH-Verlag GmbH: Germany, 2005; pp 224-276. 65 Vinogradova, E. V.; Park, N. H.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2013, 15, 1394-1397. 66 Lu, B. Z.; Wei, H.-H.; Zhang, Y.; Zhao, W.; Dufour, M.; Li, G.; Farina, V.; Senanayake, C. H. J. Org. Chem. 2013, 78, 4558-4562. 67 Li, J.; Liu, L.; Ding, D.; Sun, J.; Ji, Y.; Dong, J. Org. Lett. 2013, 15, 2884-2887.

185

Rhodium-catalyzed MCRs have also been reported. Scheidt and coworkers68 described a RhII-

catalyzed diazo decomposition followed by trapping with an imine to generate an azomethine

ylide. This 1,3-dipole then underwent cycloaddition with an alkyne. Subsequent elimination and

aromatization furnished the pyrrole (Eqn 4.8).

A MCR based on RhI-catalyzed addition of arylboronic acids onto olefins was reported by Osuka

and coworkers.69 Taking advantage of difference in rates of reaction, a vinylrhodium was first

formed via carborhodation of the symmetrical alkyne. This intermediate then underwent a Heck-

type coupling with the acrylate in aqueous media to access the diene (Eqn 4.9).

4.2 Research plan

As the use of multiple metal catalysts significantly enlarges the number of transformations

available in reaction design, the potential for developing (MC)2Rs can be realized. For example,

J. Tsoung in the group demonstrated the use of Rh/Pd-catalyzed (MC)2R for the synthesis of

benzodiazepines.70 In addition, as described in Chapter 3, A. Jang is currently developing an

enantioselective (MC)2R. With the aim to develop (MC)2R based on the compatible and robust

68Galliford, C. V.; Karl A. Scheidt, K. A. J. Org. Chem. 2007, 72, 1811-1813. 69 Kurahashi, T.; Shinokubo, H.; Osuka, A. Angew. Chem. Int. Ed. 2006, 45, 6336-6338. 70 Tsoung, J.; Panteleev, J.; Tesch, M. Lautens, M. Org. Lett. 2014, 16, 110-113.

186

Rh/Pd system, we further expanded the catalysis with the incorporation of copper. Following a

Rh/Pd-catalyzed conjugate addition/C-N cross coupling, a subsequent Cu-catalyzed Goldberg

amidation can occur to access N-aryl dihydroquinolinones (Figure 4.1). Members of this class of

products exhibit a number of important biological properties, including Aripiprazole, the second

top selling drug in 2012 (Figure 4.2).

Figure 4.1 One-pot Rh/Pd/Cu (MC)2R: synthesis of N-aryl dihydroquinolinones.

Figure 4.2 Bioactive dihydroquinolinones

4.3 Reaction optimization

We began our study with the optimization of Rh-catalyzed conjugate addition of o-

chlorophenylboronic acid 4.1a onto an acrylamide. In our investigation, the ortho-chloro group

on the boronic acid seemed to be sensitive to the reaction. We observed a complex mixture of

products when N-substituted acrylamides were used (Eqn 4.10). No desired product was

observed. β-substituted acrylamides did not afford any conversion (Eqn 4.11). However, good

reactivity was observed when unsubstituted acrylamide 4.2a was used (Table 4.1). Employing

187

catalytic amounts of [Rh(cod)OH]2 and BINAP L1 with dioxane/MeOH as solvent (entry 1) the

conjugate addition afforded the desired product 4.3a in good yields.

We then tested the compatibility of the conjugate addition with conditions that were typically

employed in Pd-catalyzed amidation reactions. We obtained excellent yields using K3PO4, t-

BuOH, and tert-amyl alcohol (t-am-OH) (entries 2, 3). We next focused our attention on the

development of Pd-catalyzed intramolecular amidation. We were able to realize the reaction

employing Pd(OAc)2 and XPhos L2 in the presence of K3PO4 and t-BuOH (entry 4). We tested

the compatibility of both metal-catalyzed reactions in one synthetic operation and were pleased

with an initial conversion to 4.3a and 4.4a in a yield of 49 and 35%, respectively (entry 5). In

addition, we did not observe the Pd-catalyzed Heck coupling of the aryl chloride onto

acrylamide, possibly due to the faster Rh-catalyzed conjugate addition. Elevating the reaction

temperature to 110 °C gave a smooth reaction to afford the desired dihydroquinolinone 4.4a in

74% yield (entry 6). We opted for the use of t-am-OH as solvent due to its ease of handling.

Further improvements in yield were achieved by switching the Pd-catalyst to [Pd(allyl)Cl]2

(entry 7). We also observed a benefit by omitting BINAP (entry 8). Consequently, no catalyst

premixing was required in the reaction setup, which improved the operational practicality of the

reaction. Lowering the amount of boronic acid to 1.05 equivalents not only improved the

efficiency of the conjugate addition but also the subsequent step. This effect probably resulted

from diminished protodeborylation to form chlorobenzene, a possible inhibitory byproduct for

the Pd-catalyzed step. Finally, the use of a more cost-effective catalyst, [Rh(cod)Cl]2, provided

favorable reactivity (entry 9).

188

Table 4.1 Optimization of Rh/Pd-catalyzed conjugate addition/amidation

Entry [Rh]/L1 [Pd]/L2 Sol/MeOH (10:1) t (°C) % yield 4.3a/4.4a

1b [Rh(cod)OH]2 - Dioxane 100 84/-

2 [Rh(cod)OH]2 - t-BuOH 100 89/-

3 [Rh(cod)OH]2 - t-am-OH 100 92/-

4c - [Pd(OAc)2] t-BuOH 100 -/99

5d [Rh(cod)OH]2 [Pd(OAc)2] t-BuOH 110 49/35

6 [Rh(cod)OH]2 [Pd(OAc)2] t-BuOH 110 -/74

7 [Rh(cod)OH]2 [Pd(allyl)Cl2] t-am-OH 110 -/73

8e [Rh(cod)OH]2 no L1 [Pd(allyl)Cl2] t-am-OH 110 -/76

9e,f [Rh(cod)Cl]2 no L1 [Pd(allyl)Cl2] t-am-OH 110 -/89 (87) a Yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard. [Rh] and L1 were

premixed separately from [Pd] and L2, each in 1 mL of solvent for 15 min. The mixtures were transferred to a vial containing 4.1a

(1.5 equiv), 4.2a (0.4 mmol), base (2.2 equiv) under an argon atmosphere. The vial was stirred at r.t. for 15 min, sealed, and heated

at the described temperature for 16 h. b K2CO3 was used instead of K3PO4. c Reaction conducted with 4.3a as substrate. d No MeOH

as cosolvent. e No catalyst premixing; 1.05 equiv 4.1a. f Isolated yield in parentheses. t-am-OH = 2-Methyl-2-butanol (tert-amyl

alcohol).

4.4 Reaction scope

We next examined the scope of the domino Rh/Pd catalysis (Table 4.2). Good reactivity was

observed with pinacol protected boronic esters and these boronates could be accessed reliably

from phenols (see Experimental section).71

71 Barluenga, J.; Jiménez-Aquin, A.; Aznar F.; Valdés, C. J. Am. Chem. Soc. 2009, 131, 4031-4041.

189

Table 4.2 Scope of the Rh/Pd-catalyzed dihydroquinolinone synthesisa

MeO2C

B(pin)

ClF3C

B(pin)

ClMeO

Cl

B(pin)

Cl

B(pin)

F Cl

B(OH)2

Cl

B(OH)2F3C

Cl

B(OH)263

96

92

80

64

NH

O

[Rh(cod)Cl]2 (2 mol %)Pd(allyl)Cl]2 (2.5 mol %)

XPhos (10 mol %)

K3PO4t-am-OH/MeOH

110 C, 16 h 4.4

B(OR)2

Cl NH2

O+

4.1 4.2a

entry 4.1 4.4 % yield entry 4.1 4.4 % yield

1

2

3

4

5

6

7

4.1b

4.1c

4.1d

4.1e

4.1f

4.1g

4.1h

4.4b

4.4c

4.4d

4.4e

4.4f

4.4g

4.4h

RR

87

78

B(pin)

Cl4.1i

4.4i8

B(pin)

Cl

O

O

4.1j

4.4j9

53

54

a See Experimental section for reaction procedures.

Good to high yields were observed with a variety of substituted boronic esters. The reaction

tolerated substituents at various positions on the aryl ring. While electron poor aryl groups

afforded the highest yields, electron neutral aryl groups gave modest yields. Employing

functionalized aryl boronates such as 4.1h to 4.1j, tricyclic lactams were accessed (entries 7-9).

We also explored the scope of the Michael acceptor and observed reactivity with α-substituted

acrylamides and α-aminomethylacrylates (Table 4.3). While methacrylamide (4.2b) provided the

desired quinolinone (entry 1), larger α-alkyl substituents were less reactive in the Rh-catalyzed

step. α-Phenyl acrylamide (4.2c) gave smooth conversion in the conjugate addition. The poor

reactivity of the intermediate in the amidation step was the main obstacle, even with the use of a

190

sequential catalyst/ligand addition protocol. Due to the attenuated reactivity of the

aforementioned acrylamides, we investigated an alternative approach with acrylates bearing an

α-aminomethyl group (4.2d and 4.2e). The more electrophilic acrylates facilitated the conjugate

addition while the amino group could efficiently cyclize after the conjugate addition. This

annulation strategy provided access to tetrahydroquinolines 4.4m-o in good yields.

Table 4.3 Scope of the Rh/Pd catalysis with respect to the Michael acceptora

a See Experimental section for reaction procedures. b Performed with stepwise addition of [Pd(allyl)Cl]2/XPhos after completion of

Rh-catalyzed step. c Reaction performed with dioxane/MeOH as solvent. d RuPhos was used instead of XPhos.

As the Rh/Pd-catalyzed synthesis of dihydroquinolinones was robust, we sought to achieve the

goal of conducting additional metal-catalyzed transformations in the same vessel without any

workup/purification. Doing so would further add a level of efficiency and highlight the (MC)2R.

We attempted to functionalize the quinolinone amide, as a means to address the limitation of the

Rh-catalyzed addition with respect to N-substituted acrylamides. Our efforts in the Pd-catalyzed

191

arylation of the amide were unsuccessful (Table 4.4, entry 1-4). However, the copper-catalyzed

amidation of aryl iodides was a complementary method to palladium catalysis.72 Following

optimization, we could perform the Cu-catalysis in the same reaction solvent with CuI, a diamine

ligand, an aryl iodide, molecular sieves, and the same base at an elevated temperature (entry 7).

Control studies on this step indicated the necessity of Cu, as the Rh and Pd used in the

dihydroquinoline synthesis did not promote the reaction.

Table 4.4 Optimization of the arylation of dihydroquinolinones

NH

O

[M]/LAr-X

K3PO4, solventT, 16 h

N O

Ar

entry Ar-X (equiv) [M] (mol %) L (mol %) Solvent/additive T (°C) % yield

1 Ph-Br (1.2) [Pd(allyl)Cl]2 (2) XPhos (8) t-am-OH 100 0

2 3,4-(Me)2C6H3-Cl (1.2) [Pd(allyl)Cl]2 (2) XPhos (8) t-am-OH 100 0

3 4-MeO2C-C6H4-Br (1.2) [Pd(allyl)Cl]2 (2) XPhos (8) t-am-OH 100 0

4 4-MeO2C-C6H4-Br (1.2) Pd2dba3 (2) XantPhos (4) dioxane 100 0

5 Ph-I (2) CuI (10) trans-1,2-diamino

cyclohexane (20) dioxane/MeOH 120 47


cyclohexane (20) t-am-OH/MeOH 110 9


cyclohexane (20)

t-am-OH/MeOH

/4Å MS 130 79

The Cu-catalyzed amidation was highly chemoselective, as iodoanilines and iodohalobenzenes

(Table 4.5, entry 6-8) could be used even in the presence of Pd and the desired reactivity for Cu

catalysis was observed. Products over three catalytic cycles could be accessed in good to high

yields.

72 For reviews of Cu-catalyzed cross coupling, see (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-2439. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337-2364. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054-3131.

192

Table 4.5 Two-step one-pot Rh/Pd/Cu-catalyzed (MC)2Ra

B(OH)2

Cl+

CuI (10 mol %)trans-1,2-cyclohexanediamine (20 mol %)

ArI (2.5 equiv)

K3PO44 Å MS

130 C, 16 h

N O

Ar

[Rh(cod)Cl]2 (2 mol %)Pd(allyl)Cl]2 (2.5 mol %)

XPhos (10 mol %)

K3PO4t-am-OH/MeOH

110 C, 16 h 4.54.1

4.2a

R1 R1

entry R1 Ar 4.5 % yield

1 H Ph 4.5a 80

2 H 4-Me-C6H4 4.5b 75

3 H 3-Me-C6H4 4.5c 74

4 H 4-MeO-C6H4 4.5d 71

5 H 3-CF3-C6H4 4.5e 60

6 H 3-NH2-C6H4 4.5f 77

7 H 4-Br-C6H4 4.5g 53

8 H 3,4-Cl2-C6H3 4.5h 62

9 3-Me Ph 4.5i 57

10 3-Me 4-MeO-C6H4 4.5j 54

11 3-MeO Ph 4.5k 47

12 3-F Ph 4.5l 59

13 5-CF3 Ph 4.5m 58 a See Experimental section for reaction procedures.

4.5 Current and future work: copper/palladium catalyzed (MC)2R: synthesis of fully substituted 1,2,3-triazoles

The original concepts for the work described below were conceived by the author, with efforts in

the initial reaction development. The subsequent experiments were conducted by T. Bruun, an

undergraduate student, and J. Y. Kim, an MSc student, with experimental and intellectual

guidance from the author.

Our work on Rh/Pd-catalyzed domino reactions and (MC)2R led us to explore the combination of

different metal catalysts that could promote other types of transformations. Another attractive

compatible metal combination would be copper and palladium. The use of this combination has

been widely reported, notably in cross coupling reactions, such as the Sonogashira73 and Stille.74

Copper is also a well-studied catalyst for the azide-alkyne Huisgen cycloaddition, which is a

highly robust reaction. Therefore, pairing the click reaction with palladium catalysis can provide

73 Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467-4470. 74 Mee, S. P. H.; Lee, V. Baldwin, J. E. Angew. Chem. Int. Ed. 2004, 43, 1132-1136.

193

compatible reaction conditions and opportunities to access functionalized 1,2,3-triazole motifs.

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is very regioselective for terminal

alkynes75 or iodinated/brominated alkynes.76 Recently, the use of thioalkynes in the iridium-

catalyzed AAC has been reported.77 However, non-strained internal alkynes remain difficult in

the CuAAC. A successful Huisgen cycloaddition of internal alkynes was reported by Fokin and

coworkers under ruthenium catalysis, accessing fully-substituted 1,2,3-triazoles.78 A different

mechanism of catalysis in comparison to copper was proposed. Regioselectivity of the RuAAC

became an issue, as only alkynes displaying a hydrogen bond donating directing group or

electronically biased alkynes provided products with high regioselectivities.

Thus, the development of a general, efficient, regioselective synthesis of fully substituted 1,2,3-

triazoles is of interest. Our initial attempts at utilizing RuAAC to access a triazole in a

regioselective manner with an alkyne bearing a chloride group were unsuccessful.

Decomposition was observed, which was likely attributed to the ortho-halogen (Eqn 4.13).

Consequently, we resorted to another substrate system, whereby a CuAAC of an iodoalkyne

would furnish an iodotriazole intermediate, which could be functionalized under palladium

catalysis (Scheme 4.1).

75 Rostovtsev, V. V.; Green, L. G.; Fokin V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. 76 (a) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless K. B.; Fokin, V. V. Angew. Chem. Int. Ed. 2009, 48, 8018-1821. (b) Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett 2005, 3059-3062. 77 Ding, S.; Jia, G.; Sun, J. Angew. Chem. Int. Ed. 2014, 53, 1877-1880. 78 Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923-8930.

194

Scheme 4.1 Cu/Pd-catalyzed synthesis of fully substituted 1,2,3-triazoles

The Pd-catalyzed functionalization of the iodotriazole has been reported, including the Suzuki-

Miyaura, Heck, and Sonogashira cross coupling.79 Attempts at the Buchwald-Hartwig C-N

coupling did not yield desired products, and significant amounts of de-halogenation were

observed. Attempts to combine the two metals in catalysis did not provide products of the Heck

or Suzuki reaction, probably due to inhibition by copper. As copper is beneficial for the

Sonogashira coupling, we elected to investigate the development of a one step, domino

AAC/Sonogashira coupling (Eqn 4.14).

It was expected that a number of side reactions could occur in this transformation. For example,

both copper and palladium could catalyze the alkyne-iodoalkyne coupling to form the diyne, and

both terminal and iodoalkynes were suitable substrates for the AAC. Thus, the success of the

Cu/Pd-catalyzed AAC/Sonogashira coupling would depend on chemoselectivity and time

resolution. Fortunately, the Cu/TBTA catalyst demonstrated strong chemoselectivity toward the

79 (a) Schulman, J. M.; Friedman, A. A.; Panteleev, J.; Lautens, M. Chem. Commun. 2012, 48, 55-57. (b) Deng, J.; Wu, Y. M.; Chen, Q.-Y. Synthesis 2005, 16, 2730–2738. (c) Bogdan, A. R.; James, K. Org. Lett. 2011, 13, 4060-4063.

195

AAC of the iodoalkyne, even in the presence of the terminal acetylene. This effect was also

observed by James and coworkers.79c In addition, solvent effects were crucial. The use of toluene

readily promoted the diyne coupling at room temperature in the presence of Pd(OAc)2 and a base

(Eqn 4.15). In THF, the diyne coupling was slower.80

The choice of the palladium catalyst was also important in affording the desired reactivity. The

optimal palladium precursor was found to be XPhos-Pd-G3, a palladacycle recently developed

by the Buchwald group. Coincidentally, the XPhos palladium catalyst could catalyze the

Sonogashira coupling without any copper, and excess copper proved to be deleterious.80,81 With

extensive optimization, J. Y. Kim was able to achieve the Cu/Pd-catalyzed (MC)2R. With all

three components (iodoalkyne, terminal alkyne, and organic azide) in the vessel at once, the only

extra operation required was a change in temperature. This highly efficient and practical method

provided a direct and regioselective route to access the fully substituted 1,2,3-triazole in high

yields (Eqn 4.16). Efforts on expanding the scope are ongoing.

80 Kim, J. Y. Multicomponent One-Pot One-Step Synthesis of 1,2,3-Triazoles via Cu/Pd Catalysis. M.Sc. Thesis, University of Toronto, Toronto, ON, 2014. 81 Gelman, D.; Buchwald, S. L. Angew. Chem. Int. Ed. 2003, 42, 5993-5996.

