investigations in transition metal catalysis: development ... · palladium catalyzed...
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Investigations in Transition Metal Catalysis: Development of a Palladium Catalyzed
Carboesterification of Olefins and
Synthesis of Chiral Sulfoxide Pincer Ligands
by
Katherine Jane Jardine
A thesis submitted in conformity with the requirements for the degree of Master of Science
Graduate Department of Chemistry University of Toronto
© Copyright by Katherine Jane Jardine, 2010
ii
Investigations in Transition Metal Catalysis: Development of a
Palladium Catalyzed Carboesterification of Olefins and Synthesis
of Chiral Sulfoxide Pincer Ligands
Katherine Jane Jardine
Master of Science
Graduate Department of Chemistry
University of Toronto
2010
Abstract
The development of a palladium-catalyzed intramolecular carboesterification of unactivated
olefins is described. Olefin difunctionalization is a powerful tool for adding complexity to a
molecule, and this formal [3+2] cycloaddition generates highly functionalized fused ring
systems. Initially discovered by Dr. Yang Li in our group, it was found that when propiolic acids
with a pendant terminal olefin were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of
copper (II) chloride, and 3 equivalents of lithium chloride in acetonitrile at 50 °C, cyclization
occurred in up to 90% yield. The optimization of this reaction and the extension to
propiolamides and propargyl alcohols is described in this thesis. A mechanism involving a novel
palladium-carboxylate species is proposed.
Preliminary investigations into the synthesis of chiral sulfoxide pincer ligands are also described.
The nucleophilic aromatic substitution of 1,3-dibromobenzene and 2,6-dichloropyridine with
various thiols, followed by oxidation of the sulfides to sulfoxides is investigated as a route to the
desired proligands.
iii
Acknowledgments
First and foremost, I would like to thank Dr. Yang Li, who developed the idea for the palladium-
catalyzed carboesterification project, and worked with me on it. I would also like to thank all the
members of the Dong group for their help, especially Peter Dornan for answering endless
questions and being an awesome cubicle buddy, and Elena Dimitrijevic and Marija Antonic for
always being there to lend a hand.
Numerous people and groups helped to make this work possible: I would like to thank the groups
of Professors Mark Taylor, Andrei Yudin, Rob Batey, and Mark Lautens for the use of chemicals
and equipment. A special thanks to Prof. Rob Batey for reading my thesis. I would also like to
thank NSERC for providing a graduate fellowship to pursue this work.
I owe a great debt of gratitude to Prof. Jamie Donaldson for all of his help, and for believing in
me despite everything.
Finally, I would like to thank my supervisor, Prof. Vy Dong, for all of her help and support.
iv
Table of Contents
Acknowledgments .......................................................................................................................... iii
List of Figures .............................................................................................................................. viii
List of Tables .................................................................................................................................. x
List of Abbreviations ..................................................................................................................... xi
List of Appendices ....................................................................................................................... xiv
Chapter 1 ......................................................................................................................................... 1
1 Introduction ................................................................................................................................ 1
Chapter 2 ......................................................................................................................................... 2
2 Palladium-Catalyzed Carboesterification of Olefins ................................................................. 2
2.1 Background ......................................................................................................................... 2
2.1.1 Olefin Difunctionalization ...................................................................................... 2
2.1.2 Transition Metal-Catalyzed [3+2] Cycloadditions with Propargyl Alcohols
and Amines ............................................................................................................. 9
2.2 Plan of Study: Development of a Palladium-Catalyzed Carboesterification of Olefins ... 11
2.3 Results and Discussion: Development of a Palladium-Catalyzed Carboesterification
of Olefins .......................................................................................................................... 12
2.3.1 Synthesis of 3-(2-(allyloxy)phenyl)propiolic acid (4) .......................................... 12
2.3.2 Initial Results ........................................................................................................ 13
2.3.3 Synthesis of 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10) ............................... 13
2.3.4 Solvent Screen with 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10) .................. 14
2.3.5 Optimization of Catalyst Loading and Temperature with 3-(2-(but-3-
enyloxy)phenyl)propiolic acid (10) ...................................................................... 16
2.3.6 Optimization of Catalyst Loading and Temperature with 3-(2-
(allyloxy)phenyl)propiolic acid (4) ....................................................................... 17
v
2.3.7 Optimization of Oxidant Loading and Chloride Source ....................................... 18
2.3.8 Base Screen ........................................................................................................... 20
2.3.9 Optimization of Substrate Concentration .............................................................. 21
2.3.10 Optimized Conditions ........................................................................................... 21
2.3.11 Scope of Carboxylic Acid Substrates ................................................................... 22
2.3.12 Extension to Non-Carboxylic Acid Substrates ..................................................... 23
2.3.13 Retrosynthetic Analysis of Propargyl Alcohol Substrates .................................... 23
2.3.14 Synthesis of Propargyl Alcohol Substrates by the Sonogashira Reaction ............ 23
2.3.15 Synthesis of Propargyl Alcohol Substrate 22 by Reduction ................................. 25
2.3.16 Cyclization of Propargyl Alchohol 22 .................................................................. 25
2.3.17 Synthesis and Reactivity of Tertiary Alcohol Substrate 24 .................................. 26
2.3.18 Synthesis of Propiolamide 25 ............................................................................... 27
2.3.19 Cyclization of Amide Substrate 25 ....................................................................... 27
2.4 Proposed Mechanism for the Palladium-Catalyzed Carboesterification of Olefins ......... 28
2.4.1 Proposed Mechanism ............................................................................................ 28
2.4.2 Mechanistic Experiments ...................................................................................... 29
2.5 Summary and Future Work: Palladium-Catalyzed Carboesterification of Olefins .......... 30
2.5.1 Summary ............................................................................................................... 30
2.5.2 Future Work .......................................................................................................... 30
Chapter 3 ....................................................................................................................................... 32
3 Development of Chiral Sulfoxide Pincer Ligands ................................................................... 32
3.1 Introduction ....................................................................................................................... 32
3.1.1 Common Properties of Pincer Ligands ................................................................. 32
3.1.2 Enantioselective Catalysis with Chiral Pincer Ligands ........................................ 33
3.1.3 Sulfoxide-Based Pincer Ligands ........................................................................... 36
3.2 Plan of Study: Development of Novel Chiral Sulfoxide-Based Pincer Ligands .............. 37
vi
3.3 Results and Discussion ..................................................................................................... 37
3.3.1 Retrosynthetic Analysis of Phenyl-Based Sulfoxide Pincer Ligands ................... 37
3.3.2 Formation of a Grignard Reagent from 1,3-Dibromobenzene .............................. 38
3.3.3 Formation of a Lithiated Species from 1,3-Dibromobenzene .............................. 39
3.3.4 Nucleophilic Aromatic Substitution of 1,3-Dibromobenzene with
Cyclohexanethiol .................................................................................................. 40
3.3.5 Formation of Various 1,3-Disulfide Compounds from 1,3-Dibromobenzene by
Nucleophilic Aromatic Substitution ..................................................................... 40
3.3.6 Oxidation of Disulfide 29 to the Disulfoxide ....................................................... 41
3.3.7 Pyridine-Based Sulfoxide Pincer Ligands ............................................................ 42
3.3.8 Retrosynthetic Analysis of Pyridine-Based Sulfoxide Pincer Ligands with No
Methylene Spacer .................................................................................................. 42
3.3.9 Nucleophilic Aromatic Substitution of 2,6-Dichloropyridine with Alkyl Thiols . 43
3.3.10 Retrosynthetic Analysis of Pyridine-Based Pincer Ligands with a Methylene
Spacer .................................................................................................................... 43
3.3.11 Initial Progress Towards Compound 37 ............................................................... 44
3.4 Summary and Future Work ............................................................................................... 45
3.4.1 Summary ............................................................................................................... 45
3.4.2 Future Work .......................................................................................................... 45
Chapter 4 ....................................................................................................................................... 46
4 Experimental ............................................................................................................................ 46
4.1 General Considerations ..................................................................................................... 46
4.2 Experimental Section for the Carboesterification of Olefins ............................................ 47
4.2.1 Typical Procedures ................................................................................................ 47
4.2.2 Synthesis and Cyclization of Carboxylic Acid Substrates .................................... 49
4.2.3 Synthesis and Cyclization of Non-Carboxylic Acid Substrates ........................... 51
4.3 Experimental Section for the Preparation of Sulfoxide Pincer Ligands ........................... 54
4.3.1 Typical Procedures ................................................................................................ 54
vii
4.3.2 Synthesis of Sulfoxide Pincer Ligands ................................................................. 54
References ..................................................................................................................................... 71
viii
List of Figures
Figure 2.1 Sharpless asymmetric dihydroxylation of olefins. ........................................................ 2
Figure 2.2 Palladium-catalyzed diacetoxylation of olefins developed by Dong and Song. ........... 3
Figure 2.3 Mechanism of the palladium-catalyzed diacetoxylation of olefins. .............................. 3
Figure 2.4 Wolfe's palladium-catalyzed carboetherification of olefins to form substituted
tetrahydrofurans. ............................................................................................................................. 4
Figure 2.5 Mechanism of Wolfe's palladium-catalyzed synthesis of tetrahydrofurans. ................. 4
Figure 2.6 Wolfe's palladium-catalyzed carboamination of olefins to form substituted
pyrrolidines. .................................................................................................................................... 5
Figure 2.7 Sorensen's palladium-catalyzed aminoacetoxylation of olefins. ................................... 5
Figure 2.8 Mechanism of Sorensen's palladium-catalyzed aminoacetoxylation of olefins. ........... 6
Figure 2.9 Stahl's palladium-catalyzed aminoacetoxylation of olefins. ......................................... 6
Figure 2.10 Michael's palladium-catalyzed diamination of olefins. ............................................... 7
Figure 2.11 Palladium-catalyzed diamination of olefins reported by Muniz. ................................ 7
Figure 2.12 Lu's palladium-catalyzed cyclization of allylic alkynoates. ........................................ 8
Figure 2.13 Mechanism of Lu's palladium-catalyzed cyclization of allylic alkynoates. ................ 9
Figure 2.14 Palladium-catalyzed [3+2] cyclization of methylenecyclopropane with norbornene. 9
Figure 2.15 Palladium-catalyzed [3+2] cyclization of propargyl alcohols and amines with
activated olefins. ........................................................................................................................... 10
Figure 2.16 Mechanism of the palladium-catalyzed [3+2] cyclization of propargyl alcohols with
activated olefins. ........................................................................................................................... 11
Figure3.1 Development of the first pincer ligand. ........................................................................ 32
ix
Figure 3.2 Sites of modification of typical pincer ligands. ........................................................... 33
Figure 3.3 Reactivity of Nishiyama's chiral PheBox rhodium pincer complexes. ....................... 34
Figure 3.4 Reactivity of Venanzi's chiral PCP platinum pincer complex..................................... 35
Figure 3.5 Longmire's chiral PCP platinum pincer complex. ....................................................... 35
Figure 3.6 Chiral at phosphorus pincer complex developed by van Koten. ................................. 36
Figure 3.7 Pincer ligands incorporating sulfoxides as chelating moieties. ................................... 36
x
List of Tables
Table 2.1 Solvent optimization for the palladium-catalyzed carboesterification of (10). ............ 16
Table 2.2 Optimization of catalyst loading and temperature for the carboesterification of 10. ... 17
Table 2.3 Optimization of catalyst loading and temperature for the carboesterification of 4. ..... 18
Table 2.4 Optimization of the chloride source for the Pd-catalyzed carboesterification of 4. ..... 19
Table 2.5 Optimization of base in the Pd-catalyzed carboesterification of 4. .............................. 20
Table 2.6 Optimization of substrate concentration for the Pd-catalyzed carboesterification of 4. 21
Table 2.7 Conditions for the synthesis of 2-(3-hydroxylprop-1-ynyl)phenol by Sonogashira
coupling. ........................................................................................................................................ 24
Table 2.8 Conditions for the alkylation of 2-(3-hydroxylprop-1-ynyl)phenol with allyl bromide.
....................................................................................................................................................... 24
Table 3.1 Grignard formation from 1,3-dibromobenzene. ........................................................... 39
Table 3.2 Lithiation of 1,3-dibromobenzene. ............................................................................... 39
Table 3.3 Nucleophilic aromatic substitution of 1,3-dibromobenzene with cyclohexanethiol. ... 40
xi
List of Abbreviations
A Angstrom
Ac acetate
acac acetylacetonato
aq aqueous
Ar aromatic
B base
Bn benzyl
Boc tert-butoxycarbonyl
br broad
Bu butyl
cat catalytic
COE cyclooctene
d days
d doublet
δ chemical shift (in parts per
million)
dba dibenzylideneacetone
DCE dichloroethane
DCM dichloromethane
DIBAL-H diisobutylaluminum hydride
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
dppe diphenylphospinoethane
dppp diphenylphosphinopropane
ee enantiomeric excess
EDG electron donating group
equiv equivalents
ESI electrospray ionization
Et ethyl
EtOAc ethyl acetate
EI electron impact ionization
EWG electron withdrawing group
FT Fourier transform
g grams
GC gas chromatography
h hour
Hz Hertz
xii
i iso
IR infrared spectroscopy
J coupling constant (in Hertz)
L ligand
LC liquid chromatography
M mega
M metal
m milli
m multiplet
m meta
mCPBA meta-chloroperoxybenzoic
acid
Me methyl
MeCN acetonitrile
min minutes
mol moles
MS mass spectrometry
MS molecular sieves
NMR nuclear magnetic resonance
nuc nucleophile
o ortho
p para
Ph phenyl
Phth phthalimide
ppm parts per million
Pr propyl
q quartet
quant quantitative
R alkyl group
rt room temperature
s singlet
sat saturated
t triplet
t tert
TBS tert-butyldimethylsilyl
temp temperature
TEMPO 2,2,6,6-
Tetramethylpiperidine-1-oxyl
Tf triflate
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
xiii
TMS trimethylsilyl
tol toluene
Ts toluenesulfonyl
X halogen
SN2 bimolecular nucleophilic
substitution
Ns nitrobenzenesulfonyl
List of Appendices
Appendix 1. NMR Spectra………………………………………………………………………58
xiv
1
Chapter 1
1 Introduction
The development of new transition metal catalyzed reactions is an important goal of organic
chemistry, both for the development of new “greener” reactions that avoid producing
stoichiometric amounts of waste, and for achieving reactivity patterns that are not otherwise
possible. Transition metal catalysis has become important in industry, showcasing both its
versatility and efficiency.
