zirconium and palladium catalyzed telescopic synthesis of ... · zirconium and palladium catalyzed...
TRANSCRIPT
Zirconium and Palladium Catalyzed Telescopic Synthesis of (E)-Alkenes
by
Jordan Anthony Evans
A thesis submitted in conformity with the requirements for the degree of Master of Science
Department of Chemistry University of Toronto
© Copyright by Jordan Anthony Evans 2014
ii
Zirconium and Palladium Catalyzed
Telescopic Synthesis of (E)-Alkenes
Jordan Anthony Evans
Master of Science
Department of Chemistry
University of Toronto
2014
Abstract
Alkenes are remarkably versatile motifs as they can be further functionalized by a vast array of
addition, reduction, and oxidation reactions. Thus their efficient synthesis is highly desired.
Over the past 35 years, the Suzuki-Miyaura cross-coupling reaction has emerged as a powerful
synthetic tool for the formation of carbon-carbon bonds. Herein is described the development of
a one-pot two-step protocol for the synthesis of (E)-alkenes comprising palladium-catalyzed
Suzuki-Miyaura cross-coupling of aryl or heteroaryl halides, including chlorides, with alkenyl
pinacolboronates, prepared in situ via solvent-free zirconium-catalyzed hydroboration of
terminal alkynes. Avoiding isolation of intermediates saves time and reduces waste. The regio-
and stereochemistry of the alkene is set by initial hydrozirconation of the alkyne. Addition of
water to the second step deactivates the zirconocene catalyst, which is otherwise deleterious to
cross-coupling. Thus this sequence exploits the water tolerance of the Suzuki-Miyaura reaction.
iii
Acknowledgments
I would like to thank my supervisor, Mark Lautens, for giving me the tremendous opportunity to
study in his laboratory and for fostering such a stimulating and supportive environment. It was
truly a privilege to work among such thoughtful, talented, and self-directed people. Thank you
to my colleagues, especially Dave and Christine, for their friendship and willingness to share
their expertise. I could not have done this without you. Thank you to Mark Taylor for reviewing
this thesis. I would also like to thank my friends and family for their support.
iv
Table of Contents
Acknowledgments .......................................................................................................................... iii
Table of Contents ........................................................................................................................... iv
List of Tables ................................................................................................................................. vi
List of Figures ............................................................................................................................... vii
List of Schemes ............................................................................................................................ viii
List of Abbreviations ..................................................................................................................... ix
1 Introduction ................................................................................................................................ 1
1.1 Domino Chemistry in Organic Synthesis ........................................................................... 1
1.1.1 Transition Metal-Catalysis in Domino Chemistry .................................................. 1
1.2 Suzuki-Miyaura Reaction in Organic Synthesis ................................................................. 5
1.2.1 Proposed Mechanism of the Suzuki-Miyaura Reaction .......................................... 5
1.2.2 Brief History of the Suzuki-Miyaura Reaction ....................................................... 8
1.2.3 Development and Activity of Dialkylbiaryl Phosphine Ligands for the Suzuki-
Miyaura Reaction .................................................................................................. 12
1.3 Preparation of Organoboron Coupling Partners for the Suzuki-Miyaura Reaction .......... 18
1.3.1 Rhodium-Catalyzed Hydroboration ...................................................................... 21
1.3.2 Zirconium-Catalyzed Hydroboration .................................................................... 25
1.4 Alkenes in Organic Synthesis ........................................................................................... 29
1.4.1 Bimetallic Catalyzed One-Pot Synthesis of Alkenes ............................................ 29
1.4.2 Palladium-Catalyzed Zirconium-Negishi Cross-Coupling Reaction .................... 30
1.4.3 Proposed Methodology ......................................................................................... 32
2 Results and Discussion ............................................................................................................. 33
2.1 Preparation of Alkenylboronates ...................................................................................... 33
2.1.1 Solvent-Free Zr-Catalyzed Hydroboration of Terminal Alkynes ......................... 33
2.1.2 Solvent-Free Zr-Catalyzed Hydroboration of Internal Alkynes ........................... 37
v
2.1.3 Selecting a Solvent for Zr-Catalyzed Hydroboration ........................................... 38
2.2 Optimization of the Suzuki Cross-Coupling Reaction ...................................................... 40
2.2.1 Base and Solvent Screen ....................................................................................... 40
2.2.2 Further Optimization ............................................................................................. 41
2.3 Initial Conditions for One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-Catalyzed
Suzuki Coupling Sequence ............................................................................................... 43
2.3.1 Substrate Scope of Initial Conditions ................................................................... 43
2.4 Optimization of One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-Catalyzed Suzuki
Coupling Sequence ........................................................................................................... 46
2.4.1 Optimization with Aryl Bromides and Iodides ..................................................... 46
2.4.2 Extension to Aryl Chlorides .................................................................................. 47
2.5 Bimetallic Catalyzed Domino Attempt ............................................................................. 51
2.6 Optimized Conditions for One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-
Catalyzed Suzuki Coupling Sequence .............................................................................. 55
2.6.1 Substrate Scope of Optimized Conditions for Aryl Bromides .............................. 55
2.6.2 Substrate Scope of Optimized Conditions for Aryl Chlorides .............................. 57
2.6.3 Synthesis of (E)-2-Styrylbenzoxazole .................................................................. 59
2.7 Conclusions and Future Outlook ...................................................................................... 61
3 Experimental ............................................................................................................................ 63
3.1 General Considerations ..................................................................................................... 63
3.2 Synthesis of Starting Materials ......................................................................................... 65
3.3 Synthesis of Alkenylboronates ......................................................................................... 69
3.4 Synthesis of (E)-Alkenes .................................................................................................. 71
Appendix: Selected Spectra .......................................................................................................... 84
vi
List of Tables
Table 1.2-1: Initial Results Reported by Suzuki and Miyaura ........................................................ 9
Table 1.2-2: Cross-Coupling of Heterocycles with Pd-XPhos ..................................................... 16
Table 1.3-1: Hydroboration of Alkynes with Pinacolborane ........................................................ 25
Table 1.3-2: Zirconium-Catalyzed Hydroboration of Alkynes with Pinacolborane ..................... 26
Table 2.1-1: Solvent-Free Zr-Catalyzed Hydroboration of Phenylacetylene ............................... 34
Table 2.1-2: Solvent-Free Zr-Catalyzed Hydroboration of N-Propargyl Indole .......................... 37
Table 2.1-3: Solvent-Free Zr-Catalyzed Hydroboration of Internal Alkynes ............................... 37
Table 2.1-4: Zr-Catalyzed Hydroboration of Phenylacetylene in Toluene ................................... 38
Table 2.1-5: Zr-Catalyzed Hydroboration of N-Propargyl Indole in Toluene .............................. 39
Table 2.2-1: Base and Solvent Screen for SMC ........................................................................... 40
Table 2.2-2: Further Optimization of SMC .................................................................................. 41
Table 2.3-1: Substrate Scope of Initial Conditions ....................................................................... 44
Table 2.4-1: Optimization with Aryl Bromides and Iodides ........................................................ 46
Table 2.4-2: Ligand Screen for Suzuki Coupling of Aryl Chlorides ............................................ 48
Table 2.4-3: Optimization with Aryl Chlorides using XPhos ....................................................... 48
Table 2.4-4: Optimization with Pd-XPhos-G2 ............................................................................. 50
Table 2.5-1: Effect of SMC Components on Zr-Catalyzed Hydroboration .................................. 52
Table 2.5-2: Effect of Cp2ZrHCl on Suzuki Coupling ................................................................. 54
Table 2.6-1: Substrate Scope of Optimized Conditions for Aryl Bromides ................................. 55
Table 2.6-2: Substrate Scope of Optimized Conditions for Aryl Chlorides ................................. 57
Table 2.6-3: Solvent and Base Screen for SMC with 2-Chlorobenzoxazole ................................ 59
vii
List of Figures
Figure 1.1-1: Classification of Transition Metal Catalysis in Domino Reactions .......................... 2
Figure 1.2-1: Catalytic Cycle for the Suzuki-Miyaura Reaction .................................................... 6
Figure 1.2-2: Dialkylbiaryl Phosphine Ligands ............................................................................ 13
Figure 1.2-3: Stabilizing Interactions in Pd-SPhos Complexes .................................................... 15
Figure 1.2-4: Structural Features of Dialkylbiaryl Phosphine Ligand and Their Effect on the
Efficacy of Metal-Ligand Complexes in Catalysis ............................................................... 17
Figure 1.3-1: Organoborons Commonly Used in the Suzuki-Miyaura Reaction ......................... 18
Figure 1.3-2: Relationship Between Regioselectivity and Cyclic Transition State ...................... 20
Figure 1.3-3: Catalytic Cycle for the Rhodium-Catalyzed Hydroboration of Alkenes ................ 23
Figure 1.3-4: Catalytic Cycle for the Zirconium-Catalyzed Hydroboration of Alkynes .............. 27
Figure 1.3-5: Synthetic Applications of Zirconocene Hydrochloride (Schwartz’s Reagent) ....... 28
Figure 2.4-1: 2nd Generation XPhos Precatalyst .......................................................................... 49
viii
List of Schemes
Scheme 1.1-1: Domino Formation of Dihydroquinolines .............................................................. 3
Scheme 1.1-2: Domino Formation of Aza-Dihydrodibenzoxepines .............................................. 4
Scheme 1.2-1: Possible Roles of Base in Transmetallation ............................................................ 7
Scheme 1.2-2: B-Alkyl Suzuki-Miyaura Reaction ....................................................................... 10
Scheme 1.2-3: Alkyl-Alkyl SMC of Alkyl Bromides that Possess β-Hydrogens ........................ 11
Scheme 1.2-4: Nickel-Catalyzed Alkyl-Alkyl SMC of Unactivated Secondary Bromides ......... 12
Scheme 1.2-5: Highly Fluoronated Aromatics via Pd-SPhos Catalyzed SMC ............................ 14
Scheme 1.2-6: Pd-SPhos Catalyzed SMC in Synthesis of Quinine and Quinidine ...................... 14
Scheme 1.3-1: Chemoselectivity of Uncatalyzed vs. Catalyzed Hydroboration .......................... 22
Scheme 1.3-2: Preparation of Chiral Alcohols ............................................................................. 24
Scheme 1.4-1: [Rh-Pd]-Catalyzed Hydrosilylation/Hiyama Cross-Coupling Sequence .............. 29
Scheme 1.4-2: Platinum-Catalyzed Diboration/Palladium-Catalyzed SMC Sequence ................ 29
Scheme 1.4-3: Hydrozirconation/Palladium-Catalyzed Cross-Coupling Sequence ..................... 30
Scheme 1.4-4: Pd-Catalyzed Zr-Negishi Coupling Toward Total Synthesis of (-)-Motuporin ... 31
Scheme 1.4-5: Coupling of Alkenylzirconocenes with Alkyl Halides ......................................... 31
Scheme 1.4-6: Proposed Methodology ......................................................................................... 32
Scheme 2.3-1: Initial Conditions for One-Pot Two-Step Sequence ............................................. 43
Scheme 2.5-1: Domino Attempt ................................................................................................... 51
Scheme 2.5-2: One-Pot Two-Step under Anhydrous Conditions ................................................. 53
Scheme 2.6-1: One-Pot Two-Step Synthesis of (E)-2-Styrylbenzoxazole ................................... 60
ix
List of Abbreviations
Ac acetyl
acac acetylacetonate
Ar aryl
2-BuOH 2-butanol
9-BBN 9-borabicyclo[3.3.1]nonane
BINAP 2,2’-bis(diphenylphosphino)-1-1’-binapthyl
Bmim 1-butyl-3-methylimidazolium
BMS borane dimethylsulfide
Boc tert-butyloxycarbonyl
n-Bu n-butyl
t-Bu tert-butyl
n-BuLi n-butyllithium
n-BuOH n-butanol
cat catalyst or catalytic or catecholato
Cbz carbobenzyloxy
cod 1,5-cyclooctadiene
Cp cyclopentadienyl
Cy cyclohexyl
DART Direct Analysis in Real Time
dba dibenzylideneacetone
DCE dichloroethane
DCM dichloromethane
DI deionized
dioxane 1,4-dioxane
DME dimethoxyethane
DMF dimethylformamide
dppb 1,4-bis(diphenylphosphino)butane
dppf 1,1’-bis(diphenylphosphino)ferrocene
ee enantiomeric excess
ESI electrospray ionization
x
equiv equivalent(s)
Et ethyl
EtOAc ethyl acetate
GC gas chromatography
h hour(s)
HBpin pinacolborane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
HBcat catecholborane, 1,3,2-benzodioxaborole
HetAr heteroaryl
HRMS high resolution mass spectrometry
Hz hertz
IR infrared
L generic ligand
LDA lithium diisopropylamide
M generic metal or molar concentration
m meta
Me methyl
MHz megahertz
MIDA methyliminodicarbonic acid
min minute(s)
mol mole
MP melting point
Ms mesyl, methanesulfonyl
MW microwave irradiation
N/A not applicable
nm nanometres
NMP N-methyl-2-pyrrolidone
NMR nuclear magnetic resonance
o ortho
OTf triflate, trifluoromethanesulfonate
P product
p para
Ph phenyl
xi
PhMe toluene
pin pinacolato
ppm parts per million
R generic group
QPhos 1,2,3,4,5-pentaphenyl-1’-(di-tert-butylphosphino)ferrocene
QUINAP 1-(2-diphenylphosphino-1-naphthyl)isoquinoline
rt room temperature
RuPhos 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl
SM starting material
SMC Suzuki-Miyaura cross-coupling
SPhos 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl
TBAF tetra-n-butylammonium fluoride
Temp temperature
THF tetrahydrofuran
TLC thin-layer chromatography
TMB 1,3,5-trimethoxybenzene
Ts tosyl, p-toluenesulfonyl
UV ultraviolet
X generic halide
XPhos 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl
XPhos-Pd-G2 2nd Generation XPhos Precatalyst, Chloro(2-dicyclohexylphosphino-2′,4′,6′-
triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)
Y generic group
1
1 Introduction
1.1 Domino Chemistry in Organic Synthesis
That “it is better to prevent waste in the first place than to treat or clean it up afterwards” is one
of the basic tenets of green chemistry.1 To this end, domino chemistry is an ideal approach, as
multiple bond forming events occur under a single set of reaction conditions, rapidly generating
complex structures without the need to isolate intermediates. This saves time and reduces waste,
making it attractive to industry; thus a wide variety of domino processes have been developed. 2
1.1.1 Transition Metal-Catalysis in Domino Chemistry
Domino chemistry is a “chemical philosophy” that takes its cue from nature, wherein enzymes
catalyze the formation of multiple bonds in a single step within the highly complex environment
of a cell. Although not nearly as efficient, organic synthesis does have its advantages, such as
the ability to use reagents and catalysts that are unavailable to and/or incompatible with
biological systems. For example, transition metal catalysts can facilitate transformations that are
perhaps impossible in nature.
In 2001, Poli and co-workers3 introduced a classification system for transition metal-catalyzed
domino reactions (Figure 1.1-1), differentiating between “pure” and “pseudo” domino processes.
In a “pure” process, a single catalyst conducts a domino sequence within a single catalytic cycle;
whereas in a “pseudo” process, either a single (Type I) or multiple catalysts (Type II) conduct
two or more transformations in separate catalytic cycles with the formation of discrete
intermediates. Under the classification system put forth by MacMillan and co-workers,4 a
bimetallic “pseudo” domino process is equivalent to “cascade catalysis.” Such processes, in
which two transition metal catalysts operate independently in a domino fashion, are challenging
for a few reasons: chemoselectivity is often an issue as different catalysts can react differently
with different functional groups; additionally, redox reactions or the exchange of supporting
1 Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 2000.
2 For reviews on domino chemistry, see: a) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. 1993, 32, 131. b) Tietze,
L. F. Chem. Rev. 1996, 96, 115. c) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. 3 Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456.
4 Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633.
2
ligands between two metals can lead to deactivation of one or both catalysts. Nevertheless,
examples of bimetallic cascade catalysis have been reported,5 although one-pot two-step
protocols, in which the second catalyst is added upon completion of the first, are more common.
Figure 1.1-1: Classification of Transition Metal Catalysis in Domino Reactions
Our group has also contributed to the field of bimetallic cascade catalysis. Dihydroquinolines
were prepared via a rhodium-catalyzed hydroarylation/palladium-catalyzed C-N coupling
sequence employing a ([Rh(cod)OH]2/BINAP) / (Pd(OAc)2/XPhos) catalyst system (Scheme
1.1-1).6 Based on
31P NMR spectroscopy, it was revealed that while palladium could bind to both
phosphine ligands, rhodium did not bind XPhos to a measurable degree. This was crucial to the
5 For selected examples, see: a) Zimmermann, B.; Herwig, J.; Beller, M. Angew. Chem. Int. Ed. 1999, 38, 2372. b)
Crossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459. c) Ko, S.; Lee, C.; Choi, M. –G.; Na, Y.; Chang, S.
J. Org. Chem. 2003, 68, 1607. d) Kammerer, C.; Prestat, G.; Gaillard, T.; Madec, D.; Poli, G. Org. Lett. 2008, 10,
405. e) Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124. f) Takahashi, K.; Yamashita, M.; Ichihara,
T.; Nakano, K.; Nozaki, K. Angew. Chem. Int. Ed. 2010, 49, 4488. 6 Panteleev, J.; Zhang, L.; Lautens, M. Angew. Chem. Int. Ed. 2011, 50, 9089.
3
success of the domino reaction as Pd-BINAP was inactive in C-N coupling; therefore, any ligand
exchange between the two metals would have been deleterious. Indeed, when BINAP loading
exceeded 5.5 mol%, the reaction stalled at the arylated intermediate. This could not be remedied
by addition of excess XPhos as this also resulted in diminished yields, likely due to saturation of
the coordination sites on the palladium sphere. Thus a fine balancing of catalysts and ligands
was necessary to furnish the desired products in domino fashion.
Scheme 1.1-1: Domino Formation of Dihydroquinolines
More recently, our group reported the synthesis of aza-dihydrodibenzoxepines via a rhodium-
catalyzed hydroarylation/palladium-catalyzed C-O coupling sequence (Scheme 1.1-2).7
Arylation proceeded very rapidly, going to completion within a few minutes at room
temperature, whereas C-O coupling required higher temperatures and longer reaction times.
Domino reactivity was affected by pyridine electronics. While electron-poor pyridines reacted
smoothly in a domino fashion, electron-rich pyridines gave mixtures of product and arylated
intermediate. An asymmetric variant of this reaction was developed using β-substituted alkenyl
pyridines and a chiral diene ligand.
From this work, it is clear that thoughtful planning and careful optimization of reaction
parameters can lead to the development of domino reactions in which two metals operate without
interference. Given our group’s continued interest in this field, we endeavored to develop a one-
pot bimetallic catalyzed hydroboration/Suzuki-Miyaura cross-coupling sequence.
7 Friedman, A. A.; Panteleev, J.; Tsoung, J.; Huynh, V.; Lautens, M. Angew. Chem. Int. Ed. 2013, 52, 9755.
4
Scheme 1.1-2: Domino Formation of Aza-Dihydrodibenzoxepines
5
1.2 Suzuki-Miyaura Reaction in Organic Synthesis
Carbon-carbon bond formation is arguably the most fundamental transformation in organic
synthesis. Over the past four decades, cross-coupling reactions including the Mizoroki-Heck,8
Stille,9 Negishi coupling,
10 Suzuki-Miyaura,
11 and Hiyama coupling
12 reactions have emerged as
powerful tools for the chemo-, regio-, and stereoselective synthesis of carbon-carbon bonds.
Among these, the Suzuki-Miyaura cross-coupling (SMC) reaction, defined as the transition
metal-catalyzed coupling of an organoboron reagent with an organic halide, is arguably the most
useful for several reasons: relatively mild and versatile reaction conditions; low catalyst loading;
wide scope and functional group tolerance; commercial availability as well as ease of preparation
and handling of diverse boronic acid and ester coupling partners that are environmentally safer
than many other organometallic reagents; low toxicity and relative ease of removal of boron-
derived by-products; and tolerance of water. Given these advantages as well as its continuous
and extensive development, SMC has had a tremendous impact on organic synthesis.13
1.2.1 Proposed Mechanism of the Suzuki-Miyaura Reaction14
The proposed mechanism of the palladium(0)-catalyzed Suzuki cross-coupling of an aryl halide
with a generic aryl, alkenyl, or alkyl boronic acid or boronate in the presence of hydroxide as a
representative base is depicted below (Figure 1.2-1). As with other cross-coupling reactions, the
catalytic cycle is thought to begin with oxidative addition of the aryl halide to palladium(0),
which proceeds in a cis fashion, to form an arylpalladium(II) halide intermediate (A) that rapidly
8 For a recent review on the Mizoroki-Heck Reaction, see: de Meijere, A., Bräse, S. In Metal-Catalyzed Cross-
Coupling Reactions, Second Edition; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2008; Chapter 5. 9 For a recent review on the Stille reaction, see: Mitchell, T. In Metal-Catalyzed Cross-Coupling Reactions, Second
Edition; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2008; Chapter 3. 10
For a recent review on Negishi coupling, see: Negishi, E., Zeng, X., Tan, Z., Qian, M., Hu, Q., Huang, Z. In
Metal-Catalyzed Cross-Coupling Reactions, Second Edition; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New
York, 2008; Chapter 15. 11
For reviews on the Suzuki-Miyaura reaction, see: a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147. c) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419. d)
Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions, Second Edition; Diederich, F., de Meijere, A., Eds.;
Wiley-VCH: New York, 2008; Chapter 2. 12
For a recent review on Hiyama coupling, see: Denmark, S. E., Sweis, R. F. In Metal-Catalyzed Cross-Coupling
Reactions, Second Edition; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York, 2008; Chapter 4. 13
a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. b) For a recent review on the application of
SMC to total synthesis, see: Heravi, M. M.; Hashemi, E. Tetrahedron 2012, 68, 9145. 14
a) Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749. b) Miyarua, N. J. Organomet. Chem. 2002, 653, 54.