196

Our work on the Pd-catalyzed functionalization of the iodotriazoles led to the investigation of

Pd-catalyzed C-H functionalization of triazoles and the possibility of a CuAAC/C-H

functionalization (MC)2R. Several examples of direct arylation of 1,2,3-triazoles have been

reported by Gevorgyan,82 Ackermann,83 Fagnou,84 and our group.85 Ackermann and coworkers

have demonstrated a copper-catalyzed one-pot click/direct arylation sequence (Eqn 4.17).82a Our

group demonstrated the intramolecular C-H functionalization of iodotriazoles, where the aryl C-

H donor was N- or C-tethered on the triazole (Scheme 4.2).

R2 N3

R1

NN

NR1

R2

Ar-I

LiOtBu NN

NR1

R2Ar

(4.17)CuI (10 mol %)

DMF+

Scheme 4.2 Pd-catalyzed direct arylation of iodotriazoles

Our initial efforts in the Cu/Pd catalyzed AAC/direct arylation of iodotriazoles were

unsuccessful. The presence of copper seemed to inhibit the palladium catalysis and the solvent

compatibility was an issue. Thus, we modified our strategy toward the functionalization of

triazoles. J. Y. Kim found that Gevorgyan reported an alkyne carbopalladation/C-H

functionalization of indoles that appeared as a promising lead (Eqn 4.18).86

82 Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett., 2007, 9, 2333-2336. 83 (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett., 2008, 10, 3081-3084. (b) Ackermann, L.; Vicente, R. Org. Lett., 2009, 11, 4922-4925. 84 Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem., 2009, 74, 1826-1834. 85 Schulman, J. M.; Friedman, A. A.; Panteleev, J.; Lautens, M. Chem. Commun. 2012, 48, 55-57. 86 Chernyak, N.; Tilly, D.; Li, Z.; Gevorgyan, V. Chem. Commun. 2010, 46, 150-152.

197

The similarity in substrate structure prompted us to adapt this reaction toward triazoles. After

optimization, we were able to achieve the same reactivity for triazoles and suppress the direct

arylation pathway. Employing the Herrmann-Beller palladacycle (HBP), the carbopalladation/C-

H functionalization could afford the tricyclic heterocycle with a high yield (Eqn 4.19).

Preliminary examination of the scope also demonstrated regioselectivity for the carbopalladation

with electronically biased alkynes. We were interested in taking this transformation a step further

by developing a Cu/Pd-catalyzed (MC)2R that incorporates a C-H functionalization of triazoles.

Having both an internal alkyne and a terminal alkyne would further confer differentiation in the

CuAAC, thus leading to a more controlled reaction sequence. This advantage may prevent the

need to perform extra operations in the reaction setup, such as the manipulation of temperature.

The optimization is currently in progress, but preliminary (MC)2R can achieve a 60% yield (Eqn

4.20).

NN

N

nBuI

Ph

Ph

+

HBP (5 mol %)Et3N (5 equiv)

PivOH (50 mol %)DMA, 130 C

NN

N

nBuPh Ph

87%

(4.19)

PPd

OOPd

O OP

Ar Ar

ArAr

Ar = o-tolHBP

N3

I

nBuPh

Ph

+

HBP (5 mol %)CuI (2 mol %)

TBTA (10 mol %)

Et3N (5 equiv)PivOH (50 mol %)

DMF, 130 C

NN

N

nBuPh Ph

60%

(4.20)+

The AAC with C-H functionalization of triazoles can also potentially be realized by a Cu/RhIII

system to access a different class of heterocycles. The use of a terminal alkyne with a directing

group would lead to a triazole that could direct a RhIII-catalyzed C-H activation (Eqn 4.21). As

CuII is a common oxidant in the RhIII-catalyzed C-H activation, the CuI/RhIII system should be

very compatible.

198

The 1,2,3-triazole is an important motif in a number of bioactive compounds, and has seen

application in bioconjugation and crop protection. Recently, N-sulfonyl 1,2,3-triazoles has

become a functional group that serves as a precursor for imino metalocarbenes. These carbenes

have found unique synthetic utility in heterocycle synthesis.87 Often these sulfonyl triazoles were

generated in situ from alkynes and sulfonyl azides via copper catalysis and subsequently

decomposed by rhodium(II) to generate the carbene in a one-pot manner. Thus, exploring

Cu/RhII catalysis can further access important chemical transformations.

4.6 Conclusions

We have developed an efficient Rh/Pd conjugate addition/amidation sequence for the synthesis

of dihydroquinolinones. The Rh/Pd-catalyzed annulation strategy was also applied to substituted

acrylates to access tetrahydroquinolines. Combining Rh/Pd with Cu highlighted the potential,

operational practicality, and efficiency of the (MC)2R. Further developments in the Cu/Pd-

catalyzed (MC)2R offered a direct and regioselective approach to fully substituted 1,2,3-triazoles.

The Cu/Pd combination could also access the C-H activation mode of catalysis. Further work to

develop Cu/RhIII catalysis could lead to novel classes of heterocycles.


Synthesis of 2-Chloro-Arylboronates

General procedure A for the preparation of arylboronates from aryltriflates

In an oven dried round bottom flask under an atmosphere of nitrogen was placed

[Pd(dppf)Cl2]DCM complex (5 mol %), B2Pin2 (1.5 equiv), KOAc (3 equiv), and the aryltriflate

87 For a review, see: (a) Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151-5162. For selected examples, see: (b) Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 194-196. (c) Miura, T.; Tanaka, T.; Yada, A.; Murakami, M. Chem. Lett. 2013, 42, 1308-1310. (d) Miura, T.; Tanaka, T.; Biyajima, T.; Yada A.; Murakami, M. Angew. Chem. Int. Ed. 2013, 52, 3883-3886. (e) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 2272-2275. (f) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 13652-13655.

199

(1 equiv). To the flask was added freshly distilled 1,4-dioxane (0.5 M). The mixture was

degassed with N2. The flask was equipped with a reflux condenser and heated at 100 °C for 3 h

under a nitrogen atmosphere. Upon reaction completion, the mixture was filtered through a pad

of celite, washed with EtOAc:hex 1:1 and concentrated in vacuo to afford the crude. Subjecting

the crude to silica gel chromatography afforded the desired product.

2-(2-chloro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.1c

The titled compound was prepared from 2-chloro-4-methoxyphenyl trifluoromethanesulfonate89

according to general procedure A (2.91 g, 10 mmol). Purified on SiO2 column with 0-5% Et2O in

Hex to afford 2.04 g of 4.1c as a yellow oil, 76%. 1H NMR (399 MHz, CDCl3) δ 7.65 (d, J = 8.4

Hz, 1H), 6.91 – 6.88 (m, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 3.80 (s, 3H), 1.35 (s, 12H).; 13C

NMR (100 MHz, CDCl3) δ 162.3, 141.2, 138.1, 115.2, 112.2, 83.9, 55.5, 24.9.; IR (NaCl, neat,

cm-1): 2979, 1600, 1550, 1462, 1380, 1352, 1318, 1287, 1226, 1167, 1146, 1106, 1042, 1026,

963, 856, 670, 657.; HRMS (DART): calcd for C13H19BClO3: 269.1116; Found: 269.1106.

MeO2C Cl

B(pin)

methyl 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 4.1d

The titled compound was prepared from methyl 3-chloro-4-

(((trifluoromethyl)sulfonyl)oxy)benzoate88 according to general procedure A (3.19g, 10 mmol).

Purified on SiO2 column with 0-5% Et2O in Hex to afford 1.82 g of 4.1d as a white solid, 61%. 1H NMR (399 MHz, CDCl3) δ 8.00 (d, J = 1.3 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.73 (d, J = 7.7 Hz,

88 Dressel, J.; Fey, P.; Hanko, R.; Hubsch, W.; Kramer, T.; Mueller, U. E.; Mueller-Gliemann, M.; Beuck, M.; Kazda, S.; Wohlfeil, S.; Knorr, A.; Stasch, J.- P.; Zaiss, S. (Bayer AG., USA). Trisubstituted biphenyls. US Patent 586,393,0, January 26, 1999.

200

1H), 3.92 (s, 3H), 1.37 (d, J = 10.3 Hz, 12H).; 13C NMR (100 MHz, CDCl3) δ 166.1, 139.8,

136.4, 133.4, 130.3, 126.8, 84.7, 52.6, 25.0.; IR (NaCl, CHCl3, cm-1): 2982, 1728, 1494, 1384,

1349, 1280, 1238, 1149, 1106, 1039, 913, 854, 763, 742, 733.; M.p.: 97-98 °C.; HRMS

(DART): calcd for C14H22BClNO4[M+NH4+]: 314.1330; Found: 314.1329.

2-(2-chloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.1f

The titled compound was prepared from 2-chloro-4-(trifluoromethyl)phenyl

trifluoromethanesulfonate89 according to general procedure A (1.64g, 5 mmol). Purified on SiO2

column with Hex to afford 1.03g of 4.1f as a yellow oil, 67%. 1H NMR (300 MHz, CDCl3) δ

7.80 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.47 (dd, J = 7.8, 0.8 Hz, 1H), 1.38 (s, 13H).; 13C NMR

(126 MHz, CDCl3) δ 140.2 (s), 137.0 (s), 135.1 (s), 133.9 (q, J = 33.0 Hz), 126.2 (q, J = 3.9 Hz),

123.4 (q, J = 272.8 Hz), 122.6 (q, J = 3.7 Hz), 84.8 (s), 24.9 (s).; 19F NMR (282 MHz, CDCl3) δ

-63.26; IR (NaCl, neat, cm-1): 2982, 2935, 1779, 1622, 1496, 1387, 1358, 1318, 1253, 1172,

1135, 1080, 1043, 963, 889, 846, 789, 717, 670.; HRMS (DART): calcd for

C13H19BClF3NO2[M+NH4+]: 324.1150; Found: 324.1147.

2-(1-chloronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.1h

The titled compound was prepared from 1-chloronaphthalen-2-yl trifluoromethanesulfonate10

according to general procedure A (3.10g, 10 mmol). Purified on SiO2 column with hex to afford

2.16g of 4.1h as a white solid, 75%. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 7.5 Hz, 1H),

7.82 (dd, J = 6.9, 2.0 Hz, 1H), 7.71 (q, J = 8.3 Hz, 2H), 7.62 – 7.50 (m, 2H), 1.42 (s, 12H).; 13C

NMR (126 MHz, CDCl3) δ 138.3, 135. 7, 130.9, 130.8 128.0, 127.3, 126.9, 126.1, 125.3, 84.3,

24.9.; IR (NaCl, CHCl3, cm-1): 3057, 2978, 2930, 1596, 1469, 1381, 1346, 1316, 1295, 1138,

201

1113, 981, 963, 852, 819, 747.; M. p.: 63-65 °C.; HRMS (DART): calcd for C16H19BClO2:

289.1167; Found: 289.1160.

2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.1i

The titled compound was prepared from 6-chloro-2,3-dihydro-1H-inden-5-yl

trifluoromethanesulfonate according to general procedure A (750 mg, 2.5 mmol). Purified on

SiO2 column with 0 – 20% DCM in hex to afford 400 mg of 4.1i as a clear colourless oil, 57%. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.20 (s, 1H), 2.92 – 2.78 (m, 4H), 2.06 (p, J = 7.5


32.2, 25.6, 24.9.; IR (NaCl, CHCl3, cm-1): 2978, 2941, 2846, 1607, 1561, 1482, 1446, 1415,

1371, 1358, 1338, 1318, 1294, 1272, 1253, 1214, 1145, 1100, 967, 934, 880, 857, 731.; HRMS

(DART): calcd for C15H21BClO2: 279.1323; Found: 279.1327.

2-(6-chlorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4.1j

The titled compound was prepared from 6-chlorobenzo[d][1,3]dioxol-5-yl

trifluoromethanesulfonate according to general procedure A (1.52g, 5 mmol). Purified on SiO2

column with 0 - 30% DCM in Hex to afford 1.16 g of 4.1j as a white solid, 82%. 1H NMR (400

MHz, CDCl3) δ 7.12 (s, 1H), 6.83 (s, 1H), 5.97 (s, 2H), 1.35 (s, 12H).; 13C NMR (101 MHz,

CDCl3) δ 150.5, 146.3, 133.1, 114.9, 110.7, 101.9, 84.1, 24.9.; IR (NaCl, CHCl3, cm-1): 2980,

2930, 2900, 1616, 1505, 1439, 1350, 1318, 1271, 1239, 1214, 1166, 1149, 1129, 1083, 1039,

970, 946, 858, 836, 726.; M. p.: 74-75 °C.; HRMS (DART): calcd for C13H17BClO4: 283,0908;

Found: 283.0915.

202

General procedure B for the dual Rh/Pd-catalyzed synthesis of dihydroquinolinones: To a

dry 2 dram screw cap vial under argon atmosphere was added [Rh(cod)Cl]2 (4.0 mg, 4 mol %

[Rh]), [Pd(allyl)Cl]2 (3.7mg, 5 mol % [Pd]), XPhos (19mg, 10 mol %), arylboronic acid or

arylboronate (1.05 equiv), anhydrous ground K3PO4 (Alfa Aesar) (187 mg, 2.2 equiv), and

acrylamide (28.4 mg, 0.4 mmol). The vial was purged with argon. To the mixture was added t-

amyl alcohol (2 mL) and methanol (0.2 mL). The reaction vial was sealed with cap, and placed

in an oil bath at 110oC and stirred vigourously for 16 hours. The reaction was allowed to cool to

r.t., filtered through silica gel pad, and washed with EtOAc. The resultant filtrate was evaporated

under reduced pressure and then subjected to silica gel column chromatography to yield purified

compounds.

7-methyl-3,4-dihydroquinolin-2(1H)-one 4.4b

The titled compound was prepared from (2-chloro-4-methylphenyl)boronic acid following

general procedure B. The product was purified with SiO2 column chromatography with 20%

EtOAc in Hex to provide 40.6 mg of 4.4b as a white solid in 63% yield. 1H NMR (500 MHz,

CDCl3) δ 10.02 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 2.90 (t, J

= 7.6 Hz, 2H), 2.63 (dd, J = 8.3, 6.8 Hz, 2H), 2.28 (s, 3H).; 13C NMR (126 MHz, CDCl3) δ

173.0, 137.4, 137.3, 127.6, 123.7, 120.5, 116.3, 30.9, 24.9, 21.0. Spectroscopic data are in

accordance with literature.89

7-methoxy-3,4-dihydroquinolin-2(1H)-one 4.4c

The titled compound was prepared from 4.1c following general procedure B. The product was

purified with SiO2 column chromatography with 30% EtOAc in hex to provide 61.7 mg of 4.4c

as a white solid in 87% yield. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 7.04 (d, J = 8.2 Hz,

1H), 6.52 (dd, J = 8.3, 2.5 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 3.78 (s, 3H), 2.98 – 2.80 (m, 2H),

203

2.62 (dd, J = 8.4, 6.7 Hz, 2H).; 13C NMR (100 MHz, CDCl3) δ 172.4, 159.4, 138.4, 128.7, 115.9,

108.4, 101. 8, 55.6, 31.2, 24.7.; IR (NaCl, neat, cm-1): 2999, 2955, 1678, 1625, 1593, 1523,

1492, 1383, 1166, 1038, 856, 798.; M. p.: 142-147 °C.; HRMS (ESI+): calcd for C10H11NO2

(M+H)+: 178.08680; Found: 178.08694.

methyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate 4.4d

The titled compound was prepared from 4.1d following general procedure B. The product was

purified with SiO2 column chromatography with 30% EtOAc in Hex to provide 52.5 mg of 4.4d

as a white solid in 64% yield. 1H NMR (399 MHz, CDCl3) δ 8.74 (s, 1H), 7.67 (dd, J = 7.8, 1.6

Hz, 1H), 7.49 (d, J = 1.3 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 3.91 (s, 3H), 3.06 – 2.97 (m, 2H),


128.2, 124.5, 116.4, 52.4, 30.4, 25.7; IR (NaCl, CHCl3, cm-1): 3201, 3098, 2951, 2358, 2339,

1717, 1683, 1586, 1487, 1401, 1373, 1305, 1289, 1228, 1193, 1103, 892, 762, 732.; M.p.: 192-

194 °C.; HRMS (DART): calcd for C11H12NO3: 206.0817; Found: 206.0819.

NH

OF

7-fluoro-3,4-dihydroquinolin-2(1H)-one 4.4e

The compound was prepared from (2-chloro-4-fluorophenyl)boronic acid following general

procedure B. The product was purified with SiO2 column chromatography with 30% EtOAc in

Hex to provide 61.4 mgs of 4.4e as an off-white solid in 92% yield. 1H NMR (500 MHz, CDCl3)

δ 9.09 (s, 1H), 7.14 – 7.02 (m, 1H), 6.67 (td, J = 8.5, 2.5 Hz, 1H), 6.58 (dd, J = 9.3, 1.8 Hz, 1H),

2.93 (t, J = 7.6 Hz, 2H), 2.73 – 2.49 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 172.2 (s), 162.2

(d, J = 244.4 Hz), 138.7 (d, J = 10.5 Hz), 129.2 (d, J = 9.2 Hz), 119.3 (d, J = 3.2 Hz), 109.6 (d, J

204

= 21.4 Hz), 103.2 (d, J = 25.4 Hz), 30.8 (s), 24.8 (s). Spectroscopic data are in accordance with

literature.89

7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one 4.4f

The compound was prepared from 4.1f following general procedure B. The product was purified

with SiO2 column chromatography with 20% EtOAc in hex to provide 67.1 mgs of 4.4f as a

white solid in 78% yield. 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.31 – 7.19 (m, 2H), 7.10

(s, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.68 (dd, J = 8.4, 6.8 Hz, 2H).; 13C NMR (100 MHz, CDCl3) δ

172.5 (s), 138.1 (2C), 130.2 (q, J = 32.7 Hz), 128.3 (d, J = 47.7 Hz), 127.6 (d, J = 1.2 Hz), 124.2

(q, J = 265 Hz), 119.9 (q, J = 3.8 Hz), 112.5 (q, J = 3.8 Hz), 30.3 (s), 25.4 (s).; IR (NaCl, neat,

cm-1): 3047, 3002, 2898, 1684, 1596, 1490, 1407, 1331, 1166, 1119, 1072, 883, 823, 695.; M. p.:

164-167 °C.; HRMS (ESI+): calcd for C10H9F3NO (M+H)+: 216.06362; Found: 216.06428.