This work will investigate two areas of transition metal catalysis: the development of new
catalytic reactions, and the synthesis of chiral ligands for asymmetric transition metal catalysis.
Specifically, the first section of the thesis describes the development of an intramolecular
palladium-catalyzed formal [3+2] cycloaddition resulting in the difunctionalization of
unactivated olefins. Propiolic acids are used as the three-atom subunit to form fused 6,7,5-
tricyclic ring systems. Optimization, substrate scope, and the extension to propiolamides and
propargyl alcohols as the three-atom subunit are described. This project was initiated by Dr.
Yang Li, a postdoctoral fellow in the Dong Group, who discovered the reaction. The second part
of the thesis describes the development of novel sulfoxide-based pincer ligands that introduce
chirality at the sulfur atom. Sulfoxide groups are relatively unexplored as chelating groups in
pincer ligands, and optically pure sulfoxide-based pincer ligands have not been prepared. Initial
investigations into the synthesis of sulfoxide ligands with either phenyl or pyridyl backbones are
described.
2
Chapter 2
2 Palladium-Catalyzed Carboesterification of Olefins
2.1 Background
2.1.1 Olefin Difunctionalization
Alkene difunctionalization is a powerful method of adding complexity to a molecule. The olefin
moiety is readily accessible from various reactions, and therefore is a desirable substrate for
further elaboration of complex organic molecules.1 The Sharpless asymmetric dihydroxylation
2
is perhaps the most well known example of olefin difunctionalization – the formation of a diol
from an alkene (Figure 2.1). However, the Sharpless dihydroxylation uses a toxic and expensive
osmium catalyst to effect the transformation. Recently, a number of olefin difunctionalizations
catalyzed by palladium have been achieved which broaden the scope of alkene functionalization
and have the advantage of using less toxic and less expensive reagents.
Figure 2.1 Sharpless asymmetric dihydroxylation of olefins.
2.1.1.1 Olefin Diacetoxylation
In 2008, the Dong and Song groups published a palladium-catalyzed dioxygenation of olefins
(Figure 2.2).3 This methodology utilizes an inexpensive and relatively non-toxic palladium salt
as the catalyst and hypervalent iodine as an oxidant to generate syn-diacetoxylated products.
Moreover, 1,1- and 1,2-disubstituted as well as trisubstituted olefins could be used in this
reaction. Trisubstituted olefins are challenging substrates for the Sharpless dihydroxylation.4
Promising initial investigations have shown that chiral ligands can be used to promote some
degree of enantioselectivity.5 This reaction is therefore shows promise as an alternative to the
3
Sharpless dihydroxylation. Jiang and coworkers later showed that oxygen could be used as the
oxidant to perform similar chemistry.6
Figure 2.2 Palladium-catalyzed diacetoxylation of olefins developed by Dong and Song.
The reaction is thought to proceed via a novel Pd(II)/(IV) pathway (Figure 2.3). Trans-
acetoxypalladation of the olefin generates a palladium(II) alkyl species. Subsequent oxidation to
palladium(IV) occurs in the presence of hypervalent iodine. SN2-type reductive elimination to
regenerate the palladium(II) catalyst occurs via formation of an acetoxonium ion which reacts
with water to form a hydroxyacetate. Treatment with acetic anhydride generates the
diacetoxylated product.
Figure 2.3 Mechanism of the palladium-catalyzed diacetoxylation of olefins.
2.1.1.2 Carboamination and Carboetherification of Olefins
Wolfe has developed a palladium-catalyzed synthesis of tetrahydrofurans via the
carboetherification of alkenes (Figure 2.4).7 Using a palladium catalyst and tri-ortho-
4
tolylphosphine as a ligand, in the presence of an aryl bromide and sodium tert-butoxide, in
toluene at 110 °C, tetrahydrofurans are formed with a moderate to excellent diastereoselectivity.
Terminal and 1,2-disubstituted olefins can be used. Electron rich or electron neutral aryl
bromides work well with this methodology; electron poor aryl bromides give moderate yields.
Figure 2.4 Wolfe's palladium-catalyzed carboetherification of olefins to form substituted tetrahydrofurans.
The reaction is proposed to proceed via initial oxidative addition of the aryl bromide to give a
Pd(II) complex (Figure 2.5).8 In the presence of sodium tert-butoxide, substitution of the
bromide by the alcohol gives a palladium alkoxide intermediate. Syn-oxypalladation of the
alkene and subsequent C–C bond forming reductive elimination generate the tetrahydrofuran
product, resulting in overall formation of a new C–C bond and a new C–O bond at the expense
of the olefin π-bond. Syn-oxypalladation, involving alkene insertion into the palladium-oxygen
bond, is uncommon, but through deuterium labeling studies Wolfe was able to provide
compelling evidence for this reaction pathway.9
Figure 2.5 Mechanism of Wolfe's palladium-catalyzed synthesis of tetrahydrofurans.
5
This methodology can also be extended to the synthesis of pyrrolidines via carboamination of
olefins. Electron-rich aryl bromides give the best results. Competing N-arylation is observed for
electron-poor aryl bromides.7
Figure 2.6 Wolfe's palladium-catalyzed carboamination of olefins to form substituted pyrrolidines.
2.1.1.3 Aminoacetoxylation of Olefins
In 2005, Sorensen reported an intramolecular aminoacetoxylation of alkenes (Figure 2.7).10
Using palladium(II) acetate, hypervalent iodine, and tetrabutylammonium acetate in acetonitrile,
protected amines were converted into the corresponding nitrogen-containing heterocycles. Both
five- and six-membered rings were formed. For 1,2-disubstituted alkenes, the reaction was
shown to be stereoselective for the trans difunctionalization product.
Figure 2.7 Sorensen's palladium-catalyzed aminoacetoxylation of olefins.
The reaction is proposed to begin with trans-aminopalladation of the alkene, which is believed to
be reversible (Figure 2.8). Irreversible deprotonation of the resulting intermediate generates a
neutral palladium(II) complex. This species is further oxidized to Pd(IV) by hypervalent iodine,
and subsequent C–O bond forming reductive elimination generates the product and reforms the
active palladium(II) catalyst.
6
Figure 2.8 Mechanism of Sorensen's palladium-catalyzed aminoacetoxylation of olefins.
Subsequently, Stahl showed an intermolecular variation using phthalimide as the nitrogen source
(Figure 2.9).11
The reaction is proposed to proceed through a cis-aminopalladation step and SN2-
type C–O bond forming reductive elimination from a palladium (IV) intermediate.
Figure 2.9 Stahl's palladium-catalyzed aminoacetoxylation of olefins.
2.1.1.4 Diamination of Olefins
Michael and coworkers have recently reported that N-fluorobenzenesulfonimide can be used as a
nitrogen source in the palladium-catalyzed diamination of unactivated alkenes (Figure 2.10).12
The reaction is proposed to proceed via aminopalladation of the alkene, followed by oxidative
addition of N-fluorobenzenesulfonimide to Pd(II) to generate a Pd(IV) complex. Reductive
elimination then gives the desired diamination product and regenerates the palladium(II) catalyst.
The reaction generates two differently protected amines, allowing for selective deprotection and
functionalization.
7
Figure 2.10 Michael's palladium-catalyzed diamination of olefins.
Muniz reported an intramolecular diamination of olefins in 2005 (Figure 2.11).13
The reaction
uses a palladium(II) catalyst, and hypervalent iodine as the oxidant. Various fused nitrogen-
containing ring systems were formed, though the methodology worked best for the formation of
pyrrolidine rings. Piperidine formation required 25 mol % Pd(OAc)2, and formation of 7-
membered rings required 10 mol % of the catalyst. Monosubstituted and 1,1-disubstituted
olefins were effective substrates for this methodology. Deprotection of the diamine core could
be achieved in high yields by treating the products with lithium aluminum hydride, followed by
HCl.
Figure 2.11 Palladium-catalyzed diamination of olefins reported by Muniz.
2.1.1.5 Olefin Difunctionalization Initiated by Halopalladation of Propargyl Esters
Lu has developed a cyclization of allylic alkynoates that is initiated by halopalladation of a
propargyl ester (Figure 2.12).14
Treatment with 5 mol % of a palladium(II) catalyst, with
copper(II) chloride and lithium chloride in acetonitrile at ambient temperature for 72 hours gave
a mixture of two regioisomers. The major product results from initial trans-chloropalladation of
the alkyne, whereas the minor product arises from cis-chloropalladation. The selectivity for the
trans-chloropalladation product was found to increase with increased concentration of chloride
ions. A 78:22 ratio of trans- to cis-chloropalladation products was seen when 2 equivalents of
lithium chloride was used. When the chloride concentration was increased to 6 equivalents of
8
lithium chloride, the ratio increased to 95:5 in favour of the trans-product.14
The solvent polarity
also affects the selectivity, with polar solvents favouring trans-halopalladation, and non-polar
solvents giving poor selectivity for either product.15
The bromo-analogues of these products can
also be formed by using a palladium(II) catalyst, copper(II) bromide, and lithium bromide.14
Figure 2.12 Lu's palladium-catalyzed cyclization of allylic alkynoates.
The reaction is proposed to proceed via initial halopalladation16
of the alkyne, with the trans-
halopalladation pathway predominating (Figure 2.13). The palladation occurs such that
palladium becomes bonded to the α-carbon of the conjugated ester. This regioselectivity is
determined by the polarity of the triple bond due to the electron-withdrawing ester moiety.15
Nucleophilic attack by the chloride anion at the most electrophilic site of the alkyne therefore
results in formation of solely the 5-membered ring products. The resulting palladium(II)
intermediate then undergoes carbopalladation to give a lactone ring with an exocyclic double
bond. The reductive elimination to form the desired product and regenerate the palladium(II)
catalyst is mediated by copper(II) chloride.14
9
Figure 2.13 Mechanism of Lu's palladium-catalyzed cyclization of allylic alkynoates.
2.1.2 Transition Metal-Catalyzed [3+2] Cycloadditions with Propargyl Alcohols and Amines
Cycloaddition reactions are important methods of generating cyclic architectures from acyclic
precursors. Transition metal catalyzed [3+2] cycloadditions have been extensively investigated
as efficient methods of synthesizing highly functionalized 5-membered rings.17,18
Cycloadditions that involve olefins as the 2-atom subunit, and therefore result in an overall olefin
difunctionalization generally require highly activated Michael acceptors or strained alkenes. For
example, the formation of carbocycles can be achieved by reacting methylenecyclopropanes or
trimethylenemethanes with strained or activated alkenes (such as norbornene), using a
palladium(0) catalyst (Figure 2.14).
Figure 2.14 Palladium-catalyzed [3+2] cyclization of methylenecyclopropane with norbornene.
10
Alternatively, heterocycles can be synthesized through incorporation of the heteroatom into the
3-atom subunit of the [3+2] cycloaddition.19
Balme and coworkers have demonstrated that
propargyl alcohols20
and amines21
can react with activated alkenes to form substituted
tetrahydrofurans and pyrrolidines, respectively (Figure 2.15). The reaction is catalyzed by base
and a palladium catalyst, in order to activate both the heteroatom and the alkyne, and proceeds
via a Michael addition-carbocyclization process. Treatment of an activated alkene and propargyl
alcohol or N-methyl propargyl amine with 10 mol % n-butyllithium and 5 mol %
[Pd(OAc)2(PPh3)] in tetrahydrofuran at room temperature results in formation of
tetrahydrofurans and pyrrolidines, respectively (Figure 14).
Figure 2.15 Palladium-catalyzed [3+2] cyclization of propargyl alcohols and amines with activated olefins.
The mechanism is proposed to proceed via deprotonation of the propargyl species and
subsequent Michael addition to give a stabilized enolate (Figure 2.16). Activation of the alkyne
by a palladium hydride species formed by the insertion of palladium into an alkyne C–H bond
results in carbopalladation of the alkyne. Reductive elimination reforms the palladium catalyst
and results in formation of a substituted methylenetetrahydrofuran.20
11
Figure 2.16 Mechanism of the palladium-catalyzed [3+2] cyclization of propargyl alcohols with activated olefins.
2.2 Plan of Study: Development of a Palladium-Catalyzed Carboesterification of Olefins
Recently in our lab, Dr. Yang Li discovered that propiolic acids could be added across an
unactivated alkene in a formal [3+2] cycloaddition (Figure 2.17). Proparyl alcohols and amines
have been investigated in [3+2] cycloaddition chemistry,17
but propiolic acids have not
previously been used. The addition across an unactivated olefin is also of note: most palladium-
catalyzed cycloaddition reactions use the high reactivity of Michael acceptors or strained
trimethylenecyclopropanes.18,19
Figure 2.17 Formal [3+2] cycloaddition of propiolic acids with unactivated olefins.