6
isomerizes to a more stable trans configuration (B).15
Rate-determining16
transmetallation with
the boronic acid or ester followed by reductive elimination from the resulting di-
organopalladium(II) complex (C) gives the desired coupled product (D) and regenerates
palladium(0). Isomerization to the cis isomer is necessary before reductive elimination can
occur. If R = alkyl, then competing β-hydride elimination can occur to give an undesired
dehalogenation product.
Figure 1.2-1: Catalytic Cycle for the Suzuki-Miyaura Reaction
Transmetallation proceeds with retention of stereochemistry set by both the organoboron and
halide,17
indicating a four-centered hydroxo μ2-bridged transition state (Scheme 1.2-1, TS);
however, the mechanism by which this model arises (path A or B) is unresolved.18
Organoborons are highly inert to RPd(II)X and do not undergo transmetallation in the absence of
15 Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954.
16 For a computational study of the transmetallation process in SMC, see: Braga, A. C. C.; Morgon, N. H.; Ujaque,
G.; Lledós, A.; Maseras, F. J. Organomet. Chem. 2006, 691, 4459. 17
Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458. 18
Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
7
base; however, boron “ate” complexes (e.g. [ArBF3]K)19
readily undergo coupling with organic
electrophiles, indicating that quaternization of the boron centre enhances nucleophilicity of the
organic group. Therefore, R2B(OH)3
− may undergo transmetallation with R
1Pd(II)X via a
hydroxyborate-palladium complex (path A). Alternatively, a hydroxo-, alkoxo-, or
(acetoxo)Pd(II) complex may form via ligand exchange between R1Pd(II)X and base. Such
complexes readily undergo transmetallation with organoborons in the absence of base;20
therefore, the transition state may arise via coordination of the OH ligand to the boron sphere of
R2B(OH)2 (path B), a process which may be rate limiting.
21 The reactivity of R
1PdOH can be
attributed to the high basicity of such species22
as well as the high oxophilicity of the boron
centre. Soderquis and Matos18
postulated that palladium-catalyzed SMC of 9-alkyl-9-BBN with
iodobenzene in aqueous KOH proceeds via path A, whereas the less Lewis acidic 9-oxa-10-
borabicyclo[3.3.2]decane proceeds via path B, suggesting that the Lewis acidity of the
organoboron reagent may determine, at least in part, which path predominates.
Scheme 1.2-1: Possible Roles of Base in Transmetallation
More recently, Amatore et al.23
investigated the role of hydroxide in SMC and made several
interesting observations favouring path B: trans-[ArPdBr(PPh3)2] did not react with Ar’B(OH)2
in the absence of hydroxide, but trans-[ArPd(OH)(PPh3)2] did; furthermore, a large excess of
hydroxide inhibited the latter reaction, indicating that Ar’B(OH)3− does not undergo
19 Darses, S.; Genet, J. –P.; Brayer, J. –L.; Demoute, J. –P. Tetrahedron Lett. 1997, 38, 4393.
20 Miyaura, N.; Yamada, K.; Suginome, A.; Suzuki A. J. Am. Chem. Soc. 1985, 107, 972.
21 Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149.
22 Otsuka, S. J. Organomet. Chem. 1980, 191, 200.
23 Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J. 2011, 17, 2492.
8
transmetallation with ArPd(OH)(PPh3)2. Additionally, PhB(OH)3− did not react with [(p-NC-
C6H4)PdBr(PPh3)2] (in the presence of excess bromide ions to quell the formation of the
hydroxopalladium species), disfavouring path A. In addition to its crucial role in the rate-
determining transmetallation process, the authors also observed that hydroxide increased the rate
of reductive elimination.
1.2.2 Brief History of the Suzuki-Miyaura Reaction
Akira Suzuki and Norio Miyaura introduced their eponymous cross-coupling reaction in 1979.24
In their seminal reports, the authors described the tetrakis(triphenylphosphine)palladium(0)-
catalyzed coupling of alkenylboronates with aryl, heteroaryl, and alkenyl halides in the presence
of a strong base to yield (E)-alkenes and conjugated alkadienes (Table 1.2-1). The authors noted
several features that have become characteristic of SMC; namely, that the reaction proceeded
with retention of configuration with respect to the alkenylboronate, the expected coupled product
was not obtained in the absence of base, Lewis bases such as triethylamine did not facilitate the
reaction, and electron poor aryl halides were more reactive than their electron rich analogues,
which is consistent with the effect of electron density on oxidative addition of aryl halides to
palladium(0).25
The authors also noted that aryl iodides were more reactive than aryl bromides
and that aryl chlorides, such as chlorobenzene (entry 6), were inert under their conditions. These
findings are in agreement with those of Fu and co-workers,26
who conducted chemoselective
Suzuki reactions with substrates bearing more than one halide/triflate and determined the order
of reactivity to be I > Br > OTf >> Cl under their catalyst system. Other reports have reversed
the reactivity of bromides and triflates.11
24 For pioneering work by Suzuki and Miyaura, see: a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437. b) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866. c) Miyaura, N.; Yano, T.;
Suzuki, A. Tetrahedron Lett. 1980, 21, 2865. d) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
e) Miyaura, N.; Suzuki, A. J. Organomet. Chem. 1981, 213, C53. 25
Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434. 26
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
9
Table 1.2-1: Initial Results Reported by Suzuki and Miyaura
Entry R-X mol% Pd Time (h) Yield (%)a
1 1 2 80
2
1 2 80
3
1 2 81
4 PhI 1 2 100
5 PhBr 1 4 98
6 PhCl 1 2 3
7 o-MePhBr 3 4 93
8 o-OMePhBr 3 4 81
9 p-ClPhBr 1 3 100
10
1 2 83
a Yield based on alkenyl or aryl halide and determined by GC.
10
In the decade following their initial report of sp2-sp
2 cross-coupling, Suzuki and co-workers
27
reported the first palladium(0)-catalyzed inter- and intramolecular coupling of an sp2 hybridized
iodide or bromide with an sp3 hybridized primary or secondary organoborane, generated in situ,
and coined it the B-alkyl Suzuki-Miyaura cross-coupling reaction (Scheme 1.2-2).28
Scheme 1.2-2: B-Alkyl Suzuki-Miyaura Reaction
The key to the success of these sp2-sp
3 cross-couplings was careful choice of the catalyst,
dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) [PdCl2(dppf)].29
As mentioned
above (1.2.1), the problem with coupling organometallic reagents that possess β-hydrogens is the
tendency of alkylpalladium complexes to undergo β-hydride elimination instead of reductive
elimination, generating a hydridopalladium species that reduces the halide. The [PdCl2(dppf)]
catalyst suppresses this undesired side-reaction as the large “bite angle” of the bidentate dppf
ligand forces the alkyl group and its coupling partner closer together about the square planar
Pd(II) complex, enforcing a cis geometry and promoting reductive elimination.30
Suzuki and co-
workers reported that secondary alkylboranes were significantly less reactive than primary
alkylboranes under their conditions, likely due to the slow rate of transmetallation of the former.
In 2008, Crudden and co-workers31
reported that secondary alkylboronate pinacol esters could be
27 a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1986, 27, 6369. b) Miyarua, N.;
Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Soc. Chem. 1989, 111, 314. b) Sato, M.;
Suzuki, A. Chem. Lett. 1989, 1405. 28
For a review on B-alkyl SMC and its application in the total synthesis of natural products, see: Chemler, S. R.;
Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4544; and related references therein. 29
Hayahsi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158. 30
Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta. 1994, 220, 249. 31
Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024.
11
successfully coupled with aryl iodides and bromides by employing silver oxide (Ag2O) as base,
which is believed to activate organoboron species toward transmetallation.32
In 2001, Fu and co-workers33
reported the first Suzuki coupling of primary alkyl bromides that
possess β-hydrogens by employing the bulky and electron rich tricyclohexylphosphine ligand
(PCy3) (Scheme 1.2-3). Prior to this, sp3 hybridized halides had proven to be challenging
substrates for SMC due to their slow rate of oxidative addition to palladium(0) and (if the alkyl
palladium(II)halide complex formed at all) the proclivity of β-hydride elimination to outcompete
cross-coupling. The authors reported that the reactions proceed under mild conditions at room
temperature. The following year, the Fu group extended their methodology to alkyl chlorides
using the same catalyst system, although higher reaction temperatures (90 °C) were required.34
Scheme 1.2-3: Alkyl-Alkyl SMC of Alkyl Bromides that Possess β-Hydrogens
Over the past several years, organic chemists have become increasingly interested in the use of
nickel catalysts for the Suzuki reaction. The allure of nickel is owed to its cheapness and earth-
abundance relative to palladium, as well as the broad range of traditionally challenging organic
electrophiles that can be successfully coupled in the presence of the appropriate nickel complex.
For example, Fu and co-workers have developed effective nickel-catalyzed methods for coupling
unactivated alkyl bromides and iodides with aryl35
and even alkylboranes (Scheme 1.2-4).36
Despite these advantages, the practicality of nickel-catalyzed SMC on an industrial scale is
presently limited as relatively high catalyst loadings and excess of external supporting ligands
are often required; furthermore, many nickel catalysts are air and moisture sensitive.37
32 a) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756. b) Hirabayashi, K.;
Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Org. Lett. 1999, 1, 299. 33
Netherton, M. R.; Dai, C.; Neuschütz, Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. 34
Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew Chem. Int. Ed. 2002, 41, 1945. 35
a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. b) González-Bobes, F.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 5360. 36
Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602. 37
For a recent review on Ni-catalyzed SMC, see: Han, F. –S. Chem. Soc. Rev. 2013, 42, 5270.
12
Scheme 1.2-4: Nickel-Catalyzed Alkyl-Alkyl SMC of Unactivated Secondary Bromides
1.2.3 Development and Activity of Dialkylbiaryl Phosphine Ligands for the Suzuki-Miyaura Reaction38
Prior to 1998, effective Suzuki coupling of electron-neutral and -rich aryl chlorides had not been
achieved.39
This was viewed as a serious limitation as aryl chlorides are the cheapest and most
readily available aryl halides, making them especially attractive to industry.40
The recalcitrance
of aryl chlorides can be attributed to the strength of the C-Cl bond (bond dissociation energies
for Ph-X at 298 K are: Cl: 96 kcal/mol; Br: 81 kcal/mol; I: 65 kcal/mol).41
Traditionally
employed palladium(0) catalysts supported by triarylphosphine ligands (e.g. Pd(PPh3)4) are not
sufficiently electron-rich to promote oxidative addition of aryl chlorides.42
Thus there was an
impetus to develop catalysts for the Suzuki reaction that could efficiently couple aryl chlorides.
In 1998, Buchwald and co-workers, through the course of developing dialkylbiaryl phosphine
ligands for C-N coupling,43
found that DavePhos (Figure 1.2-2, L1), in addition to being
effective for aminations, was also an effective supporting ligand for palladium-catalyzed Suzuki
couplings of aryl chlorides, including unactivated aryl chlorides.44
In the same year, Fu and co-
38 For a comprehensive overview of dialkylbiaryl phosphine ligands, see: Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461. 39
Activated, electron-poor aryl chlorides, particularly heteroaryl chlorides, have long been known to be suitable for
SMC. For a review on Pd-catalyzed reactions of heterocycles, see: Kalinin, V. N. Synthesis 1992, 413. 40
For a review on Pd-catalyzed coupling reactions of aryl chlorides, see: Littke, A. F.; Fu, G. C. Angew. Chem. Int.
Ed. 2002, 41, 4176; and related references therein. 41
Grushin, V.; Alper, H. Chem Rev. 1994, 94, 1047 42
It is well known that oxidative addition is faster with the use of electron-rich phosphine ligands. For a report, see:
Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665. 43
For recent examples of Pd-catalyzed amidations, see: a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 13001. b) Biscoe, M. R.; Barder, T. E.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007,
46, 7232. 44
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722.
13
workers reported efficient Suzuki coupling of both unactivated and hindered aryl chlorides using
the sterically encumbered and electron-rich Pd(PtBu3)2 catalyst.45
Figure 1.2-2: Dialkylbiaryl Phosphine Ligands
Buchwald and co-workers46
found that palladium catalysts with JohnPhos (L2) were significantly
more reactive than those with DavePhos (L1) for Suzuki couplings of both aryl bromides and
chlorides, indicating the dimethylamino group of DavePhos (L2) was not necessary for effective
catalysis. While CyJohnPhos (L3) provided a very active catalyst system for the coupling of
hindered substrates, JohnPhos (L2), its di-tert-butyl analogue, gave better results at room
temperature.47
The superior activity of catalysts supported by sterically demanding JohnPhos
(L2) was attributed to increased concentrations of monoligated complexes, L1Pd(0) and
L1Pd(II)(Ar)X, throughout the catalytic cycle (relative to the corresponding diligated species), as
oxidative addition of aryl halides to monoligated palladium(0) complexes is known to be much
faster than it is to more coordinatively crowded species.48
The reason for this reactivity is
intuitive: L1Pd(0) is smaller than L2Pd(0) and can therefore get closer to the aryl halide, which is
45 Littke, A. F.; Fu, G. C. Angew. Chem. 1998, 110, 3586; Angew. Chem. Int. Ed. 1998, 37, 3387.
46 Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed. 1999, 38, 2413.
47 Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550.
48 a) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373. b) Barrios-Landeros, F.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 6944.
14
crucial for oxidatively adding aryl chlorides to palladium centers. The authors proposed that
transmetallation was also faster with monoligated complexes for the same reason.
At this point in the development of dialkylbiaryl ligands, a catalyst system for the effective
coupling of hindered arenes remained elusive. A further tuning of steric and electronic
properties led to the development of SPhos (L4), which proved to be the most universal ligand
developed to date. Palladium catalysts derived from SPhos (L4) exhibited unprecedented
activity, efficiently coupling ortho, ortho’-substituted aryl halides with ortho-substituted boronic
acids at exceedingly low catalyst loadings.49
Electron-poor boronic acids, which are traditionally
reluctant coupling partners due to their low nucleophilicity50
and susceptibility to metal-
catalyzed protodeboronation,51
were also effectively coupled (Scheme 1.2-5).52
Scheme 1.2-5: Highly Fluoronated Aromatics via Pd-SPhos Catalyzed SMC
SPhos (L4) has also seen extensive application in the synthesis of natural products.38
Shortly
after its development, SPhos (L4) was used by Jacobsen in the first catalytic asymmetric total
syntheses of the anitpyretic quinine and its enantiomer, quinidine (Scheme 1.2-6).53
Scheme 1.2-6: Pd-SPhos Catalyzed SMC in Synthesis of Quinine and Quinidine
49 Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871. b)
50 Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087.
51 Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666.
52 Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
53 Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706.
15
Buchwald and co-workers attributed the longevity of catalysts supported by SPhos (L4) to the
stabilization of palladium intermediates via favourable interactions between the aryl ring and the
metal sphere (Figure 1.2-3). X-ray crystallography revealed that the SPhos (L4)/Pd(0) complex
possessed a Pd(0) η1-arene interaction with the ipso carbon of the bottom ring (A),
49 which may
confer stability.54
Based on computational studies,55
the most energetically favourable structures
for oxidative addition intermediates possessed either a Pd(II)-ipso carbon interaction (B) or a
Pd(II)-O interaction with either of the o-methoxy groups on the bottom ring (C). Compared to
other dialkylbiaryl phosphine ligands, this Pd-O interaction may further stabilize intermediates
throughout the catalytic cycle. In addition to stability, these Pd-arene interactions may also
improve reactivity by increasing steric bulk. Buchwald and co-workers also suggested that
monoligation may be directed by Pd-ipso carbon interactions, as they believed diligated species
would be too large to accommodate these favourable interactions.
Figure 1.2-3: Stabilizing Interactions in Pd-SPhos Complexes
The efficiency of Pd-SPhos (L4) in the coupling of aryl chlorides is the result of a fine balance
struck between ligand size and ability to enforce monoligation throughout the catalytic cycle.
Ligand L5 is substantially less electron-rich than SPhos (L4), but is nearly as effective as a
supporting ligand in the coupling of hindrered substrates at low temperatures. This implies that
while the electron-donating capacity of the phosphorus centre is important, it is secondary to size
for this ligand class.52
While the ortho, ortho-substituents on the bottom ring further increase the
size of the ligand, they also dramatically improve stability by preventing cyclometallation.56
54 Kočovosky, P.; Vyskočil, S.; Císařová, I.; Sejbal, J.; Tišlerová, I.; Smrčina, M.; Lloyd-Jones, G. C.; Stephen, S.
C.; Butts, C. P.; Murray, M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714. 55
Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics 2007, 26, 2183. 56
Streiter, E. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 925.
16
Nitrogen heterocycles are ubiquitous motifs in biologically and medicinally active compounds
and their efficient synthesis is highly desired; however, heteroaryl boronic acids have proven to
be difficult substrates in cross-coupling reactions, limiting their application in drug
development.57
While Pd-SPhos (L4) effectively coupled 3-thiophene boronic acid with
heteroaryl bromides, low yields were obtained with heteroaryl chlorides. The slow rate of
oxidative addition of heteroaryl chlorides combined with the tendency of 3-thiophene boronic
acids to decompose over time via protodeboronation makes such couplings particularly
challenging; however, Pd-XPhos (L6) proved effective.58
Pd-XPhos (L6) further proved itself to
be meritorious by efficiently coupling thiophene and pyridylboronic acids with a myriad of
heteroaryl chlorides, including conventionally challenging chloroaminopyridines (Table 1.2-2),
providing a fairly general method for the synthesis of heterobiaryls and increasing the scope of
the Suzuki-Miyaura reaction.
Table 1.2-2: Cross-Coupling of Heterocycles with Pd-XPhos
57 For a review on the synthesis and application of heterocyclic boronic acids, see: Tyrell, E.; Brookes, P. Synthesis
2003, 4, 469. 58
Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
17
Figure 1.2-4: Structural Features of Dialkylbiaryl Phosphine Ligand and Their Effect on
the Efficacy of Metal-Ligand Complexes in Catalysis
18
1.3 Preparation of Organoboron Coupling Partners for the Suzuki-Miyaura Reaction
A variety of organoboron compounds are used as coupling partners for organic halides in the
Suzuki-Miyaura cross-coupling reaction (Figure 1.3-1), including boranes (I, II), boronic acids
(III), trifluoroborate salts (IV), and boronate esters (V – VIII).
Figure 1.3-1: Organoborons Commonly Used in the Suzuki-Miyaura Reaction
Boronic acids (III) are attractive coupling partners in Suzuki reactions as they are air-stable,
virtually non-toxic, and easy to handle crystalline solids; furthermore, a plethora of boronic acids
are commercially available. They do, however, have drawbacks. Under anhydrous conditions,
boronic acids form their cyclotrimeric anhydrides, boroxines, although this is inconsequential in
Suzuki reactions as they proceed regardless of hydrated state. More severe, many small boronic
acids are amphiphilic, which can complicate purification efforts. This problem can be remedied
by converting boronic acids to their corresponding esters, significantly reducing polarity.59
One of the cheapest and oldest methods of preparing boronic acids is the trapping of an
organometallic intermediate (Li, Mg) with a borate ester [B(OR)3] followed by an aqueous acidic
workup;60
however this method is limited by functional group compatibility. In the 1990s,
Miyaura and co-workers introduced a more tolerant method of preparing boronic acids and esters
that involved the palladium-catalyzed coupling of an aryl or alkenyl halide or triflate with a
59 For a comprehensive overview on boronic acids, see: Boronic Acids: Preparation and Applications in Organic
Synthesis, Medicines and Materials; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011; pp 1 – 123. 60
Gilman, H.; Moore, L. O. J. Am. Chem. Soc. 1958, 80, 3609.