6-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one 4.4g

The compound was prepared from (2-chloro-5-(trifluoromethyl)phenyl)boronic acid following

general procedure B. The product was purified with SiO2 column chromatography with 20%

EtOAc in hex to provide 82.4 mg of 4.4g as an off-white solid in 96% yield. 1H NMR (300

MHz, CDCl3) δ 8.05 (s, 1H), 7.40 – 7.34 (m, 2H), 6.77 (d, J = 8.9 Hz, 1H), 3.00 – 2.93 (t, J =

8.5, 6.7 Hz, 2H), 2.61 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 172.8 (s), 140.5 (d, J = 1.2 Hz),

125.7 (q, J = 272 Hz), 125.2 (q, J = 32.9 Hz), 125.1 (m), 124.9 (q, J = 3.9 Hz), 124.0 (s), 115.8

89 McCall, J. M.; Romero, D. (Bioenergenix, USA). Heterocyclic compounds for the inhibition of PASK. World Patent WO201294462, July 12, 2012.

205

(s), 30.3 (s), 25.1 (s).; 19F NMR (282 MHz, CDCl3) δ -61.98. IR (NaCl, CHCl3, cm-1): 3215,

3182, 3072, 2958, 2985, 2924, 1680, 1608, 1514, 1381, 1192, 1163, 1134, 1107, 1074.; M. p.:

124-126oC.; HRMS (ESI+) calculated for C10H8FNO [M + H]+ 216.06322, found 216.06362.

3,4-dihydrobenzo[h]quinolin-2(1H)-one 4.4h

The titled compound was prepared from 4.1h following general procedure B. The product was

purified with SiO2 column chromatography with 30% Et2O in hex to provide 63.1 mg of 4.4h as

an off-white solid in 80% yield. 1H NMR (399 MHz, CDCl3) δ 9.07 (s, 1H), 7.96 (d, J = 6.9 Hz,

1H), 7.84 (d, J = 7.9 Hz, 1H), 7.60 – 7.44 (m, 3H), 7.30 (d, J = 8.3 Hz, 1H), 3.22 – 2.97 (m, 2H),


126.18, 125.9, 123.1, 122.5, 119.6, 119.5, 31.1, 26.1.; IR (NaCl, CHCl3, cm-1): 3216, 3122,

2362, 1679, 1670, 1578, 1527, 1476, 1395, 1273, 1248, 1183, 816, 759.; M. p.: 191-192 °C.;

HRMS (DART): calcd for C13H12NO: 198.0919; Found: 198.0921.

3,4,7,8-tetrahydro-1H-cyclopenta[g]quinolin-2(6H)-one 4.4i

The titled compound was prepared from 4.1i following general procedure B. The product was

purified with SiO2 column chromatography with 30% EtOAc in hex to provide 39.7 mg of 4.4i

as a white solid in 53% yield. 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 7.00 (s, 1H), 6.75 (s,

1H), 2.91 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.3 Hz, 4H), 2.61 (dd, J = 8.3, 6.7 Hz, 2H), 2.18 – 1.96

(m, 2H).; 13C NMR (101 MHz, CDCl3) δ 172.7, 143.7, 139.0, 135.7, 123.7, 121.6, 111.9, 32.8,

32.4, 31.1, 25.7, 25.5.; IR (NaCl, CHCl3, cm-1): 3195, 3111, 2944, 2840, 1721, 1493, 1436,

1409, 1375, 1331, 1301, 873, 814, 763, 667.; M. p.: 166-167 °C.; HRMS (DART): calcd for

C12H14NO: 188.1075; Found: 188.1077.

206

7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-6(5H)-one 4.4j

The titled compound was prepared from 4.1i following general procedure B. The product was

purified with SiO2 column chromatography with 40% EtOAc in hex to provide 41.2 mg of 4.4j

as a white solid in 54% yield. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 6.63 (s, 1H), 6.37 (s,

1H), 5.91 (s, 2H), 2.95 – 2.76 (m, 2H), 2.59 (dd, J = 8.5, 6.6 Hz, 2H).; 13C NMR (101 MHz,

CDCl3) δ 171.7, 147.0, 143.5, 131.5, 116.2, 108.3, 101.3, 97.9, 31.0, 25.5. Spectroscopic data are

in accordance with literature.90

General procedure C for the one-pot Rh/Pd/Cu-catalyzed synthesis of

dihydroquinolinones: To a dry 2 dram screw cap vial under argon atmosphere was added

[Rh(cod)Cl]2 (4.0 mg, 4 mol % [Rh]), [Pd(allyl)Cl]2 (3.7 mg, 5 mol % [Pd]), XPhos (19 mg, 10

mol %), arylboronic acid or arylboronate (1.05 equiv), anhydrous ground K3PO4 (Alfa Aesar)

(187 mg, 2.2 equiv), and acrylamide (28.4 mg, 0.4 mmol). The vial was purged with argon. To

the mixture was added t-amyl alcohol (2 mL) and methanol (0.2 mL). The reaction vial was

sealed with cap, and placed in an oil bath at 110oC and stirred vigourously for 16 hours. The

reaction was taken out of the oil bath and cooled to r.t. To that mixture was added CuI (7.6 mg,

10 mol %), 4Å MS (50 mg), aryliodide (2.5 equiv), anhydrous K3PO4 (187 mg, 2.2 equiv), and

trans-1,2-diaminocyclohexane (9.6 uL, 20 mol %). The mixture was purged with argon, sealed,

and stirred at r.t. for 10 min. The mixture was then heated at 130 °C for 16 h. The reaction was

allowed to cool to r.t., filtered through silica gel pad, and washed with EtOAc. The resultant

90 Nicolaou, K. C.; Stepan, A. F.; Lister, T.; Li, A.; Montero, A.; Tria, G. S.; Turner, C. I.; Tang, Y.; Wang, J.; Denton, R. M.; Edmonds, D. J. J. Am Chem. Soc. 2008, 130 , 13110-13119.

207

filtrate was evaporated under reduced pressure and then subjected to silica gel column

chromatography to yield purified compounds.

1-phenyl-3,4-dihydroquinolin-2(1H)-one 4.5a

The titled compound was prepared following general procedure C. The product was purified

with SiO2 column chromatography with 0-20% Et2O in hex to provide 71.4 mg of 4.5a as a

white solid in 80% yield. 1H NMR (400 MHz, CDCl3) δ 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4

Hz, 1H), 7.21 (dd, J = 12.4, 7.5 Hz, 3H), 7.05 – 6.95 (m, 2H), 6.35 (d, J = 7.9 Hz, 1H), 3.16 –

2.93 (m, 2H), 2.82 (dd, J = 8.4, 6.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.2, 141.8,

138.6, 129.9, 129.1, 128.2, 127.9, 127.2, 125.7, 123.0, 117.1, 32.3, 25.7. Spectroscopic data are

in accordance with literature.91

1-(p-tolyl)-3,4-dihydroquinolin-2(1H)-one 4.5b


with SiO2 column chromatography with 0-1% EtOAc in DCM to provide 71.1 mg of 4.5b as an

off-white solid in 75% yield. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J

= 7.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.06 – 6.99 (m, 1H), 6.96 (td, J = 7.4, 1.0 Hz, 1H), 6.38

(d, J = 8.0 Hz, 1H), 3.16 – 2.97 (m, 2H), 2.81 (dd, J = 8.5, 6.2 Hz, 2H), 2.41 (s, 3H).; 13C NMR

91 a) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew. Chem. Int. Ed. 2008, 47, 6414–6417. b) Capozzi, G.; Chimirri, A.; Grasso, S.; Romeo, G. Heterocycles 1984, 22, 1759-1762.

208

(101 MHz, CDCl3) δ 170.4, 141.9, 138.1, 135.8, 130.6, 128.8, 127.8, 127.2, 125.7, 122.9, 117.1,

32.3, 25.8, 21.3.; IR (NaCl, CHCl3, cm-1): 3030, 2919, 2845, 1679, 1603, 1511, 1493, 1458,

1358, 1332, 1293, 1267, 1222, 1180, 815, 755.; M. p.: 144-146 °C.; HRMS (DART): calcd for

C16H16NO: 238.1232; Found:238.1225.

1-(m-tolyl)-3,4-dihydroquinolin-2(1H)-one 4.5c


with SiO2 column chromatography with 0-1% EtOAc in hex to provide 70.0 mg of 4.5c as an

off-white solid in 74% yield. 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 7.6 Hz, 1H), 7.25 – 7.15

(m, 2H), 7.07 – 6.99 (m, 3H), 6.97 (td, J = 7.4, 1.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 3.13 – 2.95

(m, 2H), 2.82 (dd, J = 8.5, 6.2 Hz, 2H), 2.38 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 170.3,

141.8, 140.0, 138.4, 129.7, 129.6, 129.1, 127.8, 127.2, 126.0, 125.7, 123.0, 117.1, 32.3, 25.8,

21.4.; IR (NaCl, CHCl3, cm-1): 3027, 2963, 2839, 1674, 1603, 1495, 1456, 1358, 1336, 1302,

1268, 1189, 754, 698.; M. p.: 62-63 °C.; HRMS (DART): calcd for C16H16NO: 238.1232;

Found: 238.1233.

1-(4-methoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 4.5d


with SiO2 column chromatography with 30% Et2O in hex to provide 71.6 mg of 4.5d as an off-

white solid in 71% yield. 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.08 (m, 3H), 7.09 – 6.92 (m,

209

4H), 6.39 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.12 – 2.95 (m, 2H), 2.81 (dd, J = 8.5, 6.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.5, 159.2, 142.0, 131.0, 130.0, 127.8, 127.2, 125.6, 122.9,

117.0, 115.2, 55.5, 32.3, 25.7.; IR (NaCl, CHCl3, cm-1): 3047, 3021, 2966, 2940. 2916, 2837,

1695, 1616, 1511, 1436, 1360, 1333, 1306, 1290, 1270, 1251, 1235, 1184, 1170, 1105, 1028,

862, 819, 806, 758, 688.; M. p.: 156-158 °C.; HRMS (DART): calcd for C16H16NO2: 254.1181;

Found: 254.1179.

1-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one 4.5e


with SiO2 column chromatography with 0-25% Et2O in hex to provide 70.3 mg of 4.5e as an off-

white solid in 60% yield. 1H NMR (400 MHz, CDCl3) δ 7.65 (dt, J = 15.5, 7.8 Hz, 2H), 7.53 (s,

1H), 7.46 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.11 – 6.95 (m, 2H), 6.31 (d, J = 7.8 Hz,

1H), 3.15 – 2.97 (m, 2H), 2.84 (dd, J = 8.4, 6.2 Hz, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.0

(s), 141.0 (s), 139.1 (s), 132.7 (d, J = 1.0 Hz), 132.1 (q, J = 32.8 Hz), 130.3 (s), 127.9 (s), 127.1

(s), 126.0 (q, J = 3.8 Hz), 125.8 (s), 124.8 (q, J = 3.7 Hz), 123. 6 (q, J = 272.6 Hz), 123.3 (s),

116.6 (2C), 32.0 (s), 25.4 (s).; 19F NMR (376 MHz, CDCl3) δ -62.63.; IR (NaCl, CHCl3, cm-1):

3069, 3031, 2972, 2910, 2848, 1697, 1662, 1589, 1496, 1456, 1436, 1326, 1308, 1296, 1267,

1218, 1196, 1158, 1122, 1093, 1070, 1032, 1004, 972, 918, 894, 861, 803, 788, 772.; M. p.: 96-

98 °C; HRMS (DART): calcd for C16H13F3NO: 292.0949; Found: 292.0954.

1-(3-aminophenyl)-3,4-dihydroquinolin-2(1H)-one 4.5f

210


with SiO2 column chromatography with 0-20% Et2O in DCM to provide 73.4 mg of 4.5f as an

off-white solid in 77% yield. 1H NMR (399 MHz, CDCl3) δ 7.26 (t, J = 7.9 Hz, 1H), 7.19 (d, J =

7.2 Hz, 1H), 7.05 (td, J = 7.8, 1.6 Hz, 1H), 6.97 (td, J = 7.4, 1.2 Hz, 1H), 6.71 (ddd, J = 8.1, 2.3,

0.8 Hz, 1H), 6.60 (ddd, J = 7.8, 1.8, 0.9 Hz, 1H), 6.53 (t, J = 2.1 Hz, 1H), 6.47 (dd, J = 8.1, 1.0

Hz, 1H), 3.77 (s, 2H), 3.13 – 2.95 (m, 2H), 2.90 – 2.72 (m, 2H).; 13C NMR (100 MHz, CDCl3) δ

170.2, 148.2, 141.7, 139.5, 130.6, 127.7, 127.2, 125.6, 123.0, 118.7, 117.3, 115.6, 115.1, 32.3,

25.8.; IR (NaCl, CHCl3, cm-1): 3447, 3355, 3230, 1674, 1603, 1496, 1460, 1363, 1313, 1269,

1195, 1153, 910, 755, 730, 695.; M. p.: 132-134 °C.; HRMS (DART): calcd for C15H15N2O:

239.1184; Found: 239.1180.

N O

Br

1-(4-bromophenyl)-3,4-dihydroquinolin-2(1H)-one 4.5g


with SiO2 column chromatography with DCM to provide 64.5 mg of 4.5g as an off-white solid in

53% yield. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 1H), 7.68 – 7.54 (m, 1H), 7.20 (d,

J = 7.2 Hz, 1H), 7.15 – 7.08 (m, 1H), 7.08 – 6.93 (m, 3H), 6.36 (d, J = 8.0 Hz, 1H), 3.18 – 2.91

(m, 2H), 2.86 – 2.70 (m, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.2, 170.1, 141.32, 141.29,

139.1, 138.3, 137.6, 133.12, 131.11, 130.9, 128.09, 127.98, 127.3, 125.8, 123.3, 122.1, 117.00,

116.97, 93.6, 32.3, 25.6.; IR (NaCl, CHCl3, cm-1): 3026, 2902, 2841, 1687, 1667, 1602, 1493,

1456, 1361, 1335, 1291, 1266, 1159, 1068, 1014, 829, 763.; M. p.: 194-196 °C.; HRMS

(DART): calcd for C15H13BrNO: 302.0181; Found: 302.0173.

211

1-(3,4-dichlorophenyl)-3,4-dihydroquinolin-2(1H)-one 4.5h


with SiO2 column chromatography with DCM to provide 73.0 mg of 4.5h as an off-white solid in

62% yield. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H),

7.22 (d, J = 7.1 Hz, 1H), 7.15 – 6.94 (m, 3H), 6.38 (d, J = 8.0 Hz, 1H), 3.12 – 3.00 (m, 2H), 2.81

(dd, J = 8.4, 6.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3) δ 170.2, 141.0, 137.9, 133.7, 132.5,

131.5, 131.3, 128.7, 128.1, 127.4, 125.9, 123.6, 116.9, 32.2, 25.6.; IR (NaCl, CHCl3, cm-1):

3069, 2917, 2849, 1681, 1603, 1496, 1469, 1458, 1356, 1296, 1268, 1176, 1129, 1033, 752.; M.

p.: 120-122°C.; HRMS (DART): calcd for C15H12Cl2NO: 292.0296; Found: 292.0292.

7-methyl-1-phenyl-3,4-dihydroquinolin-2(1H)-one 4.5i


with SiO2 column chromatography with 0-20% Et2O in hex to provide 54.1 mg of 4.5i as an off-

white solid in 57% yield. 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m, 2H), 7.47 – 7.42 (m,

1H), 7.28 – 7.23 (m, 2H), 7.11 (d, J = 7.6 Hz, 1H), 6.85 – 6.80 (m, 1H), 6.18 (s, 1H), 3.09 – 3.01

(m, 2H), 2.86 – 2.79 (m, 2H), 2.17 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 170.4, 141.5, 138.5,

137.0, 129.8, 129.1, 128.1, 127.6, 123.6, 122.7, 117.7, 32.5, 25.3, 21.3.; IR (NaCl, neat, cm-1):

2914, 1683, 1612, 1417, 1355, 1332, 1297, 1183, 806, 762, 700.; M. p.: 118-120 °C.; HRMS

(ESI+): calcd for C16H15NO (M+H)+: 238.12319; Found: 238.12335.

212

1-(4-methoxyphenyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one 4.5j


with SiO2 column chromatography with 0-10% Et2O in DCM to provide 57.6 mg of 4.5j as an

off-white solid in 54% yield. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.8 Hz, 2H), 7.07 (d, J

= 7.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 7.5 Hz, 1H), 6.20 (s, 1H), 3.85 (s, 3H), 3.06

– 2.95 (m, 2H), 2.79 (dd, J = 8.4, 6.2 Hz, 2H), 2.16 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ

170.7, 159.2, 141.9, 137.1, 131.08, 130.07, 127.7, 123.6, 122.7, 117.6, 115.2, 55.5, 32.5, 25.4,

21.4.; M. p.: 152-154 °C.; HRMS (DART): calcd for C17H18NO: 268.1338, Found: 268.1344.

7-methoxy-1-phenyl-3,4-dihydroquinolin-2(1H)-one 4.5k


with SiO2 column chromatography with 0-30% Et2O in hex to provide 47.6 mg of 4.5k as an off-

white solid in 47% yield. 1H NMR (500 MHz, CDCl3) δ 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.5

Hz, 1H), 7.24 – 7.20 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.53 (dd, J = 8.3, 2.5 Hz, 1H), 5.93 (d, J

= 2.5 Hz, 1H), 3.63 (s, 3H), 3.01 (dd, J = 8.4, 6.2 Hz, 2H), 2.87 – 2.73 (m, 2H).; 13C NMR (126

MHz, CDCl3) δ 170.5, 158.9, 142.8, 138.5, 130.0, 129.1, 128.5, 128.4, 118.0, 107.2, 104.5, 55.4,

32.7, 25.0.; IR (NaCl, CHCl3, cm-1) 2934, 1688, 1615, 1510, 1354, 1267, 1204, 1176, 854, 771,

697.; M. p. 95-102 °C.; HRMS (ESI+): calcd for C16H15NO2 (M+H)+: 254.11810; Found:

254.11854.

213

7-fluoro-1-phenyl-3,4-dihydroquinolin-2(1H)-one 4.5l


with SiO2 column chromatography with 0-5% Et2O in DCM to provide 57.2 mg of 4.5l as an off-

white solid in 59% yield. 1H NMR (500 MHz, CDCl3) δ 7.52 (t, J = 7.6 Hz, 2H), 7.46 – 7.42 (m,

1H), 7.24 – 7.19 (m, 2H), 7.17 – 7.10 (m, 1H), 6.67 (td, J = 8.3, 2.5 Hz, 1H), 6.08 (dd, J = 10.7,

2.5 Hz, 1H), 3.03 (d, J = 7.7 Hz, 2H), 2.91 – 2.73 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ

170.1 (s), 161.9 (d, J = 243.5 Hz), 143.1 (d, J = 10.0 Hz), 138.1 (s), 130.2 (s), 129.0 (s), 128.9 (d,

J = 9.2 Hz), 128.7 (s), 121.2 (d, J = 3.2 Hz), 109.4 (d, J = 21.5 Hz), 104.9 (d, J = 27.0 Hz), 32.3

(s), 25.2 (s).; 19F NMR (377 MHz, CDCl3) δ -114.05 (dd, J = 17.3, 7.6 Hz).; IR (NaCl, CHCl3,

cm-1): 2364, 1702. 1687, 1620, 1599, 1504, 1429, 1354, 1296, 1258, 1171, 1103, 1072, 854, 767,

696.; M. p.: 125-127 °C.; HRMS (DART): calcd for C15H13FNO: 242.0981; Found: 242.0983.