The goal of this project is to determine the optimal conditions for the formal [3+2] cycloaddition
of propiolic acids across unactivated olefins. Furthermore, propiolic acid derivatives such as
propiolamides will be investigated to determine if this reactivity can be extended to other
12
functional groups. This transformation creates fused polycyclic ring systems that could be of use
in medicinal chemistry or natural product synthesis.
2.3 Results and Discussion: Development of a Palladium-Catalyzed Carboesterification of Olefins
2.3.1 Synthesis of 3-(2-(allyloxy)phenyl)propiolic acid (4)
Initial studies began with propiolic acid 4, which was derived from salicylaldehyde in four steps
(Figure 2.18). This substrate was chosen because successful cyclization would generate a 6,7,5-
fused tricyclic framework that maps onto the core of a family of natural products with anti-HIV
activity.22
Figure 2.18 Synthesis of 3-(2-(allyloxy)phenyl)propiolic acid (4).
Treatment of salicylaldehyde with potassium carbonate and allyl bromide in DMF at ambient
temperature gave 1 in 95% yield after 2 days. Following purification by flash column
chromatography the aldehyde was transformed into the propiolic ester via the Corey-Fuchs
alkyne synthesis.23
Carbon tetrabromide and triphenylphosphine reacted at 0 °C under argon
atmosphere to form the phosphorus ylide, which added to the aldehyde to give vinyl dibromide 2
after 20 hours at ambient temperature. Chromatography was necessary to remove the
triphenylphosphine oxide which forms over the course of the reaction, and the vinyl dibromide
was isolated in 90% yield. Treatment with methyllithium at -78 °C for 1 hour, followed by the
addition of methyl chloroformate gave the propiolic ester 3 in 90% yield after 3 hours.
13
Hydrolysis with 20% aqueous KOH in methanol gave the desired propiolic acid substrate 4 in
92% yield.
2.3.2 Initial Results
Initial investigation of the reaction was performed by Dr. Yang Li using conditions developed by
Lu for his chloropalladation of propargylic esters.14
Lu has shown that polar solvents and high
chloride concentrations favour trans-chloropalladation. Therefore, a vial was charged with 4,
copper(II) chloride, and lithium chloride. Acetic acid was added, then a stock solution of
Pd(MeCN)2Cl2 in acetic acid. The solution was heated to 50 °C and monitored by TLC and
LCMS. After 14 hours, the reaction mixture was extracted into ethyl acetate and washed with
water. It was found that with 0.5 mol% Pd(MeCN)2Cl2, three equivalents of copper(II) chloride,
and six equivalents of lithium chloride in acetic acid at 50 °C, substrate 4 cyclised give fused
tricyclic compound 5 in 50% yield by 1H NMR (using 1,3,5-trimethoxybenzene as an internal
standard). Upon increasing the amount of lithium chloride to twelve equivalents, the yield
increased to 63% (Figure 2.19).
Figure 2.19 Initial results for the palladium-catalyzed intramolecular carboesterification of (4).
While these initial results were quite promising, especially considering the low catalyst loading,
ideally the conditions could be improved by reducing the amount of copper(II) chloride and
lithium chloride required, and by moving to a solvent with greater functional group
compatibility. Therefore, the catalyst loading, oxidant, chloride source, solvent, and temperature
need to be optimized to improve the yield.
2.3.3 Synthesis of 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10)
Substrate 10 was made in five steps from 3-buten-1-ol and salicylaldehyde (Figure 2.20). Its
synthesis is analogous to the synthesis of substrate 4.
14
Figure 2.20 Synthesis of 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10).
3-Buten-1-ol was converted to the tosylate by treatment with p-toluenesulfonyl chloride, with
pyridine functioning as both a base and the solvent. The reaction was allowed to proceed for 4
hours, warming from 0 °C to ambient temperature, and tosylate 6 was isolated in 72 % yield after
column chromatography to remove excess p-toluenesulfonyl chloride. Alkylation of
salicylaldehyde with 6 proceeded in 95 % yield after 4 days at ambient temperature in DMF,
using potassium carbonate as the base. Vinyl dibromide 8 was achieved in 90 % yield using
carbon tetrabromide and triphenylphosphine. Treatment with methyllithium in THF at -78 °C
for 1 hour, followed by the addition of methyl chloroformate afforded methyl ester 9 in 94%
yield. Hydrolysis of the ester with potassium hydroxide gave propiolic acid 10 in 80% yield
after recrystallization from diethyl ether and pentane.
2.3.4 Solvent Screen with 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10)
Optimization of the solvent was initially performed using substrate 10, which cyclised to give a
mixture of two products, 11 and 12, as determined by 1H NMR spectroscopy by Dr. Yang Li
(Figure 2.21). These products arise from coordination of the olefin to palladium with different
regioselectivity, which is possible due to increased flexibility of the homoallyl group compared
with the allyl group of substrate 4. Three equivalents of copper(II) chloride and twelve
equivalents of lithium chloride were used in all cases, and the reaction was heated to 80 °C.
15
Progress was monitored by TLC and LCMS, and the reactions were stopped when the starting
material was consumed or after 15 hours.
Figure 2.21 Palladium-catalyzed carboesterification of (10).
In methanol, a 13% conversion to 11 was observed (Table 2.1). In ethanol, no cyclised product
was observed, but isopropanol gave 19% conversion to 11. Therefore polar, protic solvents
show some success, and favour the formation of product 11. In acetone no product was
observed, and no starting material could be recovered. Ethyl acetate gave a 39% overall yield of
11 and 12, as did a mixture of acetic acid and acetonitrile. Acetonitrile alone gave a 45% overall
yield, with approximately a 1:1 mixture of 11 to 12. Strongly coordinating solvents such as
DMSO and DMF gave no conversion, but showed improved starting material stability.
Therefore the catalyst loading was increased to 10 mol % in DMF to see if higher catalyst
loading could improve the reactivity of the substrate in this solvent. However, complete starting
material decomposition was observed, and no desired product was formed. Chlorinated solvents
such as dichloromethane and dichloroethane gave no desired product, even at 10 mol % catalyst
loading. In tetrahydrofuran, 10 % of product 11 was observed. Acetonitrile was therefore
determined to be the best solvent for the reaction in terms of overall conversion.
16
Table 2.1 Solvent optimization for the palladium-catalyzed carboesterification of (10).
2.3.5 Optimization of Catalyst Loading and Temperature with 3-(2-(but-3-enyloxy)phenyl)propiolic acid (10)
The effect of catalyst loading and temperature on the reaction was investigated with substrate 10
(Table 2.2). The reactions were performed in acetonitrile, with three equivalents of copper(II)
chloride and 12 equivalents of lithium chloride. When 0.5 mol % Pd(MeCN)2Cl2 was used, no
cyclised product was observed at 50 °C (entry 1). By NMR, 25% decomposition of the starting
material was observed under these conditions. When the temperature was increased to 80 °C,
50% of the starting material decomposed, but still no product was observed (entry 2). At 110 °C
(entry 3) no product formed and there was no starting material remaining after 14 hours.
Therefore this substrate appears to be somewhat unstable at higher temperatures. When the
catalyst loading was increased to 10 mol %, a 45% overall yield of cyclised product was
observed after 14 hours at 80 °C. Lowering the catalyst loading to 2 mol % had no effect on the
yield or product ratio. With 5 mol % catalyst loading, the temperature could also be lowered to
50 °C with no decrease in the yield.
17
Table 2.2 Optimization of catalyst loading and temperature for the carboesterification of 10.
2.3.6 Optimization of Catalyst Loading and Temperature with 3-(2-(allyloxy)phenyl)propiolic acid (4)
Further optimization of the catalyst loading was performed using substrate 4 (Table 2.3). The
screen was performed using three equivalents of copper(II) chloride and 12 equivalents of
lithium chloride in MeCN. At 80 °C with 0.5 mol % Pd(MeCN)2Cl2, the cyclised product was
observed in 70% conversion by 1H NMR (entry 1) with 1,3,5-trimethoxybenzene as an internal
standard. Increasing the catalyst loading to 2 mol % increased the conversion to 75% (entry 2).
By lowering the temperature to 50 °C, 80% conversion was observed, and a 76% isolated yield
(entry 3). It was found that the catalyst loading could be lowered to 1 mol % without affecting
the conversion (entry 4). In accordance with the results found from optimization with substrate
10, increasing the catalyst loading does not improve the yield significantly. Higher temperatures
can also lead to increased decomposition and therefore lower yields.
18
Table 2.3 Optimization of catalyst loading and temperature for the carboesterification of 4.
2.3.7 Optimization of Oxidant Loading and Chloride Source
Next, the effect of the oxidant loading and chloride source was investigated (Table 2.4). The
oxidant, copper(II) chloride, is needed to regenerate the palladium(II) catalyst and turn over the
catalytic cycle. The chloride source and concentration of chloride ions is also important, as high
concentrations of chloride ions in solution have been found to facilitate trans-chloropalladation
of propargyl esters,14
and therefore may help the trans-chloropalladation of propiolic acids as
well.
19
Table 2.4 Optimization of the chloride source for the Pd-catalyzed carboesterification of 4.
In acetic acid, 12 equivalents of lithium chloride was optimal and gave a 63% yield of the
desired product (Table 2.4), and lowering the chloride concentration resulted in poor yields. In
acetonitrile, when 12 equivalents of lithium chloride were added, the conversion increased to
81%. However, lithium chloride is less soluble in acetonitrile than in acetic acid. It was
observed that not all of the lithium chloride was soluble in acetonitrile at this loading. When the
amount of lithium chloride was lowered to three equivalents, the salt was fully soluble and 83%
conversion was observed. With three equivalents of copper(II) chloride and no lithium chloride,
only 48% conversion was observed. Therefore a source of chloride ions in solution is important
for achieving high yield of the desired product. Tetrabutylammonium chloride was also
investigated as a chloride source, as it is more soluble in acetonitrile than lithium chloride and
therefore might be a better chloride source. With three equivalents of copper(II) chloride and
one equivalent of tetrabutylammonium chloride, 76% conversion was observed. Therefore,
tetrabutylammonium chloride can successfully be used as a chloride source in this reaction.
However, lithium chloride is less expensive and gave higher conversion.
Decreasing the copper(II) chloride loading was also attempted. With two equivalents of
copper(II) chloride and three equivalents of lithium chloride, the conversion dropped slightly to
20
77% (entry 5). Using tetrabutylammonium chloride in combination with lithium chloride was
also attempted, but the conversion dropped to 71% (entry 6). Reducing the copper(II) chloride
loading further to 1.5 equivalents led to decreased yields, even with increased catalyst loading
(entries 7-9).
2.3.8 Base Screen
Over the course of the reaction, HCl is produced as a byproduct of the cyclization. The addition
of base might therefore improve the yield of the reaction by neutralizing the acid, or by initial
deprotonation of the carboxylic acid moiety prior to cyclization (Table 2.5).
Table 2.5 Optimization of base in the Pd-catalyzed carboesterification of 4.
Using 2 mol % Pd(MeCN)2Cl2, three equivalents of copper(II) chloride, and 12 equivalents of
lithium chloride in acetonitrile, addition of one equivalent of triethylamine decreased the
conversion from 80% to 32% (entry 2). One equivalent of potassium carbonate gave a 51%
conversion (entry 3). Using a different set of conditions for the copper(II) chloride and lithium
chloride loading (1.5 equivalents of CuCl2, 1 equivalent of LiCl, and 0.2 equivalents of
nBu4NCl), it was found that sodium acetate, sodium bicarbonate, potassium carbonate, and
cesium carbonate all decreased the conversion significantly. Addition of 1 equivalent of
21
potassium hydrogen phosphate gave a comparable yield, but was not a significant improvement.
Therefore it was determined that addition of base did not improve the yield of the reaction.
2.3.9 Optimization of Substrate Concentration
A final experiment was carried out to determine the optimal substrate concentration at which to
perform the reaction. A concentration range of 0.025 M to 0.1 M in acetonitrile was investigated
(Table 2.6).
Table 2.6 Optimization of substrate concentration for the Pd-catalyzed carboesterification of 4.
Using 2 mol % Pd(MeCN)2Cl2, three equivalents of copper(II) chloride and twelve equivalents
of lithium chloride, a substrate concentration of 0.025 M gave 74% yield (entry 1). In
comparison, increasing the concentration to 0.05 M in substrate increased the yield to 80% (entry
2). The same trend was seen when tetrabutylammonium chloride was used as the chloride source
instead of lithium chloride, with a concentration of 0.025 M giving 64% conversion, while 0.05
M gave 76% conversion. However, further increasing the concentration to 0.1 M did not
increase the yield, resulting in 68% conversion. Therefore 0.05 M was determined to be the
optimal concentration of substrate in MeCN for the reaction.
2.3.10 Optimized Conditions
The highest yield of cyclised product was obtained using 1 mol % Pd(MeCN)2Cl2, 3 equivalents
of copper(II) chloride, and 3 equivalents of lithium chloride, in acetonitrile at 0.05 M in
substrate. An 83% conversion to 5 was obtained when 3-(2-(allyloxy)phenyl)propiolic acid (4)
22
was subjected to these conditions (0.2 mmol scale). When performed on 1 mmol scale with
respect to substrate, the product was isolated in 82% yield as an off-white solid.
Figure 2.22 Optimized conditions for the palladium-catalyzed carboesterification of olefins.