19
diboryl ester such as bis(pinacolato)diboron.61
This method, known as “Miyaura borylation,”
was recently used in a one-pot two-step synthesis of unsymmetrical biaryls and heterobiaryls
derived from aryl and heteroaryl chlorides via a Pd-SPhos catalyzed Miyaura borylation/Suzuki
cross-coupling sequence.62
Organotrifluoroborate salts (IV), which can be prepared from reacting the appropriate boronic
acid or ester with potassium bifluoride,63
are monomeric, air-stable, easy to handle crystalline
solids that can be used in many of the reactions that use free boronic acids, including SMC.64
MIDA (methyliminodicarbonic acid) protected boronic acids (VIII) are monomeric, bench-top
and chromatography stable crystalline solids. Unlike polyenylboronic acids, polyenyl MIDA
boronates are stable; therefore, iterative Suzuki couplings of MIDA-protected
haloalkenylboronic acid building blocks are possible.65
Since its discovery by Herbert C. Brown in 1956,66
hydroboration of alkenes and alkynes with
various hydroborating reagents has been the most widely used approach to the preparation of
organoboron compounds. The addition of H-B across a C-C bond occurs in a cis fashion with
boron adding preferentially to the less substituted carbon; a trend that was exploited by Brown
shortly after his initial discovery in order to effectively hydrate alkenes in an anti-Markovnikov
fashion in his renowned hydroboration-oxidation sequence.67
Regioselectivity for the least
sterically hindered carbon is not absolute, however, and is in fact determined by a combination
of steric and electronic effects. In the hydroboration of alkenes,68
electrophilic borane is attacked
by the π electrons of the alkene. Since the C-B bond forms slightly faster than the C-H bond, a
partial negative charge builds on boron in the transition state (Figure 1.3-2). If boron adds to the
terminal carbon, then the more substituted carbon is electron deficient in the transition state (A);
conversely, if boron adds to the internal carbon, then the less substituted carbon is electron
deficient (B). Since electron donating alkyl groups have a stabilizing effect, transition state A is
61 Ishiyama, T.; Murata, M.; Miyarua, N. J. Org. Chem. 1995, 60, 7508.
62 Billingsley, K.; Barder, T. E.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 5359.
63 Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020.
64 For a review on organotrifluoroboronates, see: Darses, S.; Genêt. J. –P. Eur. J. Org. Chem. 2003, 4313.
65 Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466.
66 Brown, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1956, 78, 5694.
67 Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1959, 81, 247.
68 a) Brown, H.C.; Zweifel, G. J. Am. Chem. Soc. 1960, 82, 4708. b) Brown, H. C.; Sharp, R. L. J. Am. Chem. Soc.
1966, 88, 5851.
20
lower in energy that of B; therefore hydroboration proceeds in an anti-Markovnikov fashion. To
complicate matters, if R is an aromatic group, then substituents on the ring have a directing effect
on hydroboration. In the case of styrenes, electron donating para-substituents can stabilize
partial positive charges at the benzylic position, improving regioselectivity for borylation at the
β-carbon (relative to styrene), whereas electron withdrawing substituents have a destabilizing
effect, resulting in an undesirable mixture of regioisomers.
Figure 1.3-2: Relationship Between Regioselectivity and Cyclic Transition State
Hydroboration of alkynes proceeds in a similar fashion.69
While hydroboration of terminal
alkynes is highly regioselective for borylation at the terminal position, a mixture of regioisomers
is usually obtained from internal alkynes. Whereas small hydroborating reagents can
dihydroborate alkynes, sterically hindered boranes (such as 9-BBN) stop after one pass to yield
the monohydroborated product.70
Among hydroborating reagents, the bulky dialkylborane 9-borobicyclo-[3.3.1]nonane (9-BBN),
which can be prepared from the reaction of 1,5-cyclooctadiene with borane, is the most
regioselective (>99.9% borylation at terminal carbon of 1-hexene, 98.5% borylation at β-carbon
of styrene);71
thus the resultant trialkylboranes (I) are popular for Suzuki couplings.
Dialkoxyboranes such as 4,4,6-trimethyl-1,3,2-dioxaborinane,72
1,3,2-benzodioxaborole
(catecholborane, HBcat),73
and 4,4,5,5-tetramethyl-1-3,2-dioxaborolane (pinacolborane,
HBpin)101
may also be used as hydroborating reagents to give organoboron compounds V, VI,
69 Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 3834.
70 Brown, H. C.; Scouten, C. G.; Liotta, R. J. Am. Chem. Soc. 1979, 101, 96.
71 Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc. 1974, 96, 7765.
72 Woods, W. G.; Strong, P. L. J. Am. Chem. Soc. 1966, 88, 4667.
73 a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1971, 93, 1816. b) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc.
1972, 94, 4370. c) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5249.
21
and VII respectively. The disadvantage of using these reagents is that they are less reactive than
dialkylboranes. Whereas hydroboration with 9-BBN typically proceeds at room temperature,
hydroboration of alkynes and alkenes with HBcat requires temperatures of 70 and 100 °C
respectively and reaction times of one to 24 hours.73c
However, there are advantages since
trialkoxyboranes are sensitive to air and moisture and thus must be prepared in situ, whereas
cyclic aliphatic boronate esters prepared from pinacol (VII) are bench-top and silica gel
chromatography stable, protected from the approach of water by a phalanx of methyl groups.
The hydroboration of alkenes and alkynes with less reactive dialkoxyboranes can be catalyzed by
transition metals.74
To date, a variety of transition metals have been used with varying degrees
of success, including nickel,75
iridium,76
rhodium,77
ruthenium,78
titanium,79
zirconium,103,105
samarium,80
and, recently, iron.81
The palladium-catalyzed hydroboration of enynes, generating
allenylboronates, has also been reported.82
Rhodium, the most commonly used, and zirconium
will be discussed in detail.
1.3.1 Rhodium-Catalyzed Hydroboration
In 1975, Kono and Ito reported that catecholborane can oxidatively add to Wilkinson’s catalyst
[Rh(PPh3)3Cl],83
but it was not until a decade later that a rhodium-catalyzed hydroboration
process was envisioned by Männig and Nöth, who reported that Wilkinson’s catalyst facilitates
the addition of catecholborane across alkenes and alkynes.84
While uncatalyzed hydroboration
with catecholborane requires heating at elevated temperatures for several hours,73c
Männig and
74 For reviews on transition metal-catalyzed hydroboration, see: a) Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991,
91, 1179. b) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957. 75
a) Gridnev, I. D.; Suzuki, A. Organometallics 1993, 12, 589. b) Kabalka, G. W.; Narayana, C.; Reddy, N. K.
Synth. Commun. 1994, 24, 1019. 76
a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 58, 5307. b) Ohmura, T.; Yamamoto, Y.;
Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990. c) Yamamoto, Y.; Fujikawa, R.; Umemoto, T.; Miyaura, N.
Tetrahedron 2004, 60, 10695. 77
For selected examples, see: a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988, 110, 6917. b)
Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426. c) Endo, K.; Hirokama, M.; Takeuchi, K.;
Shibata, T. Synlett 2008, 3231. 78
Burgess, K.; Jaspars, M. Organometallics 1993, 12, 4197. 79
He, X.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 1696. 80
Harrison, K. N.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 9220. 81
Zhang, L.; Peng, D.; Leng, X.; Huang, Z. Angew. Chem. Int. Ed. 2013, 52, 3676. 82
a) Satoh, M.; Nomoto, Y.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1989, 30, 3789. b) Matsumoto, Y.; Naito,
M.; Hayashi, T. Organometallics 1992, 11, 2732. 83
Kono, H.; Ito, K.; Nagai, Y. Chem. Lett. 1975, 1095. 84
Männig, D.; Nöth, H. Angew. Chem. Int. Ed. 1985, 24, 878.
22
Nöth observed that the catalyzed variant went to completion within minutes at room temperature
in the presence of Wilkinson’s catalyst (0.05 mol%, 45 mmol scale). Following distillative
workup, good yields were obtained from cyclopentene (83%) and 1-octene (77%) and a fair yield
from 1-hexyne (53%). Additionally, the authors noted that rhodium-catalyzed hydroboration
possessed markedly different chemoselectivity to that of the uncatalyzed variant, which was later
harnessed in the total synthesis of (+)-ptilocaulin (Scheme 1.3-1).85
In the presence of
Wilkinson’s catalyst, the terminal alkene was preferentially hydroborated over the ketone to give
desired product B following oxidation; whereas, in the absence of catalyst, catecholborane did
not touch the alkene, instead reducing the ketone to give A.
Scheme 1.3-1: Chemoselectivity of Uncatalyzed vs. Catalyzed Hydroboration
The mechanism of rhodium-catalyzed hydroboration of an alkene with catecholborane proposed
by Burgess and co-workers (Figure 1.3-3)86
begins with the dissociation of a triphenylphosphine
ligand from Wilkinson’s catalyst87
to generate a catalytically active 14-electron rhodium(I)
species (A). Oxidative addition of the B-H bond of catecholborane to A gives a 16-electron
boryl rhodium(III)hydride complex (B). The triisopropyl analogue of B has been isolated and
characterized.88
Coordination of the alkene with B trans to the chloride89
gives C, in which the
boryl and hydride ligands are also trans.90
Subsequent migratory insertion of the alkene into the
85 Cossy, J.; BouzBouz, S. Tetrahedron Lett. 1996, 37, 5091.
86 Burgess, K.; van der Donk, W. A.; Westcott, S. A.; Marder, T. B.; Baker, R. T.; Calabrese, J. C. J. Am. Chem.
Soc. 1992, 114, 9350. 87
Mechanism is general, can be applied to a variety hydroborating reagents and Rh sources. 88
Westcott, S. A.; Taylor, N. J.; Marder, T. B.; Baker, R. T.; Jones, N. L.; Calabrese, J. C. J. Chem. Soc. Chem.
Commun. 1991, 304. 89
Musaev, D. G.; Mebel, A. M.; Morokuma, K. J. Am. Chem. Soc. 1994, 116, 10693. 90
Widauer, C.; Grützmacher, H.; Zeigler, T. Organometallics 2000, 19, 2097.
23
rhodium-hydride bond gives regioisomeric alkyl boryl rhodium(III) complexes D and E, from
which rate-limiting89,90
reductive elimination gives boronates F and G, respectively, and
regenerates rhodium(I) species A. Originally, Evans and Fu91
proposed a mechanism in which
coordination of the alkene to complex B proceeds with concurrent dissociation of a phosphine
ligand. Both mechanisms have been supported by subsequent studies; the debate continues.92
Figure 1.3-3: Catalytic Cycle for the Rhodium-Catalyzed Hydroboration of Alkenes
While the uncatalyzed hydroboration of alkenes gives the anti-Markovnikov boronate as the
major product (Figure 1.3-2, A), the catalyzed variant can give either the anti-Markovnikov or
the Markovnikov boronate as the major product depending on the ligands on the catalyst as well
as the steric and electronic properties of the reacting alkene.93
The anti-Markovnikov boronate is
the major product of rhodium-catalyzed hydroboration of aliphatic alkenes; whereas the
regioselectivity is usually reversed in the case of vinylarenes. Zhang et al. reported that the
hydroboration of styrene with catecholborane in the presence of Wilkinson’s catalyst gave the
Markovnikov or α-boronate as the major product (α:β was 94:6).94
To account for this, Hayashi
91 a) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1990, 55, 2280. b) Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am.
Chem. Soc. 1992, 114, 6679. 92
For a review, see: Huang, X., Lin, Z. Y. In Computational Modelling of Homogeneous Catalysts; Maseras, F.,
Lin, Z. Y., Eds; Kluwer: Dordrecht, 2002. 93
Smith III, M. R. Prog. Inorg. Chem. 1999, 48, 505. 94
Zhang, J.; Lou, B.; Guo, G.; Dai, L. J. Org. Chem. 1991, 56, 1670.
24
proposed a modified mechanism for the rhodium-catalyzed hydroboration of vinylarenes that
proceeds through an η3-benzylrhodium complex (Figure 1.3-3, H).
95 Reductive elimination from
this key intermediate gives the α-boronate regioselectively.
An asymmetric variant of rhodium-catalyzed hydroboration has been developed using chiral
supporting ligands,96
particularly the axially chiral diphosphine ligands BINAP97
and QUINAP
(Scheme 1.3-2).98
The C-B bond of the chiral organoboron can be converted to a C-C,31,99
C-
N,100
or C-O95
bond with retention of stereochemistry, making them useful synthons for a variety
of functional groups.
Scheme 1.3-2: Preparation of Chiral Alcohols
95 Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron: Asymmetry 1991, 2, 601.
96 For a review on enantioselective Rh-catalyzed hydroboration of alkenes. see: Carroll, A. –M.; O’Sullivan, T. P.;
Guiry, P. J. Adv. Synth. Catal. 2005, 347, 609. 97
a) Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1988, 53, 5178. b) Sato, M.; Miyaura, N.; Suzuki, A. Tetrahedron
Lett. 1990, 31, 231. 98
a) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743. b) Alcock, N. W.; Brown, J.
M.; Hulmes, D. I. J. Chem. Soc. Chem. Commum. 1995, 395. 99
Chen, A.; Ren, L.; Crudden, C. M. J. Org. Chem. 1999, 64, 9704. 100
Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M. Chem. Eur. J. 2000, 6, 1840.
25
1.3.2 Zirconium-Catalyzed Hydroboration
In 1992, Knochel introduced pinacolborane (HBPin) or 4,4,5,5-tetramethyl-1-3,2-dioxaborolane
as an effective hydroborating reagent for alkynes and alkenes.101
Prepared from the addition of
borane dimethylsulfide (BMS) to a solution of pinacol in dry DMC, the resulting pinacolborane
solution was treated directly with alkyne or alkene (0.5 equiv) to yield the corresponding pinacol
boronate after several hours stirring at room temperature (Table 1.3-1). The use of less than 2
equivalents pinacolborane relative to alkyne or alkene led to incomplete conversion. The authors
noted that while pinacolborane could be distilled prior to use, it was unnecessary.
Table 1.3-1: Hydroboration of Alkynes with Pinacolborane
Entry R1 R
2 A : B : C
a Yield (%)
b
1 n-hexyl H 98 : 1 : 1 88
2 Ph H 96 : 4 : 0 64
3 Ph Me
85 : 0 : 15
(73 : 0 : 27)c
69
4 cyclohexene N/A 73
a Product ratio determined by GC.
b Isolated yield.
c Ratio of isomers obtained using catecholborane.
Knochel and co-workers highlighted several advantages afforded by the use of pinacolborane as
a hydroborating reagent instead of catecholborane; namely, milder reaction conditions, increased
101 Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57, 3482.
26
thermal stability, superior regioselectivity in the case of internal alkynes (Table 1.3-1, entry 3),
and stability of the resulting boronate esters to air, aqueous work-up, and silica gel
chromatography. In contrast, catechol boronates are sensitive to hydrolysis due to their Lewis
acidity and distillation yields unstable “glassy” solids.102
Table 1.3-2: Zirconium-Catalyzed Hydroboration of Alkynes with Pinacolborane
Entry R1
R2
A : B : C : Da
Yield (%)b
1 n-hexyl H 98 : 2 : 0 : 0 93
2 Ph H 97.2 : 0.8 : 0.7 : 0.9 75
3 i-propyl Me 96.9 : 2.2 : 0 0.9 94
4 t-butyl Me 100 : 0 : 0 : 0 91.5
5 Et Et 100 : 0 : 0 : 0 93
6 (EtO)2CH- H 81.9 : 10.8 : 7.3 : 0 82
a Product ratio determined by GC.
b Isolated yield.
In 1995, Srebnik and Pereira103
reported that zirconocene hydrochloride (Schwartz’s reagent)104
effectively catalyzes the hydroboration of alkynes at room temperature with stoichiometric
102 Zaidlewicz, M.; Meller, J. Collect. Czech. Chem. Commun. 1999, 64, 1049.
103 Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
104 Prepared via reduction of Cp2ZrCl2 with LiAlH4, see: Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24,
405. For use in organic synthesis, see: a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. b) Schwartz,
J.; Labinger, J. A. Angew. Chem. Int. Ed. 1976, 15, 333.
27
quantities of pinacolborane to give the corresponding pinacol boronates in excellent yields and
with excellent regio- and stereoselectivities (Table 1.3-2). Regioisomers were negligible with
the exception of 3,3-diethoxyprop-1-yne (entry 6), which the authors attributed to possible
coordination of pinacolborane with the oxygen atoms of the acetal. This was the first report of
transition metal-catalyzed hydroboration using pinacolborane.
Srebnik and Pereira proposed the following mechanism for hydroboration of alkynes catalyzed
by Schwartz’s reagent (Figure 1.3-4): hydrozirconation of the alkyne in a cis fashion, placing Zr
on the least sterically hindered carbon, followed by vinyl-hydride exchange between the resultant
organozirconocene chloride and pinacolborane to give the corresponding (E)-alkenylboronate
and regenerate the catalyst. It is interesting to note that the hydride reducing the alkyne initially
comes from the catalyst rather than pinacolborane.
Figure 1.3-4: Catalytic Cycle for the Zirconium-Catalyzed Hydroboration of Alkynes
The following year, Srebnik and Pereira reported that Schwartz’s reagent also catalyzes the
hydroboration of alkenes with pinacolborane.105,106
In the case of trans-4-octene, the terminal
105 Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909.
106 Pereira, S.; Srebnik, M. Tetrahedron Lett. 1996, 37, 3283.
28
alkyl boronate was obtained. This was expected as hydrozirconation of internal alkenes proceeds
to place Zr on the least hindered carbon via a series of additions/β-hydride eliminations.104b
In addition to catalyzing hydroboration, Schwartz’s reagent, named after its earliest champion,
Jeffery Schwartz at Princeton, has many applications in organic synthesis (Figure 1.3-5)107
and
has greatly expanded the field of organozirconium chemistry.108
Figure 1.3-5: Synthetic Applications of Zirconocene Hydrochloride (Schwartz’s Reagent)
107 For a review on the synthetic applications of organozirconocene complexes, see: Wipf, P.; Jahn, H. Tetrahedron
2004, 52, 12853; and related references therein. 108
For a review on organozirconium chemistry, see: Negishi, E. Dalton Trans. 2005, 827.
29
1.4 Alkenes in Organic Synthesis
Alkenes are highly versatile motifs in organic synthesis as they can be further functionalized by a
vast array of addition, reduction, and oxidation reactions. Their fundamental nature is evidenced
by the fact that many of the first reactions taught to fledgling chemists are those of the carbon-
carbon double bond. Thus the efficient synthesis of alkenes is highly desired.
1.4.1 Bimetallic Catalyzed One-Pot Synthesis of Alkenes
Given the importance of alkenes as well as the numerous benefits afforded by cascade catalysis
(outlined at the beginning of this chapter), organic chemists have sought to develop efficient one-
pot syntheses of alkenes, including bimetallic catalyzed protocols. Selected recent examples
from the literature are depicted below, including a [Rh-Pd]-catalyzed hydrosilylation/Hiyama
cross-coupling sequence (Scheme 1.4-1),109
a microwave-assisted platinum-catalyzed
diboration/palladium-catalyzed Suzuki cross-coupling sequence (Scheme 1.4-2),110
and a
hydrozirconation/palladium-catalyzed cross-coupling sequence (Scheme 1.4-3).111
Scheme 1.4-1: [Rh-Pd]-Catalyzed Hydrosilylation/Hiyama Cross-Coupling Sequence
Scheme 1.4-2: Platinum-Catalyzed Diboration/Palladium-Catalyzed SMC Sequence
109 Thiot, C.; Schmutz, M.; Wagner, A.; Mioskowski, C. Chem. Eur. J. 2007, 13, 8971.
110 Prokopcová, H.; Ramírez, J.; Fernández, E.; Kappe, C. O. Tetrahedron Lett. 2008, 49, 4831.
111 Huang, B.; Wang, P.; Hao, W.; Cai, M. – Z. J. Organomet. Chem. 2011, 696, 2685.
30
Scheme 1.4-3: Hydrozirconation/Palladium-Catalyzed Cross-Coupling Sequence
It should be noted that zirconium was not catalytic in the last example (Scheme 1.4-3); in fact, a
10% excess of zirconocene hydrochloride (Schwartz’s reagent) was required in the first step.
1.4.2 Palladium-Catalyzed Zirconium-Negishi Cross-Coupling Reaction
At a glance, hydrozirconation of alkynes and alkenes is an attractive process as the resultant
alkenyl- and alkylzirconocene chlorides are obtained with high regio- and stereoselectivities
under mild conditions; however, these organozirconium derivatives have proven to be poor
nucleophiles in comparison to organolithium and Grignard reagents, typically only reacting with
small electrophiles. For example, carbon monoxide readily inserts into the C-Zr bond to give the
corresponding aldehyde following an aqueous acidic work-up (Figure 1.3-5, A).112
Intrigued by the synthetic potential of organozirconium species, Negishi and co-workers turned
from conventional polar reactions to transmetallation. In the late 1970s, the group reported the
first nickel- and palladium-catalyzed cross-couplings of alkenylzirconocene chlorides with aryl
and alkenyl halides (Figure 1.3-5, G).113
The mechanism is believed to be analogous to the
Suzuki coupling of organoboron species with organic halides (Figure 1.2-1).114
Soon after, Negishi and co-workers discovered that the addition of zinc chloride significantly
improved the cross-coupling of sterically hindered alkenylzirconocenes and alkenyl halides.115
Presumeably, a transmetallation of the organic group from bulky zirconocene to the less
sterically demanding zinc salt precedeed the usual catalytic cycle. This Zr-to-Zn-to-Pd sequence
112 Bertelo, C. A.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 228.
113 a) Negishi, E.; Van Horn, D. E. J. Am. Chem. Soc. 1977, 99, 3168. b) Okukado, N.; Van Horn, D. E.; Klima, W.