1-phenyl-6-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one 4.5m


with SiO2 column chromatography with 0-2.5% Et2O in DCM to provide 57.6 mg of 4.5m as an

off-white solid in 58% yield. 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.46 (ddd, J =

7.3, 3.9, 1.2 Hz, 2H), 7.31 – 7.27 (m, 1H), 7.22 (dd, J = 8.4, 1.3 Hz, 2H), 6.44 (d, J = 8.5 Hz,

1H), 3.20 – 3.06 (m, 2H), 2.93 – 2.80 (m, 2H).; 13C NMR (126 MHz, CDCl3) δ 170.0 (s), 144.6

(s), 138.0 (s), 130.2 (s), 129.0 (s), 128.8 (s), 126.1 (s), 125.1 (q, J = 33 Hz), 125.0 (q, J = 3.9

Hz), 124.6 (q, J = 3.9 Hz), 124.2 (q, J = 270 Hz), 117.1 (s), 31.9 (s), 25. 7 (s).; 19F NMR (377

MHz, CDCl3) δ -62.03.; IR (NaCl, CHCl3, cm-1): 3056, 2991, 2917, 1697, 1684, 1622, 1504,

1493, 1453, 1424, 1354, 1332, 1302, 1268, 1224, 1190, 1162, 1149, 1128, 1106, 1077, 1033,

1009, 956, 913, 863, 837, 757 cm-1; M. p.: 135-138 °C.; HRMS (DART): calcd for

C16H13F3NO: 292.0949; Found: 292.0952.

214

3-methyl-3,4-dihydroquinolin-2(1H)-one 4.4k

The titled compound was prepared following general procedure B. The product was purified with

SiO2 column chromatography with 0-20% EtOAc in hex to provide 36.8 mg of 4.4k as an off-

white solid in 57% yield. 1H NMR (399 MHz, CDCl3) δ 9.01 (s, 1H), 7.14 (dd, J = 13.7, 7.2 Hz,

2H), 6.95 (td, J = 7.5, 0.9 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 2.98 (dd, J = 14.8, 5.2 Hz, 1H), 2.66

(ddt, J = 13.6, 12.4, 8.8 Hz, 2H), 1.27 (d, J = 6.7 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ

175.0, 137.4, 128.1, 127.6, 123.6, 123.0, 115.3, 35.1, 33.5, 15.5. Spectroscopic data are in

accordance with literatrure.92

3-phenyl-3,4-dihydroquinolin-2(1H)-one 4.4l

To a dry 2 dram screw cap vial under argon atmosphere was added [Rh(cod)Cl]2 (4.0 mg, 4 mol

% [Rh]), 2-chlorophenylboronic acid (65 mg, 1.05 equiv), anhydrous ground K3PO4 (Alfa

Aesar) (187 mg, 2.2 equiv), and 2-phenylacrylamide (58.8 mg, 0.4 mmol). The vial was purged

with argon. To the mixture was added t-amyl alcohol (2 mL) and methanol (0.2 mL). The

reaction vial was sealed with cap, and placed in an oil bath at 110 oC and stirred vigourously for

16 hours. The reaction was taken out of the oil bath and cooled to r.t. To that mixture was added

[Pd(allyl)Cl]2 (3.7mg, 5 mol % [Pd]) and XPhos (19mg, 10 mol %). The mixture was purged

with argon, sealed, and stirred at 110 °C for 16 h. The reaction was allowed to cool to r.t.,

filtered through silica gel pad, and washed with EtOAc. The resultant filtrate was evaporated

under reduced pressure and then subjected to silica gel column chromatography 0-10% EtOAc in

92 Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron 2009, 65, 1982–1987.

215

hex to provide 18.8 mg of 4.4l as an off-white solid in 21% yield. 1H NMR (400 MHz, CDCl3):

δ 8.80 (s, 1H), 7.36 – 7.24 (m, 5H), 7.20 – 7.14 (m, 2H), 6.99 (td, J = 7.4, 1.2 Hz, 1H), 6.80 (dd,

J = 8.0, 1.0 Hz, 1H), 3.88 (dd, J = 8.9, 6.8 Hz, 1H), 3.34 – 3.17 (m, 2H).; 13C NMR (100 MHz,

CDCl3): δ172.1, 138.3, 137.0, 128.6, 128.1, 128.0, 127.7, 127.3, 123.21, 123.18, 115.3, 46.5,

33.5.; IR (NaCl, neat, cm-1): 3214, 3061, 2925, 2358, 1678 1595, 1491, 1378, 1266, 725, 697;

M. p.: 161-164 °C.; HRMS (ESI+): calcd for C15H13NO (M+H)+: 224.10754; Found:

224.10775.

tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxylate 4.4m

The titled compound was prepared following general procedure B, using tert-butyl 2-

((phenylamino)methyl)acrylate 4.2d with the use of dioxane instead of t-am-OH and RuPhos

(18.7 mg, 10 mol %) instead of XPhos. The product was purified with SiO2 column

chromatography with 0-20% DCM in hex to provide 95.2 mg of 4.4m as a clear, slightly yellow

oil in 77% yield. 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 7.8 Hz, 2H), 7.25 – 7.14 (m, 2H),

7.09 (t, J = 7.2 Hz, 2H), 6.93 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 3.88 – 3.77 (m, 1H),

3.70 (t, J = 10.3 Hz, 1H), 3.06 (t, J = 7.2 Hz, 2H), 2.98 – 2.87 (m, 1H), 1.41 (d, J = 2.4 Hz, 9H).; 13C NMR (101 MHz, CDCl3) δ 172.7, 148.0, 143.8, 129.7, 129.5, 126.7, 124.9, 124.0, 122.9,

118.9, 115.9, 81.0, 52.1, 39.7, 30.3, 28.1.; IR (NaCl, neat, cm-1): 2927, 1724, 1603, 1476, 1367,

1256, 1152, 846, 748, 692.; HRMS (ESI+): calcd for C20H23NO2 (M+H)+: 310.18070; Found:

310.18004.

tert-butyl 1-tosyl-1,2,3,4-tetrahydroquinoline-3-carboxylate 4.4n

216

The compound was prepared following general procedure B with 4.2e (122.4 mg, 0.40 mmol),

and 4.1a (65.52 mg, 0.42 mmol, 1.05 equiv) as substrates and dioxane was instead of t-am-OH.

The resultant filtrate was evaporated under reduced pressure and then subjected to column

chromatography (hexanes/EtOAc= 10:3) to provide 106 mgs of 4.4n as a white solid in 69%

yield. 1H NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 8.2, 0.8 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H),

7.24 – 7.13 (m, 3H), 7.12 – 6.98 (m, 2H), 4.35 (dd, J = 13.7, 4.6 Hz, 1H), 3.47 (dd, J = 13.7, 10.3

Hz, 1H), 2.66 – 2.56 (m, 2H), 2.52 – 2.28 (m, 4H), 1.42 (s, 9H).; 13C NMR (75 MHz, CDCl3) δ

171.6, 143.9, 136.5, 136.3, 129.8, 129.3, 129.1, 127.2, 126.9, 125.4, 124.9, 81.5, 47.7, 39.1, 29.5,

28.1, 21.7.; IR (NaCl, CHCl3, cm-1): 1724, 1367, 1354, 1166.; M.p.: 97-99 oC.; HRMS (ESI+)

calculated for C21H29N2O4S [M + NH4]+ 405.18514, found 405.18480.

N

O

Ot-Bu

Ts

F3C

tert-butyl 1-tosyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxylate 4.4o

The compound was prepared following procedure B utilizing 4.2e (122.4 mg, 0.40 mmol) and

4.1g (94.24 mg, 0.42 mmol) as substrates and dioxane was used instead of t-am-OH. The

resultant filtrate was evaporated under reduced pressure and then subjected to column

chromatography (hexanes/EtOAc= 20:1) to provide 134.3 mgs of 4.4o as a white solid in 71%

yield. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.40 (dd,

J = 8.7, 1.6 Hz, 1H), 7.31 (d, J = 0.9 Hz, 1H), 7.25 – 7.20 (m, 2H), 4.34 (ddd, J = 13.5, 4.5, 0.7

Hz, 1H), 3.52 (dd, J = 13.5, 10.0 Hz, 1H), 2.74 (dd, J = 8.0, 3.5 Hz, 2H), 2.48 (tdd, J = 9.8, 6.5,

4.5 Hz, 1H), 2.37 (s, 3H), 1.41 (s, 9H).; 13C NMR (126 MHz, CDCl3) δ 171.0 (s), 144.4 (s),

139.5 (d, J = 1.2 Hz), 136.1 (s), 130.0 (s), 128.8 (s), 127.1 (s), 126.7 (q, J = 32.7 Hz), 126.5 –

126.3 (m, J = 3.8 Hz), 124.03 (s), 124.02 (q, J = 271.8 Hz), 123.9 – 123.7 (m, J = 3.7 Hz), 81.8

(s), 47.6 (s), 38.7 (s), 29.7 (s), 28.0 (s), 21.6 (s).; 19F NMR (282 MHz, CDCl3) δ -62.36.; IR

(NaCl, CHCl3, cm-1): 2980, 2958, 2926, 1728,1359, 1332, 1296, 1259, 1084, 812, 707, 692.;

M.p.: 94-96 oC.; HRMS (ESI+) calculated for C22H24F3NO4S [M + NH4]+ 473. 1721, found

473.1716.

217

tert-butyl 2-((4-methylphenylsulfonamido)methyl)acrylate 4.2e.

To a flame dried flask under argon was added toluene sulphonamide (5.13 g, 30.0 mmol) in

CH2Cl2 (30 mL). 1,4-Diazabicyclo[2.2.2]octane was added (744.80 mg, 6.65 mmol) and then

tert-butyl 2-(bromomethyl)acrylate (1.1 g, 5.0 mmol) was added in a solution of CH2Cl2 (20 mL)

dropwise over 2 hours. The reaction was stirred over night. The mixture was poured into a

separatory funnel and water was added. The aqueous was extracted with CH2Cl2 (3 x 15 mL) and

the collected organic phase was washed with water (2 x 15 mL) and sat. NaCl (15 mL). The

organic solution was dried with Na2SO4 and evaporated under reduced pressure. The crude

product was purified by column chromatography (Hexanes/ EtOAc: 5:1) to afford 1.41 g of 4.2e

as a pink-white solid in 91% yield. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.28

(d, J = 8.0 Hz, 2H), 6.05 (d, J = 0.9 Hz, 1H), 5.67 (q, J = 1.2 Hz, 1H), 5.09 (br. s, 1H), 3.76 (d, J

= 6.7 Hz, 2H), 2.41 (s, 3H), 1.43 (s, 9H).; 13C NMR (75 MHz, CDCl3) δ 165.0, 143.4, 137.2,

136.8, 129.7, 127.0, 81.6, 77.4, 44.8, 28.0, 21.5.; Spectroscopic data are in accordance with

literature.93

93 Sibi, M.P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571-2573.

218

Appendices 1-4

219

Appendix 1: Rhodium-Catalyzed Enantioselective Desymmetrization of Oxabicyclic Alkenes Using Silyl Ketene

Acetals/Enol Ethers

220

400 MHz, CDCl3

100 MHz, CDCl3

221

400 MHz, CDCl3

100 MHz, CDCl3

222

400 MHz, CDCl3

100 MHz, CDCl3

223

300 MHz, CDCl3

75 MHz, CDCl3

224

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)

2.83

2.80

9.05

1.01

1.00

1.01

0.98

0.99

0.99

1.01

0.98

2.26

2.07

1.05

1.99

O

OSi

CH3

CH3

CH3

CH3CH3

500 MHz, CDCl3

125 MHz, CDCl3

225

500 MHz, CDCl3

125 MHz, CDCl3

226

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

3.06

2.73

8.94

1.07

1.04

0.99

3.14

1.00

1.00

0.99

2.01

0.98

3.49

2.09

O

O

CH3

OSi

CH3

CH3

CH3

CH3CH3

400 MHz, CDCl3

100 MHz, CDCl3

227

400 MHz, CDCl3

100 MHz, CDCl3

228

2.97

3.25

9.99

6.53

1.10

2.04

0.95

1.02

1.00

1.03

1.13

3.66

100 MHz, CDCl3

400 MHz, CDCl3

229

500 MHz, CDCl3

125 MHz, CDCl3

230

8.66

1.03

1.02

0.99

0.97

1.02

1.01

1.05

1.14

3.52

3.04

3.01

500 MHz, CDCl3

125 MHz, CDCl3

231

400 MHz, CDCl3

100 MHz, CDCl3

232

400 MHz, CDCl3

100 MHz, CDCl3

233

400 MHz, CDCl3

100 MHz, CDCl3

234

f1 (p

pm)

235

400 MHz, CDCl3

100 MHz, CDCl3

237

500 MHz, CDCl3

125 MHz, CDCl3

239

100 MHz, CDCl3

400 MHz, CDCl3

240

400 MHz, CDCl3

100 MHz, CDCl3

241

400 MHz, CDCl3

75 MHz, CDCl3

242

400 MHz, CDCl3

100 MHz, CDCl3

243

400 MHz, CDCl3

100 MHz, CDCl3

244

500 MHz, CDCl3

125 MHz, CDCl3

245

375 MHz, CDCl3

246

400 MHz, CDCl3

100 MHz, CDCl3

247

500 MHz, CDCl3

125 MHz, CDCl3

250

600 MHz, CDCl3

150 MHz, CDCl3

253

500 MHz, CDCl3

125 MHz, CDCl3

254

600 MHz, CDCl3

150 MHz, CDCl3

257

HPLC Traces:

Racemic >99:1 e.r.

Racemic >99:1 e.r.

258

Racemic >99:1 e.r.

>99:1 e.r.

259

Racemic >99:1 e.r.

(R,S)+ (S,R) >99:1 e.r.

260

racemic

OH

O OMe

>99:1 e.r.

OH

O OMe

Racemic >99:1 e.r.

(R,S) + (S,R) >99:1 e.r.

261

(R,S) + (S,R) >99:1 e.r.

Racemic >99:1 e.r.

262

Racemic 98:2 e.r.

Racemic 99:1 e.r.

263

Racemic >99:1 e.r.

Racemic 97:3 e.r.

264

Racemic 97:3 e.r.

Racemic 98:2 e.r.

265

RS + SR 98:2 e.r.

Racemic 94:6 e.r.

266

Racemic 98:2 e.r.

Racemic 91:9 e.r.

267

Racemic 85:15 e.r.

NHTs

CO2Et

RS + SR

NHTs

CO2Et

95:5 e.r.

Racemic 95:5 e.r.

269

Table 1. Crystal data and structure refinement for d1314.

Identification code d1314

Empirical formula C22 H18 O2

Formula weight 314.36

Temperature 147(2) K

Wavelength 1.54178 Å

Crystal system Monoclinic

Space group P 21

Unit cell dimensions a = 5.4036(5) Å a= 90°.

b = 24.156(2) Å b= 90.837(3)°.

c = 5.9769(6) Å g = 90°.

Volume 780.08(13) Å3

Z 2

Density (calculated) 1.338 Mg/m3

Absorption coefficient 0.666 mm-1

F(000) 332

Crystal size 0.22 x 0.09 x 0.06 mm3

Theta range for data collection 7.33 to 66.56°.

Index ranges -6<=h<=6, -23<=k<=28, -7<=l<=7

Reflections collected 18109

270

Independent reflections 2473 [R(int) = 0.0236]

Completeness to theta = 66.56° 96.6 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7528 and 0.6930

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2473 / 1 / 221

Goodness-of-fit on F2 1.099

Final R indices [I>2sigma(I)] R1 = 0.0243, wR2 = 0.0640

R indices (all data) R1 = 0.0244, wR2 = 0.0641

Absolute structure parameter 0.06(16)

Largest diff. peak and hole 0.099 and -0.150 e.Å-3

271

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x

103)

for d1314. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______________________________________________________________________________

__

x y z U(eq)

______________________________________________________________________________

__

O(1) 2533(2) 9107(1) 11193(1) 26(1)

O(2) 5872(2) 9563(1) 4237(2) 33(1)

C(1) 4590(2) 8874(1) 7749(2) 22(1)

C(2) 3750(2) 8669(1) 10042(2) 20(1)

C(3) 2038(2) 8173(1) 9865(2) 21(1)

C(4) 294(2) 8069(1) 11491(2) 26(1)

C(5) -1185(2) 7600(1) 11383(2) 30(1)

C(6) -934(2)7228(1) 9624(2) 28(1)

C(7) 809(2) 7326(1) 8006(2) 27(1)

C(8) 2316(2) 7796(1) 8103(2) 22(1)

C(9) 4188(2) 7907(1) 6422(2) 26(1)

C(10) 5284(2) 8397(1) 6263(2) 25(1)

C(11) 6684(2) 9298(1) 8013(2) 24(1)

272

C(12) 7120(2) 9633(1) 5929(2) 24(1)

C(13) 9070(2) 10072(1) 5940(2) 22(1)

C(14) 10692(2) 10154(1) 7706(2) 22(1)

C(15) 12475(2) 10586(1) 7642(2) 21(1)

C(16) 14203(2) 10678(1) 9407(2) 24(1)

C(17) 15864(2) 11105(1) 9308(2) 27(1)

C(18) 15899(2) 11458(1) 7434(2) 27(1)

C(19) 14282(2) 11377(1) 5694(2) 26(1)

C(20) 12525(2) 10942(1) 5743(2) 22(1)

C(21) 10830(2) 10845(1) 3957(2) 25(1)

C(22) 9177(2) 10423(1) 4037(2) 25(1)

______________________________________________________________________________

__

273

Table 3. Bond lengths [Å] and angles [°] for d1314.