2.3.11 Scope of Carboxylic Acid Substrates
Dr. Yang Li performed a scope study with the optimized conditions, to show that a variety of
propiolic acid derivatives could be used in this reaction. The results are shown in Figure 2.23.
All reactions were performed on a 0.2 mmol scale.
Figure 2.23 Scope of propiolic acid substrates performed by Dr. Yang Li.
23
2.3.12 Extension to Non-Carboxylic Acid Substrates
The addition of the propiolic acid moiety across an olefin results in the formation of a lactone
ring. The extension of this methodology to substrates other than propiolic acids would allow for
the formation of different types of heterocycles. For instance, propargyl alcohols would generate
fused tetrahydrofurans, while amides could give rise to lactams. Therefore, formation of
substrates of these types is of interest in extending the scope of this methodology.
2.3.13 Retrosynthetic Analysis of Propargyl Alcohol Substrates
Substrate 22 could be made via a Sonogashira reaction24,25
from 2-bromophenol (Figure 2.24).
The allyl group could be attached by alkylation either before or after the Sonogashira coupling.
Selective allylation of the phenol group in the presence of a primary alcohol should be possible
since the phenolic proton is more acidic and therefore easier to deprotonate. However, palladium
catalysts are known to remove allyl groups, so performing the Sonogashira reaction prior to
allylation may be a better route.
Figure 2.24 Retrosynthetic analysis of propargyl alcohol 22.
2.3.14 Synthesis of Propargyl Alcohol Substrates by the Sonogashira Reaction
Initially, 2-bromophenol was treated with Pd(PPh3)2Cl2, copper(I) iodide and triethylamine in
THF at ambient temperature, with tetrahydropyran-protected propargyl alcohol as a coupling
partner (Table 2.7). The Sonogashira cross coupling was unsuccessful, so the more reactive 2-
iodophenol was used instead. However, this resulted only in some decomposition of the starting
materials. Next, the cross coupling was attempted with unprotected propargyl alcohol.26
Using
2-bromophenol, no product was observed under Sonogashira conditions at either ambient
24
temperature or 80 °C. However, with 2-iodophenol, the desired product was isolated in 70%
yield after 16 hours at ambient temperature.
Table 2.7 Conditions for the synthesis of 2-(3-hydroxylprop-1-ynyl)phenol by Sonogashira coupling.
Alkylation of the phenol group with allyl bromide would give the desired substrate 22.
However, a number of alkylation methods were attempted without success (Table 2.8).
Table 2.8 Conditions for the alkylation of 2-(3-hydroxylprop-1-ynyl)phenol with allyl bromide.
Treatment with allyl bromide and potassium carbonate in DMF at ambient temperature resulted
in no reaction. Increasing the temperature to 50 °C had no effect, and using acetone as a solvent
was also unsuccessful. In a refluxing mixture of ethanol and water, the reaction likewise failed.
The addition of sodium iodide to create a better electrophile in situ was not effective. Lastly, a
stronger base was used for the deprotonation. With sodium hydride in DMF, however, no
desired product was observed.
25
2.3.15 Synthesis of Propargyl Alcohol Substrate 22 by Reduction
Another method to synthesize substrate 22 could be via reduction of methyl ester 3, which is an
intermediate in the synthesis of propiolic acid 4 (Figure 2.25). Originally, it was thought that
selective reduction of the ester moiety in the presence of the alkyne could be challenging.
However, treatment of 3 with 2 equivalents of DIBAL-H resulted in a 60% yield of the desired
propargyl alcohol after 9.5 hours at -78 °C.27
The reaction did not go to completion despite the
addition of a second aliquot of DIBAL-H after 4 hours, so the product was isolated from the
starting material by chromatography. The yield based on recovered starting material was 97%.
Figure 2.25 DIBAL-H reduction of methyl 3-(2-(allyloxy)phenyl)propiolate.
2.3.16 Cyclization of Propargyl Alchohol 22
Initial cyclization experiments were performed using the conditions optimized for the carboxylic
acid substrates. Consequently, substrate 22 was treated with 1 mol % Pd(MeCN)2Cl2, three
equivalents of copper(II) chloride and three equivalents of lithium chloride in acetonitrile, and
the reaction mixture was heated to 50 °C for 13 hours. The reaction mixture was concentrated,
taken up into chloroform, and the insoluble material was filtered off with a plug of cotton.
Purification by column chromatography on silica in 10 % ethyl acetate in hexanes gave a yellow
oil which was isolated in 45 %.
Figure 2.26 Palladium-catalyzed cyclization of 3-(2-(allyloxy)phenyl)prop-2-yn-1-ol (22).
26
Further optimization of the reaction conditions was unsuccessful. Increasing the temperature to
80 °C resulted in decomposition, as did increasing the catalyst loading to 5 mol %. When one
equivalent of either potassium carbonate or potassium hydrogen phosphate was added, the
reaction did not go to completion. Addition of 10 mol % 12-crown-4 as a chloride phase transfer
agent did not improve the yield.
The exact structure of the product remains unclear. By analogy to the carboxylic acid substrates,
product 23a would be expected. However, the regioselectivity of chloropalladation of the alkyne
is determined by the polarity of the alkyne,15
with the chloride anion attacking the most
electrophilic site. In the case of the propiolic acid substrates, the presence of the electron
withdrawing carboxyl group directs the chloropalladation such that nucleophilic attack of the
chloride ion occurs at the β-carbon of the propiolic acid. With 22, there is no strongly electron-
withdrawing substituent, and the regioselectivity of the chloropalladation is more difficult to
determine. Chloropalladation with the opposite regioselectivity would generate product 23b.
Therefore, further investigation is needed to determine which of the two products, 23a or 23b, is
formed in the course of the reaction.
2.3.17 Synthesis and Reactivity of Tertiary Alcohol Substrate 24
Figure 2.27 Synthesis and cyclization of 4-(2-(allyloxy)phenyl-2-methylbut-3-yn-2-ol (24).
Tertiary alcohol substrate 24 was also synthesized. Treatment of methyl ester 3 with three
equivalents of methyllithium in THF at -78 °C gave substrate 24 in 58% yield after 4.5 hours.
This substrate was synthesized in the hope that the cyclised product would be less prone to
decomposition than primary alcohol 22. However, using the conditions optimized for the
cyclization of the propiolic acids, no reaction was observed and only starting material was
recovered.
27
2.3.18 Synthesis of Propiolamide 25
Figure 2.28 Synthesis of 3-(2-(allyloxy)phenyl)-N-phenylpropiolamide (25).
Substrate 25 was made from vinyl dibromide 2. 2 was treated with methyllithium in THF at -78
°C for one hour, followed by the addition of phenyl isocyanate to afford 25 in 34% yield after
one hour (Figure 2.28).
2.3.19 Cyclization of Amide Substrate 25
Cyclization of substrate 25 was first attempted using the standard conditions of 1 mol %
palladium catalyst, 3 equivalents of copper(II) chloride and 3 equivalents of lithium chloride in
acetonitrile (Figure 2.29). The product was isolated in 48 % yield after 20 hours. Furthermore,
when 0.5 equivalents of potassium hydrogen phosphate was added to the reaction mixture, a 67
% conversion was observed by 1H NMR, using 1,3,5-trimethoxybenzene as an internal standard.
Figure 2.29 Palladium-catalyzed cyclization of 3-(2-(allyloxy)phenyl)-N-phenylpropiolamide (26a).
Some lactone was also observed and isolated by preparatory TLC following the cyclization of
25. Therefore, a secondary reaction pathway could be cyclization through the amide oxygen,
resulting in 26b, which could hydrolyze either under the reaction conditions or on silica to give
lactone 5 (Figure 2.30). Further experiments are necessary to determine how predominant this
pathway is compared to cyclization via nitrogen, and whether the major product isolated from
the reaction is 26a, or in fact 26b.
28
Figure 2.30 Cyclization of 3-(2-(allyloxy)phenyl)-N-phenylpropiolamide (25) through oxygen.
2.4 Proposed Mechanism for the Palladium-Catalyzed Carboesterification of Olefins
2.4.1 Proposed Mechanism
Figure 2.31 Proposed mechanism of the palladium-catalyzed carboesterification of olefins.
We propose that the reaction is initiated by trans-chloropalladation of the alkyne with the
palladium(II) catalyst (Figure 2.31). Both trans- and cis-chloropalladation of alkynes is well
precedented;16
however, propiolic acids are unexplored substrates for halopalladation. A high
concentration of choride anions in solution has been shown to favour trans-chloropalladation
over cis-chloropalladation for propargylic esters.14
The regioselectivity of the trans-
chloropalladation is controlled by the polarity of the alkyne induced by the electron-withdrawing
carboxylic acid group.15
Therefore, we propose that trans-chloropalladation would give a
29
palladium-carboxylate species (I), capable of coordinating to the unactivated alkene. Following
this, two pathways can be imagined. In Path A, oxypalladation28
of the alkene would give
palladacycle IIA. Subsequent C–C bond forming reductive elimination would generate the
product. Alternatively, carbopalladation of the alkene would generate palladacycle IIB.
Reductive elimination could generate the product; however, direct C–O bond forming reductive
elimination from a palladium(II) species is not precedented. SN2-type reductive elimination via
formation of chloride intermediate III could also give the product. However, III was never
observed as a side product of the reaction for any substrate.
2.4.2 Mechanistic Experiments
In order to further investigate the mechanism, as well as the scope of the reaction, substrate 27
was synthesized by Dr. Yang Li, and subjected to the reaction conditions (Figure 2.32). Both
Path A and Path B would be expected to give trans-28 as the only product, so the experiment
cannot distinguish between the two pathways. However, formation of trans-28 would provide
support for one of these mechanisms, whereas formation of the cis isomer could indicate that
both of the proposed mechanisms are incorrect.
Figure 2.32 Palladium-catalyzed carboesterification of a 1,2-disubstituted olefin.
In fact, when subjected to the reaction conditions by Dr. Yang Li, a 3:1 mixture of trans-28 and
cis-28 was isolated in 69% overall yield. Two possibilities are evident from this result. First,
multiple pathways might be operating, and a minor pathway gives the cis-isomer. Alternatively,
substrate 27 could isomerize to the Z-isomer under the reaction conditions,29
resulting in a
product mixture, or the product itself could isomerize.
Therefore, in order to test for isomerization of the product, trans-28 was resubjected to the
reaction conditions. No isomerization was observed. To ensure that the presence of HCl formed
over the course of the reaction did not facilitate isomerization, trans-28 was also subjected to the
30
reaction conditions in the presence of substrate 4. Over the course of the cyclization of propiolic
acid 4, no isomerization of trans-28 was observed. Therefore the products do not isomerize
under the reaction conditions, and any isomerisation must occur before or during the cyclization.
An isomerization experiment was performed in an attempt to determine whether the olefin of the
starting material isomerizes. Substrate 27 was subjected to the reaction conditions, and the
reaction was halted at partial completion. The starting material was reisolated to determine if
any had isomerized to the Z-isomer. No olefin isomerization products of the starting material
could be observed with certainty by 1H NMR or LC-MS. However, it is possible that the starting
material isomerizes only to a very small degree, but the Z-isomer reacts faster, resulting in the
formation of a significant amount of cis-28.30
Therefore, while there is no direct evidence for formation of cis-28 by olefin isomerization, it
cannot be ruled out, and one of the proposed mechanisms may be the sole reaction pathway.
Alternatively, there may be another minor reaction pathway operating which gives cis-28
directly from 27 without isomerization.
2.5 Summary and Future Work: Palladium-Catalyzed Carboesterification of Olefins
2.5.1 Summary
A novel formal [3+2] cycloaddition resulting in the carboesterification of unactivated olefins was
investigated. Optimized conditions were found for the cyclization of propiolic acids in which the
substrates were treated with 1 mol % Pd(MeCN)2Cl2, 3 equivalents of copper(II) chloride and 3
equivalents of lithium chloride in acetonitrile at 50 °C. Isolated yields up to 90% were achieved.
The reaction is proposed to proceed via initial chloropalladation of the alkyne, followed by
oxypalladation of the alkene and subsequent C–C bond forming reductive elimination to generate
a fused ring system incorporating a 5-membered lactone. Preliminary results for propargyl
alcohols and amides indicate that they are also promising substrate classes for this reaction.
2.5.2 Future Work
Future work should extend the scope of this transformation beyond propiolic acids. The
preliminary results with propargyl alcohols and amides are promising, but further investigation is
31
necessary to confirm the structures of the products formed from these substrates. The conditions
also need to be further optimized for these substrates, and a scope study performed. Propargyl
amines could also be investigated in this transformation.
More mechanistic experiments are needed to support the proposed mechanism, such as
deuterium labeling studies and kinetics experiments. Calculations could also be used to help
determine if the proposed mechanistic pathway is the most likely. Synthesis and cyclization of
the Z-olefin analogue of substrate 27 would give results that would be interesting to compare to
those obtained for the cyclization of 27.
Finally, this reaction creates one new stereogenic carbon centre in the case of terminal olefins,
and two for 1,2-disubstituted alkenes. Therefore, the potential for asymmetric induction could be
investigated by testing the effect of performing the reaction in the presence of a chiral ligand.
32
Chapter 3
3 Development of Chiral Sulfoxide Pincer Ligands
3.1 Introduction
A pincer ligand is a tridentate ligand with meridional binding. The first pincer ligand was
synthesized by Moulton and Shaw in 1976 (Figure 3.1).31
Tridentate metal complexes were
synthesized by reacting 1,3-bis(bromomethyl)benzene with di-tert-butylphosphine, followed by
heating the proligand to reflux in ethanol with a metal salt. The ligand was called a PCP pincer
ligand, since it was coordinated to the metal centre through phosphorous, carbon, and another
phosphorus atom. New pincer ligands have continued to be developed because of the unusual
reactivity and stability that this ligand class has shown.