L.; Negishi, E. Tetrahedron Lett. 1978, 1027. 114
Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393. 115
Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem. Soc. 1978, 100, 2254.
31
has been employed in key steps in a number of syntheses of complex natural products, including
motuporin, isolated from a marine sponge (Scheme 1.4-4).116
Scheme 1.4-4: Pd-Catalyzed Zr-Negishi Coupling Toward Total Synthesis of (-)-Motuporin
Initally limited to aryl and alkenyl halides, the palladium-catalyzed cross-coupling of
alkenylzirconocenes with alkyl halides was reported by the Fu group in 2004, the key feature
being the absence of a specialized ligand (Scheme 1.4-5).117
Scheme 1.4-5: Coupling of Alkenylzirconocenes with Alkyl Halides
Negishi recognized that using a stoichiometric amount of relatively expensive zirconocene was a
limitation and its use as a catalyst was highly desired. In 1978, Negishi and co-workers reported
the first successful zirconocene dichloride (Cp2ZrCl2)-catalyzed methylalumination of alkynes
with trimethylaluminum (Me3Al).118
The resulting alkenylalanes can be applied to a number of
116 Ho, T.; Panek, J. S. J. Org. Chem. 1999, 64, 3000.
117 Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 82.
118 a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252. b) Matsushita, H.; Negishi, E. J. Am. Chem.
Soc. 1981, 103, 2882.
32
conventional polar reactions as well as nickel- and palladium-catalyzed cross-coupling reactions
as either the alkenylaluminum derivative or the corresponding iodide to which it can be readily
converted. The utility of zirconium-catalyzed carboalumination is evidenced by its application
in the total synthesis of more than 100 natural products.119
1.4.3 Proposed Methodology
Hydrozirconation of alkynes is an attractive approach to synthesizing alkenes given its mild
conditions as well as its excellent regio- and stereoselectivity; however, cost is a serious concern,
particularly in large scale reactions. While zirconium may be an inexpensive metal,
zirconocenes, although less expensive than many transition metal catalysts, may not be
considered inexpensive chemicals; thus their catalytic use in the synthesis of alkenes is highly
desirable. While zirconium-catalyzed carboalumination has proven incredibly useful,
trialkylaluminum reagents are highly pyrophoric, thus a milder approach would be welcomed.
Given our group’s history with bimetallic catalyzed domino reactions, we endeavored to develop
a one-pot two-step protocol for the efficient synthesis of alkenes with defined regio- and
stereoselectivity via a zirconium-catalyzed hydroboration/palladium-catalyzed Suzuki cross-
coupling sequence (Scheme 1.4-6) with the possibility of domino catalysis in mind.
Scheme 1.4-6: Proposed Methodology
119 For a review on Zr-catalyzed carboalumination and its application to total synthesis, see: Negishi, E.; Tan, Z.
Top. Organomet. Chem. 2004, 8, 139.
33
2 Results and Discussion
2.1 Preparation of Alkenylboronates
We began developing a one-pot two-step Zr-catalyzed hydroboration/Pd-catalyzed Suzuki cross-
coupling protocol by examining the hydroboration of terminal alkynes with pinacolborane
(HBpin) catalyzed by zirconocene hydrochloride (Schwartz’s reagent). While the initial
conditions reported by Srebnik and Pereira employed DCM as a solvent,103
Wang et al. reported
in 2005 that hydrocarbon terminal alkynes readily underwent hydroboration with pinacolborane
at ambient temperature in the presence of catalytic amounts of Schwartz’s reagent (10 mol%) in
the absence of solvent, but did not elaborate further.120
In addition to being a greener approach,
the use of solvent-free or neat conditions was attractive as it eliminated the possibility of solvent
incompatibility with a sequential Suzuki cross-coupling. Thus the utility of solvent-free Zr-
catalyzed hydroboration of alkynes was determined.
2.1.1 Solvent-Free Zr-Catalyzed Hydroboration of Terminal Alkynes
We investigated the effects of reaction time, catalyst loading, temperature, and scale on the Zr-
catalyzed hydroboration of phenylacetylene with HBpin, as well as the sensitivity of the reaction
to both light and water (Table 2.1-1). All reactions employed a 10% excess of HBpin relative to
phenylacetylene and were carried out in 2 dram vials sealed under argon. In all cases,
appropriate care was taken to exclude both air and moisture from the reaction (except when
water was added deliberately).121
Styrene, presumably formed via protodemetallation of the
alkenylzirconocene intermediate, was detected in all cases, but in negligible amounts.
Hydroboration of phenylacetylene with HBpin at ambient temperature in the presence of 10
mol% Schwartz’s reagent gave the desired trans-β-styryl pinacolboronate (3.1) in excellent yield
after 24 hours (Entry 3). Neither regio- nor stereoisomers of the product were detected using 1H
NMR analysis of the crude mixture, which was quite clean. Although Schwartz’s reagent is light
120 Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett. 2005, 46, 8777.
121 Although Schwartz’s reagent was measured out in air, exposure was minimized as much as possible and the
reagent was stored under argon in a dessicator when not in use. Pinacolborane, sensitive to both air and moisture
according to its MSDS, was transferred to the reaction vessel under argon via syringe and stored under argon in a
refrigerator (4 °C) when not in use.
34
sensitive according to its MSDS, covering the reaction vial with aluminum foil to reduce
exposure to light provided only a slight boost to the already excellent yield (Entry 4).
Regardless, reaction vials were covered in subsequent trials in an effort to maximize consistency.
Table 2.1-1: Solvent-Free Zr-Catalyzed Hydroboration of Phenylacetylene
Entry Scale
(mmol)
mol%
Zr cat
Temp
(°C)
Time
(h)
Add.
(equiv)
Yield A
(%)b
Yield B
(%)b
1 0.5 none rt 24 -- 0 0
2 0.5 none 110 30 -- 33 2
3 1.1 10 rt 24 -- 93 2
4a
1.1 10 rt 24 -- 95 2
5a
0.5 10 rt 24 -- 92 2
6a
0.2 10 rt 24 -- 65 3
7a
1.1 10 rt 16 -- 96(81) 2
8a
1.1 10 rt 12 -- 88 3
9a
1.1 5 rt 16 -- 85 2
10 1.1 5 45 16 -- 88 2
11 1.0 10 rt 16 H2O (1.0) 0 14
a Reaction vial covered with aluminum foil to reduce exposure to light.
b Yield determined using
1H NMR analysis
of crude with TMB as internal standard. Isolated yield following chromatography shown in parenthesis.
Decreasing the scale of the reaction from 1.1 to 0.5 mmol had no effect on yield (Entry 5);
however, the yield dropped significantly when the scale was further decreased to 0.2 mmol
(Entry 6). The cause was likely mechanical in nature: there was simply not enough material in
35
the 2 dram reaction vial for the reagents to mix sufficiently. Use of a smaller reaction vessel
would presumably remove this limitation.
Reducing the reaction time from 24 to 16 hours did not affect the yield (Entry 7) and 81% of the
desired styrylboronate (3.1) was isolated following chromatography.122
Further reducing the
reaction time to 12 hours (Entry 8) resulted in a slight but noticeable drop in yield as well as the
detection of starting material in the crude reaction mixture. Thus a reaction time of 16 hours
appeared to be ideal for these conditions.
Reducing the catalyst loading from 10 to 5 mol% resulted in a roughly ten percent decrease in
yield (Entry 7 versus 9 respectively), which was somewhat restored by heating the latter at 45 °C
(Entry 10). Based on these data, two sets of reaction conditions of comparable efficacy emerged
for the Zr-catalyzed hydroboration of phenylacetylene with HBpin: 16 hours at ambient
temperature in the presence of 10 mol% Schwartz’s reagent (Entry 7), or 16 hours at 45 °C in the
presence of 5 mol% Schwartz’s reagent (Entry 10).
No desired product was observed when water was deliberately added to the reaction (Entry 11)
either due to deactivation of the catalyst or degradation of pinacolborane or both.
Knochel and co-workers101
reported that alkynes, including phenylacetylene, readily underwent
uncatalyzed hydroboration with HBpin, prepared in situ, at ambient temperature (Table 1.3-1);
however, we observed no reactivity in the absence of catalyst at ambient temperature with
commercially obtained HBpin (Entry 1). Some product was obtained after heating the same
reaction at 110 °C for 30 hours, but the yield was poor (Entry 2). Our conditions differed to
those of Knochel and co-workers, who employed 2.0 equivalents of HBpin (as opposed to our
1.1 equiv) and conducted their hydroborations in DCM; however, when we attempted to
reproduce Knochel’s conditions with phenylacetylene and commercially obtained HBpin (2.0
equiv) in distilled DCM, no product was detected using 1H NMR analysis, even after 30 hours.
Our results somewhat echo those of Srebnik and Pereira,103
who reported that hydroboration of
1-octyne with HBpin (1.05 equiv) in DCM in the absence of Schwartz’s reagent afforded only a
122 Product tended to trail on silica gel column, the majority eluting over several fractions and the remainder over
many more. Switching to an alumina column and/or increasing the polarity of the solvent system once the desired
product began eluting did little to remedy this issue.
36
2% yield of the corresponding octenylboronate when HBpin was prepared in situ (using
Knochel’s procedure) or a 20% yield when HBpin was distilled prior to use. Srebnik and Pereira
attributed these differences to the fact that Knochel used 2.0 equivalents of HBpin, whereas they
used only 1.05 equivalents.
Fürstner and co-workers123
prepared styryl pinacolboronate (3.1) as a reagent for the total
synthesis of marine oxylipins on a 110 mmol scale in 89% yield under solvent-free conditions in
the absence of catalyst; however, the reaction was heated at 140 °C for 5 days. Their source of
HBpin was not specified, but it was presumably commercial. Whereas HBpin prepared in situ
from the reaction of pinacol with borane dimethylsulfide (BMS) in DCM and treated directly
with an alkyne gives the corresponding alkenylboronate in good yields at ambient temperature in
the absence of catalyst, it appears that commercially obtained HBpin does not.
Knochel and co-workers initially reported that Wilkinson’s catalyst does not catalyze the
hydroboration of alkynes or alkenes with HBpin,101
but Srebnik and Pereira later reported that it
is an excellent catalyst for such reactions.105
It is conceivable that the lack of reactivity observed
by Knochel was due to the presence of unreacted BMS and/or by-product(s) of HBpin
preparation. It would be useful to prepare HBpin in situ according to Knochel’s procedure and
compare its reactivity to that of HBpin obtained from a commercial source as well as determine
the effect of BMS on hydroboration with HBpin.
We applied our conditions for the Zr-catalyzed hydroboration of phenylacetylene with HBpin to
a non-hydrocarbon substrate in order to test the scope of the reaction. N-Propargyl indole (1.2)
proved suitable for our conditions (Table 2.1-2). The reaction proceeded smoothly at ambient
temperature to give boronate 3.2 in a good yield (Entry 1). Heating the reaction at 45 °C
improved the yield and decreased the formation of the N-allyl side-product (Entry 2); however, a
further increase in temperature afforded no additional benefit (Entry 3). Reducing the catalyst
loading to 5 mol% with compensatory heating at 45 °C gave a yield that was comparable to that
of the reaction conducted at ambient temperature in the presence of 10 mol% Schwartz’s reagent
(Entry 4 versus 1 respectively).
123 Hickman, V.; Kondoh, A.; Gabor, B.; Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2011, 133, 13471.
37
Table 2.1-2: Solvent-Free Zr-Catalyzed Hydroboration of N-Propargyl Indole
Entry mol% Zr cat Temp (°C) Yield A (%)b
Yield B (%)b
1 10 rt 76 9
2 10 45 87 1
3 10 60 87 1
4 5 45 79(65) 5
a Reactions carried out on 0.50 mmol scale.
b Yield determined using
1H NMR analysis of crude with TMB as
internal standard. Isolated yield following chromatography shown in parenthesis.
2.1.2 Solvent-Free Zr-Catalyzed Hydroboration of Internal Alkynes
Hydroboration of internal alkynes proved sluggish under our conditions and heating at 60 °C for
60 hours was required to obtain moderate yields of the corresponding alkenylboronates (Table
2.1-3). A mixture of regioisomers was obtained from 1-phenyl-1-propyne (Entries 4 – 6) with
borylation occurring predominately at the least sterically hindered carbon, in conformity with the
trend of hydrozirconation of unsymmetrical internal alkynes.104
Regioselectivity decreased with
increased heating. Knochel and co-workers101
reported that uncatalyzed hydroboration of 1-
phenyl-1-propyne with HBpin (2.0 equiv), prepared in situ, provided the corresponding boronate
in a moderate yield after only several hours at ambient temperature in DCM (Table 1.3-1, Entry
3); however, the ratio of regioisomers they obtained was identical to the ratio we obtained from
heating at 60 °C for 60 hours (Entry 6).
Table 2.1-3: Solvent-Free Zr-Catalyzed Hydroboration of Internal Alkynes
38
Entry R1
R2
Temp (°C) Yield A (%)b
A : Bc
1 Et Et rt 13 N/A
2 Et Et 45 41 N/A
3 Et Et 60 67 N/A
4 Ph Me rt 25 92 : 8
5 Ph Me 45 46 86 : 14
6 Ph Me 60 63 85 : 15
a Reactions carried out on 1.1 mmol scale.
b Yield determined using
1H NMR analysis of crude with TMB as
internal standard. c Regioisomeric ratios determined using
1H NMR analysis of crude.
2.1.3 Selecting a Solvent for Zr-Catalyzed Hydroboration
Solvent-free hydroboration is amenable to a one-pot two-step protocol in which a suitable
solvent for SMC is added upon completion of the first step; however, a domino reaction would
require a solvent that was suitable for both steps. We screened several solvents for the Zr-
catalyzed hydroboration of phenylacetylene with HBpin and found the reaction worked
moderately well in toluene at 60 °C (Table 2.1-4, Entry 3). This held promise for domino
reactivity as Suzuki reactions are often conducted in toluene.11
Ethereal solvents THF and
dioxane, also common reaction media for SMC, proved to be incompatible.
Table 2.1-4: Zr-Catalyzed Hydroboration of Phenylacetylene in Toluene
Entry mol% Zr cat Temp (°C) Time (h) Yield A (%)b
Yield B (%)b
1 10 rt 16 33 6
2 10 45 16 58 4
39
3 10 80 24 67 2
4 none 80 24 11 0
a Reactions carried out on 0.22 mmol scale. Concentration: 0.55 M.
b Yield determined using
1H NMR analysis of
crude with TMB as internal standard.
Toluene proved to be an even better solvent for the Zr-catalyzed hydroboration of N-propargyl
indole (1.2) (Table 2.1-5). A good yield of boronate 3.2 was obtained after 16 hours at 45 °C in
the presence of 5 mol% Schwartz’s reagent (Entry 2).
Table 2.1-5: Zr-Catalyzed Hydroboration of N-Propargyl Indole in Toluene
Entry [1.2] (M) mol% Zr cat Temp (°C) Yield A (%)b
Yield B (%)b
1 1.0 10 rt 38 16
2 2.0 5 45 70 8
a Reactions carried out on 0.50 mmol scale.
b Yield determined using
1H NMR analysis of crude with TMB as
internal standard.
N-Propargyl isatin (1.4) proved to be an unsuitable substrate for Zr-catalyzed hydroboration.
The desired boronate was not detected using 1H NMR analysis of the crude, only a complex
mixture of decomposed starting material. This result was not surprising as ketones are known to
be reduced competitively with hydrozirconation of alkynes and alkenes in the presence of
Schwartz’s reagent.107
40
2.2 Optimization of the Suzuki Cross-Coupling Reaction
For our optimization of the Suzuki coupling step we used trans-styryl pinacolboronate (3.1) as
the organoboron species and 4’-iodoacetophenone as its coupling partner. The latter was chosen
primarily for diagnostic purposes. In addition to being an ideal organic halide for Suzuki
couplings given the ease of oxidative addition of Ar-I bonds to Pd(0) – enhanced by the
electrophilic character imparted by the electron-withdrawing p-substituent – 4’-
iodoacetophenone was an easy-to-handle solid, and the acetyl group gave a distinct singlet in a
1H NMR spectrum that was sufficiently shifted in the spectrum of the coupled trans-stilbene
product to enable calculation of NMR yields using an internal standard. Lastly, stilbenes, true to
their name derived from the Greek word Stilbos, meaning “shining,” fluoresce under UV light,
making such products easy to detect using TLC analysis. 4-Acetyl-trans-stilbene (4.1) was also
visible on a silica gel column under UV light, making for easy purification by chromatography.
Tetrakis(triphenylphosphine)palladium(0) was chosen as the catalyst and, given its performance
in the Zr-catalyzed hydroboration step, toluene was chosen as the solvent.
2.2.1 Base and Solvent Screen
Among bases screened, Cs2CO3 was found to be the most effective in toluene (Table 2.2-1, Entry
3), significantly outperforming K2CO3 (Entry 2), implying the importance of the countercation.
In all cases, a 10:1 toluene/water mixture proved to be a more effective solvent system than dry
toluene (Entries 4 – 6), presumably due to increased solubility of the base and/or rate
enhancement of transmetallation by hydroxide.
Table 2.2-1: Base and Solvent Screen for SMC
Entry Base (equiv) Solvent Yield (%)b
1 K3PO4 (2.0) PhMe 46
41
2 K2CO3 (2.0) PhMe 19
3 Cs2CO3 (2.0) PhMe 87
4 K3PO4 (2.0) PhMe/H2O (10:1) 90
5 K2CO3 (2.0) PhMe/H2O (10:1) 36
6 Cs2CO3 (2.0) PhMe/H2O (10:1) 96
a Reactions carried out on 0.20 mmol scale. Concentration: 0.2 M (aryl iodide in toluene).
b Yield determined by
1H
NMR analysis of crude with TMB as internal standard.
2.2.2 Further Optimization
The reaction was optimized for efficiency using toluene/water (10:1) as the solvent and Cs2CO3
as the base. The best yield of coupled product 4.1 was obtained using 1.2 equivalents of
boronate 3.1 and 5 mol% Pd catalyst (Entry 1); however, a satisfactory yield was obtained using
1.1 equivalents of 3.1 and only 1 mol% Pd catalyst (Entry 5). Although the yield of the latter
reaction was lower, we thought it was an acceptable result given the catalyst loading was reduced
by a factor of five, thus these conditions were chosen for the SMC step.
Table 2.2-2: Further Optimization of SMC
Entry equiv Cs2CO3 equiv 3.1 mol% Pd cat Yield (%)b
1 2.0 1.2 5.0 99(86)
2 2.0 1.1 5.0 99
3 2.0 1.0 5.0 84
4 2.0 1.1 2.5 89
42
5 2.0 1.1 1.0 89(70)
6 1.2 1.1 1.0 66
a Reactions carried out on 0.20 mmol scale. Concentration: 0.2 M (aryl iodide in toluene).
b Yield determined using
1H NMR analysis of crude with TMB as internal standard. Isolated yield following chromatography shown in
parenthesis.
43
2.3 Initial Conditions for One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-Catalyzed Suzuki Coupling Sequence
Our next objective was to combine the individual steps into a one-pot two-step bimetallic
catalyzed hydroboration/SMC sequence. To this end, Zr-catalyzed hydroboration of
phenylacetylene (1.1 equiv) with HBpin was carried out following our previously established
solvent-free procedure (Table 2.1-1, Entry 4). After stirring at ambient temperature for 24 hours,
the reaction was stopped and the crude boronate intermediate (3.1) was dissolved in toluene. To
this mixture, water, 4’-iodoacetophenone (1.0 equiv), Cs2CO3, and Pd(PPh3)4 (1 mol%) were
added in accordance with our previously established procedure for SMC (Table 2.2-2, Entry 5).
The reaction vial was sealed under argon and stirred at 100 °C. After 16 hours, the reaction was
stopped and 55% of the desired trans-stilbene (4.1) was isolated following work-up and
purification by chromatography (Scheme 2.3-1). Neither regio- nor stereoisomers of the product
were detected using 1H NMR analysis of the crude reaction mixture, although some of the
boronate intermediate (3.1) was present.
Scheme 2.3-1: Initial Conditions for One-Pot Two-Step Sequence
2.3.1 Substrate Scope of Initial Conditions
We were eager to attempt to apply the conditions for the one-pot two-step synthesis of 4-acetyl-
trans-stilbene (4.1, Scheme 2.3-1) to the synthesis of various (E)-alkenes, thus a substrate scope
was conducted (Table 2.3-1).
44
Table 2.3-1: Substrate Scope of Initial Conditions
Entry Alkyne Aryl Halide Product Yield (%)b
1
58
2
48
3
50
4
39
5
62
6
48
7
63
45
8
73
9
55
10
>10c
a Reactions carried out on 1.0 mmol scale in 3 dram vials. Concentration of coupling reaction: 0.25 M (aryl halide
in toluene). b Isolated yield following chromatography based on amount of aryl halide used.
c Based on conversion
of aryl chloride determined using 1H NMR analysis of crude.