_____________________________________________________

O(1)-C(2) 1.4268(15)

O(1)-H(1O) 0.90(2)

O(2)-C(12) 1.2189(15)

C(1)-C(10) 1.5065(18)

C(1)-C(11) 1.5321(17)

C(1)-C(2) 1.5324(17)

C(1)-H(1A) 1.0000

C(2)-C(3) 1.5159(17)

C(2)-H(2A) 1.0000

C(3)-C(4) 1.3869(17)

C(3)-C(8) 1.4024(18)

C(4)-C(5) 1.387(2)

C(4)-H(4A) 0.9500

C(5)-C(6) 1.390(2)

C(5)-H(5A) 0.9500

C(6)-C(7) 1.3800(19)

C(6)-H(6A) 0.9500

C(7)-C(8) 1.3981(19)

274

C(7)-H(7A) 0.9500

C(8)-C(9) 1.4605(18)

C(9)-C(10) 1.3285(19)

C(9)-H(9A) 0.9500

C(10)-H(10A) 0.9500

C(11)-C(12) 1.5066(18)

C(11)-H(11A) 0.9900

C(11)-H(11B) 0.9900

C(12)-C(13) 1.4944(18)

C(13)-C(14) 1.3763(18)

C(13)-C(22) 1.4209(18)

C(14)-C(15) 1.4200(18)

C(14)-H(14A) 0.9500

C(15)-C(16) 1.4163(18)

C(15)-C(20) 1.4257(17)

C(16)-C(17) 1.3700(19)

C(16)-H(16A) 0.9500

C(17)-C(18) 1.408(2)

C(17)-H(17A) 0.9500

C(18)-C(19) 1.3628(19)

275

C(18)-H(18A) 0.9500

C(19)-C(20) 1.4154(19)

C(19)-H(19A) 0.9500

C(20)-C(21) 1.4157(19)

C(21)-C(22) 1.3579(18)

C(21)-H(21A) 0.9500

C(22)-H(22A) 0.9500

C(2)-O(1)-H(1O) 108.1(13)

C(10)-C(1)-C(11) 112.47(10)

C(10)-C(1)-C(2) 111.04(10)

C(11)-C(1)-C(2) 110.61(10)

C(10)-C(1)-H(1A) 107.5

C(11)-C(1)-H(1A) 107.5

C(2)-C(1)-H(1A) 107.5

O(1)-C(2)-C(3) 109.47(9)

O(1)-C(2)-C(1) 109.62(10)

C(3)-C(2)-C(1) 112.43(10)

O(1)-C(2)-H(2A) 108.4

C(3)-C(2)-H(2A) 108.4

276

C(1)-C(2)-H(2A) 108.4

C(4)-C(3)-C(8) 119.27(11)

C(4)-C(3)-C(2) 121.05(11)

C(8)-C(3)-C(2) 119.57(10)

C(3)-C(4)-C(5) 120.89(12)

C(3)-C(4)-H(4A) 119.6

C(5)-C(4)-H(4A) 119.6

C(4)-C(5)-C(6) 119.97(12)

C(4)-C(5)-H(5A) 120.0

C(6)-C(5)-H(5A) 120.0

C(7)-C(6)-C(5) 119.65(13)

C(7)-C(6)-H(6A) 120.2

C(5)-C(6)-H(6A) 120.2

C(6)-C(7)-C(8) 120.85(13)

C(6)-C(7)-H(7A) 119.6

C(8)-C(7)-H(7A) 119.6

C(7)-C(8)-C(3) 119.36(11)

C(7)-C(8)-C(9) 121.89(12)

C(3)-C(8)-C(9) 118.75(11)

C(10)-C(9)-C(8) 121.73(12)

277

C(10)-C(9)-H(9A) 119.1

C(8)-C(9)-H(9A) 119.1

C(9)-C(10)-C(1) 121.69(11)

C(9)-C(10)-H(10A) 119.2

C(1)-C(10)-H(10A) 119.2

C(12)-C(11)-C(1) 113.43(10)

C(12)-C(11)-H(11A) 108.9

C(1)-C(11)-H(11A) 108.9

C(12)-C(11)-H(11B) 108.9

C(1)-C(11)-H(11B) 108.9

H(11A)-C(11)-H(11B) 107.7

O(2)-C(12)-C(13) 118.93(11)

O(2)-C(12)-C(11) 121.34(12)

C(13)-C(12)-C(11) 119.71(10)

C(14)-C(13)-C(22) 119.61(12)

C(14)-C(13)-C(12) 123.21(11)

C(22)-C(13)-C(12) 117.16(11)

C(13)-C(14)-C(15) 120.72(11)

C(13)-C(14)-H(14A) 119.6

C(15)-C(14)-H(14A) 119.6

278

C(16)-C(15)-C(14) 122.37(11)

C(16)-C(15)-C(20) 118.57(12)

C(14)-C(15)-C(20) 119.06(11)

C(17)-C(16)-C(15) 120.74(12)

C(17)-C(16)-H(16A) 119.6

C(15)-C(16)-H(16A) 119.6

C(16)-C(17)-C(18) 120.50(12)

C(16)-C(17)-H(17A) 119.8

C(18)-C(17)-H(17A) 119.8

C(19)-C(18)-C(17) 120.23(13)

C(19)-C(18)-H(18A) 119.9

C(17)-C(18)-H(18A) 119.9

C(18)-C(19)-C(20) 120.94(13)

C(18)-C(19)-H(19A) 119.5

C(20)-C(19)-H(19A) 119.5

C(19)-C(20)-C(21) 122.29(12)

C(19)-C(20)-C(15) 119.01(12)

C(21)-C(20)-C(15) 118.70(12)

C(22)-C(21)-C(20) 121.13(12)

C(22)-C(21)-H(21A) 119.4

279

C(20)-C(21)-H(21A) 119.4

C(21)-C(22)-C(13) 120.75(12)

C(21)-C(22)-H(22A) 119.6

C(13)-C(22)-H(22A) 119.6

_____________________________________________________________

Symmetry transformations used to generate equivalent atoms:

280

Table 4. Anisotropic displacement parameters (Å2x 103) for d1314. The anisotropic

displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________

O(1) 27(1) 24(1) 27(1) -9(1) 0(1) 0(1)

O(2) 39(1) 32(1) 28(1) 2(1) -8(1) -13(1)

C(1) 22(1) 20(1) 25(1) 0(1) -1(1) 0(1)

C(2) 19(1) 20(1) 23(1) -1(1) 0(1) 2(1)

C(3) 20(1) 20(1) 24(1) 1(1) -3(1) 3(1)

C(4) 26(1) 24(1) 26(1) -3(1) 3(1) 1(1)

C(5) 26(1) 28(1) 36(1) 4(1) 8(1) -1(1)

C(6) 27(1) 19(1) 39(1) 1(1) 2(1) -4(1)

C(7) 33(1) 19(1) 30(1) -2(1) 0(1) 0(1)

C(8) 24(1) 18(1) 25(1) 1(1) -2(1) 3(1)

C(9) 33(1) 20(1) 27(1) -4(1) 6(1) 3(1)

C(10) 27(1) 24(1) 24(1) 0(1) 6(1) 0(1)

C(11) 23(1) 23(1) 26(1) 0(1) -1(1) -4(1)

C(12) 25(1) 20(1) 26(1) -2(1) 0(1) 1(1)

C(13) 22(1) 18(1) 25(1) -2(1) 2(1) 0(1)

281

C(14) 23(1) 18(1) 24(1) 2(1) 2(1) 1(1)

C(15) 20(1) 18(1) 24(1) -1(1) 3(1) 3(1)

C(16) 24(1) 22(1) 25(1) 2(1) -1(1) 2(1)

C(17) 24(1) 26(1) 32(1) -4(1) -4(1) -1(1)

C(18) 24(1) 20(1) 37(1) -1(1) 2(1) -2(1)

C(19) 27(1) 21(1) 30(1) 2(1) 4(1) -1(1)

C(20) 22(1) 19(1) 26(1) -1(1) 4(1) 3(1)

C(21) 28(1) 23(1) 24(1) 4(1) 0(1) 0(1)

C(22) 26(1) 25(1) 23(1) 1(1) -3(1) -1(1)

______________________________________________________________________________

282

Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3)

for d1314.

______________________________________________________________________________

__

x y z U(eq)

______________________________________________________________________________

__

H(1A) 3152 9068 7024 27

H(2A) 5250 8559 10936 25

H(4A) 110 8321 12695 31

H(5A) -2369 7532 12510 36

H(6A) -1957 6909 9536 34

H(7A) 988 7071 6811 33

H(9A) 4633 7620 5416 32

H(10A) 6537 8448 5184 30

H(11A) 6284 9553 9253 29

H(11B) 8230 9101 8427 29

H(14A) 10617 9921 8981 26

H(16A) 14209 10440 10675 29

H(17A) 17001 11164 10512 33

283

H(18A) 17054 11754 7382 32

H(19A) 14334 11615 4431 31

H(21A) 10849 11080 2682 30

H(22A) 8080 10361 2806 30

H(1O) 3520(40) 9218(9) 12330(30) 52(5)

______________________________________________________________________________

__

284

Table 6. Torsion angles [°] for d1314.

________________________________________________________________

C(10)-C(1)-C(2)-O(1) -165.50(10)

C(11)-C(1)-C(2)-O(1) 68.89(12)

C(10)-C(1)-C(2)-C(3) -43.50(13)

C(11)-C(1)-C(2)-C(3) -169.11(10)

O(1)-C(2)-C(3)-C(4) -30.35(15)

C(1)-C(2)-C(3)-C(4) -152.45(11)

O(1)-C(2)-C(3)-C(8) 153.53(10)

C(1)-C(2)-C(3)-C(8) 31.43(15)

C(8)-C(3)-C(4)-C(5) -0.59(19)

C(2)-C(3)-C(4)-C(5) -176.73(12)

C(3)-C(4)-C(5)-C(6) -0.2(2)

C(4)-C(5)-C(6)-C(7) 0.7(2)

C(5)-C(6)-C(7)-C(8) -0.5(2)

C(6)-C(7)-C(8)-C(3) -0.31(19)

C(6)-C(7)-C(8)-C(9) 179.49(12)

C(4)-C(3)-C(8)-C(7) 0.83(18)

C(2)-C(3)-C(8)-C(7) 177.03(11)

C(4)-C(3)-C(8)-C(9) -178.98(11)

285

C(2)-C(3)-C(8)-C(9) -2.79(17)

C(7)-C(8)-C(9)-C(10) 166.94(13)

C(3)-C(8)-C(9)-C(10) -13.26(19)

C(8)-C(9)-C(10)-C(1) -2.4(2)

C(11)-C(1)-C(10)-C(9) 155.74(12)

C(2)-C(1)-C(10)-C(9) 31.17(17)

C(10)-C(1)-C(11)-C(12) 71.30(14)

C(2)-C(1)-C(11)-C(12) -163.90(10)

C(1)-C(11)-C(12)-O(2) 0.49(18)

C(1)-C(11)-C(12)-C(13) 178.78(10)

O(2)-C(12)-C(13)-C(14) -175.02(12)

C(11)-C(12)-C(13)-C(14) 6.65(18)

O(2)-C(12)-C(13)-C(22) 6.53(18)

C(11)-C(12)-C(13)-C(22) -171.80(11)

C(22)-C(13)-C(14)-C(15) -0.24(18)

C(12)-C(13)-C(14)-C(15) -178.65(11)

C(13)-C(14)-C(15)-C(16) -178.84(12)

C(13)-C(14)-C(15)-C(20) 1.60(18)

C(14)-C(15)-C(16)-C(17) -178.66(12)

C(20)-C(15)-C(16)-C(17) 0.91(18)

286

C(15)-C(16)-C(17)-C(18) -0.59(19)

C(16)-C(17)-C(18)-C(19) -0.2(2)

C(17)-C(18)-C(19)-C(20) 0.7(2)

C(18)-C(19)-C(20)-C(21) -179.65(12)

C(18)-C(19)-C(20)-C(15) -0.36(18)

C(16)-C(15)-C(20)-C(19) -0.43(17)

C(14)-C(15)-C(20)-C(19) 179.15(11)

C(16)-C(15)-C(20)-C(21) 178.88(11)

C(14)-C(15)-C(20)-C(21) -1.54(17)

C(19)-C(20)-C(21)-C(22) 179.42(12)

C(15)-C(20)-C(21)-C(22) 0.14(18)

C(20)-C(21)-C(22)-C(13) 1.25(19)

C(14)-C(13)-C(22)-C(21) -1.21(19)

C(12)-C(13)-C(22)-C(21) 177.30(12)

________________________________________________________________


287

Table 7. Hydrogen bonds for d1314 [Å and °].

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

____________________________________________________________________________

O(1)-H(1O)...O(2)#1 0.90(2) 1.89(2) 2.7722(13) 167.3(19)

____________________________________________________________________________


#1 x,y,z+1

289

Table 7. Crystal data and structure refinement for d13218_b.

Identification code d13218_b

Empirical formula C25 H23 N O3 S

Formula weight 417.51

Temperature 147(2) K

Wavelength 1.54178 Å

Crystal system Triclinic

Space group P 1

Unit cell dimensions a = 9.812(3) Å a= 90.700(13)°.

b = 10.110(3) Å b= 109.487(7)°.

c = 11.039(3) Å g = 91.427(8)°.

Volume 1031.7(5) Å3

Z 2

Density (calculated) 1.344 Mg/m3

Absorption coefficient 1.612 mm-1

F(000) 440

Crystal size 0.510 x 0.050 x 0.050 mm3

Theta range for data collection 4.249 to 66.618°.

Index ranges -11<=h<=9, -11<=k<=12, -12<=l<=13

Reflections collected 20182

290

Independent reflections 6343 [R(int) = 0.0218]

Completeness to theta = 67.679° 93.6 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7528 and 0.6312

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 6343 / 3 / 551

Goodness-of-fit on F2 1.053

Final R indices [I>2sigma(I)] R1 = 0.0411, wR2 = 0.1143

R indices (all data) R1 = 0.0423, wR2 = 0.1186

Absolute structure parameter 0.080(5)

Extinction coefficient n/a

Largest diff. peak and hole 0.666 and -0.356 e.Å-3

291

Table 8. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x

103)

for d13218_b. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______________________________________________________________________________

__

x y z U(eq)

______________________________________________________________________________

__

S(1A) 8961(1) 6811(1) 1750(1) 25(1)

O(1A) 6433(3) 4249(3) -1545(3) 36(1)

O(2A) 10180(3) 7574(3) 2606(3) 36(1)

O(3A) 7674(3) 6640(3) 2029(3) 33(1)

N(1A) 9603(4) 5368(3) 1641(3) 25(1)

C(1A) 8684(5) 4171(4) 1166(4) 26(1)

C(2A) 8840(4) 3213(4) 2272(4) 22(1)

C(3A) 9208(4) 3646(4) 3529(4) 27(1)

C(4A) 9406(4) 2760(4) 4523(4) 32(1)

C(5A) 9210(5) 1411(5) 4231(5) 43(1)

C(6A) 8806(5) 970(4) 2975(5) 41(1)

C(7A) 8614(4) 1841(4) 1980(4) 28(1)

C(8A) 8191(4) 1382(4) 640(4) 31(1)

292

C(9A) 8388(5) 2152(4) -255(4)34(1)

C(10A) 9136(4) 3498(4) 94(4) 29(1)

C(11A) 8976(4) 4329(4) -1089(4) 31(1)

C(12A) 7456(4) 4619(4) -1886(4) 28(1)

C(13A) 7199(4) 5376(4) -3096(4) 26(1)

C(14A) 8298(5) 5702(4) -3580(4) 31(1)

C(15A) 7983(5) 6348(4) -4743(4) 35(1)

C(16A) 6584(5) 6687(4) -5406(4) 35(1)

C(17A) 5490(5) 6401(4) -4919(4) 33(1)

C(18A) 5797(5) 5734(4) -3765(4) 30(1)

C(19A) 8511(4) 7565(3) 233(4) 23(1)

C(20A) 9632(5) 7882(4) -227(4)29(1)

C(21A) 9305(5) 8533(4) -1390(4) 31(1)

C(22A) 7912(5) 8864(4) -2076(4) 32(1)

C(23A) 6817(5) 8532(4) -1606(4) 31(1)

C(24A) 7104(4) 7875(4) -442(4)28(1)

C(25A) 7623(7) 9605(5) -3316(5) 48(1)

S(1B) 2697(1) 2160(1) -1641(1) 25(1)

O(1B) 2474(3) 4870(3) 1554(3) 34(1)

O(2B) 1216(3) 2431(3) -2141(2) 34(1)

293

O(3B) 3359(4) 1347(3) -2363(3) 40(1)

N(1B) 3648(4) 3536(3) -1362(3) 27(1)

C(1B) 3127(4) 4788(4) -1017(4) 24(1)

C(2B) 2691(4) 5741(4) -2144(4) 21(1)

C(3B) 2269(4) 5284(4) -3420(4) 24(1)

C(4B) 1899(4) 6177(4) -4423(4) 29(1)

C(5B) 1924(5) 7510(4) -4176(4) 33(1)

C(6B) 2338(4) 7986(4) -2907(4) 30(1)

C(7B) 2731(4) 7093(4) -1888(4) 22(1)

C(8B) 3199(4) 7577(3) -543(4)24(1)

C(9B) 3933(4) 6813(4) 402(4) 26(1)

C(10B) 4335(4) 5441(3) 147(3) 24(1)

C(11B) 4795(4) 4608(4) 1375(4) 24(1)

C(12B) 3687(4) 4371(4) 1987(4) 23(1)

C(13B) 4070(4) 3587(4) 3176(4) 23(1)

C(14B) 2990(4) 3236(4) 3698(4) 26(1)

C(15B) 3341(5) 2544(4) 4823(4) 29(1)

C(16B) 4747(5) 2201(4) 5458(4) 32(1)

C(17B) 5823(5) 2534(4) 4939(4) 33(1)

C(18B) 5483(4) 3203(4) 3810(4) 27(1)

294

C(19B) 3002(4) 1389(3) -143(4)22(1)

C(20B) 1847(4) 1075(4) 257(4) 25(1)

C(21B) 2079(5) 406(4) 1392(4) 28(1)

C(22B) 3457(5) 38(4) 2131(4) 28(1)

C(23B) 4606(5) 377(4) 1707(4) 33(1)

C(24B) 4394(5) 1048(4) 585(4) 28(1)

C(25B) 3679(6) -733(5)3340(4) 45(1)

______________________________________________________________________________

__

295

Table 9. Bond lengths [Å] and angles [°] for d13218_b.