Figure3.1 Development of the first pincer ligand.
3.1.1 Common Properties of Pincer Ligands
Since the development of the first PCP pincer ligand by Shaw, the synthesis of new pincer
ligands has been a growing field.32
The tridentate scaffold imparts rigidity, which stabilizes the
metal-ligand bond, limits the number of active sites, and prevents ligand exchange. 33
The
resultant high stability of the metal-ligand complex allows it to function at high temperatures and
therefore catalyze challenging reactions under harsh conditions. The metal centre in a pincer
complex is often quite electron rich, imparting a nucleophilic character to the metal.33
As well,
in pincer ligands with an aryl backbone, the aryl ring is nearly coplanar with the d8 metal
coordination plane, which allows for an unusual overlap between the filled metal dxz orbital and
the antibonding π* orbital of the arene.33
Importantly, there is high correlation between ligand
33
modifications and the properties of the metal centre, therefore allowing systematic improvements
in reactivity and stability.33
Figure 3.2 Sites of modification of typical pincer ligands.
Figure 3.2 shows a standard pincer ligand with an aryl backbone.34
The metal centre, M, is
bound to the ligand in three locations, and often the metal will bind at least one counterion.
Common metals include, but are not limited to, palladium, platinum, rhodium, iridium, and
ruthenium. The metal binding affinity of the ligand can be tuned by changing Y or the donor
sites E. Y is most commonly carbon or nitrogen. This has a significant effect on the electronics
of the ligand , as if Y=C, the ligand is monoanionic, but if Y=N, the ligand is neutral. The size
of the cavity is also affected by substituents on the arms A, and the donor sites E. The donor
sites E can affect the reactivity and stability through both electronic and steric factors:
substitutents on E will block approach to the metal, and the hardness or softness of E will affect
the binding affinity for different metals. The metal’s electronic properties will be affected by the
electron donating or electron withdrawing nature of E. Commonly, E is phosphorus (PR2),
nitrogen (NR2), sulphur (SR), or oxygen (OR). The arms of the pincer ligand, A, are commonly
modified by adding substituents to change steric constraints or introduce chirality. Electronic
properties can also be modified by changing the nature of A. Most often, CR2, NR, and O are
used at this position. Finally, R can be changed to effect remote electronic modulations, or can
be used as an anchoring site for solid supports.
3.1.2 Enantioselective Catalysis with Chiral Pincer Ligands
Enantioselective catalysis with chiral pincer ligands is less well developed than the use of
bidentate ligands for asymmetric catalysis. Often, higher enantioselectivities can be achieved
with more traditional bidentate ligands than with the chiral pincer ligands that have currently
34
been developed. However, promising developments have recently been made, and the continued
investigation of new chiral pincer ligands promises further improvements.
Nishiyama and coworkers recently reported a series of PheBox-type pincer ligands that have
shown both high reactivity and enantioselectivity in a number of different reactions.35
The
ligand is an NCN pincer ligand, and the rhodium complex has chirality imparted by the
bis(oxazoline) groups on the ligand backbone (Figure 3.3). The asymmetric allylation of
aldehydes with methallylstannane gave the methallylated products in 90-99% enantioselectivity
and 82-97% yield. The reaction is not air sensitive, and the catalyst can be recovered at the end
of the reaction. The same catalyst system was also applied to the hetero-Diels-Alder reaction.
With only 2 mol % of the catalyst, yields up to 90% and enantioselectivities up to 82% were
observed. These types of catalysts have also been applied to asymmetric conjugate reductions
(with yields up to 99% and enantioselectivities up to 98%), and the Michael addition of α-
cyanocarboxylates and acrolein (with up to 99% yield and up to 86% enantioselectivity).
Figure 3.3 Reactivity of Nishiyama's chiral PheBox rhodium pincer complexes.
The first chiral PCP platinum complex was reported by Venanzi and coworkers in 1994 (Figure
3.4).36
Chirality was introduced into the ligand backbone by adding substituents to the
methylene arms, giving the ligand C2 symmetry. The PCP-platinum complex was used to
catalyze the aldol condensation of aldehydes with methyl isocyanoacetate. Using 1.5 mol % of
catalyst and 12 mol % diisopropylethylamine in dichloromethane at room temperature, yields of
the cyclic products ranged from 84 to 97%. The trans product was favoured in most cases. The
catalyst system achieved up to 65% enantioselectivity for the trans product and up to 32% for the
35
cis product. While the yields were excellent, enantioinduction was fairly low for this catalyst
system, and a long, challenging ligand synthesis also detracts from its appeal.
Figure 3.4 Reactivity of Venanzi's chiral PCP platinum pincer complex.
Longmire reported the synthesis of a similar PCP platinum complex37
with simple methyl groups
on the pendant arms of the ligand (Figure 3.5). This chiral catalyst was able to perform the same
aldol condensation as Venanzi’s catalyst with comparable yields and enantioselectivities, and
with a significantly simpler synthesis.
Figure 3.5 Longmire's chiral PCP platinum pincer complex.
The first pincer ligand that was chiral at phosphorus was developed by van Koten in 2001
(Figure 3.6).38
The complex was also investigated as a catalyst for the aldol condensation of
aldehydes with methyl isocyanoacetate. While the diastereoselectivity of 98:2 favouring the
trans product was much higher than that achieved by Venanzi’s system, which had a 70:30 ratio
of trans to cis, the enantioselectivity was less than 11% for all cases.
36
Figure 3.6 Chiral at phosphorus pincer complex developed by van Koten.
3.1.3 Sulfoxide-Based Pincer Ligands
Sulfoxides are versatile moieties to incorporate into ligands. They can bind to metals through
oxygen or sulfur,39
they are configurationally stable and chiral at sulfur, and there are many
literature reports on the synthesis of optically pure sulfoxides.40
Despite the advantages of
incorporating sulfoxide groups into ligands, only a few examples of sulfoxide-based pincer
ligands have been reported. In 1986, Riley and Oliver reported two alkyl sulfoxide pincer
ligands complexed to ruthenium (Figure 3.7, I and II).41,42
In 2002, Evans and coworkers
designed an aryl sulfoxide pincer ligand in which the sulfoxides were coordinated to palladium
through the sulfur (III).43
The most recent example of a pincer ligand incorporating a sulfoxide
moiety was in 2008, when Milstein reported a pyridine-based mixed SNN pincer ligand which
was complexed to rhodium and iridium (IV).44
The catalytic activity of these metal complexes
has not been investigated, and synthesis has been limited to the racemic complexes.
Figure 3.7 Pincer ligands incorporating sulfoxides as chelating moieties.
37
3.2 Plan of Study: Development of Novel Chiral Sulfoxide-Based Pincer Ligands
Given the limited investigation of sulfoxide-based pincer ligands, we proposed to design new
pincer ligands that use sulfoxides as chelating moieties (Figure 3.8). We envisioned variations to
our ligands in a number of areas. We wanted to first investigate whether we could achieve O-
coordination in an aryl- or pyridine-based pincer complex by changing the length of the ligand
arm. The nature of the metal could also affect the coordination mode. The R group on sulfur
would affect the reactivity of the metal complex both electronically and sterically. Finally, there
have been no attempts to synthesize a chiral sulfoxide-based pincer ligand, despite many reports
on the preparation of optically pure sulfoxides.40
Therefore, the preparation of these complexes
asymmetrically would be of interest, as well as testing their reactivity as chiral catalysts.
Figure 3.8 Target chiral sulfoxide pincer ligands.
3.3 Results and Discussion
3.3.1 Retrosynthetic Analysis of Phenyl-Based Sulfoxide Pincer Ligands
Figure 3.9 Retrosynthetic analysis of phenyl-based sulfoxide pincer ligands.
38
Retrosynthetically, two potential routes to the desired sulfoxide appeared possible (Figure 3.9).
In route A, treatment of 1,3-dibromobenzene with either n-butyllithium45,46
or magnesium47
to
give the dimetallated species, followed by treatment with a commercially available chiral
sulfinate ester could afford the desired chiral proligand in a single step. Alternatively, a two step
procedure would allow for more extensive variation of the R group on the sulfoxide: nucleophilic
aromatic substitution of 1,3-dibromobenzene with a thiol and an appropriate base could generate
the disulfide compound, and subsequent asymmetric oxidation would give the desired chiral
sulfoxide.
3.3.2 Formation of a Grignard Reagent from 1,3-Dibromobenzene
Initial attempts were directed at the formation of a Grignard reagent from 1,3-dibromobenzene,47
from which treatment with a chiral sulfinate would give the desired proligand (route A). In order
to preserve the chiral reagent, conditions for the formation of the Grignard species were tested
using other electrophiles (Table 3.1). First, 1,3-dibromobenzene was dissolved in anhydrous
THF under an argon atmosphere. Magnesium metal was added, and iodine to initiate formation
of the Grignard reagent. Heating to 70 °C resulted in some disappearance of magnesium. The
Grignard reagent was added to benzaldehyde, but no desired product was observed by 1H NMR
or LC-MS (entry 1). The reaction was repeated at 95 °C, but again no product formation was
observed (entry 2). Using DMF as the electrophile also did not result in formation of the desired
product, as confirmed by 1H NMR, despite disappearance of the magnesium (entry 3). Attempts
to form the Grignard reagent in diethyl ether as the solvent were unsuccessful, as no
disappearance of magnesium was observed, indicating formation of the Grignard reagent was
unsuccessful. As expected, treatment of this mixture with DMF resulted in no desired product
(entry 4).
39
Table 3.1 Grignard formation from 1,3-dibromobenzene.
3.3.3 Formation of a Lithiated Species from 1,3-Dibromobenzene
Next, formation of a dilithiated species45,46
was attempted (Table 3.2). 1,3-dibromobenzene was
treated with four equivalents of n-butyllithium in THF at -78 °C under an argon atmosphere for
one hour, after which DMF was added. After 30 minutes at -78 °C, less than 10% of the desired
dialdehyde was observed by 1H NMR, though some monosubstituted product was observed, as
well as unidentified byproducts (entry 1). With longer reaction times, no desired product was
observed (entry 2). Attempts to form the monosubstituted product by treatment with 1.1
equivalents of n-butyllithium resulted in no desired product (entry 3).
Table 3.2 Lithiation of 1,3-dibromobenzene.
40
3.3.4 Nucleophilic Aromatic Substitution of 1,3-Dibromobenzene with Cyclohexanethiol
As formation of the proligand in a single step via route A proved challenging, route B was
investigated. When treated with NaH, cyclohexanethiol underwent nucleophilic aromatic
substitution with 1,3-dibromobenzene48,49,50
to give mainly the monosubstituted product 30 by
GCMS when heated to 50 °C for 14 h (Table 3.3, entry 1). However, increasing the temperature
to 110 °C gave a 3:1 ratio of the desired disubstituted product 29 to monosubstituted 30 after 18
h. Using KOH as the base in DMA at 160 °C for 3 days51
gave a 2.7:1 ratio of 29:30, with a 55
% isolated yield of the desired product 29. However, when the scale was increased from 0.42
mmol to a 2 mmol scale, only 18 % of the desired product was isolated after 5 days at 160 °C
(entry 4). Interestingly, increasing the temperature to 175 °C resulted in a switch in the
selectivity, favouring 30. Despite challenges with this route, the desired product could be
isolated from the monosubstituted product in acceptable yield on small scale, so this method was
pursued for the formation of a variety of disulfide compounds.
Table 3.3 Nucleophilic aromatic substitution of 1,3-dibromobenzene with cyclohexanethiol.
3.3.5 Formation of Various 1,3-Disulfide Compounds from 1,3-Dibromobenzene by Nucleophilic Aromatic Substitution
The nucleophilic aromatic substitution of 1,3-dibromobenzene with various thiols was then
performed. When 1,3-dibromobenzene was treated with n-butylthiol and potassium hydroxide in
dimethylacetamide at 160 °C for 4 days, an approximately 1:1 mixture of the desired product 31
and the monosubstituted product was observed (Figure 3.10). The same result was seen when
41
thiophenol was used as the nucleophile, resulting in a 1:1 mixture of 32 to monosubstituted
product. For both of these substrates, it is possible that increased reaction time, optimized
reaction temperature, or sequential addition of thiol could increase the yield of the disubstituted
product. In the case of t-butylthiol, only the monosubstituted product 33 was observed by 1H
NMR, in 92 % conversion.
Figure 3.10 Nucleophilic aromatic subsitution of 1,3-dibromobenzene with various thiols.
3.3.6 Oxidation of Disulfide 29 to the Disulfoxide
Figure 3.11 Oxidation of 1,3-bis(cyclohexylthio)benzene with mCPBA.
1,3-bis(cyclohexylthio)benzene (29) was treated with meta-chloroperoxybenzoic acid in
methylene chloride at 0 °C for 15 minutes. After aqueous workup, 34a was isolated in 27%
yield. Analysis of the 13
C NMR spectrum showed a statistical 1:1 mixture of the racemic and
meso diastereomers.
42
Figure 3.12 Asymmetric oxidation of ,3-bis(cyclohexylthio)benzene.