In general, modest yields of the expected (E)-alkene were obtained over two steps. In addition to
aryl alkynes (Entries 1 and 2), cyclic enynes proved to be suitable substrates for these conditions
(Entry 5). Aliphatic alkynes were also suitable (Entry 6), although purification was somewhat
challenging as the product tended to co-elute with unreacted bromide 2.1, resulting in a
decreased isolated yield of 4.9. Yields obtained from the reactions of N-propargyl indole (1.2)
(Entries 7 – 9) were among the best; however, the first step required heating at 60 °C. When
conducted at ambient temperature, the solvent-free hydroboration of 1.2 was problematic as the
mixture remained solid and would not stir. The yield obtained from the reaction of 3-ethynyl
thiophene (Entry 3) was satisfactory given that thiophenes are conventionally challenging
substrates for SMC.58
The reaction with 3-ethynyl pyridine gave the poorest yield (Entry 4),
presumably due to the combination of an electron-poor organoboronate and an electron-rich aryl
halide. Whereas aryl and heteroaryl bromides were generally suitable coupling partners, aryl
chlorides were unreactive under our conditions (Entry 11). This was expected given Pd(0)
catalysts supported by triarylphosphine ligands are not sufficiently electron-rich to oxidatively
add aryl chlorides.42
46
2.4 Optimization of One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-Catalyzed Suzuki Coupling Sequence
The yields of (E)-alkenes obtained using our initial conditions were not satisfactory, and the high
temperatures and long reaction times required to achieve them were synthetically impractical. In
addition, the incompatibility of aryl chlorides led us to try further experiments to improve the
effectiveness, efficiency, and scope of our one-pot two-step protocol.
2.4.1 Optimization with Aryl Bromides and Iodides
Doubling the concentration of the Suzuki coupling step from 0.25 to 0.5 M and switching from 3
to 2 dram vials resulted in the most dramatic improvement in yield, presumably promoting a
more thorough mixing of the biphasic reaction. Whereas our initial protocol yielded 55% of
coupled product 4.1 (Scheme 2.3-1) and left some of intermediate 3.1 unreacted after 16 hours,
simply doubling the concentration resulted in a 71% yield (NMR) of 4.1 and full conversion of
3.1 after 16 hours (Table 2.4-1, Entry 1). As an added benefit, reducing the amount of solvent
used by half makes this procedure more attractive from a green chemistry perspective.
Table 2.4-1: Optimization with Aryl Bromides and Iodides
Entry X mol%
Zr cat
Temp 1
(°C)
Time 1
(h)
mol%
Pd cat
Temp 2
(°C)
Time 2
(h)
Yield
(%)b
1 I 11 rt 24 1.0 100 16 71
2 I 11 rt 24 2.0 100 16 72
3 Br 11 rt 24 1.0 100 16 73
4 Br 11 rt 24 1.0 80 16 76(70)
5 Br 11 rt 24 1.0 60 16 63
47
6 Br 11 rt 16 1.0 80 8 89
7 Br 5.5 rt 16 1.0 80 8 70
8 Br 5.5 45 16 1.0 80 8 89(74)
a Reactions carried out on 1.0 mmol scale in 2 dram vials. Concentration of coupling reaction: 0.5 M (aryl halide in
toluene). b Yield determined using
1H NMR analysis of crude with TMB as internal standard. Isolated yield
following chromatography shown in parenthesis.
Aryl bromides were as reactive as aryl iodides (Entry 3 versus 1 respectively), which was not
surprising in light of our recent substrate scope (Table 2.3-1). Continuing with aryl bromides,
we found that decreasing the temperature from 100 to 80 °C in the SMC step resulted in an
improved yield (Entry 4). Decreasing the temperature further, however, resulted in a drop in
yield (Entry 5), suggesting that 80 °C was an ideal temperature for this step. Halving the
reaction time of the SMC step to 8 hours resulted in a marked improvement in yield (Entry 6),
suggesting that the coupled product had been decomposing beyond this time.
Reducing the loading of Schwartz’s reagent from 10 to 5 mol% (relative to the alkyne) resulted
in a drop in yield and a messier reaction, complicating purification (Entry 7); however, heating
the hydroboration step to 45 °C afforded a clean reaction and excellent yield over two steps with
only 5 mol% Schwartz’s reagent (Entry 8). Accepting the trade-off between conducting the first
step at ambient temperature and halving the use of expensive zirconocene catalyst, we decided
the latter conditions were optimal for this reaction.
2.4.2 Extension to Aryl Chlorides
Aryl chlorides are the cheapest and most readily available aryl halides, albeit less reactive than
the more expensive bromides and iodides, thus we were eager to modify our one-pot two-step
protocol in order to be able to use them as substrates. To this end, we screened several
specialized ligands for the Suzuki coupling of alkenylboronate 3.1 with an aryl chloride,
including dialkylbiaryl phosphine ligands developed by Buchwald and co-workers, which were
discussed above (1.2.3). While SPhos (Figure 1.2-2, L4) and RuPhos (L8) were effective as
supporting ligands for the Pd-catalyzed cross-coupling of 3.1 with 4’-chloroacetophenone,
XPhos (L6) furnished the highest yields, particularly when the concentration of the reaction was
increased from 0.2 to 0.5 M (Table 2.4-2, Entry 4 and 5 respectively).
48
Table 2.4-2: Ligand Screen for Suzuki Coupling of Aryl Chlorides
Entry Pd catalyst (mol%)/
Ligand (mol%) [ArCl] (M)
b Base (equiv)
Temp
(°C) Yield (%)
c
1 Pd2dba3 (2.0)/SPhos (4.0) 0.2 Cs2CO3 (2.0) 100 52
2 Pd2dba3 (2.0)/RuPhos (4.0) 0.2 Cs2CO3 (2.0) 100 66
3 Pd2dba3 (2.0)/tBuXPhos (4.0) 0.2 Cs2CO3 (2.0) 100 8
4 Pd2dba3 (2.0)/XPhos (4.0) 0.2 Cs2CO3 (2.0) 100 76
5 Pd2dba3 (2.0)/XPhos (4.0) 0.5 Cs2CO3 (2.0) 100 87
6 Pd(crotyl)QPhosCl (1.0) 0.8 KOtBu (1.2) 80 28
a Reactions carried out on 0.20 mmol scale.
b Concentration in toluene.
c Yield determined using
1H NMR analysis
of crude with TMB as internal standard.
We employed Pd-XPhos in our one-pot two-step sequence and found, after a short optimization,
that the SMC step went to completion within 4 hours at 80 °C in the presence of 1 mol% Pd(0)
and 2 mol% XPhos ligand (Table 2.4-3, Entry 5).
Table 2.4-3: Optimization with Aryl Chlorides using XPhos
Entry mol%
Zr cat
Time 1
(h)
mol%
Pd cat/L
Temp 2
(°C)
Time 2
(h)
Yield
(%)b
1 11 24 2.0/4.0 100 16 66
49
2 11 24 2.0/4.0 80 16 80(73)
3 11 24 1.0/2.0 80 16 77
4 11 24 1.0/2.0 60 16 63
5 11 24 1.0/2.0 80 4 74
6 5.5 16 1.0/2.0 80 4 68
a Reactions carried out on 1.0 mmol scale in 2 dram vials. Concentration of coupling reaction: 0.5 M (aryl chloride
in toluene). b Yield determined using
1H NMR analysis of crude with TMB as internal standard. Isolated yield
following chromatography shown in parenthesis.
The commercially available 2nd
generation XPhos precatalyst (Figure 2.4-1) proved to be an even
more effective catalyst for the coupling of aryl chlorides (Table 2.4-4). The SMC step
completed within 2 hours at 80 °C in the presence of 1 mol% precatalyst (Entry 1). Reducing the
loading of Schwartz’s reagent to 5 mol% (relative to alkyne) in the hydroboration step resulted in
a lower yield overall (Entry 3); however, as with aryl bromides, reduced catalyst loading in the
first step could be compensated by heating at 45 °C (Entry 4). Again, preferring increased
heating to increased catalyst loading, we decided the latter conditions were optimal for a one-pot
two-step bimetallic catalyzed hydroboration/SMC sequence using aryl chlorides as substrates.
Apart from being operationally simpler, an added benefit of employing the XPhos palladacycle
(as opposed to adding Pd and XPhos ligand individually) was that only one equivalent of ligand
was used relative to Pd, improving efficiency.
Figure 2.4-1: 2nd Generation XPhos Precatalyst
50
Table 2.4-4: Optimization with Pd-XPhos-G2
Entry mol% Zr cat Temp 1 (°C) mol%
Pd-XPhos-G2 Yield (%)
b
1 11 rt 1.0 83
2 5.5 rt 1.0 73
3 5.5 rt 2.0 73
4 5.5 45 1.0 80
a Reactions carried out on 1.0 mmol scale in 2 dram vials. Concentration of coupling reaction: 0.5 M (aryl chloride
in toluene). b Yield determined using
1H NMR analysis of crude with TMB as internal standard.
51
2.5 Bimetallic Catalyzed Domino Attempt
Following optimization of two sets of conditions for the one-pot two-step synthesis of (E)-
alkenes from terminal alkynes and aryl halides via a Zr-catalyzed hydroboration/Pd-catalyzed
SMC sequence, a bimetallic catalyzed domino reaction was attempted. It was known from our
study of Zr-catalyzed hydroboration with HBpin that water must be excluded from the domino
reaction (Table 2.1-1, Entry 11); however, it was also known that dry toluene was a suitable
solvent for both Zr-catalyzed hydroboration (Table 2.1-4, Entry 3) and Pd-catalyzed SMC (Table
2.2-1, Entry 3), thus combining the two steps in domino fashion seemed plausible.
A solution of phenylacetylene and HBpin in dry toluene was added to a mixture of Schwartz’s
reagent, 4’-bromoacetophenone, Pd(PPh3)4, and Cs2CO3, and the resulting mixture was sealed
under argon and stirred at 80 °C for 16 hours (Scheme 2.5-1). Unfortunately, neither the desired
coupled product (4.1) nor the boronate intermediate (3.1) were detected using TLC or 1H NMR
analysis of the crude reaction mixture.
Scheme 2.5-1: Domino Attempt
The total absence of expected boronate intermediate 3.1 in the crude reaction mixture of the
domino attempt strongly suggested that one or more of the components of the SMC step impeded
Zr-catalyzed hydroboration. To determine which reagent(s) were deleterious, we carried out
several Zr-catalyzed hydroborations of phenylacetylene with HBpin in dry toluene, each in the
presence of one or more of the reagents used in the SMC step and in their relative amounts
(Table 2.5-1). In addition to water (Entry 2), which was already known to preclude Zr-catalyzed
hydroboration, Cs2CO3 inhibited the reaction (Entry 3), perhaps due to deprotonation of the
terminal alkyne and/or formation of an oxoborohydride species. 4’-Bromoacetophenone was
equally poor (Entry 4), likely due to the electrophilic carbonyl carbon. Proton NMR analysis of
52
the crude reaction, while messy, suggested the presence of the alcohol; however, further
experimentation would be necessary to determine the reducing capability of HBpin and
Schwartz’s reagent under these conditions. A catalytic amount of Pd(PPh3)4 did not hinder
hydroboration (Entry 5), but only trace 3.1 was obtained in the presence of both the Pd catalyst
and 4’-bromoacetophenone (Entry 6). In the latter instance, a trace amount of coupled product
4.1 was detected in the crude reaction mixture, presumably arising from transmetallation
between the arylpalladium(II)bromide complex and either alkenylboronate 3.1 or, more directly,
its alkenylzirconocene precursor. Unlike 4’-bromoacetophenone, bromobenzene had no
detectable influence on hydroboration (Entry 7), and the combination of bromobenzene and
catalytic Pd(PPh3)4 decreased the expected yield of 3.1 by only a third (Entry 8). These data
suggest that use of an aryl halide lacking competing functional group(s) may enable domino
reactivity. Regardless, the base, which is necessary for the SMC step, remains a serious
impediment to the hydroboration step. Finding a base that facilitates Pd-catalyzed SMC without
hindering Zr-catalyzed hydroboration, should it exist, may solve this problem.
Table 2.5-1: Effect of SMC Components on Zr-Catalyzed Hydroboration
Entry Additive(s) (equiv)b
Yield A (%)c
Yield B (%)c
1 none 67 2
2 H2O (10) 0 0
3 Cs2CO3 (1.8) 8 3
4 4’-BrPhAc (0.91) 8 2
5 Pd(PPh3)4 (0.0091) 69 5
6
4’-BrPhAc (0.91) &
Pd(PPh3)4 (0.0091)
trace 3
53
7 PhBr (0.91) 68 >1
8
PhBr (0.91) &
Pd(PPh3)4 (0.0091)
40 >1
a Reactions carried out on 0.22 mmol scale. Concentration: 0.55 M.
b Added directly before Cp2ZrHCl.
c Yield
determined using 1H NMR analysis of crude with TMB as internal standard.
Throughout the development of our one-pot two-step protocol, we had observed that the addition
of water to the crude product of the Zr-catalyzed hydroboration step (dissolved in toluene)
caused the mixture to lightly effervesce for a few minutes, although it did not warm to the touch.
While water was initially included in the SMC step simply because a toluene/water (10:1)
mixture provided better yields than dry toluene during optimization of the Suzuki reaction (Table
2.2-1), we now wondered if it served a dual purpose. Knowing that both Schwartz’s reagent and
HBpin are water sensitive, we hypothesized that the addition of water to the second step
deactivated the zirconocene catalyst and/or degraded any excess HBpin, either or both of which
may be deleterious to Pd-catalyzed cross-coupling. To test this, we conducted both one-pot two-
step reactions (the aryl bromide and aryl chloride variant) under anhydrous conditions (Scheme
2.5-2) and found that the addition of water to the SMC step was crucial. Whereas the optimized
one-pot two-step syntheses of 4.1 gave yields of 89% (NMR) from 4’-bromoacetophenone
(Table 2.4-1, Entry 8) and 80% (NMR) from 4’-chloroacetophenone (Table 2.4-4, Entry 4), only
10 and 17% yields, respectively, of 4.1 were obtained when water was omitted in the SMC step.
In both cases, unreacted aryl halide was present in the crude reaction mixture (85% 4’-bromo-
and 62% 4’-chloroacetophenone).
Scheme 2.5-2: One-Pot Two-Step under Anhydrous Conditions
54
To test the effect of Schwartz’s reagent on SMC, we attempted to couple 4’-bromoacetophenone
with boronate 3.1 in dry toluene with and without the zirconocene present (Table 2.5-2).
Whereas 64% of coupled product 4.1 was obtained in the absence of Schwartz’s reagent (Entry
1), only 16% of 4.1 was obtained when 5.5 mol% of the zirconocene was present (Entry 2)
(amount employed in the hydroboration step of a typical one-pot two-step sequence).
Table 2.5-2: Effect of Cp2ZrHCl on Suzuki Coupling
Entry Additive (mol %) Yield (%)b
1 -- 64
2 Cp2ZrHCl (5.5) 16
a Reactions carried out on 0.20 mmol scale. Concentration: 0.5 M (aryl bromide in toluene).
b Yield determined
using 1H NMR analysis of crude with TMB as internal standard.
Based on these findings, the one-pot two-step Zr-catalyzed hydroboration/Pd-catalyzed SMC
sequence works for two reasons: 1) while the components of the second step severely hinder the
first, the components of the first step do not appear to hinder the second provided the second step
is conducted in the presence of water; and 2) in relation to the first point, Suzuki reactions are
water tolerant.
55
2.6 Optimized Conditions for One-Pot Two-Step Zr-Catalyzed Hydroboration/Pd-Catalyzed Suzuki Coupling Sequence
Although unsuccessful in developing a bimetallic catalyzed domino reaction, we still had two
sets of optimized conditions for the efficient one-pot synthesis of (E)-alkenes from terminal
alkynes and aryl bromides or chlorides, thus we conducted a second substrate scope.
2.6.1 Substrate Scope of Optimized Conditions for Aryl Bromides
Following the optimized conditions for the one-pot two-step synthesis of 4-acetyl-trans-stilbene
(4.1) from phenylacetylene and 4’-bromoacetophenone (Table 2.4-1, Entry 8), we prepared a
variety of (E)-alkenes from various terminal alkynes and aryl- or heteroaryl bromides (Table
2.6-1). In some cases, the reaction temperature in the SMC step was increased from 80 to 100
°C and/or the Pd catalyst loading was increased from 1 to 2.5 mol% to achieve full conversion.
Reaction times were also increased in certain cases (see Experimental section).
Table 2.6-1: Substrate Scope of Optimized Conditions for Aryl Bromides
Entry Alkyne Aryl Bromide Product Yield (%)b
1
61
2
67
56
3
58
4
59
5
89
6
78
a Reactions carried out on 1.0 mmol scale in 2 dram vials. Concentration of coupling reaction: 0.5 M (bromide in
toluene). b Isolated yield following chromatography based on amount of aryl bromide used.
Compared to the scope of our initial conditions (Table 2.3-1), the optimized conditions for our
one-pot two-step protocol gave superior yields of the desired (E)-alkenes in all cases where the
same substrates were reacted (Table 2.6-1) and generally under milder conditions. The yield of
coupled product 4.3 increased from 48% in our initial study to 61% (Entry 1), 4.6 increased from
62 to 67% (Entry 2), 4.14 from 73 to 89% (Entry 5), and 4.15 from 55 to 78% (Entry 6).
N-Propargyl indole (1.2) proved to be an excellent substrate for these conditions, the SMC step
going to completion in 8 to 10 hours at 80 °C in the presence of 1 mol% Pd catalyst to give
coupled products 4.14 (Entry 5) and 4.15 (Entry 6) in great yields over two steps. The protected
propargyl amine was not as reactive, and the SMC step required heating at 100 °C for 10 hours
in the presence of 2.5 mol% Pd catalyst to give 4.12 in a modest yield (Entry 4).
As expected, (PPh3)4Pd-catalyzed SMC was chemoselective for bromides over chlorides in the
presence of aryl halides bearing both, and bromides with para-chloro substituents were more
reactive substrates than those bearing ortho-chloro substituents. TLC analysis indicated 1-
bromo-4-chlorobenzene was consumed after 8 hours at 80 °C in the presence of 1 mol% Pd
catalyst (Entry 2). In contrast, SMC of 1-bromo-2-chlorobenzene required heating at 100 °C for
12 hours in the presence of 2.5 mol% Pd catalyst to achieve conversion, albeit in a lower yield
57
(Entry 3). When the latter was subjected to the conditions of the former, only 22% of coupled
product 4.7 was obtained. Curiously, while 4.7 was a liquid at room temperature, its
constitutional isomer 4.6 was a solid with a melting point of 78 – 82 °C.
2.6.2 Substrate Scope of Optimized Conditions for Aryl Chlorides
Following the optimized conditions for the one-pot two-step synthesis of 4-acetyl-trans-stilbene
(4.1) from phenylacetylene and 4’-chloroacetophenone (Table 2.4-4, Entry 4), we prepared a
variety of (E)-alkenes from various aryl, heteroaryl, and aliphatic terminal alkynes and aryl- or
heteroarylchlorides (Table 2.6-1). In some cases, the reaction temperature in the SMC step was
increased from 80 to 100 °C and/or the Pd-XPhos precatalyst loading was increased from 1 to
2.5 mol% to achieve full conversion. Reaction times also varied (see Experimental section).
Table 2.6-2: Substrate Scope of Optimized Conditions for Aryl Chlorides
Entry Alkyne Aryl Chloride Product Yield (%)b
1
79
2
71
3
73
4
77
58
5
86
6
71
7c
41
8
decomp.
a Reactions carried out on 1.0 mmol scale in 2 dram vials. Concentration of coupling reaction: 0.5 M (chloride in
toluene). b Isolated yield following chromatography based on amount of aryl chloride used.
c Hydroboration carried
out in toluene.
The optimized conditions for our one-pot two-step protocol incorporating aryl and heteroaryl
chlorides as substrates afforded good yields of the corresponding (E)-alkenes over two steps
(Table 2.6-2), with a couple of exceptions.
N-propargyl indole proved to be an excellent substrate for these conditions, providing the
corresponding (E)-alkenes in generally high yields over two steps (Entries 5 and 6); however, 1-
propargyl triazole proved to be more challenging (Entry 7). Unlike N-propargyl indole, which
readily underwent Zr-catalyzed hydroboration with HBpin in the absence of solvent at 45 °C, 1-
propargyl triazole required the use of toluene as a solvent for this step. When hydroboration of
1-propargyl triazole was attempted under solvent-free conditions, the mixture remained solid and
would not stir, even when the temperature was increased to 60 °C. Furthermore, SMC of the
corresponding boronate of 1-propargyl triazole required heating at 100 °C for 24 hours in the
presence of 2.5 mol% Pd catalyst to achieve conversion, whereas coupling of the corresponding
boronate (3.2) of N-propargyl indole went to completion within only 2 hours at 80 °C in the
presence of 1 mol% Pd catalyst and gave much higher yields of the resulting (E)-alkenes.