_____________________________________________________

S(1A)-O(3A) 1.403(3)

S(1A)-O(2A) 1.449(3)

S(1A)-N(1A) 1.622(3)

S(1A)-C(19A) 1.771(4)

O(1A)-C(12A) 1.235(5)

N(1A)-C(1A) 1.472(5)

N(1A)-H(1NA) 0.92(4)

C(1A)-C(2A) 1.538(5)

C(1A)-C(10A) 1.551(5)

C(1A)-H(1AA) 1.0000

C(2A)-C(3A) 1.375(6)

C(2A)-C(7A) 1.415(5)

C(3A)-C(4A) 1.391(6)

C(3A)-H(3AA) 0.9500

C(4A)-C(5A) 1.391(7)

C(4A)-H(4AA) 0.9500

C(5A)-C(6A) 1.374(7)

C(5A)-H(5AA) 0.9500

296

C(6A)-C(7A) 1.383(6)

C(6A)-H(6AA) 0.9500

C(7A)-C(8A) 1.462(6)

C(8A)-C(9A) 1.327(6)

C(8A)-H(8AA) 0.9500

C(9A)-C(10A) 1.512(6)

C(9A)-H(9AA) 0.9500

C(10A)-C(11A) 1.528(6)

C(10A)-H(10A) 1.0000

C(11A)-C(12A) 1.496(6)

C(11A)-H(11A) 0.9900

C(11A)-H(11B) 0.9900

C(12A)-C(13A) 1.497(6)

C(13A)-C(18A) 1.387(6)

C(13A)-C(14A) 1.389(6)

C(14A)-C(15A) 1.392(6)

C(14A)-H(14A) 0.9500

C(15A)-C(16A) 1.377(7)

C(15A)-H(15A) 0.9500

C(16A)-C(17A) 1.378(7)

297

C(16A)-H(16A) 0.9500

C(17A)-C(18A) 1.394(6)

C(17A)-H(17A) 0.9500

C(18A)-H(18A) 0.9500

C(19A)-C(24A) 1.379(6)

C(19A)-C(20A) 1.389(6)

C(20A)-C(21A) 1.393(6)

C(20A)-H(20A) 0.9500

C(21A)-C(22A) 1.376(7)

C(21A)-H(21A) 0.9500

C(22A)-C(23A) 1.376(7)

C(22A)-C(25A) 1.514(6)

C(23A)-C(24A) 1.400(6)

C(23A)-H(23A) 0.9500

C(24A)-H(24A) 0.9500

C(25A)-H(25A) 0.9800

C(25A)-H(25B) 0.9800

C(25A)-H(25C) 0.9800

S(1B)-O(2B) 1.407(3)

S(1B)-O(3B) 1.445(3)

298

S(1B)-N(1B) 1.623(3)

S(1B)-C(19B) 1.773(4)

O(1B)-C(12B) 1.247(5)

N(1B)-C(1B) 1.469(5)

N(1B)-H(1NB) 1.08(6)

C(1B)-C(2B) 1.533(5)

C(1B)-C(10B) 1.555(5)

C(1B)-H(1BA) 1.0000

C(2B)-C(7B) 1.390(5)

C(2B)-C(3B) 1.398(5)

C(3B)-C(4B) 1.395(6)

C(3B)-H(3BA) 0.9500

C(4B)-C(5B) 1.370(6)

C(4B)-H(4BA) 0.9500

C(5B)-C(6B) 1.397(6)

C(5B)-H(5BA) 0.9500

C(6B)-C(7B) 1.407(5)

C(6B)-H(6BA) 0.9500

C(7B)-C(8B) 1.474(5)

C(8B)-C(9B) 1.323(6)

299

C(8B)-H(8BA) 0.9500

C(9B)-C(10B) 1.500(5)

C(9B)-H(9BA) 0.9500

C(10B)-C(11B) 1.546(5)

C(10B)-H(10B) 1.0000

C(11B)-C(12B) 1.475(5)

C(11B)-H(11C) 0.9900

C(11B)-H(11D) 0.9900

C(12B)-C(13B) 1.484(5)

C(13B)-C(18B) 1.396(6)

C(13B)-C(14B) 1.405(5)

C(14B)-C(15B) 1.378(6)

C(14B)-H(14B) 0.9500

C(15B)-C(16B) 1.378(6)

C(15B)-H(15B) 0.9500

C(16B)-C(17B) 1.396(6)

C(16B)-H(16B) 0.9500

C(17B)-C(18B) 1.370(6)

C(17B)-H(17B) 0.9500

C(18B)-H(18B) 0.9500

300

C(19B)-C(20B) 1.379(6)

C(19B)-C(24B) 1.388(6)

C(20B)-C(21B) 1.384(6)

C(20B)-H(20B) 0.9500

C(21B)-C(22B) 1.388(6)

C(21B)-H(21B) 0.9500

C(22B)-C(23B) 1.395(6)

C(22B)-C(25B) 1.509(6)

C(23B)-C(24B) 1.377(6)

C(23B)-H(23B) 0.9500

C(24B)-H(24B) 0.9500

C(25B)-H(25D) 0.9800

C(25B)-H(25E) 0.9800

C(25B)-H(25F) 0.9800

O(3A)-S(1A)-O(2A) 121.05(18)

O(3A)-S(1A)-N(1A) 108.82(17)

O(2A)-S(1A)-N(1A) 104.47(17)

O(3A)-S(1A)-C(19A) 107.17(18)

O(2A)-S(1A)-C(19A) 106.34(17)

301

N(1A)-S(1A)-C(19A) 108.48(17)

C(1A)-N(1A)-S(1A) 123.2(3)

C(1A)-N(1A)-H(1NA) 121(2)

S(1A)-N(1A)-H(1NA) 114(2)

N(1A)-C(1A)-C(2A) 110.2(3)

N(1A)-C(1A)-C(10A) 109.0(3)

C(2A)-C(1A)-C(10A) 110.3(3)

N(1A)-C(1A)-H(1AA) 109.1

C(2A)-C(1A)-H(1AA) 109.1

C(10A)-C(1A)-H(1AA) 109.1

C(3A)-C(2A)-C(7A) 119.3(4)

C(3A)-C(2A)-C(1A) 122.1(3)

C(7A)-C(2A)-C(1A) 118.6(3)

C(2A)-C(3A)-C(4A) 121.3(4)

C(2A)-C(3A)-H(3AA) 119.3

C(4A)-C(3A)-H(3AA) 119.3

C(3A)-C(4A)-C(5A) 119.0(4)

C(3A)-C(4A)-H(4AA) 120.5

C(5A)-C(4A)-H(4AA) 120.5

C(6A)-C(5A)-C(4A) 120.2(4)

302

C(6A)-C(5A)-H(5AA) 119.9

C(4A)-C(5A)-H(5AA) 119.9

C(5A)-C(6A)-C(7A) 121.3(4)

C(5A)-C(6A)-H(6AA) 119.3

C(7A)-C(6A)-H(6AA) 119.3

C(6A)-C(7A)-C(2A) 118.9(4)

C(6A)-C(7A)-C(8A) 121.8(4)

C(2A)-C(7A)-C(8A) 119.4(4)

C(9A)-C(8A)-C(7A) 120.9(4)

C(9A)-C(8A)-H(8AA) 119.5

C(7A)-C(8A)-H(8AA) 119.5

C(8A)-C(9A)-C(10A) 120.9(4)

C(8A)-C(9A)-H(9AA) 119.6

C(10A)-C(9A)-H(9AA) 119.6

C(9A)-C(10A)-C(11A) 112.1(3)

C(9A)-C(10A)-C(1A) 110.0(3)

C(11A)-C(10A)-C(1A) 115.6(3)

C(9A)-C(10A)-H(10A) 106.1

C(11A)-C(10A)-H(10A) 106.1

C(1A)-C(10A)-H(10A) 106.1

303

C(12A)-C(11A)-C(10A) 115.4(3)

C(12A)-C(11A)-H(11A) 108.4

C(10A)-C(11A)-H(11A) 108.4

C(12A)-C(11A)-H(11B) 108.4

C(10A)-C(11A)-H(11B) 108.4

H(11A)-C(11A)-H(11B) 107.5

O(1A)-C(12A)-C(11A) 120.5(4)

O(1A)-C(12A)-C(13A) 120.7(4)

C(11A)-C(12A)-C(13A) 118.8(3)

C(18A)-C(13A)-C(14A) 119.3(4)

C(18A)-C(13A)-C(12A) 118.0(4)

C(14A)-C(13A)-C(12A) 122.7(4)

C(13A)-C(14A)-C(15A) 120.1(4)

C(13A)-C(14A)-H(14A) 119.9

C(15A)-C(14A)-H(14A) 119.9

C(16A)-C(15A)-C(14A) 120.1(4)

C(16A)-C(15A)-H(15A) 120.0

C(14A)-C(15A)-H(15A) 120.0

C(15A)-C(16A)-C(17A) 120.4(4)

C(15A)-C(16A)-H(16A) 119.8

304

C(17A)-C(16A)-H(16A) 119.8

C(16A)-C(17A)-C(18A) 119.7(4)

C(16A)-C(17A)-H(17A) 120.2

C(18A)-C(17A)-H(17A) 120.2

C(13A)-C(18A)-C(17A) 120.4(4)

C(13A)-C(18A)-H(18A) 119.8

C(17A)-C(18A)-H(18A) 119.8

C(24A)-C(19A)-C(20A) 121.2(4)

C(24A)-C(19A)-S(1A) 121.0(3)

C(20A)-C(19A)-S(1A) 117.7(3)

C(19A)-C(20A)-C(21A) 118.4(4)

C(19A)-C(20A)-H(20A) 120.8

C(21A)-C(20A)-H(20A) 120.8

C(22A)-C(21A)-C(20A) 121.5(4)

C(22A)-C(21A)-H(21A) 119.2

C(20A)-C(21A)-H(21A) 119.2

C(21A)-C(22A)-C(23A) 119.1(4)

C(21A)-C(22A)-C(25A) 119.3(4)

C(23A)-C(22A)-C(25A) 121.6(4)

C(22A)-C(23A)-C(24A) 121.1(4)

305

C(22A)-C(23A)-H(23A) 119.5

C(24A)-C(23A)-H(23A) 119.5

C(19A)-C(24A)-C(23A) 118.7(4)

C(19A)-C(24A)-H(24A) 120.6

C(23A)-C(24A)-H(24A) 120.6

C(22A)-C(25A)-H(25A) 109.5

C(22A)-C(25A)-H(25B) 109.5

H(25A)-C(25A)-H(25B) 109.5

C(22A)-C(25A)-H(25C) 109.5

H(25A)-C(25A)-H(25C) 109.5

H(25B)-C(25A)-H(25C) 109.5

O(2B)-S(1B)-O(3B) 120.55(18)

O(2B)-S(1B)-N(1B) 109.74(16)

O(3B)-S(1B)-N(1B) 104.53(17)

O(2B)-S(1B)-C(19B) 107.37(18)

O(3B)-S(1B)-C(19B) 106.64(17)

N(1B)-S(1B)-C(19B) 107.34(17)

C(1B)-N(1B)-S(1B) 123.4(3)

C(1B)-N(1B)-H(1NB)126(3)

S(1B)-N(1B)-H(1NB) 110(3)

306

N(1B)-C(1B)-C(2B) 112.1(3)

N(1B)-C(1B)-C(10B) 108.7(3)

C(2B)-C(1B)-C(10B) 110.1(3)

N(1B)-C(1B)-H(1BA)108.6

C(2B)-C(1B)-H(1BA) 108.6

C(10B)-C(1B)-H(1BA) 108.6

C(7B)-C(2B)-C(3B) 119.2(3)

C(7B)-C(2B)-C(1B) 119.1(3)

C(3B)-C(2B)-C(1B) 121.7(3)

C(4B)-C(3B)-C(2B) 120.3(4)

C(4B)-C(3B)-H(3BA) 119.8

C(2B)-C(3B)-H(3BA) 119.8

C(5B)-C(4B)-C(3B) 120.7(4)

C(5B)-C(4B)-H(4BA) 119.7

C(3B)-C(4B)-H(4BA) 119.7

C(4B)-C(5B)-C(6B) 119.9(4)

C(4B)-C(5B)-H(5BA) 120.1

C(6B)-C(5B)-H(5BA) 120.1

C(5B)-C(6B)-C(7B) 119.9(4)

C(5B)-C(6B)-H(6BA) 120.1

307

C(7B)-C(6B)-H(6BA) 120.1

C(2B)-C(7B)-C(6B) 120.1(3)

C(2B)-C(7B)-C(8B) 119.2(3)

C(6B)-C(7B)-C(8B) 120.7(3)

C(9B)-C(8B)-C(7B) 120.6(3)

C(9B)-C(8B)-H(8BA) 119.7

C(7B)-C(8B)-H(8BA) 119.7

C(8B)-C(9B)-C(10B) 121.6(3)

C(8B)-C(9B)-H(9BA) 119.2

C(10B)-C(9B)-H(9BA) 119.2

C(9B)-C(10B)-C(11B) 112.1(3)

C(9B)-C(10B)-C(1B) 110.3(3)

C(11B)-C(10B)-C(1B) 114.9(3)

C(9B)-C(10B)-H(10B) 106.3

C(11B)-C(10B)-H(10B) 106.3

C(1B)-C(10B)-H(10B) 106.3

C(12B)-C(11B)-C(10B) 116.2(3)

C(12B)-C(11B)-H(11C) 108.2

C(10B)-C(11B)-H(11C) 108.2

C(12B)-C(11B)-H(11D) 108.2

308

C(10B)-C(11B)-H(11D) 108.2

H(11C)-C(11B)-H(11D) 107.4

O(1B)-C(12B)-C(11B) 120.9(3)

O(1B)-C(12B)-C(13B) 120.3(3)

C(11B)-C(12B)-C(13B) 118.7(3)

C(18B)-C(13B)-C(14B) 118.6(4)

C(18B)-C(13B)-C(12B) 121.9(3)

C(14B)-C(13B)-C(12B) 119.4(3)

C(15B)-C(14B)-C(13B) 120.0(4)

C(15B)-C(14B)-H(14B) 120.0

C(13B)-C(14B)-H(14B) 120.0

C(16B)-C(15B)-C(14B) 120.9(4)

C(16B)-C(15B)-H(15B) 119.6

C(14B)-C(15B)-H(15B) 119.6

C(15B)-C(16B)-C(17B) 119.5(4)

C(15B)-C(16B)-H(16B) 120.3

C(17B)-C(16B)-H(16B) 120.3

C(18B)-C(17B)-C(16B) 120.2(4)

C(18B)-C(17B)-H(17B) 119.9

C(16B)-C(17B)-H(17B) 119.9

309

C(17B)-C(18B)-C(13B) 120.8(4)

C(17B)-C(18B)-H(18B) 119.6

C(13B)-C(18B)-H(18B) 119.6

C(20B)-C(19B)-C(24B) 120.6(4)

C(20B)-C(19B)-S(1B) 119.7(3)

C(24B)-C(19B)-S(1B) 119.6(3)

C(19B)-C(20B)-C(21B) 119.6(4)

C(19B)-C(20B)-H(20B) 120.2

C(21B)-C(20B)-H(20B) 120.2

C(20B)-C(21B)-C(22B) 121.1(4)

C(20B)-C(21B)-H(21B) 119.5

C(22B)-C(21B)-H(21B) 119.5

C(21B)-C(22B)-C(23B) 118.1(4)

C(21B)-C(22B)-C(25B) 120.2(4)

C(23B)-C(22B)-C(25B) 121.6(4)

C(24B)-C(23B)-C(22B) 121.5(4)

C(24B)-C(23B)-H(23B) 119.3

C(22B)-C(23B)-H(23B) 119.3

C(23B)-C(24B)-C(19B) 119.1(4)

C(23B)-C(24B)-H(24B) 120.4

310

C(19B)-C(24B)-H(24B) 120.4

C(22B)-C(25B)-H(25D) 109.5

C(22B)-C(25B)-H(25E) 109.5

H(25D)-C(25B)-H(25E) 109.5

C(22B)-C(25B)-H(25F) 109.5

H(25D)-C(25B)-H(25F) 109.5

H(25E)-C(25B)-H(25F) 109.5

_____________________________________________________________


311

Table 10. Anisotropic displacement parameters (Å2x 103) for d13218_b. The anisotropic

displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________

S(1A) 37(1) 18(1) 21(1) -1(1) 10(1) 1(1)

O(1A) 24(2) 49(2) 38(2) 2(1) 16(1) -3(1)

O(2A) 48(2) 27(1) 27(1) -3(1) 6(1) -2(1)

O(3A) 43(2) 28(1) 35(1) 3(1) 21(1) 7(1)

N(1A) 21(2) 23(2) 30(2) -1(1) 7(1) 0(1)

C(1A) 30(2) 20(2) 28(2) -4(1) 10(2) 1(2)

C(2A) 17(2) 20(2) 30(2) 2(1) 8(2) 0(1)

C(3A) 23(2) 26(2) 34(2) 0(2) 10(2) -1(2)

C(4A) 23(2) 44(2) 31(2) 6(2) 10(2) 2(2)

C(5A) 47(3) 37(2) 51(3) 20(2) 24(2) 8(2)

C(6A) 41(3) 24(2) 62(3) 9(2) 21(2) 4(2)

C(7A) 21(2) 20(2) 45(2) -1(2) 15(2) 0(1)

C(8A) 22(2) 24(2) 50(3) -8(2) 16(2) -3(2)

C(9A) 32(2) 31(2) 38(2) -10(2) 11(2) 5(2)

C(10A) 22(2) 31(2) 31(2) -7(2) 8(2) 4(2)

312

C(11A) 19(2) 38(2) 40(2) 0(2) 16(2) 2(2)

C(12A) 25(2) 30(2) 26(2) -9(2) 6(2) -2(2)

C(13A) 24(2) 30(2) 25(2) -7(2) 8(2) -3(2)

C(14A) 25(2) 42(2) 30(2) -8(2) 12(2) -2(2)

C(15A) 40(3) 37(2) 34(2) -4(2) 19(2) -5(2)

C(16A) 42(3) 34(2) 29(2) -1(2) 12(2) 0(2)

C(17A) 36(2) 33(2) 30(2) 0(2) 10(2) 4(2)

C(18A) 26(2) 34(2) 31(2) 0(2) 13(2) -1(2)

C(19A) 29(2) 15(2) 24(2) 0(1) 10(2) 0(1)

C(20A) 28(2) 29(2) 29(2) 0(2) 9(2) 2(2)

C(21A) 40(2) 29(2) 30(2) 1(2) 19(2) -3(2)

C(22A) 48(3) 21(2) 24(2) -3(2) 7(2) -3(2)

C(23A) 29(2) 26(2) 30(2) 0(2) -1(2) -1(2)

C(24A) 27(2) 22(2) 33(2) 0(2) 9(2) -2(2)

C(25A) 79(4) 33(2) 31(2) 5(2) 15(2) 1(2)

S(1B) 40(1) 16(1) 22(1) -1(1) 12(1) -2(1)

O(1B) 21(2) 43(2) 40(2) 12(1) 14(1) 6(1)

O(2B) 34(2) 28(1) 32(1) 2(1) 1(1) -7(1)

O(3B) 68(2) 24(1) 38(2) -5(1) 31(2) -5(1)

N(1B) 32(2) 20(1) 33(2) 0(1) 17(1) 0(1)

313

C(1B) 34(2) 16(2) 22(2) -2(1) 11(2) -1(1)

C(2B) 20(2) 22(2) 24(2) -2(1) 10(1) -1(1)

C(3B) 21(2) 24(2) 24(2) -2(1) 7(2) -2(1)

C(4B) 30(2) 34(2) 23(2) 2(2) 10(2) -1(2)

C(5B) 36(2) 32(2) 28(2) 10(2) 7(2) 1(2)

C(6B) 33(2) 21(2) 35(2) 4(2) 10(2) 1(2)

C(7B) 16(2) 23(2) 27(2) 1(1) 8(2) -1(1)

C(8B) 23(2) 17(2) 32(2) -5(1) 11(2) 0(1)

C(9B) 28(2) 23(2) 29(2) -4(1) 12(2) -3(2)

C(10B) 22(2) 24(2) 28(2) -2(1) 12(2) -4(1)

C(11B) 17(2) 24(2) 33(2) 1(1) 12(2) 0(1)

C(12B) 21(2) 26(2) 23(2) -4(1) 8(2) -7(2)

C(13B) 24(2) 22(2) 25(2) -4(1) 12(2) -1(1)

C(14B) 25(2) 26(2) 28(2) -2(2) 12(2) -2(2)

C(15B) 32(2) 31(2) 30(2) -3(2) 19(2) -3(2)

C(16B) 38(2) 33(2) 30(2) 4(2) 19(2) 3(2)

C(17B) 29(2) 37(2) 37(2) 8(2) 14(2) 7(2)

C(18B) 25(2) 30(2) 30(2) 1(2) 14(2) 0(2)

C(19B) 25(2) 18(2) 22(2) -1(1) 8(2) 0(1)

C(20B) 24(2) 18(2) 31(2) -1(1) 9(2) 2(1)

314

C(21B) 37(2) 22(2) 32(2) -1(2) 20(2) -2(2)

C(22B) 40(2) 19(2) 25(2) 1(1) 9(2) 0(2)

C(23B) 31(2) 23(2) 37(2) 3(2) -1(2) 2(2)

C(24B) 26(2) 22(2) 38(2) 1(2) 13(2) -5(2)

C(25B) 70(4) 32(2) 27(2) 8(2) 9(2) -2(2)

______________________________________________________________________________

315

Table 11. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3)

for d13218_b.