Asymmetric oxidation of 1,3-bis(cyclohexylthio)benzene was performed using hydrogen
peroxide and a vanadium-Schiff base catalyst system that has been shown to work well for the
oxidation of sulfides to sulfoxides.52,53
The desired product 34b was isolated in 37% yield after
1.5 h at 0 °C in dichloromethane. Analysis of the 13
C NMR spectrum showed a 3:1 mixture of
diastereomers. This indicates that the first oxidation affects the second oxidation in this system,
and a non-statistical mixture of meso and racemic diastereomers was achieved.
3.3.7 Pyridine-Based Sulfoxide Pincer Ligands
The pyridine moiety is a common backbone for many pincer ligands. While phenyl-based pincer
ligands are anionic, pyridine-based pincer ligands are neutral. This has implications for both the
reactivity and stability of the metal-ligand complex. Therefore, investigation of both phenyl-
based and pyridine-based pincer ligands is of interest.
3.3.8 Retrosynthetic Analysis of Pyridine-Based Sulfoxide Pincer Ligands with No Methylene Spacer
Figure 3.13 Retrosynthetic analysis of pyridine-based sulfoxide pincer ligands.
Treatment of 2,6-dichloropyridine with a thiol could result in the formation of the corresponding
disulfide via nucleophilic aromatic substitution. Asymmetric oxidation would generate the
desired proligand, which could be complexed to a metal to give the disulfoxide catalyst.
Oxidation to the sulfoxide could also result in oxidation of the pyridine to the N-oxide; however,
N-oxides can be reduced in the presence of sulfoxides by acetic acid and elemental iron.54
43
3.3.9 Nucleophilic Aromatic Substitution of 2,6-Dichloropyridine with Alkyl Thiols
Figure 3.14 shows the nucleophilic aromatic substitution of 2,6-dichloropyridine with various
thiols. The reactions were performed using the same conditions as for the phenyl analogues: 2,6-
dichloropyridine was dissolved in DMA, thiol and KOH were added, and the reaction mixture
was heated to 160 °C. However, the reactions proceeded much faster, and were only left for one
day. When cyclohexanethiol was used, the desired product 35 was isolated in quantitative yield.
The reaction was also carried out with n-butylthiol (36) and t-butylthiol (37), resulting in 100%
and 80% yields, respectively. Nucleophilic aromatic substitution at the 2- and 6-position of the
pyridine ring is facile compared with the corresponding reaction performed on a phenyl ring.
This is evident in the high yields and shorter reaction times. Indeed, formation of 1,3-bis(t-
butylthio)benzene was not possible via SNAr, resulting in only the monosubstituted product
when attempted. However, the corresponding pyridine analogue was isolated in 80% yield.
Figure 3.14 Nucleophilic aromatic substitution of 2,6-dichloropyridine with various thiols.
3.3.10 Retrosynthetic Analysis of Pyridine-Based Pincer Ligands with a Methylene Spacer
Figure 3.15 Retrosynthetic analysis of pyridine-based sulfoxide pincer ligands with a methylene spacer.
44
Figure 3.15 shows the retrosynthetic analysis of a pyridine-based proligand that incorporates a
methylene group into the arms of the pincer. The compound could be synthesized via lithiation
of 2,6-lutidine and subsequent treatment with a commercially available chiral sulfinate ester.54
This route has the benefit of introducing the chiral moiety from a commercially available chiral
source, therefore avoiding the potential for poor enantioselectivity in the chiral oxidation step.
3.3.11 Initial Progress Towards Compound 37
Figure 3.16 Initial progress towards pyridine-based sulfoxide pincer ligands with a methylene spacer.
Proligand 40 (Figure 3.16) has been previously investigated as an organocatalyst for the
asymmetric allylation of N-benzoylhydrazones.54
However, it has not previously been
coordinated to a metal and used as a ligand for transition metal catalysis. The reported synthesis
begins with the oxidation of the pyridine nitrogen to the N-oxide with meta-chloroperoxybenzoic
acid. This reaction was performed, and the desired N-oxide 38 was generated in quantative
yield. The 1H NMR spectrum was consistent with the literature data. From here, treatment of
the N-oxide with n-butyllithium forms the dilithiated species, which gives the chiral disulfoxide
39 upon addition of the sulfinate ester. The N-oxide can be reduced to the corresponding
pyridine in the presence of the sulfoxide groups using iron and acetic acid to generate the desired
proligand 40.
45
3.4 Summary and Future Work
3.4.1 Summary
Initial steps towards the synthesis of novel chiral sulfoxide pincer ligands were performed. A
series of phenyl- and pyridyl-based bis(sulfides) were successfully synthesized by SNAr, using
1,3-dibromobenzene and 2,6-dichloropyridine, respectively. Both racemic and asymmetric
oxidation of 1,3-bis(cyclohexylthio)benzene (29) was performed. The synthesis of a pyridyl-
based sulfoxide ligand that incorporates methylene groups into the arms of the pincer ligand was
also investigated and the first step was performed.
3.4.2 Future Work
Oxidation of the synthesized phenyl- and pyridyl-based bis(sulfides), both racemically and
asymmetrically remains to be completed, as well as the synthesis of the pyridyl-based sulfoxide
with methylene groups in the arms of the pincer. From there, these compounds need to be
complexed to different metals. Following characterization of the metal complexes, it would be
interesting to test their catalytic activity and enantioselectivity in various reactions.
46
Chapter 4
4 Experimental
4.1 General Considerations
Commercial reagents were purchased from Sigma Aldrich, Strem or Alfa Aesar and used without
further purification unless otherwise noted. All reactions were carried out under an atmosphere
of air unless otherwise indicated. Reactions were carried out at ambient temperature unless
otherwise noted. Reactions were monitored using thin-layer chromatography (TLC) on EMD
Silica Gel 60 F254 plates. Visualization of the developed plates was performed under UV light
(254 nm) or KMnO4 stain. Organic solutions were concentrated under reduced pressure on a
Büchi rotary evaporator. Column chromatography was performed with Silicycle Silia-P Flash
Silica Gel. All salts were purchased from Aldrich and used without purification. Solvents were
purchased from Caledon. Dichloromethane and tetrahydrofuran were sparged with argon and
passed through two alumina columns to remove water.
1H and
13C NMR spectra were recorded using a Varian Mercury 300, Varian Mercury 400, or a
VRX-S (Unity) 400 spectrometer. NMR spectra were obtained in CDCl3 and internally
referenced to the residual solvent signal. Data for 1H NMR are reported as follows: chemical
shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad), integration, coupling constant (Hz). Data for 13
C NMR are reported in terms of chemical
shift (δ ppm). High resolution mass spectra (HRMS) were obtained on a micromass 70S-250
spectrometer (EI) or an ABI/Sciex Qstar Mass Spectrometer (ESI). Low resolution mass spectra
(LRMS) were obtained on a Waters 2795 LC with a Waters Micromass ZQ. Infrared (IR) spectra
were obtained on a Perkin-Elmer Spectrum 1000 FT-IR Systems spectrometer and are reported
in terms of frequency of absorption (cm-1
). Melting point ranges were determined on a Fisher-
Johns Melting Point Apparatus.
47
4.2 Experimental Section for the Carboesterification of Olefins
4.2.1 Typical Procedures
Method A – A typical procedure for the allylation of phenols: To a stirred solution of the phenol
derivative in N,N-dimethylformamide (0.7 M) was added allyl bromide (1.5 equiv) and K2CO3
(1.5 equiv). The resulting mixture was stirred for 24 hours or until complete consumption of the
starting material was achieved as determined by TLC. The crude reaction mixture was then
diluted with ethyl acetate and successively washed with aqueous 20% KOH (2x10 mL), water
(3x10 mL) and brine (1x10 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated to dryness in vacuo. The product was isolated by flash column chromatography in
ethyl acetate and hexanes.
Method B – A typical procedure for the dibromovinylation of an aldehyde: To a flame dried
round-bottom flask was added triphenylphosphine (3 equiv) and anhydrous dichloromethane (0.3
M). The resulting solution was maintained under argon and cooled to 0 °C. Carbon tetrabromide
(1.5 equiv) was added and the orange solution was stirred at 0 °C for 15 min. A solution of the
aldehyde in dichloromethane (2 M) was added. The resulting mixture was warmed to ambient
temperature and stirred until TLC showed complete consumption of the starting material.
Hexanes (30 mL per 10 mmol aldehyde) was added and the dark brown slurry was stirred for 15
min, then filtered. The filtrate was concentrated in vacuo. The product was isolated by flash
column chromatography in ethyl acetate and hexanes.55
48
Method C – A general procedure for the formation of methyl propiolates: A solution of the
dibromide in anhydrous tetrahydrofuran (0.1 M) in a flame dried round-bottom flask under argon
was cooled to –78 °C. Methyllithium (3 equiv, 1.6M in hexanes) was added and the resulting
solution was stirred at –78 °C for 1 hour. Methyl chloroformate (6 equiv) was added quickly and
the solution was maintained at –78 °C for 1 hour or until TLC showed complete consumption of
the starting material. Water (10 mL per 10 mmol scale) was added and the mixture was stirred at
room temperature for 10 minutes, then concentrated in vacuo to remove the tetrahydrofuran. The
residue was taken up in diethyl ether and the organic layer was washed with water (3x10mL) and
brine (1x10mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was
isolated by flash column chromatography in ethyl acetate and hexanes.55
Method D – General procedure for the hydrolysis of methyl propiolates: To a solution of the
methyl propiolate derivative in methanol (0.2 M) was added aqueous 20% KOH (20 equiv), and
the resultant solution was stirred until TLC showed complete consumption of the starting
material. The reaction mixture was cooled to 0 °C, and concentrated H2SO4 was added slowly
until the pH value was less than 1. H2O (30 mL) was added and this mixture was extracted with
EtOAc (3x50 mL). The combined organic layers were then washed with water (15 mL) and brine
(15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was isolated via
recrystallization from diethyl ether and hexanes.
49
Method E – General procedure for the cyclization of propiolic acids with Pd(MeCN)2Cl2: To a
solution of the propiolic acid derivative (0.2 mmol), LiCl (26 mg, 0.6 mmol, 3 equiv) and CuCl2
(80 mg, 0.6 mmol, 3 equiv) in acetonitrile (3.6 mL) was added a stock solution of Pd(MeCN)2Cl2
(0.52 mg in 0.4 mL MeCN, 0.002 mmol). The mixture was heated at 50 oC for 14 to 20 hours.
The resulting solution was concentrated directly in vacuo. The product was isolated by flash
column chromatography in diethyl ether and hexanes.
4.2.2 Synthesis and Cyclization of Carboxylic Acid Substrates
2-allyloxybenzaldehyde (1)
The title compound was prepared according to Method A from salicylaldehyde
(2.0 g, 16.4 mmol) to yield the product (2.7 g, 100%) as a pale yellow oil after
flash column chromatography in 10% ethyl acetate in hexanes. This compound is
also commercially available. 1H NMR (300 MHz) δ 4.66 (d, J = 5.1 Hz, 2H), 5.34 (dd, J1 = 10.6
Hz, J2 = 1.3 Hz, 1H), 5.46 (dd, J1 = 17.3 Hz, J2 = 1.4 Hz, 1H), 6.02-6.15 (m, 1H), 6.98 (d, J = 8.5
Hz, 1 H), 7.03 (t, J = 7.6 Hz, 1H), 7.50-7.56 (m, 1H), 7.84 (dd, J1 = 7.7 Hz, J2 = 1.7 Hz, 1H),
10.54 (s, 1H) ppm; 13
C NMR (100 MHz) δ 69.1, 112.8, 118.0, 120.8, 125.0, 128.3, 132.3, 135.8,
160.9, 189.6 ppm; IR (neat) 3078, 2862, 2762, 1683, 1598, 1482, 1456, 1285, 1239, 994, 757
cm-1
; LRMS (ESI+) m/z 163.0 (M+1), 185.1 (M+23).
1-(allyloxy)-2-(2,2-dibromovinyl)benzene (2)
The title compound1 was prepared according to Method B from 2-
allyloxybenzaldehyde (2.7 g, 16.4 mmol) to yield the product (4.7 g, 90%) as a
yellow oil after flash column chromatography in 5% ethyl acetate in hexanes.