59
2-Chloroquinoline proved to be a suitable coupling partner, furnishing good yields of the
corresponding 2-alkenylquinolines (Entries 3 and 4), but 2-chlorobenzoxazole decomposed
within 2 hours under these conditions and no desired product was detected using 1H NMR
analysis of the crude reaction mixture (Entry 8).
2.6.3 Synthesis of (E)-2-Styrylbenzoxazole
In 2007, Buchwald and co-workers58
reported the cross-coupling of aryl boronic acids with a
myriad of conventionally challenging heteroaryl chlorides employing Pd-XPhos as the catalyst,
n-butanol as the solvent, and K3PO4 as the base. Although it was not among the heteroaryl
halides coupled, we applied Buchwald’s conditions to the SMC of 2-chlorobenzoxazole with 3.1
as the coupling partner (Table 2.6-3).
Table 2.6-3: Solvent and Base Screen for SMC with 2-Chlorobenzoxazole
Entry Solventb mol%
Pd-XPhos-G2 Base Temp (°C) Yield (%)
c
1 PhMe (distilled) 2.5 Cs2CO3 100 decomp.
2 n-BuOH (reagent A.C.S.) 2.5 Cs2CO3 100 26
3 n-BuOH (reagent A.C.S.) 2.5 K3PO4 100 47
4 2-BuOH (anhydrous) 2.5 K3PO4 100 58
5 2-BuOH (anhydrous) 2.5 K3PO4 80 55
6 2-BuOH (anhydrous) 5.0 K3PO4 100 48
a Reactions carried out on 0.20 mmol scale.
b Concentration: 0.5 M.
c Yield determined by
1H NMR analysis of
crude with TMB as internal standard.
The combination of n-butanol and K3PO4 gave 4.18 in a modest yield (Entry 3), which was
improved by switching to 2-butanol (Entry 4). The superior performance of 2-butanol was
60
presumably due to its higher grade as opposed to some special property conferred by it being a
branched rather than a linear alcohol. Distillation of n-butanol would presumably improve its
utility as a solvent.
Although some product formed, 2-chlorobenzoxazole still decomposed in butanol and was not
detected in the reaction mixture after 4 hours. Increasing the catalyst loading from 2.5 to 5.0
mol% had a negative impact on yield (Entry 6), suggesting the oxidative addition product was
unstable. For this substrate, it appeared cross-coupling was in competition with decomposition.
The rate of transmetallation was presumably enhanced in the alcohol relative to toluene, perhaps
through formation of a butoxypalladium(II) or butoxyborate species, thus cross-coupling was fast
enough to generate some desired product even in the presence of a decomposition pathway.
We applied the modified conditions for SMC of 2-chlorobenzoxazole with 3.1 to our one-pot
two-step protocol and isolated coupled product 4.18 in a 49% yield (Scheme 2.6-1), which was
deemed satisfactory given the challenging nature of this substrate.
Scheme 2.6-1: One-Pot Two-Step Synthesis of (E)-2-Styrylbenzoxazole
61
2.7 Conclusions and Future Outlook
Two sets of conditions have been described for the one-pot two-step or telescopic synthesis of
(E)-alkenes. In the first step, zirconium-catalyzed hydroboration of a terminal alkyne with
pinacolborane generates the corresponding alkenyl pinacolboronate intermediate, which can then
undergo palladium-catalyzed cross-coupling with an aryl or heteroaryl halide in the same
reaction vessel. A variety of terminal alkynes can be used including aryl and aliphatic alkynes,
cyclic enynes, and propargylic indoles, benzotriazoles, and amines. Initial hydrozirconation of
the alkyne sets the regio- and stereochemistry of the resulting alkenylboronate, which is retained
in the cross-coupling step. Aryl and heteroaryl chlorides, which are unreactive under traditional
Suzuki conditions employing palladium catalysts derived from triarylphosphine ligands, can be
used as coupling partners when bulky, electron-rich, dialkylbiaryl phosphine ligands are
employed. Among catalysts screened, the preformed XPhos palladacycle proved to be the most
efficient under these conditions.
This bimetallic catalyzed sequence has several key features: relative ease of set-up; mild
conditions for the hydroboration step; lack of need to isolate boronate intermediate, which saves
time, reduces waste, and likely improves overall yield; and low catalyst loading in the cross-
coupling step. Furthermore, zirconium is much less expensive and more earth-abundant than
many other transition metals employed in catalyzed hydroboration, particularly rhodium. This
sequence was not amenable to domino reactivity as the components of the cross-coupling step
hinder hydroboration. In kind, the components of the hydroboration step hinder cross-coupling;
however, the addition of water to the second step prevents this from happening by deactivating
the otherwise deleterious zirconocene catalyst and/or degrading excess pinacolborane. Thus this
sequence succeeds by exploiting the water tolerance of the Suzuki-Miyaura reaction.
In general, the desired (E)-alkenes were isolated in good yields over two steps on a 1.0 mmol
scale. N-Propargyl indole proved to be a particularly effective substrate for these conditions,
thus an efficient method for the one-pot synthesis of N-cinnamyl indole derivatives has been
provided. These conditions are also applicable to the efficient synthesis of 2-alkenylquinolines.
62
In 2010, Lam and co-workers124
reported the asymmetric rhodium-catalyzed addition of boronic
acids to alkenylheteroarenes using chiral diene ligands and 2-hexenylquinoline (4.10) as the
model substrate. In light of Lam’s work, and the fact that rhodium does not bind XPhos as
previous work by our group has demonstrated,6 we propose that our conditions may be amenable
to a sequential rhodium-catalyzed hydroarylation step.
124 Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010, 132, 14373.
63
3 Experimental
3.1 General Considerations
All metal-catalyzed reactions were carried out under an inert atmosphere of dry argon or dry
nitrogen using glassware that was oven- or flame-dried and cooled under nitrogen. Work-up and
isolation of products of all reactions was conducted on the bench-top using standard techniques.
Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator and a
high vaccum pump in tandem. Unless otherwise stated, yields quoted are isolated yields.
Commercial reagents were purchased from Sigma-Aldrich, Strem Chemicals, Alfa Aesar,
Combi-Blocks, or BDH Chemicals and were used without further purification. Zirconocene
hydrochloride (Schwartz’s reagent) was purchased from Alfa Aesar and palladium catalysts from
Strem Chemicals. Pinacolborane was purchased from Sigma-Aldrich and stored under argon in a
refrigerator (4°C). Anhydrous cesium carbonate was ground and stored under argon in a
dessicator. Toluene and tetrahydrofuran were distilled over sodium; dichloromethane was
distilled over calcium hydride; 2-butanol was purchased from Alfa Aesar and N,N-
dimethylformamide from Fisher Scientific and both were used as received.
Reactions were monitored by thin layer chromatography (TLC) on EMD Silica Gel 60 F254
plates. Visualization of the developed plates was enabled with UV light (254 or 365 nm) and/or
by staining with either KMnO4 or p-anisaldehyde. Silica gel flash column chromatography was
performed on Silicycle 230 – 400 mesh silica gel.
NMR characterization data were collected on a Varian Mercury 300 or a Bruker Avance III
spectrometer operating at 300 or 400 MHz for 1H NMR, 75 or 100 MHz for
13C NMR, 128 MHz
for 11
B NMR, and 377 MHz for 19
F NMR. 1H NMR spectra were internally referenced to the
residual solvent signal (CDCl3 = 7.26 ppm) or TMS. 13
C NMR spectra were internally
referenced to the residual solvent signal (CDCl3 = 77.0 ppm). Chemical shifts (δ) are reported in
ppm and are given to the nearest 0.01 ppm. Coupling constants (J) are reported in Hz and are
given to the nearest 0.1 Hz. Signal multiplicities are as follows: s = singlet, d = doublet, t =
triplet, q = quartet, p = pentet, m = mulitplet, br = broad. Regioisomeric ratios reported were
obtained by 1H NMR analysis of crude reaction mixtures with a 10 second relaxation delay.
64
NMR yields were obtained by 1H NMR analysis of crude reaction mixtures with a 10 second
relaxation delay and 1,3,5-trimethoxybenzene (TMB) as the internal standard.
Melting points reported were determined using a Fisher-Johns melting point apparatus and are
uncorrected. Infrared (IR) spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR
spectrometer as thin films from dichloromethane or chloroform. High resolution mass spectra
(HRMS) were obtained using a JEOL AccuTOF JMS-T1000LC equipped with an IONICS®
Direct Analysis in Real Time (DART) ion source or an ABI/Sciex Qstar mass spectrometer (ESI)
at Advanced Instrumentation for Molecular Structure (AIMS) in the Department of Chemistry at
the University of Toronto.
65
3.2 Synthesis of Starting Materials
1,1-dibromo-4-phenyl-1-butene – Synthesized by adaptation of the
procedure reported by Gibtner et al.125
To a solution of CBr4 (2.0 equiv, 8.0
mmol, 2.65 g) and PPh3 (4.0 equiv, 16.0 mmol, 4.2 g) in DCM (10 mL) was added
hydrocinnamaldehyde (1.0 equiv, 4.0 mmol, 537 mg) at 0 °C. The mixture was stirred at this
temperature for 10 minutes then allowed to warm to room temperature. After 15 minutes at this
temperature, the mixture was concentrated in vacuo to give an intractable purple gum. Filtration
through a pad of silica gel with hexanes:EtOAc (50:50 v/v) (300 mL) as the eluent gave the
crude product as a pale yellow oil. Purification by silica gel flash column chromatography using
hexanes:EtOAc (49:1 v/v) as the eluent gave the gem-dibromoolefin as a clear colourless oil (630
mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.27 (m, 2H), 7.25 – 7.17 (m, 3H), 6.43 (t, J =
7.2 Hz, 1H), 2.75 (t, J = 8.2 Hz, 2H), 2.43 (dt, J = 8.2, 7.2 Hz, 2H). 13
C NMR (100 MHz,
CDCl3) δ 140.49, 137.58, 128.49, 128.34, 126.23, 89.46, 34.63, 33.84. The spectroscopic data
are in agreement with literature values.126
4-phenyl-1-butyne (1.1) – Synthesized by adaptation of the procedure reported
by Gibtner et al.125
To a flame-dried 100 mL round-bottom flask under an
atmosphere of argon was added (4,4-dibromobut-3-en-1-yl)benzene (1.0 equiv, 2.76 mmol, 800
mg) and dissolved in dry THF (10 mL). LDA (3.0 equiv, 0.5 M in dry THF, 16.6 mL) was
added dropwise with stirring at -78 °C, and the mixture was stirred at this temperature for 30
minutes then allowed to warm to room temperature and stirred for an additional 1 hour. At this
time, TLC analysis of the reaction mixture indicated incomplete conversion of starting material.
The mixture was re-cooled to -78 °C and n-BuLi (1.0 equiv, 2.34 M in hexanes, 1.18 mL) was
added dropwise. The mixture was stirred at this temperature for 15 minutes, after which TLC
125 Gibtner, T.; Hampel, F.; Gisselbrecht, J. –P.; Hirsh, A. Chem. Eur. J. 2008, 9, 408.
126 Yokota, M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9, 4639.
66
analysis indicated complete conversion of the gem-dibromoolefin. The reaction was quenched
with 2M HCl solution (14 mL) followed by dilution with hexanes (30 mL). The aqueous phase
was extracted with hexanes (3 x 20 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo to afford the crude product an an orange oil.
Purification by silica gel flash column chromatography using hexanes:EtOAc (24:1 v/v) as the
eluent gave the alkyne as a clear colourless oil (144 mg, 40%). 1H NMR (300 MHz, CDCl3) δ
7.34 – 7.24 (m, 2H), 7.24 – 7.15 (m, 3H), 2.83 (t, J = 7.6 Hz, 2H), 2.46 (td, J = 7.6, 2.6 Hz, 2H),
1.95 (t, J = 2.6 Hz, 1H). 13
C NMR (75 MHz, CDCl3) δ 140.31, 128.32, 128.31, 126.27, 83.69,
68.88, 34.76, 20.49. The spectroscopic data are in agreement with literature values.127
1-(prop-2-yn-1-yl)-1H-indole (1.2) – Synthesized according to the procedure
reported by Haider & Käferböck.128
No measures were taken to exclude air or
moisture. To a solution of indole (1.0 equiv, 10.0 mmol, 1.17 g) and propargyl bromide (80% in
toluene, 1.5 equiv, 15.0 mmol, 1.67 mL) in toluene (30 mL) were added tetrabutylammonium
bromide (0.050 equiv, 0.50 mmol, 161 mg) and 50% aqueous NaOH (6 mL), and the two-phase
mixture was stirred vigorously at room temperature. After 1 hour, the reaction mixture was
diluted with water (20 mL), the layers were separated, and the aqueous phase was extraced with
Et2O (20 mL). The combined organic layers were washed with water (3 x 20 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel flash column
chromatography using hexanes:EtOAc (19:1 v/v) as the eluent gave the propargylated indole as a
yellow oil that eventually solidified to a beige solid (1.13g, 71%, MP = 64 °C (lit. 65 – 69)128
).
1H NMR (400 MHz, CDCl3) δ 7.65 (apparent dt, 1H), 7.42 (apparent dq, 1H), 7.29 – 7.23 (m,
1H), 7.22 (d, J = 3.2 Hz, 1H), 7.15 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 6.54 (dd, J = 3.3, 0.9 Hz, 1H),
4.89 (d, J = 2.6 Hz, 2H), 2.40 (t, J = 2.6 Hz, 1H). 13
C NMR (100 MHz, CDCl3) δ 135.76,
128.87, 127.19, 121.86, 121.10, 119.85, 109.27, 102.08, 77.70, 73.48, 35.77. The spectroscopic
data are in agreement with literature values.128
127 Beshai, M.; Dhudshia, B.; Mills, R.; Thadani, A.N. Tetrahedron Letters 2008, 49, 6794.
128 Haider, N.; Käferböck, J. Tetrahedron 2004, 60, 6495.
67
1-(prop-2-yn-1-yl)-1H-benzo[d][1,2,3]triazole (1.3) – Synthesized according
to the procedure reported by Katritzky et al.129
To a flame-dried 25 mL round-
bottom flask under an atmosphere of argon was added NaH (60 wt% in mineral
oil, 9.5 mmol, 380 mg) and suspended in dry DMF (3.5 mL). To the suspension was added a
solution of benzotriazole (1.0 equiv, 10.0 mmol, 1.19 g) in dry DMF (1.5 mL) at 0 °C, and the
mixture was stirred at this temperature for 20 minutes then allowed to warm to room temperature
and stirred for an additional 20 minutes. The mixture was cooled to 0 °C and propargyl bromide
(80% in toluene, 1.1 equiv, 11.0 mmol, 1.23 mL) was added dropwise, after which the mixture
was allowed to warm to room temperature. After stirring at this temperature for 2 hours, the
reaction was quenched with saturated NaHCO3 (10 mL), and the aqueous layer was extracted
with Et2O (3 x 10 mL). The combined organic layers were washed once with saturated NaHCO3
(20 mL) followed by water (3 x 20 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification by silica gel flash column chromatography using hexanes:EtOAc (4:1 v/v) as the
eluent gave the propargylated benzotriazole as a yellow oil that eventually solidified to a light
yellow solid (846 mg, 54%, MP = 82 – 83 °C (lit. 57)130
). 1H NMR (400 MHz, CDCl3) δ 8.08
(dt, J = 8.4, 0.9 Hz, 1H), 7.72 (dt, J = 8.3, 1.0 Hz, 1H), 7.54 (ddd, J = 8.2, 7.1, 1.0 Hz, 1H), 7.41
(ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 5.47 (d, J = 2.6 Hz, 2H), 2.50 (t, J = 2.6 Hz, 1H). 13
C NMR (100
MHz, CDCl3) δ 146.26, 132.42, 127.66, 124.16, 120.14, 109.74, 75.21, 75.04, 37.99. The
spectroscopic data are in agreement with literature values.130
1-(prop-2-yn-1-yl)indoline-2,3-dione (1.4) – Synthesized according to the
procedure reported by Leugn, C.; Tomaszewski, M.; Woo, S. New
Compounds. US Patent 185179 A1, February 5, 2007. To a solution of isatin
(1.0 equiv, 10.0 mmol, 1.47 g) in dry DMF (40 mL) was added Cs2CO3, and the mixutre was
stirred at room temperature. After 1.5 hours, propargyl bromide (80% in toluene, 1.2 equiv, 12.0
mmol, 1.34 mL) was added dropwise, and the mixture was stirred at room temperature overnight.
The reaction was quenched with saturated NaHCO3 (30 mL) and extracted into EtOAc (3 x 20
mL). The combined organic layers were washed with copious water (6 x 30 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was filtered through a pad of silica gel
with EtOAc as the eluent. Further purifiction was not necessary, and the propargylated isatin
129 Katritzky, A.R.; Button, M.A.C.; Denisenko, S.N. J. Heterocyclic Chem. 2000, 37, 1505.
130 Katritzky, A.R.; Oniciu, D.C.; Ghiviriga, I. Synth. Commun. 1997, 27, 1613.
68
was obtained as a bright orange solid (1.62 g, 88%, MP = 154 – 159 °C (lit. 156 – 158)131
). 1H
NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 2H), 7.18 (td, J = 7.5, 0.8 Hz, 1H), 7.15 – 7.10 (m,
1H), 4.54 (d, J = 2.6 Hz, 2H), 2.31 (t, J = 2.5 Hz, 1H). 13
C NMR (100 MHz, CDCl3) δ 182.48,
157.13, 149.60, 138.37, 125.46, 124.18, 117.70, 111.05, 75.66, 73.31, 29.44. The spectroscopic
data are in agreement with literature values.131
5-bromo-1-tosyl-1H-indole (2.1) – Synthesized by adaptation of the procedure
reported by Wang & Liu.132
No measures were taken to exclude ambient air or
moisture. To a solution of 5-bromoindole (1.0 equiv, 10.2 mmol, 2.0 g) in toluene (20 mL) were
added tetrabutylammonium hydrogensulfate (0.070 equiv, 0.714 mmol, 242 mg) and 50%
aqueous KOH (12 mL) followed by p-toluenesulfonyl chloride (1.2 equiv, 12.2 mmol, 2.33 g) in
toluene (8 mL), and the resultant mixture was stirred at room temperature. After 2 hours, the
reaction was diluted with water (30 mL) and extracted into EtOAc (3 x 20 mL). The combined
organic layers were washed with water (2 x 50 mL) followed by brine (30 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was filtered through a pad of
silica gel with EtOAc as the eluent. Further purification was not necessary, and the tosylated
indole was obtained as an off-white solid (3.33 g, 93%, MP = 162 °C (lit. 136 – 137)133
). 1H
NMR (400 MHz, CDCl3) δ 7.90 – 7.82 (m, 1H), 7.78 – 7.70 (m, 2H), 7.66 (d, J = 1.9 Hz, 1H),
7.56 (d, J = 3.7 Hz, 1H), 7.39 (dd, J = 8.8, 2.0 Hz, 1H), 7.26 – 7.20 (m, 2H), 6.59 (dd, J = 3.7,
0.8 Hz, 1H), 2.35 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ 145.23, 134.99, 133.51, 132.44,
129.95, 127.54, 127.42, 126.76, 124.01, 116.74, 114.92, 108.24, 21.56. The spectroscopic data
are in agreement with literature values.133
131 Bouhfid, R.; Joly, N.; Essassi, El M.; Lequart, V.; Massoui, M.; Martin, P. Synth. Commun. 2011, 41, 2096.
132 Wang, K.; Liu, Z. Synth. Commun. 2010, 40, 144.
133 Prieto, M.; Zurita, E.; Rosa, E.; Muñoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2004, 69, 6812.
69
3.3 Synthesis of Alkenylboronates
(E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (3.1) – Synthesized
by adaptation of the procedure reported by Wang et al.120
Phenylacetylene
(1.0 equiv, 1.10 mmol, 113 mg) and Cp2ZrHCl (10 mol%, 28.4 mg) were
weighed into an oven-dried 2 dram vial and purged with nitrogen for one minute. To this
mixture, pinacolborane (1.1 equiv, 1.21 mmol, 155 mg) was added dropwise. The reaction vial
was sealed under argon, covered with aluminum foil to reduce exposure to light, and the mixture
was stirred at room temperature for 16 hours. The initially pale yellow solution became bright
orange over time, presumably indicating progression. After 16 hours, the mixture was filtered
through a thin pad of silica gel with Et2O (20 mL) as the eluent and concentrated in vacuo.
Purification by silica gel flash column chromatography using hexanes:Et2O (9:1 v/v initially then
4:1 v/v once product began eluting) as the eluent gave the styrylboronate as a clear colourless oil,
which crystallized upon storage in freezer (204 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.52 –
7.45 (m, 2H), 7.40 (d, J = 18.4 Hz, 1H), 7.36 – 7.24 (m, 3H), 6.17 (d, J = 18.4 Hz, 1H), 1.30 (s,
12H). 13
C NMR (100 MHz, CDCl3) δ 149.43, 137.40, 128.81, 128.48, 126.97, 83.23, 24.74
(vinyl boron C absent). 11
B NMR (128 MHz, CDCl3) δ 30.35. The spectroscopic data are in
agreement with literature values.123
(E)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)-1H-
indole (3.2) – Synthesized by adaptation of the procedure reported by
Wang et al.120
1-Propargyl indole (1.0 equiv, 0.50 mmol, 77.6 mg)
and Cp2ZrHCl (5 mol%, 6.5 mg) were weighed into an oven-dried 2 dram vial and purged with
nitrogen for one minute. To this mixture, pinacolborane (1.1 equiv, 0.55 mmol, 70.4 mg) was
added dropwise. The reaction vial was sealed under argon, and the mixture was stirred at 45 °C.