______________________________________________________________________________

__

x y z U(eq)

______________________________________________________________________________

__

H(1AA) 7651 4430 799 31

H(3AA) 9329 4568 3722 33

H(4AA) 9671 3072 5389 39

H(5AA) 9355 794 4901 52

H(6AA) 8657 47 2786 50

H(8AA) 7770 519 408 37

H(9AA) 8053 1855 -1128 40

H(10A) 10192 3330 485 34

H(11A) 9517 5180 -803 37

H(11B) 9433 3862 -1640 37

H(14A) 9267 5483 -3117 38

H(15A) 8734 6556 -5080 42

H(16A) 6372 7119 -6204 42

316

H(17A) 4531 6658 -5367 40

H(18A) 5041 5523 -3435 35

H(20A) 10598 7660 240 34

H(21A) 10061 8753 -1717 38

H(23A) 5852 8751 -2080 37

H(24A) 6343 7649 -123 33

H(25A) 8093 9163 -3859 72

H(25B) 8012 10515 -3121 72

H(25C) 6579 9618 -3770 72

H(1BA) 2262 4591 -755 28

H(3BA) 2234 4361 -3605 28

H(4BA) 1626 5858 -5287 35

H(5BA) 1661 8110 -4865 40

H(6BA) 2355 8910 -2732 36

H(8BA) 2971 8446 -352 29

H(9BA) 4212 7140 1264 31

H(10B) 5209 5544 -122 29

H(11C) 5107 3739 1157 29

H(11D) 5646 5056 2013 29

H(14B) 2019 3477 3276 31

317

H(15B) 2604 2300 5165 35

H(16B) 4981 1742 6244 38

H(17B) 6793 2295 5369 40

H(18B) 6219 3409 3454 33

H(20B) 898 1315 -242 30

H(21B) 1283 197 1671 34

H(23B) 5557 139 2205 40

H(24B) 5189 1274 311 34

H(25D) 4701 -946 3717 68

H(25E)3088 -1554 3132 68

H(25F) 3392 -200 3957 68

H(1NA) 10570(50) 5380(40) 1740(40) 14(9)

H(1NB) 4640(60) 3410(50) -1560(50) 54(15)

______________________________________________________________________________

__

318

Table 12. Hydrogen bonds for d13218_b [Å and °].

____________________________________________________________________________

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

____________________________________________________________________________

N(1A)-H(1NA)...O(1B)#1 0.92(4) 2.02(5) 2.907(5) 161(3)

N(1B)-H(1NB)...O(1A) 1.08(6) 1.93(6) 2.880(4) 145(4)

____________________________________________________________________________


#1 x+1,y,z

319

Appendix 2: Ligand-Dependent Domino Rh/Pd-Catalyzed Synthesis of Dihydroquinolines

320

Cl

NHTs

400 MHz, CDCl3

100 MHz, CDCl3

321

Cl

NHSO2Ph

400 MHz, CDCl3

100 MHz, CDCl3

322

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

-10000

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

1E+05

1E+05

102030405060708090100110120130140150160170180190f1 (ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

Cl

NHBoc

400 MHz, CDCl3

100 MHz, CDCl3

323

Cl

HN

SO O

OMe

400 MHz, CDCl3

100 MHz, CDCl3

324

34.0

6

76.8

477

.16

77.4

882

.37

87.8

0

121.

5112

4.36

126.

6712

8.90

129.

5113

0.25

133.

2113

5.73

146.

03

150.

15

Cl

HN

SO O

NO2

100 MHz, CDCl3

400 MHz, CDCl3

325

33.5

7

41.7

0

80.5

8

92.0

2

117.

6012

1.22

123.

5012

3.55

123.

6012

3.65

124.

8312

5.74

126.

3912

6.44

126.

4912

6.54

128.

4513

1.61

132.

0513

3.94

136.

61

100 MHz, CDCl3

400 MHz, CDCl3

326

-63.

47

282 MHz, CDCl3

327

2.02

2.00

1.99

0.88

0.99

2.72

2.74

2.76

3.82

3.84

3.86

7.15

7.15

7.16

7.16

7.18

7.18

7.18

7.19

7.20

7.20

7.21

7.21

7.22

7.22

7.24

7.25

7.26

7.27

7.36

7.37

7.37

7.39

7.39

7.43

7.44

7.45

7.45

7.45

7.46

24.1

3

61.1

1

76.7

477

.16

77.5

879

.57

123.

2412

6.53

129.

0812

9.24

133.

3313

5.93

Cl

OH

300 MHz, CDCl3

75 MHz, CDCl3

328

3.58

2.39

1.02

1.12

1.06

1.00

3.16

4.27

4.29

4.86

7.22

7.23

7.24

7.25

7.26

7.75

7.76

7.77

7.78

8.36

8.37

8.37

33.6

7

41.8

5

76.8

477

.16

77.4

879

.96

91.8

6

119.

4312

2.14

141.

85

149.

1015

2.43

N Cl

NHMs

400 MHz, CDCl3

100 MHz, CDCl3

329

3.02

3.04

2.06

1.04

0.91

0.99

0.92

1.00

2.06

2.50

3.03

3.32

4.09

4.11

7.43

7.45

7.48

7.50

7.66

7.89

10.2

6

s

24.1

3

32.6

3

39.5

240

.66

80.0

4

90.0

4

115.

5211

7.43

118.

72

133.

9913

4.78

140.

71

168.

96

Cl

NHMs

AcHN

400 MHz, DMSO

100 MHz, DMSO

330

28.3

2

39.6

8

76.7

177

.03

77.3

579

.43

126.

7012

6.86

127.

9712

8.09

128.

6512

8.78

129.

5213

0.49

134.

0313

5.32

139.

4213

9.57

155.

59

NHBocCl

400 MHz, CDCl3

100 MHz, CDCl3

331

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

42.4

4

76.8

477

.16

77.4

8

126.

7012

6.89

127.

2712

8.53

128.

9712

9.17

129.

2912

9.67

130.

1713

2.80

134.

0413

4.78

137.

2113

8.62

139.

23

NHSO2PhCl

100 MHz, CDCl3

400 MHz, CDCl3

332

2.89

2.00

1.22

0.85

5.01

0.98

1.78

3.32

0.00

2.43

4.06

4.08

6.93

7.18

7.19

7.26

7.37

7.39

7.42

7.44

7.52

7.54

6.93

7.18

7.19

7.26

7.37

7.39

7.42

7.44

7.52

7.54

21.6

0

42.3

7

76.7

477

.16

77.5

8

125.

6612

5.71

126.

9312

7.15

127.

2112

9.41

129.

7312

9.76

130.

0913

1.14

134.

0213

4.32

136.

1513

6.56

142.

5414

3.72

125.

6112

5.66

125.

7112

5.76

126.

9312

7.15

127.

21

Cl NHTs

CF3 400 MHz, CDCl3

100 MHz, CDCl3

333

-63.

02

377 MHz, CDCl3

334

Cl NHTs

300 MHz, CDCl3

100 MHz, CDCl3

335

Cl NHTs

OMe

400 MHz, CDCl3

100 MHz, CDCl3

336

Cl NHTs

N Cl

300 MHz, CDCl3

75 MHz, CDCl3

337

Cl OH

400 MHz, CDCl3

100 MHz, CDCl3

338

ClOH

400 MHz, CDCl3

100 MHz, CDCl3

339

N

Ts

400 MHz, CDCl3

100 MHz, CDCl3

340

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

0

10000

20000

30000

40000

50000

60000

70000

80000

47.7

2

76.8

477

.16

77.4

8

125.

2212

6.99

127.

1012

7.15

127.

2112

8.05

128.

3412

8.40

128.

8313

0.63

132.

7513

4.24

134.

6613

7.44

138.

55

N

SO2Ph

400 MHz, CDCl3

100 MHz, CDCl3

341

3.14

2.14

1.00

1.95

1.03

2.88

6.07

0.96

3.74

4.80

6.34

6.57

6.60

7.19

7.21

7.26

7.30

7.31

7.36

7.76

7.78

N

SO

O

OMe

400 MHz, CDCl3

100 MHz, CDCl3

342

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

2.23

1.06

1.09

4.05

6.33

1.00

2.00

4.83

4.83

6.31

7.24

7.24

7.26

7.26

7.38

7.40

7.40

7.42

7.43

7.78

7.80

7.94

7.94

7.95

7.96

7.97

7.97

47.8

4

76.8

477

.16

77.4

8

121.

2912

3.51

125.

0212

7.04

127.

4512

7.92

128.

4112

8.47

128.

9212

9.17

130.

5013

3.48

134.

5413

6.94

144.

00

150.

14

N

SO

O

NO2

400 MHz, CDCl3

100 MHz, CDCl3

343

N

Ts

400 MHz, CDCl3

100 MHz, CDCl3

344

N

Ts

OMe

100 MHz, CDCl3

400 MHz, CDCl3

345

N

Ms

OMe

300 MHz, CDCl3

75 MHz, CDCl3

346

TsN

Ac

400 MHz, CDCl3

100 MHz, CDCl3

347

TsN

CF3

400 MHz, CDCl3

100 MHz, CDCl3

348

377 MHz, CDCl3

349

N

Ts

NO2

400 MHz, CDCl3

100 MHz, CDCl3

350

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

0

5000

10000

15000

20000

25000

21.6

2

47.1

9

76.8

477

.16

77.4

8

111.

66

118.

7212

4.34

125.

6612

7.13

127.

2912

7.66

129.

0913

2.66

141.

7614

3.80

N

Ts

CN

400 MHz, CDCl3

100 MHz, CDCl3

351

3.20

2.11

1.00

3.08

2.96

1.93

2.65

4.78

7.06

7.31

7.33

7.34

7.36

7.36

7.65

7.67

7.69

7.72

7.74

0102030405060708090100110120130140150160170180190200f1 (ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

6000037.8

8

46.9

7

76.8

477

.16

77.4

8

112.

00

118.

5812

4.91

125.

9412

6.18

127.

3412

8.06

129.

4613

2.93

141.

39

N

Ms

CN

100 MHz, CDCl3

400 MHz, CDCl3

352

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000

6.97.07.17.27.37.47.57.67.77.87.9f1 (ppm)

0102030405060708090100110120130140150160170180190200f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

121123125127129131133135f1 (ppm)

N

Ts

CF3

400 MHz, CDCl3

100 MHz, CDCl3

353

377 MHz, CDCl3

354

TsN

CF3

400 MHz, CDCl3

100 MHz, CDCl3

355

377 MHz, CDCl3

356

3.03

3.23

3.21

2.02

1.00

1.04

1.09

1.04

3.76

0.92

2.63

3.93

3.97

4.74

4.75

6.86

6.91

6.93

7.07

7.08

7.12

7.13

7.14

7.15

7.26

7.27

7.28

7.28

7.28

7.29

7.30

7.64

7.64

7.65

7.65

7.65

N

Ms

OMe

OMe

400 MHz, CDCl3

100 MHz, CDCl3

357

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

6.86.97.07.17.27.37.4f1 (ppm)

0102030405060708090100110120130140150160170180190200f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

116117118119120121122123124125126127128129130131f1 (ppm)

N

Ts

F400 MHz, CDCl3

100 MHz, CDCl3

358

-170-150-130-110-90-70-50-30-100102030405060708090110130150f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

-111.50-111.40-111.30-111.20f1 (ppm)

377 MHz, CDCl3

359

N

Ts

N F

400 MHz, CDCl3

100 MHz, CDCl3

360

377 MHz, CDCl3

361

N

Ts

N OEt

400 MHz, CDCl3

100 MHz, CDCl3

362

21.5

8

47.5

3

76.7

477

.16

77.5

8

120.

0312

1.08

124.

5512

6.52

126.

9212

6.94

127.

0512

7.13

127.

7612

8.86

129.

7913

0.43

134.

2913

5.58

139.

2314

3.50

N

Ts

S

300 MHz, CDCl3

75 MHz, CDCl3

363

3.34

2.22

1.04

1.02

2.07

1.11

2.21

0.91

1.24

1.01

1.03

1.04

2.28

4.59

4.59

6.12

6.37

6.38

6.38

6.92

6.94

6.97

6.98

6.99

7.00

7.16

7.18

7.20

7.20

7.22

7.22

7.25

7.26

7.27

7.27

7.27

7.29

7.29

7.41

7.42

7.42

7.60

7.74

7.76

0102030405060708090100110120130140150160170180190200f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

N

Ts

O

100 MHz, CDCl3

400 MHz, CDCl3

364

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

N

Ms

O

400 MHz, CDCl3

100 MHz, CDCl3

365

N

Ms

MeO

400 MHz, CDCl3

100 MHz, CDCl3

366

N

MsF

400 MHz, CDCl3

100 MHz, CDCl3

367

377 MHz, CDCl3

368

N

F

Ms

S

400 MHz, CDCl3

100 MHz, CDCl3

369

377 MHz, CDCl3

370

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.5f1 (ppm)

0

100

200

300

400

500

600

700

800

900

1000

1100

24.0

4

37.7

639

.31

39.5

239

.73

46.4

8

115.

6011

7.02

119.

9012

1.72

124.

5412

4.85

127.

4412

7.52

128.

4913

4.49

138.

6113

8.72

168.

40

N

Ms

S

AcHN

400 MHz, CDCl3

100 MHz, CDCl3

371

O

300 MHz, CDCl3

100 MHz, CDCl3

372

O

CN

100 MHz, CDCl3

400 MHz, CDCl3

373

O

CO2Me

400 MHz, CDCl3

100 MHz, CDCl3

374

N

S

400 MHz, CDCl3

375

O

OHOH

400 MHz, CDCl3

100 MHz, CDCl3

376

31P NMR spectra of catalyst-ligand mixtures

31P NMR spectra of Rh-ligand mixtures in benzene

[Rh(cod)OH]2 + 4 X-Phos [Rh(cod)OH]2 + 4 X-Phos

-12.

70

Figure 2, entry 1: [Rh(cod)OH]2 (4.6 mg, 0.01 mmol) and X-Phos (19.07 mg, 0.04 mmol) were dissolved in benzene and left standing for 15min.

377

-12.

70

Figure 2, entry 2: The sample prepared in entry 1 was heated at 50 °C in an oil bath for 1 h.

378

[Rh(cod)OH]2 + BINAP [Rh(BINAP)OH]2

-15.

70

52.8

955

.18

Figure 2, entry 3 [Rh(cod)OH]2 (4.6 mg, 0.01 mmol) and BINAP (12.4 mg, 0.02 mmol) were dissolved in benzene and heated at 50 °C for 1 h.

379

([Rh(cod)OH]2 + 4 X-Phos) + BINAP [Rh(BINAP)OH]2 + 4 X-Phos

-15.

70

-12.

71

52.9

255

.21

Figure 4, entry 1: [Rh(cod)OH]2 (4.6 mg, 0.01 mmol) and X-Phos (19.07 mg, 0.04 mmol) were dissolved in benzene and left standing for 1 h. To that solution was added BINAP (12.4 mg, 0.02 mmol) and heated in an oil bath at 50 °C for 2 h.

380

31P NMR spectra of Pd-ligand mixtures in dioxane

Pd(OAc)2 + 2 X-Phos [Pd(X-Phos)2OAc2]

-12.

36

0.03

41.7

7

Figure 4, entry 1: Pd(OAc)2 (4.5 mg, 0.02 mmol) and X-Phos (19.07 mg, 0.04 mmol) were weighed into a 2 dram vial, which was equipped with a stirring bar and fitted with a septum. Dioxane (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. An NMR tube was equipped with a sealed tube of H3PO4 in D2O (1:5, reference), fitted with a septum and purged with argon. An aliquot of the catalyst solution (0.5 ml) was transferred via syringe into the NMR tube.

381

Pd(OAc)2 + (R)-BINAP [Pd((R)-BINAP)(OAc)2]

0.00

25.2

8

Scheme 1: Pd(OAc)2 (4.5 mg, 0.02 mmol) and (R)-BINAP (12.45mg, 0.02 mmol) were weighed into a 2 dram vial, which was equipped with a stirring bar and fitted with a septum. Dioxane (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. An NMR tube was equipped with a sealed tube of H3PO4 in D2O (1:5, reference), fitted with a septum and purged with argon. An aliquot of the catalyst solution (0.5 ml) was transferred via syringe into the NMR tube.

382

[Pd(XPhos)2(OAc)2] + (R)-BINAP (1 equiv) [Pd((R)-BINAP)] + [Pd(X-Phos)] + X-Phos + (R)-BINAP

-15.