Spectral data was consistent with literature data. 1H NMR (400 MHz) δ 4.57 (ddd, J1 = 5.1 Hz, J2
= 1.6 Hz, J3 = 1.6 Hz, 2H), 5.30 (tdd, J1 = 1.4 Hz, J2 = 1.4 Hz, J3 = 10.5 Hz, 1H), 5.41 (tdd, J1 =
50
1.6 Hz, J2 = 1.6 Hz, J3 = 17.3 Hz, 1H), 6.06 (tdd, J1 = 5.1 Hz, J2 = 10.3 Hz, J3 = 17.2 Hz, 1H),
6.86 (d, J = 8.3 Hz, 1H), 6.97 (ddd, J1 = 0.5 Hz, J2 = 1.0 Hz, J3 = 7.7 Hz, 1H), 7.30 (ddd, J1 = 7.9
Hz, J2 = 7.9 Hz, J3 = 1.7 Hz, 1H), 7.64 (s, 1H), 7.70 (dd, J1 = 1.5 Hz, J2 = 7.7 Hz, 1H) ppm; 13
C
NMR (100 MHz) δ 69.1, 89.7, 111.9, 117.5, 120.3, 124.7, 129.2, 129.8, 132.9, 132.9, 155.5
ppm; IR (neat) 3023, 2867, 1597, 1483, 1449, 1243, 1226, 1108, 749 cm-1
; LRMS (ESI+) m/z
317.0 (M+1), 339.0 (M+23).
methyl 3-(2-(allyloxy)phenyl)propiolate (3)
The title compound1 was prepared according to Method C from 1-(allyloxy)-
2-(2,2-dibromovinyl)benzene (5.1 g, 15.9 mmol) to afford the product (3.1 g,
90%) as a pale yellow oil after flash column chromatography in 5-10% ethyl
acetate in hexanes. Spectral data was consistent with literature data. 1
H NMR (400 MHz) δ 3.81
(s, 3H), 4.61 (ddd, J1 = 4.8 Hz, J2 = 1.7 Hz, J3 = 1.7 Hz, 2H), 5.29 (tdd, J1 = 1.5 Hz, J2 = 1.5 Hz,
J3 = 10.6 Hz, 1H), 5.49 (tdd, J1 = 1.6 Hz, J2 = 1.6 Hz, J3 = 17.3 Hz, 1H), 6.03 (tdd, J1 = 4.8 Hz,
J2 = 10.5 Hz, J3 = 17.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.92 (ddd, J1 = 7.6 Hz, J2 = 7.6 Hz, J3
= 0.8 Hz, 1H), 7.33-7.38 (m, 1H), 7.50 (dd, J1 = 7.6 Hz, J2 = 1.7 Hz, 1H) ppm; 13
C NMR (100
MHz) δ 52.8, 69.3, 83.7, 84.5, 109.4, 112.5, 117.6, 120.8, 132.3, 132.6, 135.0, 154.8, 160.8 ppm;
IR (neat) 2920, 2851, 2219, 1707, 1490, 1447, 1434, 1300, 1280, 1175, 994, 750 cm-1
; LRMS
(ESI+) m/z 217.1 (M+1).
3-(2-(allyloxy)phenyl)propiolic acid (4)
The title compound was prepared according to Method D from methyl 3-(2-
(allyloxy)phenyl)propiolate (3.0 g, 13.9 mmol) to yield the product (2.6 g,
92%) as an off-white solid after recrystallization from diethyl ether and
pentane. 1H NMR (400 MHz) δ 4.65 (ddd, J1 = 4.8 Hz, J2 = 1.7 Hz, J3 = 1.7 Hz, 2H), 5.33 (tdd,
J1 = 1.5 Hz, J2 = 1.5 Hz, J3 = 10.6 Hz, 1H), 5.52 (tdd, J1 = 1.7 Hz, J2 = 1.7 Hz, J3 = 17.3 Hz, 1H),
6.06 (tdd, J1 = 4.8 Hz, J2 = 10.6 Hz, J3 = 17.3 Hz, 1H), 6.90 (d, J1 = 8.4 Hz, 1H), 6.96 (ddd, J1 =
7.6 Hz, J2 = 7.6 Hz, J3 = 0.9 Hz, 1H), 7.41 (ddd, J1 = 1.7 Hz, J2 = 7.5 Hz, J3 = 8.4 Hz, 1H), 7.55
51
(dd, J1 = 7.6 Hz, J2 = 1.7 Hz, 1H), 9.04-10.82 (bs, 1H) ppm; 13
C NMR (100 MHz) δ 69.2, 84.0,
86.2, 108.9, 112.4, 117.6, 120.7, 132.3, 132.7, 135.1, 158.3, 160.9 ppm; IR (neat): 2912.6,
2596.9, 2205.1, 1665.9, 1310.4, 1285.2, 1253.6, 1231.1, 1200.5, 989.4, 917.7, 755.8, 746.1 cm-1
;
HRMS (ESI) calc’d for C12H9O3 [M-1]- 201.0557, Found 201.0563; mp 83-85 °C.
(Z)-10-chloro-3a,4-dihydrobenzo[b]furo[3,4-e]oxepin-1(3H)-one (5)
The title compound was prepared according to Method E from 3-(2-
(allyloxy)phenyl)propiolic acid (202.2 mg, 1 mmol) and the reaction mixture
was heated at 50 °C for 14 hours to yield the product (193 mg, 82%) as an off-
white solid after flash column chromatography in diethyl ether and hexanes. 1H NMR (400
MHz) δ 3.32-3.39 (m, 1H), 3.98 (dd, J1 = 9.5 Hz, J2 = 4.4 Hz, 1H), 4.40 (dd, J1 = 9.4 Hz, J2 = 8.7
Hz, 1H), 4.48 (dd, J1 = 11.0 Hz, J2 = 10.4 Hz, 1H), 4.68 (dd, J1= 10.3 Hz, J2 = 6.2 Hz, 1H), 7.12
(dd, J1 = 8.1 Hz, J2 = 1.2 Hz, 1H), 7.22-7.26 (m, 1H), 7.39-7.43 (m, 1H), 7.83 (dd, J1 = 8.0 Hz,
J2 = 1.7 Hz, 1H) ppm; 13
C NMR (100 MHz) δ 40.5, 65.1, 81.0, 122.7, 124.1, 124.5, 129.8, 130.6,
132.2, 138.8, 156.1, 166.7 ppm; IR (neat): 2913, 1749, 1617, 1478, 1229, 1087, 1027, 763 cm-1
;
HRMS (ESI) calc’d for C12H10ClO3 [M+H]+ 237.0312, Found 237.0321; mp 62-66 °C.
4.2.3 Synthesis and Cyclization of Non-Carboxylic Acid Substrates
3-(2-(allyloxy)phenyl)prop-2-yn-1-ol (22)
A solution of methyl 3-(2-(allyloxy)phenyl)propiolate (1.08 g, 5.0 mmol) in
anhydrous tetrahydrofuran (50 mL) in a flame dried round bottom flask under
argon was cooled to -78 °C. Diisobutylaluminum hydride (1.0 M in THF, 10
mL, 10 mmol) was added slowly and the reaction was stirred for 6 h. A second aliquot of
DIBAL-H (1.0 M in THF, 3 mL, 3 mmol) was added and the reaction was stirred a further 3 h.
The mixture was quenched with aqueous saturated ammonium chloride (100 mL). The solution
was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with 1 M HCl ( 1
52
x 100 mL) to break up the aluminum salts, aqueous saturated sodium carbonate (1 x 100 mL) to
neutralize the solution, then water (2 x 100 mL) and brine (1 x 100 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (566
mg, 60 %) as a pale yellow oil after column chromatography in 20 % ethyl acetate in hexanes.
1H NMR (400 MHz) δ 7.41 (dd, J = 1.7 Hz, J = 7.6 Hz, 1H), 7.29-7.24 (m, 1H), 6.90 (dt, J = 0.9
Hz, J = 7.5 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.12-6.02 (m, 1H), 5.47 (ddd, J = 1.7 Hz, J = 3.3
Hz, J = 17.3 Hz, 1H), 5.30 (qd, J = 1.5 Hz, J = 10.6 Hz, 1H), 4.62 (td, J = 1.6 Hz, J = 5.0 Hz,
1H), 4.54 (s, 1H) ppm.
23
The product was prepared according to Method E from 3-(2-(allyloxy)phenyl)prop-2-yn-1-ol
(37.6 mg, 0.2 mmol) and the reaction mixture was heated at 50 °C for 23 h to yield the product
(20 mg, 45 %) as a yellow oil after flash column chromatography in 10 % ethyl acetate in
hexanes.
1H NMR (400 MHz) δ 7.76 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.11 (ddd, J = 1.4 Hz,
J = 7.4 Hz, J = 8.0 Hz, 1H), 7.04 (dd, J = 1.3 Hz, J = 8.0 Hz, 1H), 4.72 (dd, J = 2.2 Hz, J = 15.0
Hz, 1H), 4.61 (dd, J = 1.2 Hz, J = 15.0 Hz, 1H), 4.55 (dd, J = 5.1 Hz, J = 10.7 Hz, 1H), 4.14 (m,
1H), 3.63 (dd, J = 7.5 Hz, J = 8.7 Hz, 1H), 3.15 (m, 1H); 13
C NMR (100 MHz) δ 155.9, 142.4,
129.4, 129.2, 126.8, 122.9, 121.6, 120.1, 74.4, 72.7, 70.8, 45.3 ppm.
4-(2-(allyloxy)phenyl)-2-methylbut-3-yn-2-ol (24)
A solution of methyl 3-(2-(allyloxy)phenyl)propiolate (50 mg, 0.23 mmol) was
dissolved in 1 mL anhydrous tetrahydrofuran in a flame dried flask under
argon was cooled to -78 °C. Methyllithium (1.6 M in THF, 0.43 mL, 0.69
mmol) was added slowly and the reaction mixture was stirred for 4.5 h. Water (2 mL) was added
and the reaction was stirred for 10 minutes, then extracted with diethyl ether (3 x 5 mL), dried
over sodium sulfate, filtered, and concentrated to afford the product (28.9 mg, 58 %) as a pale
yellow oil after purification by preparatory TLC using 20 % ethyl acetate in hexanes.
53
1H NMR (300 MHz) 7.38 (dd, J = 1.7 Hz, J = 7.6 Hz, 1H), 7.25 (ddd, J = 1.7 Hz, J = 7.5 Hz, J =
8.3 Hz, 1H), 6.89 (m, 2H), 6.07 (tdd, J = 4.8 Hz, J = 10.5 Hz, J = 17.2 Hz, 1H), 5.52 (qd, J = 1.7
Hz, J = 17.2 Hz, 1H), 5.29 (qd, J = 1.6 Hz, J = 10.6 Hz, 1H), 4.59 (td, J = 1.7 Hz, J = 4.7 Hz,
2H), 2.07 (s, 1H), 1.64 (s, 6H) ppm.
3-(2-(allyloxy)phenyl)-N-phenylpropiolamide (25)
A solution of 1-(allyloxy)-2-(2,2-dibromovinyl)benzene (500 mg, 1.6 mmol)
in anhydrous tetrahydrofuran (25 mL) in a flame dried round bottom flask
under argon was cooled to -78 °C. Methyllithium (1.6 M in Et2O, 3 mL, 4.7
mmol) was added dropwise. The yellow-orange solution was stirred for 1 h at -78 °C, then
phenyl isocyanate (0.24 mL, 3.1 mmol) was added. The reaction was stirred for a further 30
minutes, then quenched with water (10 mL) and concentrated to remove most of the
tetrahydrofuran. The organic material was extracted with diethyl ether (3 x 25 mL). The organic
layer was washed with water (2 x 25 mL) and brine (1 x 25 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo to yield the product (148 mg, 34 %) as a pale yellow solid
after flash column chromatography in 20 % ethyl acetate in hexanes followed by recrystallization
in dichloromethane/ethyl acetate/pentane.
1H NMR (400 MHz) δ 7.60 (s, 1H), 7.54 (m, 3H), 7.37 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 6.95 (t,
J = 7.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.09 (m, 1H), 5.51 (dd, J = 1.1 Hz, J = 17.2 Hz, 1H),
5.34 (dd, J = 0.8 Hz, J = 10.6 Hz, 1H), 4.65 (d, J = 4.9 Hz, 2H) ppm; 13
C NMR (75 MHz) δ
160.2, 137.5, 134.5, 132.7, 131.8, 129.1, 124.7, 120.8, 119.8, 117.7, 112.4, 109.7, 87.5, 82.6,
69.3 ppm.
26
The product was synthesized according to Method E from 3-(2-
(allyloxy)phenyl)-N-phenylpropiolamide (13.9 mg, 0.05 mmol) and the
reaction mixture was heated at 50 °C for 20 h to yield the product (7.6 mg, 48
%) as a pale yellow solid after purification by preparatory TLC in 20% ethyl acetate in hexanes.
54
1H NMR (300 MHz) δ 7.93 (dd, J = 1.6 Hz, J = 8.1 Hz, 1H), 7.61-7.58 (m, 2H), 7.41-7.31 (m,
3H), 7.21-7.15 (m, 2H), 7.10 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 4.72 (dd, J = 5.4 Hz, J = 11.8 Hz,
1H), 4.21 (dd, J = 3.4 Hz, J = 11.7 Hz, 1H), 3.88-3.82 (m, 1H), 3.71 (dd, J = 8.4 Hz, J = 11.1 Hz,
1H), 3.45-3.37 (m, 1H) ppm; LRMS (ESI+) m/z 312 (M+1), 350 (M+39).
4.3 Experimental Section for the Preparation of Sulfoxide Pincer Ligands
4.3.1 Typical Procedures
Method F – General procedure for the SNAr reaction: 1,3-dibromobenzene (100 mg, 0.42
mmol) or 2,6-dichloropyridine (100 mg, 0.68 mmol) was dissolved in DMA (1 mL or 1.6 mL).
Potassium hydroxide (2.2 equivalents) was added, then thiol (2 equivalents). The vessel was
sealed and the reaction mixture was heated to 160 °C for 3-6 days. The solution was allowed to
cool, then diluted with diethyl ether, washed with water (2 × 3 mL), brine (1 × 3 mL), dried over
MgSO4, and concentrated. The resulting oil was purified by preparatory TLC in hexanes.
4.3.2 Synthesis of Sulfoxide Pincer Ligands
1,3-bis(cyclohexylthio)benzene (29)
The title compound was prepared according to Method F from 1,3-
dibromobenzene (100 mg, 0.42 mmol) and cyclohexanethiol (98.8 mg, 0.85
mmol) to yield the product (72 mg, 55%) as a pale yellow oil after 3 days. 1H NMR (400 MHz) δ
1.23-1.41 (m, 10 H), 1.61-1.63 (m, 2H), 1.75-1.77 (m, 4H), 1.97-1.99 (m, 4H), 3.08-3.14 (m,
2H), 7.16-7.23 (m, 3H), 7.40 (t, J = 1.5 Hz, 1H) ppm; 13
C NMR (100 MHz) δ 25.7, 26.0, 46.5,
128.915, 129.7, 134.1, 135.9 ppm; IR (neat) 2926.60, 2851.47, 1568.40, 1460.72, 1447.59,
1262.09, 997.07, 780.38 cm-1
; HRMS (EI+) calc’d for C18H26S2 306.1490, found 306.1476.