After 16 hours, the mixture was filtered through a thin pad of silica gel with Et2O (20 mL) as the
eluent and concentrated in vacuo. Purification by silica gel flash column chromatography using
hexanes:Et2O (9:1 v/v) as the eluent gave the title compound as an orange oil (91 mg, 65%). 1H
NMR (400 MHz, CDCl3) δ 7.65 (dt, J = 7.8, 1.0 Hz, 1H), 7.30 (dt, J = 8.3, 1.0 Hz, 1H), 7.21
(ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.13 (ddd, J = 7.9, 7.1, 1.1 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.74
(dt, J = 18.0, 4.7 Hz, 1H), 6.54 (dd, J = 3.2, 0.9 Hz, 1H), 5.38 (dt, J = 17.9, 1.8 Hz, 1H), 4.82
(dd, J = 4.7, 1.9 Hz, 2H), 1.26 (s, 12H). 13
C NMR (400 MHz, CDCl3) δ 147.35, 136.06, 128.55,
70
127.97, 121.50, 120.85, 119.33, 109.47, 101.50, 83.34, 49.82, 24.72 (vinyl boron C absent). 11
B
NMR (128 MHz, CDCl3) δ 29.83. The spectroscopic data are in agreement with literature
values.134
(Z)-2-(hex-3-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3) –
Synthesized by adaptation of the procedure reported by Wang et al.120
3-
Hexyne (1.0 equiv, 1.10 mmol, 90.4 mg) and Cp2ZrHCl (10 mol%, 28.4 mg)
were weighed into an oven-dried 2 dram vial and purged with nitrogen for one minute. To this
mixture, pinacolborane (1.1 equiv, 1.21 mmol, 155 mg) was added dropwise. The reaction vial
was sealed under argon and stirred at 60 °C. After 60 hours, the mixture was filtered through a
thin pad of silica gel with Et2O (20 mL) as the eluent and concentrated in vacuo. The yield was
calculated to be 67% using 1H NMR analysis of the crude reaction mixture.
103
(Z)-4,4,5,5-tetramethyl-2-(1-phenylprop-1-en-2-yl)-1,3,2-dioxaborolane
(3.4) – Synthesized by adaptation of the procedure reported by Wang et
al.120
1-Phenyl-1-propyne (1.0 equiv, 1.10 mmol, 128 mg) and Cp2ZrHCl
(10 mol%, 28.4 mg) were weighed into an oven-dried 2 dram vial and purged with nitrogen for
one minute. To this mixture, pinacolborane (1.1 equiv, 1.21 mmol, 1545 mg) was added
dropwise. The reaction vial was sealed under argon and stirred at 60 °C. After 60 hours, the
mixture was filtered through a thin pad of silica gel with Et2O (20 mL) as the eluent and
concentrated in vacuo. The yield was calculated to be 74% (mixture of regioisomers) using 1H
NMR analysis of the crude reaction mixture.135
The ratio of β- to α-borylation was 85:15.
134 For NMR spectra, see: Shade, R.E.; Hyde, A.M.; Olsen, J. –C.; Merlic, C.A. J. Am. Chem. Soc. 2010, 132, 1202.
135 For NMR spectra, see: Kim, H.R.; Jung, I.G.; Yoo, K.; Jang, K.; Lee, E.S.; Yun, J.; Son, S.U. Chem. Commun.
2010, 46, 758.
71
3.4 Synthesis of (E)-Alkenes
General Procedure A: Initial One-Pot Two-Step Zr-Pd Catalyzed Synthesis of Disubstituted
(E)-Alkenes from Terminal Alkynes and Aryl Bromides and Iodides
The alkyne (1.1 equiv) and Cp2ZrHCl (11 mol%) were weighed into an oven-dried 3 dram vial
and purged with nitrogen for one minute. To this mixture, pinacolborane (1.21 equiv) was added
dropwise. The reaction vial was sealed and stirred at the indicated temperature. After 24 hours,
the crude mixture containing the alkenylboronate intermediate was dissolved in toluene (4.0
mL). To the resultant solution were added water (400 µL), aryl halide (1.0 equiv), Cs2CO3 (2.0
equiv), and Pd(PPh3)4 (1.0 mol %) in succession, purging the reaction vial with nitrogen
following each addition. Upon the addition of water, the mixture effervesced for a few minutes
but did not warm. The reaction vial was sealed under argon with a Teflon cap and stirred
vigorously at 100 °C. After 16 hours, the reaction was allowed to cool to room temperature,
filtered through a thin pad of silica gel with Et2O (20 mL) as the eluent, and concentrated in
vacuo. The crude product was purified by silica gel flash column chromatography using the
indicated mobile phase.
General Procedure B: Improved One-Pot Two-Step Zr-Pd Catalyzed Synthesis of Disubstituted
(E)-Alkenes from Terminal Alkynes and Aryl Bromides and Iodides
The alkyne (1.1 equiv) and Cp2ZrHCl (5.5 mol%) were weighed into an oven-dried 2 dram vial
and purged with nitrogen for one minute. To this mixture, pinacolborane (1.21 equiv) was added
dropwise. The reaction vial was sealed under argon with a Teflon cap and stirred at 45 °C. After
16 hours, the reaction was allowed to cool to room temperature and the crude mixture containing
the alkenylboronate intermediate was dissolved in toluene (2.0 mL). To the resultant solution
72
were added water (200 µL), aryl halide (1.0 equiv), Cs2CO3 (2.0 equiv), and the indicated
amount of Pd(PPh3)4 in succession, purging the reaction vial with nitrogen following each
addition. If the aryl halide was an oil, it was added as a solution in toluene (2.0 mL). Upon the
addition of water, the mixture effervesced for a few minutes but did not warm. The reaction vial
was sealed under argon with a Teflon cap and stirred vigorously at the indicated temperature.
After the indicated time, the reaction was allowed to cool to room temperature, transferred to a
seperatory funnel with Et2O (20 mL), and quenched with saturated NH4Cl solution (20 mL). The
aqueous layer was extracted with Et2O (3 x 20 mL), and the combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel
flash column chromatography using the indicated mobile phase.
General Procedure C: One-Pot Two-Step Zr-Pd Catalyzed Synthesis of (E)-Alkenes from
Terminal Alkynes and Aryl Chlorides
The alkyne (1.1 equiv) and Cp2ZrHCl (5.5 mol%) were weighed into an oven-dried 2 dram vial
and purged with nitrogen for one minute. To this mixture, pinacolborane (1.21 equiv) was added
dropwise. The reaction vial was sealed under argon with a Teflon cap and stirred at 45 °C. After
16 hours, the reaction was allowed to cool to room temperature and the crude mixture containing
the alkenylboronate intermediate was dissolved in toluene (2.0 mL). To the resultant solution
were added water (200 µL), aryl chloride (1.0 equiv), Cs2CO3 (2.0 equiv), and the indicated
amount of XPhos-Pd-G2 in succession, purging the reaction vial with nitrogen following each
addition. If the aryl chloride was an oil, it was added as a solution in toluene (2.0 mL). Upon
the addition of water, the mixture effervesced for a few minutes but did not warm. The reaction
vial was sealed under argon with a Teflon cap and stirred vigorously at the indicated
temperature. After the indicated time, the reaction was allowed to cool to room temperature,
73
transferred to a seperatory funnel with Et2O (20 mL), and quenched with saturated NH4Cl
solution (20 mL). The aqueous layer was extracted with Et2O (3 x 20 mL), and the combined
organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by silica gel flash column chromatography using the indicated mobile phase.
Reaction Scope:
(E)-1-(4-styrylphenyl)ethanone (4.1) – 1) To a 2 dram vial were added
(E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.2 equiv, 0.24
mmol, 55.2 mg), toluene (1.0 mL), water (100 µL), 4’-iodoacetophenone
(1.0 equiv, 0.20 mmol, 246.05 mg), Cs2CO3 (2.0 equiv, 0.40 mmol, 130 mg), and Pd(PPh3)4 (5.0
mol%, 0.010 mmol, 11.6 mg) in succession, purging with nitrogen following each addition. The
reaction vial was sealed under argon with a Teflon cap and stirred at 100 °C. After 19 hours, the
mixture was filtered through a thin pad of silica gel with Et2O (10 mL) as the eluent and
concentrated in vacuo. Purification by silica gel flash column chromatography using
hexanes:EtOAc (9:1 v/v) as the eluent gave the title compound as an off-white solid (38 mg,
86%), which fluoresces under UV light (365 nm). The spectroscopic data are in agreement with
those reported below.
2) Synthesized according to general procedure A from phenylacetylene and 4’-iodoacetophenone
on a 1.0 mmol scale. Hydroboration run at room temperature. Purification by silica gel flash
column chromatography using hexanes:EtOAc (4:1 v/v) as the eluent gave the title compound as
a light brown solid (123 mg, 55%), which fluoresces under UV light (365 nm). The
spectroscopic data are in agreement with those reported below.
3) Synthesized according to general procedure B from phenylacetylene and 4’-
bromoacetophenone on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol%
Pd(PPh3)4 and was run at 80 °C for 8 hours. The crude product was purified by silica gel flash
column chromatography using hexanes:EtOAc (9:1) as the eluent, co-eluting with a yellow trace
impurity. Subsequent trituration with hexanes gave the title compound as an off-white solid (164
mg, 74%, MP = 164 – 166 °C (lit. 148 – 150)136
), which fluoresces under UV light (365 nm). 1H
136 Iyer, S.; Kulkami, G.M.; Ramesh, C. Tetrahedron 2004, 60, 2163.
74
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.57 – 7.52 (m,
2H), 7.42 – 7.35 (m, 2H), 7.34 – 7.28 (m, 1H), 7.23 (d, J = 16.4 Hz, 1H), 7.13 (d, J = 16.4 Hz,
1H), 2.61 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ 197.41, 141.98, 136.67, 135.94, 131.44,
128.84, 128.77, 128.29, 127.42, 126.79, 126.47, 26.56. The spectroscopic data are in agreement
with literature values. Only spectra for title compound synthesized by general procedure B are
shown below.137
(E)-1-(4-(4-methylstyryl)phenyl)ethanone (4.2) – Synthesized
according to general procedure A from 4-ethynyltoluene and 4’-
bromoacetophenone on a 1.0 mmol scale. Hydroboration run at room
temperature. Purification by silica gel flash column chromatography using hexanes:EtOAc (4:1
v/v) as the eluent gave the title compound as a beige solid (138 mg, 58%, MP = 167 – 170 °C),
which fluroesces under UV light (365 nm). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz,
2H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 2H), 7.21 (d, J = 16.4 Hz,
1H), 7.09 (d, J = 16.4 Hz, 1H), 2.61 (s, 3H), 2.38 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ
197.43, 142.22, 138.35, 135.75, 133.91, 131.41, 129.50, 128.84, 126.73, 126.42, 126.33, 26.55,
21.30. The spectroscopic data are in agreement with literature values.138
(E)-3-(3,5-difluorostyryl)thiophene (4.3) – 1) Synthesized according to
general procedure A from 1-ethynyl-3,5-difluorobenzene and 3-
bromothiophene on a 1.0 mmol scale. Hydroboration run at room
temperature. Purification by silica gel flash column chromatography using
hexanes as the eluent gave the title compound as a white solid (107 mg, 48%). The
spectroscopic data are in agreement with those reported below.
2) Synthesized according to general procedure B from 1-ethynyl-3,5-difluorobenzene and 3-
bromothiophene on a 1.0 mmol scale. Cross-coupling reaction employed 2.5 mol% Pd(PPh3)4
and was run at 100 °C for 8 hours. Purification by silica gel flash column chromatography using
hexanes as the eluent gave the title compound as a white solid (136 mg, 61%, MP = 92 – 93 °C).
1H NMR (400 MHz, CDCl3) δ 7.33 (tq, J = 4.1, 2.2 Hz, 3H), 7.12 (d, J = 16.2 Hz, 1H), 6.97 (dt,
137 Littke, A.F.; Fu, G.C. J. Org. Chem. 1999, 64, 10.
138 Sore, H.F.; Boehner, C.M.; MacDonald, S.J.F.; Norton, D.; Fox, D.J.; Spring, D.R. Org. Biomol. Chem. 2009, 7,
1068.
75
J = 7.1, 2.1 Hz, 2H), 6.85 (d, J = 16.2 Hz, 1H), 6.69 (tt, J = 8.8, 2.3 Hz, 1H). 13
C NMR (100
MHz, CDCl3) δ 163.28 (dd, J(C-F) = 247.5, 13.2 Hz), 140.85 (t, J(C-F) = 9.6 Hz), 139.15,
126.53, 126.43 (t, J(C-F) = 3.0 Hz), 125.32, 124.78, 123.76, 108.87 (d, J(C-F) = 6.9 Hz), 108.68
(d, J(C-F) = 6.9 Hz), 102.52 (t, J(C-F) = 25.7 Hz). 19
F NMR (377 MHz, CDCl3) δ -110.31 (t, J
= 8.1 Hz). IR (cm-1
, thin film) 1117, 1247, 1337, 1414, 1449, 1589, 1616, 2366, 3050, 3097.
HRMS (DART+) Exact mass calc’d for C12H9F2S [M + H]+: 223.03930, found: 223.03855.
Only spectra for title compound synthesized by general procedure B are shown below.
(E)-3-(4-(trifluoromethyl)styryl)thiophene (4.4) – 1) Synthesized
according to general procedure A from 3-ethynylthiophene and 4-
bromobenzotrifluoride on a 1.0 mmol scale. Hydroboration run at room
temperature. Purification by silica gel flash column chromatography using hexanes as the eluent
gave the title compound as a snow-white solid (126 mg, 50%). The spectroscopic data are in
agreement with those reported below.
2) Synthesized according to general procedure C from 3-ethynylthiophene and 4-
chlorobenzotrifluoride on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol%
XPhos-Pd-G2 and was run at 80 °C for 2 hours. Purification by silica gel flash column
chromatography using hexanes as the eluent gave the title compound as a snow-white solid (201
mg, 79%, MP = 136 – 140 °C). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.56 (d,
J = 8.4 Hz, 2H), 7.39 – 7.31 (m, 3H), 7.21 (d, J = 16.3 Hz, 1H), 6.96 (d, J = 16.3 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) δ 140.88 (q, J(C-F) = 1.5 Hz), 139.49, 129.07 (q, J(C-F) = 32.4 Hz),
127.03, 126.48, 126.30, 125.59 (q, J(C-F) = 3.8 Hz), 125.24, 124.81, 124.22 (q, J(C-F) = 271.5
Hz), 123.56. 19
F NMR (377 MHz, CDCl3) δ -62.41. IR (cm-1
, thin film) 1073, 1109, 1129,
1164, 1337, 1413, 2360, 3097. HRMS (DART+) Exact mass calc’d for C13H10F3S [M + H]+:
255.04553, found: 255.04458. Only spectra for title compound synthesized by general procedure
B are shown below.
(E)-3-(4-methylstyryl)pyridine (4.5) – Synthesized according to general
procedure A from 3-ethynylpyridine and 4-bromotoluene on a 1.0 mmol
scale. Hydroboration run at room temperature. Purification by silica gel
flash column chromatography using hexanes:EtOAc (4:1 v/v then 3:7 v/v once product began
eluting) as the eluent was attempted, but the product co-eluted with a trace impurity.
76
Recrystallization from chloroform:hexanes furnished the title compound as an off-white solid
(76 mg, 39%, MP = 130 – 132 °C), which fluroesces under UV light (365 nm). 1H NMR (400
MHz, CDCl3) δ 8.70 (d, J = 2.3 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.79 (dt, J = 8.0, 2.0 Hz,
1H), 7.46 – 7.38 (m, 2H), 7.29 – 7.22 (m, 1H), 7.18 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 16.4 Hz,
1H), 7.00 (d, J = 16.4 Hz, 1H), 2.36 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ 148.38, 148.25,
138.11, 133.79, 133.07, 132.40, 130.64, 129.40, 126.50, 123.75, 123.40, 21.20. The
spectroscopic data are in agreement with literature values.139
(E)-1-chloro-4-(2-(cyclohex-1-en-1-yl)vinyl)benzene (4.6) – 1)
Synthesized according to general procedure A from 1-ethynylcyclohexene
and 1-bromo-4-chlorobenzene on a 1.0 mmol scale. Hydroboration run at
room temperature. Purification by silica gel flash column chromatography using hexanes as the
eluent gave the title compound as a white solid (136 mg, 62%). The spectroscopic data are in
agreement with those reported below.
2) Synthesized according to general procedure B from 1-ethynylcyclohexene and 1-bromo-4-
chlorobenzene on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol% Pd(PPh3)4 and
was run at 80 °C for 8 hours. Purification by silica gel flash column chromatography using
hexanes as the eluent gave the title compound as a white solid (147 mg, 67%, MP = 78 – 82 °C).
1H NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.29 – 7.23 (m, 2H), 6.73 (d, J = 16.2 Hz,
1H), 6.38 (d, J = 16.2 Hz, 1H), 5.91 (t, J = 4.3 Hz, 1H), 2.32 – 2.13 (m, 4H), 1.79 – 1.59 (m,
4H). 13
C NMR (100 MHz, CDCl3) δ 136.55, 135.66, 133.19, 132.25, 131.49, 128.64, 127.26,
123.31, 26.16, 24.50, 22.49, 22.45. IR (cm-1
, thin film) 1013, 1091, 1171, 1268, 1403, 1490,
1694, 2861, 2935, 3029. HRMS (DART+) Exact mass calc’d for C14H16Cl [M + H]+:
219.09405, found: 219.09381. Only spectra for title compound synthesized by general procedure
B are shown below.
(E)-1-chloro-2-(2-(cyclohex-1-en-1-yl)vinyl)benzene (4.7) – Synthesized
according to general procedure B from 1-ethynylcyclohexene and 1-bromo-2-
chlorobenzene on a 1.0 mmol scale. Cross-coupling reaction employed 2.5
mol% Pd(PPh3)4 and was run at 100 °C for 12 hours. Purification by silica gel flash column
139 Kantam, M.L.; Reddy, P.V.; Srinivas, P.; Bhargava, S. Tetrahedron Lett. 2011, 52, 4490.
77
chromatography using hexanes as the eluent gave the title compound as a pale yellow oil (126
mg, 58%). 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.8, 1.7 Hz, 1H), 7.35 (dd, J = 7.9, 1.4
Hz, 1H), 7.21 (td, J = 7.6, 1.4 Hz, 1H), 7.13 (td, J = 7.6, 1.7 Hz, 1H), 6.84 (d, J = 16.1 Hz, 1H),
6.75 (d, J = 16.1 Hz, 1H), 5.96 (tt, J = 4.0, 1.6 Hz, 1H), 2.33 (tq, J = 6.2, 2.1 Hz, 2H), 2.22 (tq, J
= 5.4, 2.5 Hz, 2H), 1.81 – 1.62 (m, 4H). 13
C NMR (100 MHz, CDCl3) δ 136.06, 136.03, 135.05,
133.02, 132.00, 129.63, 127.68, 126.71, 126.09, 120.68, 26.19, 24.54, 22.48, 22.43. IR (cm-1
,
thin film) 1035, 1052, 1124, 1210, 1256, 1350, 1440, 1470, 1588, 1614, 1630, 2366, 2829, 2859,
2928, 3058. HRMS (DART+) Exact mass calc’d for C14H16Cl [M + H]+: 219.09405, found:
219.09374.
(E)-5-(2-(cyclohex-1-en-1-yl)vinyl)benzo[d][1,3]dioxole (4.8) –
Synthesized according to general procedure C from 1-ethynylcyclohexene
and 5-chloro-1,3-benzodioxole on a 1.0 mmol scale. Cross-coupling
reaction employed 1.0 mol% XPhos-Pd-G2 and was run at 80 °C for 2 hours. Purification by
silica gel flash column chromatography using hexanes:EtOAc (49:1 v/v) as the eluent gave the
title compound as a yellow tacky solid (162 mg, 71%, MP = 50 – 54 °C). 1H NMR (400 MHz,
CDCl3) δ 6.96 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 8.1, 1.7 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.62
(d, J = 16.1 Hz, 1H), 6.37 (d, J = 16.1 Hz, 1H), 5.94 (s, 2H), 5.86 (t, J = 4.2 Hz, 1H), 2.30 – 2.14
(m, 4H), 1.78 – 1.59 (m, 4H). 13
C NMR (100 MHz, CDCl3) δ 147.98, 146.62, 135.71, 132.58,
131.04, 130.09, 124.26, 120.73, 108.26, 105.29, 100.91, 26.09, 24.55, 22.55, 22.51. IR (cm-1
,
thin film) 1040, 1195, 1233, 1251, 1354, 1447, 1488, 1504, 1690, 1722, 2836, 2860, 2929, 3027.