55

-12.

49

0.03

25.1

5

41.5

9

Figure 4, entry 2: [Pd(XPhos)2(OAc)2]solution was prepared as described above in entry 1. To this solution was added (R)-BINAP (1 equiv to Pd). This solution was stirred at r.t. for 30 min, and an aliquot was transferred to an NMR tube for analysis.

383

[Pd(XPhos)2(OAc)2] + (R)-BINAP (2 equiv) [Pd((R)-BINAP)] + [Pd(X-Phos)] + X-Phos + (R)-BINAP

-15.

39

-12.

32

-0.0

0

25.3

2

41.7

6

Figure 4, entry 3: [Pd(XPhos)2(OAc)2]solution was prepared as described above in entry 1. To this solution was added (R)-BINAP (2 equiv to Pd). This solution was stirred at r.t. for 30 min, and an aliquot was transferred to an NMR tube for analysis.

384

[Pd(XPhos)2(OAc)2] + (R)-BINAP (4 equiv) [Pd((R)-BINAP)] + [Pd(X-Phos)] + X-Phos + (R)-BINAP + (R)-BINAP(O)

-15.

40-1

5.02

-12.

33

0.05

25.2

425

.31

26.3

4

41.7

5

Figure 4, entry 4: [Pd(XPhos)2(OAc)2]solution was prepared as described above in entry 1. To this solution was added (R)-BINAP (4 equiv to Pd). This solution was stirred at r.t. for 30 min, and an aliquot was transferred to an NMR tube for analysis. The observation of (R)-BINAP(O) was identified with literature data described in references 20.

385

[Pd((R)-BINAP)(OAc)2] + X-Phos (2 equiv) [Pd(BINAP)] + X-Phos + (R)-BINAP

-15.

41

-12.

35

-0.0

0

25.3

2

Figure 4, entry 5: Palladium-BINAP solution was prepared as described above in Scheme 1. To this solution was added X-Phos (2 equiv to Pd). This solution was stirred at r.t. for 30 min, after which an aliquot was transferred to an NMR tube for analysis.

386

[Pd((R)-BINAP)(OAc)2] + X-Phos (4 equiv) [Pd(BINAP)] + X-Phos + (R)-BINAP

-15.

47

-12.

41

-0.0

0

25.2

7

Figure 4, entry 5: Palladium-BINAP solution was prepared as described above in Scheme 1. To this solution was added X-Phos (4 equiv to Pd). This solution was stirred at r.t. for 30 min, after which an aliquot was transferred to an NMR tube for analysis.

387

Appendix 3: Enantioselective Sequential Multi-Metal Catalysis in the Presence of Achiral Ligands: Time Resolution and Orthogonal

Ligand Affinity Enabled Synthesis of Heterocycles

388

1.87

1.00

2.82

0.91

1.00

0.91

122.

6112

7.15

127.

7613

0.35

130.

8813

3.00

135.

0113

8.39

167.

34

500 MHz, CDCl3

125 MHz, CDCl3

389

1.97

1.00

0.87

0.97

0.92

103.

8910

6.90

110.

89

122.

0812

7.42

129.

11

138.

14

149.

0215

1.32

170.

58

400 MHz, CD3OD

100 MHz, CD3OD

390

2.95

3.06

1.00

1.03

1.01

0.91

56.6

7

60.8

8

112.

30

122.

1312

4.04

127.

4513

0.23

138.

38

146.

90

156.

31

170.

66

500 MHz, CD3OD

125 MHz, CD3OD

391

1.00

1.01

0.94

1.03

0.92

115.

8311

6.01

118.

0811

8.28

124.

2612

4.28

130.

2813

0.36

136.

5213

6.60

137.

0613

7.07

163.

4616

5.46

170.

09

500 MHz, CD3OD

125 MHz, CD3OD

392

-111

.19

-111

.18

-111

.17

-111

.15

564 MHz, CDCl3

393

2.09

1.09

1.01

1.04

0.95

1.00

114.

1211

4.31

117.

9411

8.12

123.

6212

9.98

130.

0113

1.60

131.

6713

4.57

134.

6413

7.56

137.

58

160.

4116

2.38

166.

85

125 MHz, CDCl3

500 MHz, CDCl3

394

-114

.76

-114

.75

-114

.74

-114

.72

564 MHz, CDCl3

395

1.89

1.00

0.96

1.91

0.89

119.

9212

2.09

123.

9312

3.96

123.

9912

4.02

124.

2512

4.87

126.

4212

7.36

127.

3912

7.42

127.

4512

8.19

132.

2413

2.50

132.

7713

3.04

135.

2813

6.57

136.

5813

7.10

137.

13

166.

72

400 MHz, CDCl3

125 MHz, CDCl3

396

-63.

08

377 MHz, CDCl3

397

2.20

1.13

1.05

0.99

1.01

120.

00

126.

5212

8.79

129.

1913

1.82

132.

51

167.

32

400 MHz, CDCl3

100 MHz, CDCl3

398

3.15

2.02

1.03

1.02

1.95

1.05

1.05

30.7

3

108.

1010

9.89

119.

0012

0.97

121.

7312

4.83

125.

8112

8.69

129.

37

136.

96

167.

65

125 MHz, CDCl3

500 MHz, CDCl3

399

3.00

0.95

0.97

2.10

0.86

0.94

0.85

26.7

0

123.

7612

7.06

127.

6513

0.26

130.

5013

3.37

134.

8313

6.74

166.

35

100 MHz, CDCl3

400 MHz, CDCl3

400

2.08

1.00

1.11

3.55

4.02

1.05

1.03

0.95

44.0

6

123.

5012

7.07

127.

6812

7.76

128.

0912

8.90

130.

2913

0.60

133.

2613

4.90

137.

4113

8.20

165.

47

500 MHz, CDCl3

125 MHz, CDCl3

401

1.00

0.90

1.64

1.02

2.05

1.00

1.00

2.97

1.02

120.

1012

3.89

124.

7012

7.12

127.

7912

9.24

130.

3913

0.84

133.

1013

5.08

138.

40

163.

63

500 MHz, CDCl3

125 MHz, CDCl3

402

2.00

0.94

0.97

2.05

2.97

2.38

1.97

1.06

38.5

542

.18

115.

6112

3.54

126.

9112

7.40

127.

9512

8.16

128.

6212

9.07

137.

07

141.

51

170.

39

500 MHz, CDCl3

125 MHz, CDCl3

403

2.02

3.03

3.03

1.00

2.03

2.03

2.03

1.05

0.97

38.6

941

.78

56.0

156

.04

111.

0711

1.56

115.

8212

0.09

123.

4812

7.11

128.

1012

8.40

133.

9613

7.11

148.

3114

9.36

171.

18

400 MHz, CDCl3

100 MHz, CDCl3

404

1.94

2.88

6.14

1.00

1.99

0.94

2.02

1.00

500 MHz, CDCl3

125 MHz, CDCl3

405

1.90

0.93

0.91

1.85

1.09

0.92

1.82

0.89

0.85

1.02

1.84

38.5

042

.36

115.

7412

3.55

125.

9312

6.12

126.

4512

6.76

126.

8412

7.80

127.

9312

8.24

128.

6812

8.93

132.

7713

3.66

137.

1713

8.84

170.

52

400 MHz, CDCl3

125 MHz, CDCl3

406

3.08

2.13

1.00

0.99

0.98

1.01

1.92

2.90

1.04

16.0

116

.03

38.5

041

.65

115.

8112

3.54

127.

2512

8.22

128.

4212

8.48

137.

1113

7.48

138.

40

170.

76500 MHz, CDCl3

125 MHz, CDCl3

407

3.00

2.02

1.04

0.96

0.99

1.00

0.92

2.06

1.93

0.92

26.7

6

38.2

542

.14

116.

0012

3.70

125.

7912

8.16

128.

4912

8.53

129.

1713

6.36

137.

15

147.

09

170.

29

197.

68

400 MHz, CDCl3

400 MHz, CDCl3

408

2.09

1.00

0.98

0.97

2.94

1.95

1.00

0.93

38.6

941

.48

115.

7511

5.85

116.

0212

3.63

128.

3412

8.51

129.

4212

9.48

161.

1016

3.05

170.

18

125 MHz, CDCl3

500 MHz, CDCl3

409

-115

.47

-115

.46

-115

.45

-115

.43

-115

.42

377 MHz, CDCl3

410

9.52

2.14

1.04

1.00

1.03

1.03

2.04

3.05

2.15

1.00

31.4

034

.69

38.6

941

.86

112.

90

120.

4812

3.99

127.

2712

7.99

128.

0612

8.98

151.

64

171.

04

400 MHz, CDCl3

100 MHz, CDCl3

411

5.66

2.00

1.00

2.02

1.88

1.93

4.02

1.98

0.90

38.6

242

.11

97.9

610

1.41

108.

55

119.

28

127.

4012

7.85

129.

07

141.

7614

3.75

147.

31

170.

89

400 MHz, CDCl3

100 MHz, CDCl3

412

2.05

3.02

3.01

1.00

1.97

2.04

0.99

1.99

39.7

042

.73

56.3

9

61.2

2

108.

00

128.

6612

9.78

143.

68

153.

21

172.

50

500 MHz, CD3OD

125 MHz, CD3OD

413

2.17

1.06

1.03

1.00

1.00

2.04

1.00

2.02

1.04

38.5

041

.51

103.

3410

3.54

109.

8411

0.01

127.

8412

9.10

138.

5713

8.66

141.

42

161.

4416

3.39

171.

69

500 MHz, CDCl3

125 MHz, CDCl3

414

-113

.95

-113

.94

-113

.93

-113

.91

564 MHz, CDCl3

415

2.03

1.00

0.99

1.99

0.98

1.99

1.04

38.1

3

42.2

6

127.

9412

9.23

158.

0615

9.99

170.

87

500 MHz, CDCl3

125 MHz, CDCl3

416

377 MHz, CDCl3

417

2.08

1.03

1.06

1.00

3.07

1.00

2.05

1.03

37.9

0

41.9

2

112.

5311

2.55

112.

5811

9.94

119.

9812

0.01

127.

7112

9.12

130.

89

137.

6214

0.43

170.

91

500 MHz, CDCl3

126 MHz, CDCl3

418

-62.

72

282 MHz, CDCl3

419

1.04

1.05

1.00

1.00

0.97

2.57

0.91

2.01

1.05

39.2

640

.15

127.

3712

7.70

129.

11

170.

41

125 MHz, CDCl3

500 MHz, CDCl3

420

1.00

1.11

3.88

0.93

1.14

2.55

2.65

1.19

39.3

1

55.7

0

115.

2111

8.88

129.

30

160.

44

500 MHz, CD3OD

125 MHz, CD3OD

421

0.87

1.30

2.85

1.10

0.93

1.85

1.02

0.94

3.00

0.92

28.3

1

36.0

0

40.2

0

108.

9411

4.85

116.

4911

7.70

118.

8212

1.40

126.

5512

6.93

128.

71

136.

01

141.

87

169.

47

500 MHz, CD3OD

125 MHz, CD3OD

422

2.05

3.07

1.00

0.88

0.94

0.91

1.81

1.78

2.08

29.6

1

38.8

941

.52

114.

96

123.

0912

7.22

127.

8512

7.93

128.

1112

8.91

140.

3914

1.09

169.

40

500 MHz, CDCl3

125 MHz, CDCl3

423

2.04

1.00

0.97

1.01

2.94

4.94

1.15

3.10

2.08

39.0

141

.63

46.0

8

115.

97

126.

8012

7.97

128.

7912

8.97

141.

06

169.

56

125 MHz, CDCl3

500 MHz, CDCl3

424

2.13

1.00

0.92

1.92

1.00

5.57

1.96

1.15

2.09

39.4

641

.89

117.

5012

3.37

127.

3812

7.72

127.

9112

8.34

128.

3812

9.06

129.

1013

0.01

169.

16

HPLC Traces:

400 MHz, CDCl3

100 MHz, CDCl3

425

Racemic 95% ee

426

NH

O

NH

O

racemic

Racemic 94% ee

Racemic 98% ee

427

Racemic 96% ee

NH

O

OMe

NH

O

OMe

racemic

Racemic 92% ee

428

Racemic 96% ee

Racemic 95% ee

429

Racemic 94% ee

Racemic 92% ee

430

Racemic 95% ee

Racemic 96% ee

431

Racemic 92% ee

Racemic 94% ee

432

Racemic 82% ee

Racemic 75% ee

433

Racemic 96% ee

Racemic 94% ee

434

Racemic 92% ee

Racemic 95% ee

435

Racemic 94% ee

Racemic 95% ee

436

Racemic 72% ee

Racemic 88% ee

437

Racemic 95% ee

Racemic 95% ee

438

Racemic 94% ee

N

Ph

O

Ph

N

Ph

O

Ph

racemic

Racemic 92% ee

439

Appendix 4: The Development of Multi-Metal-Catalyzed Multicomponent Reactions: (MC)2R

440

400 MHz, CDCl3

100 MHz, CDCl3

441

400 MHz, CDCl3

100 MHz, CDCl3

442

300 MHz, CDCl3

100 MHz, CDCl3

443

282 MHz, CDCl3

444

300 MHz, CDCl3

125 MHz, CDCl3

445

13.4

0

2.15

4.00

0.81

0.84

1.36

2.02

2.04

2.06

2.08

2.09

2.83

2.84

2.86

2.88

2.89

7.20

7.54

24.9

425

.61

32.1

533

.09

84.0

5

122.

20

137.

44

142.

19

149.

21

400 MHz, CDCl3

100 MHz, CDCl3

446

12.5

0

1.99

0.80

0.81

1.35

5.97

6.83

7.12

24.9

3

84.1

4

101.

86

110.

69

114.

93

133.

14

146.

31

150.

51

100 MHz, CDCl3

400 MHz, CDCl3

447

21.0

2

24.9

0

30.8

9

116.

3212

0.50

123.

7012

7.59

137.

2913

7.42

172.

96

500 MHz, CDCl3

125 MHz, CDCl3

448

24.6

8

31.1

8

55.5

6

101.

78

108.

36

115.

86

128.

70

138.

40

159.

35

172.

43

100 MHz, CDCl3

400 MHz, CDCl3

449

400 MHz, CDCl3

100 MHz, CDCl3

450

500 MHz, CDCl3

125 MHz, CDCl3

451

25.3

8

30.3

2

112.

4411

2.48

112.

5211

2.56

119.

8611

9.90

127.

5812

7.59

128.

4913

0.06

130.

38

138.

05

172.

46

400 MHz, CDCl3

100 MHz, CDCl3

452

2.04

2.07

1.00

1.89

1.06

2.67

2.69

2.69

2.71

3.02

3.04

3.06

6.90

6.92

7.26

7.43

7.45

9.10

300 MHz, CDCl3

125 MHz, CDCl3

453

282 MHz, CDCl3

454

400 MHz, CDCl3

100 MHz, CDCl3

455

2.24

2.10

4.27

2.26

0.97

1.04

1.00

2.03

2.05

2.07

2.60

2.61

2.62

2.63

2.82

2.83

2.85

2.89

2.91

2.93

6.75

7.00

9.47

400 MHz, CDCl3

100 MHz, CDCl3

456

25.5

1

30.9

5

97.8

510

1.32

108.

27

116.

21

131.

47

143.

4614

6.97

171.

73

400 MHz, CDCl3

100 MHz, CDCl3

457

2.25

2.26

1.00

2.08

3.05

1.03

2.06

2.80

2.82

2.82

2.84

3.04

3.06

3.08

6.34

6.36

6.95

6.97

6.99

7.01

7.03

7.05

7.19

7.21

7.22

7.24

7.39

7.41

7.42

7.48

7.50

7.52

25.7

4

32.3

2

117.

0912

3.02

125.

7412

7.19

127.

8512

8.23

129.

1012

9.90

138.

5514

1.75

170.

23

100 MHz, CDCl3

400 MHz, CDCl3

458

400 MHz, CDCl3

100 MHz, CDCl3

459

100 MHz, CDCl3

400 MHz, CDCl3

460

400 MHz, CDCl3

100 MHz, CDCl3

461

400 MHz, CDCl3

125 MHz, CDCl3

462

377 MHz, CDCl3

463

400 MHz, CDCl3

100 MHz, CDCl3

464

400 MHz, CDCl3

100 MHz, CDCl3

465

400 MHz, CDCl3

100 MHz, CDCl3

466

400 MHz, CDCl3

100 MHz, CDCl3

467

400 MHz, CDCl3

100 MHz, CDCl3

468

500 MHz, CDCl3

125 MHz, CDCl3

469

2.25

2.24

1.00

1.01

1.08

2.11

1.06

2.17

2.81

2.81

2.82

2.82

2.83

2.84

3.02

3.04

6.07

6.07

6.09

6.09

6.67

6.68

6.69

6.69

7.13

7.14

7.15

7.15

7.16

7.21

7.21

7.21

7.22

7.22

7.22

7.23

7.23

7.23

7.43

7.44

7.45

7.45

7.46

7.46

7.51

7.52

7.54

25.1

6

32.3

2

104.

8010

5.02

109.

3110

9.48

121.

1612

1.18

128.

6612

8.94

129.

0113

0.17

138.

1014

3.04

143.

12

160.

9616

2.89

170.

10

125 MHz, CDCl3

500 MHz, CDCl3

470

-114

.09

-114

.06

-114

.04

-114

.02

377 MHz, CDCl3

471

500 MHz, CDCl3

125 MHz, CDCl3

472

377 MHz, CDCl3

473

400 MHz, CDCl3

100 MHz, CDCl3

474

NH

Ph

O

400 MHz, CDCl3

100 MHz, CDCl3

475

400 MHz, CDCl3

100 MHz, CDCl3

476

9.05

4.00

1.97

1.00

0.98

2.00

2.87

1.85

0.91

1.42

2.38

2.41

2.43

2.44

2.45

2.45

2.46

2.61

3.43

3.46

3.47

3.51

4.32

4.33

4.36

4.38

7.01

7.02

7.02

7.04

7.04

7.05

7.06

7.06

7.08

7.08

7.10

7.11

7.16

7.17

7.19

7.19

7.21

7.49

7.52

7.74

7.74

7.77

7.77

21.6

7

28.0

929

.50

39.0

9

47.6

9

81.5

2

124.

9212

5.36

126.

9212

7.22

129.

0912

9.26

129.

8113

6.32

136.

50

143.

92

171.

63

300 MHz, CDCl3

75 MHz, CDCl3

477

500 MHz, CDCl3

125 MHz, CDCl3

478

282 MHz, CDCl3

479

300 MHz, CDCl3

75 MHz, CDCl3

rhodium-catalyzed asymmetric carbon-carbon bond … · this thesis describes the ... 2.3.2...

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