HRMS (DART+) Exact mass calc’d for C15H17O2 [M + H]+: 229.12285, found: 229.12372.
(E)-5-(hex-1-en-1-yl)-1-tosyl-1H-indole (4.9) – Synthesized according to
general procedure A from 1-hexyne and 5-bromo-1-tosyl-1H-indole on a
1.0 mmol scale. Hydroboration run at room temperature. Purification by silica gel flash column
chromatography using hexanes:EtOAc (4:1 v/v) as the eluent was attempted, but separation
proved difficult and title compound co-eluted with unreacted 5-bromo-1-tosyl-1H-indole.
Calculated yield based on isolated product (44 mg) and mixture of product and bromide was 231
mg, 65%. An additional two successive purifications by flash chromatography employing same
eluent gave the title compound as a viscous, clear, colourless oil (169 mg, 48%) along with a
mixture of product and bromide. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 1H), 7.78 –
7.71 (m, 2H), 7.52 (d, J = 3.7 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 8.7, 1.7 Hz, 1H),
78
7.19 (d, J = 8.2 Hz, 2H), 6.61 (dd, J = 3.7, 0.8 Hz, 1H), 6.43 (dt, J = 15.7, 1.5 Hz, 1H), 6.20 (dt,
J = 15.7, 6.9 Hz, 1H), 2.31 (s, 3H), 2.22 (qd, J = 7.1, 1.4 Hz, 2H), 1.51 – 1.32 (m, 4H), 0.93 (t, J
= 7.2 Hz, 3H). 13
C NMR (100 MHz, CDCl3) δ 144.81, 135.22, 133.88, 133.52, 131.11, 130.61,
129.76, 129.47, 126.69, 126.66, 122.69, 118.55, 113.48, 109.21, 32.68, 31.55, 22.21, 21.46,
13.91. IR (cm-1
, thin film) 1093, 1127, 1145, 1174, 1188, 1223, 1274, 1287, 1306, 1372, 1439,
1456, 1597, 2857, 2871, 2927, 2956. HRMS (DART+) Exact mass calc’d for C21H24NO2S [M +
H]+: 354.15277, found: 354.15305.
(E)-2-(hex-1-en-1-yl)quinoline (4.10) – Synthesized according to general
procedure C from 1-hexyne and 2-chloroquinoline on a 1.0 mmol scale.
Cross-coupling reaction employed 2.5 mol% XPhos-Pd-G2 and was run at 80 °C for 10 hours.
Purification by silica gel flash column chromatography using hexanes:EtOAc (49:1 v/v) as the
eluent gave the title compound as a pale orange oil (155 mg, 73%). 1H NMR (400 MHz, CDCl3)
δ 8.03 (dd, J = 8.5, 1.1 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.4 Hz, 1H), 7.64
(ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.47 (dd, J = 8.5, 0.9 Hz, 1H), 7.42 (ddt, J = 7.9, 6.9, 0.9 Hz, 1H),
6.81 (dt, J = 15.9, 6.6 Hz, 1H), 6.70 (dt, J = 15.9, 1.2 Hz, 1H), 2.43 – 2.22 (m, 2H), 1.59 – 1.47
(m, 2H), 1.47 – 1.34 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 13
C NMR (100 MHz, CDCl3) δ 156.38,
147.99, 137.81, 135.95, 130.95, 129.34, 129.02, 127.28, 127.01, 125.65, 118.57, 32.61, 30.93,
22.22, 13.84. The spectroscopic data are in agreement with literature values.140
(E)-2-(4-phenylbut-1-en-1-yl)quinoline (4.11) – Synthesized
according to general procedure C from but-3-yn-1-ylbenzene and 2-
chloroquinoline on a 1.0 mmol scale. Cross-coupling reaction
employed 2.5 mol% XPhos-Pd-G2 and was run at 80 °C for 10 hours. Purification by silica gel
flash column chromatography using hexanes:EtOAc (9:1 v/v) as the eluent gave the title
compound as a bright orange oil (201 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J =
8.4, 1.2 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.74 – 7.67 (m, 1H), 7.64 (ddd, J = 8.4, 6.9, 1.5 Hz,
1H), 7.44 (d, J = 8.6 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.33 – 7.25 (m, 2H), 7.25 – 7.15 (m, 3H),
6.84 (dt, J = 15.9, 6.4 Hz, 1H), 6.75 (d, J = 15.9 Hz, 1H), 2.85 (dd, J = 9.1, 6.6 Hz, 2H), 2.70 –
2.56 (m, 2H). 13
C NMR (100 MHz, CDCl3) δ 156.15, 147.98, 141.38, 136.54, 136.04, 131.51,
129.42, 129.06, 128.32 (2 signals overlapping), 127.32, 127.06, 125.89, 125.78, 118.61, 35.23,
140 Fakhfakh, M.A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadère, B. Synth. Commun. 2002, 32, 2863.
79
34.71. IR (cm-1
, thin film) 1118, 1314, 1427, 1453, 1497, 1503, 1556, 1597, 1615, 1653, 2854,
2936, 3026, 3059. HRMS (DART+) Exact mass calc’d for C19H18N [M + H]+: 260.14392,
found: 260.14382.
(E)-N,N-bis-Boc-3-(1-tosyl-1H-indol-5-yl) prop-2-en-1-amine (4.12)
– Synthesized according to general procedure B from N,N-bis-Boc-
propargyl amine141
and 5-bromo-1-tosyl-1H-indole on a 1.0 mmol scale. Cross-coupling
reaction employed 2.5 mol% Pd(PPh3)4 and was run at 100 °C for 10 hours. Purification by
silica gel flash column chromatography using hexanes:EtOAc (4:1) as the eluent gave the title
compound as an off-white tacky solid (309 mg, 59%, MP = 46 – 50 °C). 1H NMR (400 MHz,
CDCl3) δ 7.91 (d, J = 8.6 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.53 (d, J = 3.6 Hz, 1H), 7.50 – 7.43 (m,
1H), 7.34 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 3.6 Hz, 1H), 6.57 (d, J
= 15.8 Hz, 1H), 6.19 (dt, J = 15.8, 6.3 Hz, 1H), 4.32 (dd, J = 6.3, 1.4 Hz, 2H), 2.33 (s, 3H), 1.51
(s, 18H). 13
C NMR (100 MHz, CDCl3) δ 152.37, 144.93, 135.23, 134.31, 132.35, 132.26,
131.07, 128.84, 126.83, 126.75, 124.50, 122.99, 119.31, 113.55, 109.11, 82.36, 48.17, 28.10,
21.52. IR (cm-1
, thin film) 1122, 1145, 1174, 1226, 1369, 1457, 1597, 1695, 1745, 2360, 2933,
2980. HRMS (ESI+) Exact mass calc’d for C28H34N2O6NaS [M + Na]+: 549.2029, found:
549.2027.
(E)-1-(3-(4-(trifluoromethyl)phenyl)allyl)-1H-indole (4.13) – 1)
Synthesized according to general procedure A from 1-(prop-2-yn-1-
yl)-1H-indole and 4-bromobenzotrifluoride on a 1.0 mmol scale.
Hydroboration run at 60 °C. Purification by silica gel flash column chromatography using
hexanes:EtOAc (9:1 v/v then 4:1 v/v once product began eluting) as the eluent gave the title
compound as a yellow solid (190 mg, 63%). The spectroscopic data are in agreement with those
reported below.
2) Synthesized according to general procedure C from 1-(prop-2-yn-1-yl)-1H-indole and 4’-
chloroacetophenone on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol% XPhos-
Pd-G2 and was run at 80 °C for 2 hours. Purification by silica gel flash column chromatography
using hexanes:EtOAc (19:1 v/v) as the eluent gave the title compound as a yellow solid (260 mg,
141 Ko, E.; Burgess, K. Org. Lett. 2011, 13, 980.
80
86%, MP = 110 – 112 °C). 1H NMR (400 MHz, CDCl3) δ 7.68 (dt, J = 7.9, 1.0 Hz, 1H), 7.53
(d, J = 8.1 Hz, 2H), 7.42 – 7.33 (m, 3H), 7.23 (td, J = 8.0, 7.5, 1.2 Hz, 1H), 7.19 – 7.11 (m, 2H),
6.57 (dd, J = 3.1, 0.9 Hz, 1H), 6.48 – 6.37 (m, 2H, olefinic), 4.90 (dd, J = 2.6, 1.1 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) δ 139.66 (q, J(C-F) = 1.4 Hz), 136.08, 130.65, 129.60 (q, J(C-F) =
32.5 Hz), 128.75, 127.74 (2 signals overlapping), 126.61, 125.50 (q, J(C-F) = 3.8 Hz), 124.10 (q,
J(C-F) = 272.2 Hz), 121.74, 121.06, 119.60, 109.47, 101.80, 48.11 19
F NMR (377 MHz,
CDCl3) δ -62.49. IR (cm-1
, thin film) 1067, 1119, 1165, 1326, 1463, 1614, 2912, 3053. HRMS
(DART+) Exact mass calc’d for C18H15F3N [M + H]+: 302.11566, found: 302.11544. Only
spectra for title compound synthesized by general procedure C are shown below.
(E)-1-(4-(3-(1H-indol-1-yl)prop-1-en-1-yl)phenyl)ethanone (4.14)
– 1) Synthesized according to general procedure A from 1-(prop-2-
yn-1-yl)-1H-indole and 4’-bromoacetophenone on a 1.0 mmol scale.
Hydroboration run at 60 °C. Purification by silica gel flash column chromatography using
hexanes:EtOAc (4:1 v/v) as the eluent gave the title compound as a yellow solid (200 mg, 73%).
The spectroscopic data are in agreement with those reported below.
2) Synthesized according to general procedure B from 1-(prop-2-yn-1-yl)-1H-indole and 4’-
bromoacetophenone on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol%
Pd(PPh3)4 and was run at 80 °C for 8 hours. Purification by silica gel flash column
chromatography using hexanes:EtOAc (4:1 v/v) as the eluent gave the title compound as a
yellow solid (244 mg, 89%, MP = 99 – 100 °C). 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.85 (m,
2H), 7.72 – 7.65 (m, 1H), 7.43 – 7.35 (m, 3H), 7.23 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.19 – 7.11
(m, 2H), 6.58 (dd, J = 3.1, 0.9 Hz, 1H), 6.54 – 6.41 (m, 2H, olefinic), 4.93 (d, J = 3.9 Hz, 2H),
2.58 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ 197.39, 140.78, 136.22, 136.06, 130.96, 128.70,
128.69, 127.96, 127.74, 126.51, 121.71, 121.03, 119.56, 109.46, 101.77, 48.18, 26.53. IR (cm-1
,
thin film) 1182, 1267, 1314, 1357, 1410, 1463, 1484, 1511, 1602, 1678, 2918, 3052. HRMS
(DART+) Exact mass calc’d for C19H18NO [M + H]+: 276.13884, found: 276.13911. Only
spectra for title compound synthesized by general procedure B are shown below.
(E)-5-(3-(1H-indol-1-yl)prop-1-en-1-yl)-1-tosyl-1H-indole (4.15)
– 1) Synthesized according to general procedure A from 1-(prop-2-
yn-1-yl)-1H-indole and 5-bromo-1-tosyl-1H-indole on a 1.0 mmol
81
scale. Hydroboration run at 60 °C. Purification by silica gel flash column chromatography using
hexanes:EtOAc (4:1 v/v) as the eluent gave the title compound as an off-white solid (233 mg,
55%). The spectroscopic data are in agreement with those reported below.
2) Synthesized according to general procedure B from 1-(prop-2-yn-1-yl)-1H-indole and 5-
bromo-1-tosyl-1H-indole on a 1.0 mmol scale. Cross-coupling reaction employed 1.0 mol%
Pd(PPh3)4 and was run at 80 °C for 10 hours. Purification by silica gel flash column
chromatography using hexanes:EtOAc (9:1 v/v) as the eluent gave the title compound as an off-
white solid (331 mg, 78%, MP = 163 – 166 °C). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.6
Hz, 1H), 7.80 – 7.71 (m, 2H), 7.71 – 7.65 (m, 1H), 7.54 (d, J = 3.7 Hz, 1H), 7.44 (d, J = 1.6 Hz,
1H), 7.40 (dd, J = 8.2, 1.1 Hz, 1H), 7.32 (dd, J = 8.7, 1.7 Hz, 1H), 7.25 – 7.11 (m, 5H), 6.58
(ddd, J = 11.5, 3.4, 0.9 Hz, 2H), 6.44 (dt, J = 15.8, 1.6 Hz, 1H), 6.23 (dt, J = 15.8, 5.8 Hz, 1H),
4.80 (dd, J = 5.8, 1.6 Hz, 2H) 2.32 (s, 3H). 13
C NMR (100 MHz, CDCl3) δ 144.94, 136.06,
135.10, 134.39, 132.17, 131.73, 131.05, 129.81, 128.71, 127.69, 126.92, 126.68, 124.23, 122.97,
121.53, 120.92, 119.49, 119.40, 113.57, 109.55, 109.10, 101.46, 48.36, 21.47. IR (cm-1
, thin
film) 1127, 1145, 1174, 1188, 1215, 1276, 1286, 1307, 1316, 1336, 1370, 1398, 1439, 1455,
1462, 1511, 1596, 2921, 3052, 3141. HRMS (DART+) Exact mass calc’d for C26H23N2O2S [M
+ H]+: 427.14802, found: 427.14757. Only spectra for title compound synthesized by general
procedure B are shown below.
NOTE: Compound appears to be light sensitive. Upon sitting on bench-top for several days,
compound became salmon-coloured. Minor decomposition observed by TLC analysis.
Filtration through silica gel with chloroform as the eluent recovered pure compound.
(E)-1-(3-(anthracen-9-yl)allyl)-1H-indole (4.16) – Synthesized
according to general procedure C from 1-(prop-2-yn-1-yl)-1H-indole
and 9-chloroanthracene on a 1.0 mmol scale. Cross-coupling reaction
employed 1.0 mol% XPhos-Pd-G2 and was run at 80 °C for 4 hours.
Purification by silica gel flash column chromatography using hexanes:EtOAc (19:1 v/v) as the
eluent gave the title compound as a yellow solid (236 mg, 71%, MP = 134 – 136 °C), which
fluoresces under UV light (365 nm). 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.21 – 8.10
(m, 2H), 8.04 – 7.94 (m, 2H), 7.76 (dt, J = 7.9, 1.0 Hz, 1H), 7.61 (dd, J = 8.1, 1.1 Hz, 1H), 7.53 –
7.40 (m, 4H), 7.40 – 7.32 (m, 2H), 7.23 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.10 (dq, J = 16.1, 1.5
82
Hz, 1H), 6.67 (dd, J = 3.1, 0.9 Hz, 1H), 6.22 (dt, J = 16.1, 5.3 Hz, 1H), 5.15 (dd, J = 5.4, 1.8 Hz,
2H). 13
C NMR (100 MHz, CDCl3) δ 136.26, 133.23, 131.55, 131.28, 129.33, 128.84, 128.60,
128.29, 127.88, 126.50, 125.61, 125.47, 125.05, 121.75, 121.12, 119.60, 109.68, 101.85, 48.55.
IR (cm-1
, thin film) 1316, 1335, 1347, 1442, 1463, 1511, 1663, 3027, 3050. HRMS (DART+)
Exact mass calc’d for C25H20N [M + H]+: 334.15957, found: 334.15944.
(E)-1-(4-(3-(1H-benzo[d][1,2,3]triazol-1-yl) prop-1-en-1-
yl)phenyl)ethanone (4.17) – Synthesized by adaptation of general
procedure C from 1-(prop-2-yn-1-yl)-1H-benzo[d][1,2,3]triazole and
4’-chloroacetophenone on a 1.0 mmol scale. Modifications: hydroboration carried out in dry
toluene (0.5 mL), added directly before pinacolborane; 1.5 mL toluene added in coupling step.
Cross-coupling reaction employed 2.5 mol% XPhos-Pd-G2 and was run at 100 °C for 24 hours.
Purification by silica gel flash column chromatography using hexanes:EtOAc:DCM (5:4:1 v/v/v)
as the eluent gave the title compound as a white solid solid (115 mg, 41%, MP = 151 – 153 °C).
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.3
Hz, 1H), 7.48 (ddd, J = 8.2, 6.9, 1.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.40 – 7.36 (m, 1H), 6.65
(dt, J = 15.9, 1.4 Hz, 1H), 6.53 (dt, J = 15.9, 6.0 Hz, 1H), 5.47 (dd, J = 6.0, 1.4 Hz, 2H), 2.57 (s,
3H). 13
C NMR (100 MHz, CDCl3) δ 197.31, 146.22, 140.04, 136.62, 133.07, 132.86, 128.74,
127.50, 126.70, 125.09, 124.01, 120.15, 109.44, 50.16, 26.55. IR (cm-1
, thin film) 1166, 1228,
1268, 1359, 1603, 1674, 2925, 3042. HRMS (ESI+) Exact mass calc’d for C17H16N3O [M +
H]+: 278.1287, found: 278.1280.
(E)-2-styrylbenzo[d]oxazole (4.18) – Reaction was carried out on a 1.0
mmol scale. Phenylacetylene (1.1 equiv) and Cp2ZrHCl (5.5 mol%) were
weighed into an oven-dried 2 dram vial and purged with nitrogen for one
minute. To this, pinacolborane (1.21 equiv) was added dropwise. The reaction vial was sealed
under argon with a Teflon cap and stirred at 45 °C. After 16 hours, the reaction was allowed to
cool to room temperature. To the crude mixture containing the alkenylboronate intermediate
were added 2-chlorobenzoxazole (1.0 equiv) in anhydrous 2-butanol (2.0 mL), K3PO4 (2.0 equiv)
and XPhos-Pd-G2 (2.5 mol%) in succession, purging the reaction vial with nitrogen following
each addition. The reaction vial was sealed under argon with a Teflon cap and stirred vigorously
at 100 °C. After 4 hours, the reaction was allowed to cool to room temperature, filtered through
a thin pad of silica gel with EtOAc (20 mL) as the eluent, and concentrated in vacuo.
83
Purification by silica gel flash column chromatography using hexanes:EtOAc (9:1 v/v) as the
eluent gave the title compound as a yellow solid (109 mg, 49%, MP = 105 – 107 °C (lit. 79 –
80)). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 16.4 Hz, 1H), 7.76 – 7.69 (m, 1H), 7.65 – 7.57
(m, 2H), 7.53 (dt, J = 5.6, 3.4 Hz, 1H), 7.47 – 7.29 (m, 5H), 7.09 (d, J = 16.4 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) δ 162.76, 150.39, 142.18, 139.42, 135.13, 129.74, 128.94, 127.53,
125.17, 124.47, 119.85, 113.94, 110.29. The spectroscopic data are in agreement with literature
values.142
142 Evindar, G.; Batey, R.A. J. Org. Chem. 2006, 71, 1802.
84
Appendix: Selected Spectra
(Z)-4,4,5,5-tetramethyl-2-(1-phenylprop-1-en-2-yl)-1,3,2-dioxaborolane (3.4)
85
(E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (3.1)
86
87
(E)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)-1H-indole (3.2)
88
89
(E)-1-(4-styrylphenyl)ethanone (4.1)
90
(E)-1-(4-(4-methylstyryl)phenyl)ethanone (4.2)
91
(E)-3-(3,5-difluorostyryl)thiophene (4.3)
92
93
(E)-3-(4-(trifluoromethyl)styryl)thiophene (4.4)
94
95
(E)-1-chloro-4-(2-(cyclohex-1-en-1-yl)vinyl)benzene (4.6)
96
(E)-1-chloro-2-(2-(cyclohex-1-en-1-yl)vinyl)benzene (4.7)
97
(E)-5-(2-(cyclohex-1-en-1-yl)vinyl)benzo[d][1,3]dioxole (4.8)
98
(E)-5-(hex-1-en-1-yl)-1-tosyl-1H-indole (4.9)
99
(E)-2-(hex-1-en-1-yl)quinoline (4.10)
100
(E)-2-(4-phenylbut-1-en-1-yl)quinoline (4.11)
101
(E)-N,N-bis-Boc-3-(1-tosyl-1H-indol-5-yl)prop-2-en-1-amine (4.12)
102
(E)-1-(3-(4-(trifluoromethyl)phenyl)allyl)-1H-indole (4.13)
103
104
(E)-1-(4-(3-(1H-indol-1-yl)prop-1-en-1-yl)phenyl)ethanone (4.14)
105
(E)-5-(3-(1H-indol-1-yl)prop-1-en-1-yl)-1-tosyl-1H-indole (4.15)
106
(E)-1-(3-(anthracen-9-yl)allyl)-1H-indole (4.16)
107
(E)-1-(4-(3-(1H-benzo[d][1,2,3]triazol-1-yl) prop-1-en-1-yl)phenyl)ethanone (4.17)
108
(E)-2-styrylbenzo[d]oxazole (4.18)