1,3-bis(butylthio)benzene (31)
55
The title compound was prepared according to Method F from 1,3-
dibromobenzene (100 mg, 0.42 mmol) and 1-butanethiol (76.5 mg, 0.85
mmol) to yield the product as yellow oil after 3 days. 1H NMR (400 MHz)
0.85 (t, J = 7.3 Hz, 6H), 1.37 (dddd, J1 = 7.3 Hz, J2 = 14.4 Hz, 4H), 1.56 (ddd, J1 = 7.3 Hz, J2 =
15.0 Hz, 4 H), 2.84 (t, J = 7.4 Hz, 4H), 7.00-7.03 (m, 2H), 7.08-7.12 (m, 1H), 7.17 (t, J = 1.7 Hz,
1H) ppm.
1,3-bis(phenylthio)benzene (32)
The title compound was prepared according to method F from 1,3-
dibromobenzene (100 mg, 0.42 mmol) and thiophenol (93.4 mg, 0.85 mmol) to
afford the title compound after 3 days. Spectral data was consistent with literature data.51
(3-bromophenyl)(tert-butyl)sulfane (33)
The title compound was prepared according to Method F from 1,3-
dibromobenzene (100 mg, 0.42 mmol) and 2-methyl-2-propanethiol (76.5 mg,
0.85 mmol) to yield the product (92 % conversion) as a pale yellow oil. 1H NMR (400 MHz) δ
1.29 (s, 9H), 7.20 (dd, J1 = 7.8 Hz, J2 = 7.8 Hz, 1H), 7.49 (ddd, J1 = 1.1 Hz, J2 = 2.0 Hz, J3 = 8.0
Hz, 1H), 7.46 (ddd, J1 = 1.1 Hz, J2 = 1.5 Hz, J3 = 7.7 Hz, 1H), 7.70 (dd, J1 = 1.8 Hz, J2 = 1.8 Hz,
1H) ppm.
2,6-bis(cyclohexylthio)pyridine (35)
The title compound was prepared according to Method F from 2,6-
dichloropyridine (100 mg, 0.68 mmol) and cyclohexanethiol (157 mg, 1.35
mmol) to yield the product (209 mg, 100%) as a pale yellow oil after flash column
chromatography (20% ethyl acetate in hexanes) to remove trace DMA. 1H NMR (400 MHz) δ
7.22 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 3.90-3.84 (m, 2H), 2.11-2.09 (m, 4H), 1.81-
1.24 (m, 16H).
2,6-bis(butylthio)pyridine (36)
The title compound was prepared according to Method F from 2,6-
dichloropyridine (100 mg, 0.68 mmol) and 1-butanethiol (122 mg,
56
1.35 mmol) to yield the product (173 mg, 100%) as a pale yellow oil after flash column
chromatography (20% ethyl acetate in hexanes). 1H NMR (400 MHz) δ 7.28 (d, J = 8.1 Hz, 1H),
6.87 (d, J = 7.8 Hz, 2H), 3.20 (t, J = 7.3 Hz, 4H), 1.77-1.69 (m, 4H), 1.54-1.45 (m, 4H), 0.98 (t, J
= 7.3Hz, 6H) ppm.
2,6-bis(tert-butylthio)pyridine (37)
The title compound was prepared according to Method F from 2,6-
dichloropyridine (100 mg, 0.68 mmol) and 2-methyl-2-propanethiol (122
mg, 1.35 mmol) to yield the product (139 mg, 80%) after flash column chromatography. 1H
NMR (400 MHz) δ 7.35 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 1.52 (s, 18H) ppm.
2,6-bis(cyclohexylsulfinyl)pyridine (34)
Racemic oxidation:
To a solution of 1,3-bis(cyclohexylthio)benzene (67 mg, 0.22 mmol) in dichloromethane (2 mL)
was added mCPBA (70%, 75 mg, 0.44 mmol). The reaction mixture was stirred for 15 minutes,
then quenched with water (2 mL). The organic layer was extracted with dichloromethane (3 x 2
mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound (20 mg,
27%) as an off-white solid after purification by preparatory TLC (20% ethyl acetate in hexanes)
as a mixture of isomers. 1H NMR (400 MHz) δ 7.78-7.76 (m, 1H), 7.74-7.64 (m, 3H), 2.63-2.57
(m, 2H), 1.91-1.83 (m, 6H), 1.71-1.64 (m, 4H), 1.45-1.36 (m, 4H), 1.28-1.46 (m, 6H) ppm; 13
C
NMR (100 MHz) δ 143.6, 129.6, 127.2, 121.5, 121.5, 63.3, 63.2, 26.4, 26.4, 25.3, 25.3, 25.3,
25.2, 23.7, 23.5 ppm; LCMS (ESI+) m/z 361 (M + 23).
Asymmetric oxidation:
To a solution of L* (see Figure 3.12, 21.3 mg, 0.045 mmol) in dichloromethane (3.5 mL) was
added VO(acac)2 (4.0 mg, 0.015 mmol). The solution changed from yellow to blue-green, and
was stirred at ambient temperature for 45 minutes. 1,3-bis(cyclohexylthio)benzene (115 mg,
0.375 mmol) was added and the reaction mixture was stirred for 1 hour at ambient temperature,
then cooled to 0 °C. Hydrogen peroxide (30%, 0.115 mL, 1.125 mmol) was added and the
reaction was stirred for 1.5 hours. Aqueous saturated sodium thiosulfate (2 mL) was added to
57
quench the reaction, and the organic layer was extracted with dichloromethane (3 x 5 mL),
washed with brine (5 mL), dried over magnesium sulfate, filtered, and concentrated to yield the
product (37 mg, 11%) after purification by preparatory TLC (20% ethyl acetate in hexanes). 1H
NMR (400 MHz) δ 7.78-7.76 (m, 1H), 7.74-7.64 (m, 3H), 2.63-2.57 (m, 2H), 1.91-1.83 (m, 6H),
1.71-1.64 (m, 4H), 1.45-1.36 (m, 4H), 1.28-1.46 (m, 6H) ppm; 13
C NMR (100 MHz) δ 143.6,
129.6, 129.4, 127.2, 121.4, 121.4, 63.2, 63.2, 26.4, 26.3, 25.3, 25.3, 25.2, 25.2, 23.6, 23.5 ppm.
58
Appendix 1
NMR Spectra
3-(2-(allyloxy)phenyl)prop-2-yn-1-ol (22)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
500
1000
1500
2000
1.0
0
1.0
21
.03
1.9
3
0.9
11
.20
1.9
61
.84
59
Compound 23
ppm (t1)0.01.02.03.04.05.06.07.08.0
-100
0
100
200
300
400
500
600
700
800
1.0
0
1.2
21
.07
1.0
3
1.1
21
.13
1.1
4
2.3
5
1.1
8
1.1
2
ppm (t1)50100150
0
100
200
300
400
60
4-(2-(allyloxy)phenyl)-2-methylbut-3-yn-2-ol (24)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
5000
1.0
0
1.0
0
1.0
0
1.9
9
1.3
20
.93
2.0
0
0.9
3
6.3
6
61
3-(2-(allyloxy)phenyl)-N-phenylpropiolamide (25)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
500
1000
1.0
21
.03
0.9
5
2.9
8
1.0
0
2.0
5
3.8
2
0.9
40
.95
ppm (t1)50100150
-1000
0
1000
2000
3000
4000
5000
6000
16
0.2
13
13
7.4
58
13
4.5
42
13
2.6
57
13
1.7
68
12
9.0
77
12
4.7
49
12
0.8
23
11
9.8
15
11
7.7
39
11
2.4
01
10
9.7
17
87
.46
6
82
.62
8
69
.31
5
62
Compound 26
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
500
1000
1500
2000
1.0
0
1.0
6
1.0
2
1.0
0
1.2
7
0.9
2
3.1
1
2.0
00
.98
2.3
2
63
1,3-bis(cyclohexylthio)benzene (29)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
100
200
300
400
500
2.0
0
10
.21
4.0
8
4.0
0
2.3
2
2.8
3
0.8
8
ppm (t1)50100150
0
5000
10000
15000
20000
25000
13
5.8
60
13
4.1
40
12
9.6
66
12
8.9
05
46
.47
0
33
.28
3
26
.00
9
25
.72
7
64
1,3-bis(butylthio)benzene (31)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
100000000
200000000
300000000
400000000
4.0
0
4.2
6
4.1
6
6.1
8
0.9
41
.03
1.8
3
65
(3-bromophenyl)(tert-butyl)sulfane (33)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
10000000
20000000
30000000
40000000
1.0
0
1.9
4
0.9
1
9.6
0
66
2,6-bis(cyclohexylthio)pyridine (35)
ppm (t1)0.01.02.03.04.05.06.07.08.0
-100000000
0
100000000
200000000
300000000
400000000
500000000
600000000
700000000
1.0
0
1.9
2
2.0
5
4.2
5
5.0
52
.61
9.0
13
.89
67
2,6-bis(butylthio)pyridine (36)
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
50000000
100000000
150000000
200000000
250000000
300000000
350000000
2.0
0
0.9
3
4.5
4
4.8
1
4.7
1
6.6
9
68
2,6-bis(tert-butylthio)pyridine (37)
ppm (t1)0.01.02.03.04.05.06.07.08.0
-10000000
0
10000000
20000000
30000000
40000000
1.0
0
1.8
7
18
.99
69
2,6-bis(cyclohexylsulfinyl)pyridine (34) : racemic oxidation
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
5000000002
.00
5.9
9
4.1
0
4.3
0
7.4
3
0.9
42
.83
ppm (f1)50100150
0
5000
10000
14
3.5
74
12
9.5
97
12
7.2
34
12
1.4
85
12
1.4
50
63
.25
9
63
.20
3
26
.42
4
26
.35
1
25
.57
9
25
.33
3
25
.31
2
25
.26
6
25
.22
3
23
.70
0
23
.51
8
70
2,6-bis(cyclohexylsulfinyl)pyridine (34) : asymmetric oxidation
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
5000000002
.00
5.9
9
4.1
0
4.3
0
7.4
3
0.9
42
.83
ppm (t1)50100150
0
500000000
14
3.5
53
12
9.5
50
12
9.4
29
12
7.1
74
12
1.4
23
12
1.3
89
63
.22
6
63
.17
1
60
.31
0
26
.39
2
26
.32
0
25
.54
1
25
.30
0
25
.28
0
25
.22
8
25
.18
6
23
.63
9
23
.46
4
14
.12
9
71
References
1 Jensen, K.H.; Sigman, M.S. Org. Biomol. Chem. 2008, 6, 4083.
2 Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.; Sharpless, K. B. J. Am. Chem. Soc.
1988, 110, 1968.
3 Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962.
4 Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
5 Li, Y.; Antonic, M.; Song, D.; Dong, V.M. Unpublished results.
6 Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131, 3846.
7 Wolfe, J. P. Eur. J. Org. Chem. 2007, 571.
8 Wolfe, J. P. Synlett 2008, 19, 2913.
9 Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468.
10 Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690.
11 Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179.
12 Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
13 Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2005, 127, 14586.
14 Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245.
15 Lu, X.; Zhu, G.; Wang, Z. Synlett, 1998, 115.
72
16 Lu, X. Handbook of Organopalladium Chemistry for Organic Synthesis, V2 (Ed.: E. J.
Negishi), Wiley-VCH, Weinheim, 2002, pp. 2267.
17 Yamazaki, S. Chem. Eur. J. 2008, 14, 6026.
18 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
19 Welker, M. E. Chem. Rev. 1992, 92, 97.
20 Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845.
21 Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301.
22 Xiao, W.-L.; Yang, L.-M.; Gong, N.-B.; Wu, L.; Wang, R.-R.; Pu, J.-X.; Li, X.-L.; Huang, S.-
X.; Zheng, Y.-T.; Li, R.-T.; Lu, Y.; Zheng, Q.-T.; Sun, H.-D. Org. Lett. 2006, 8, 991.
23 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
24 Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467-4470.
25 Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
26 Mamane, V.; Hannen, P.; Fürstner, A. Chem. Eur. J. 2004, 10, 4556.
27 Wadsworth, D. H.; Geer, S. M.; Detty, M. R. J. Org. Chem. 1987, 52, 3662.
28 Wolfe, J. P. Synlett, 2008, 19, 2913.
29 Zhu, G.; Ma, S.; Lu, X.; Huang, Q. J. Chem Soc., Chem Commun. 1995, 271.
30 Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111.
31 Moulton, C. J.; Shaw, B. L. J. Chem. Soc., Dalton Trans. 1976, 1020.
32 Singleton, J. T. Tetrahedron 2003, 59, 1837.
33 Albrecht, M.; van Koten, G. Angew. Chem. Int. Ed. 2001, 40, 3750.
73
34 Benito-Garagorri, D.; Kirchner, K. Acc. Chem. Res. 2008, 41, 201.
35 Nishiyama, H. Chem. Soc. Rev. 2007, 36, 1133.
36 Gorla, F.; Togni, A.; Venanzi, L. M.; Albinati, A.; Lianza, F. Organometallics 1994, 13, 1607.
37 Zhang, X.; Longmire, J.M.; Shang, M. Organometallics 1998, 17, 4374-4379.
38 Williams, B. S.; Dani, P.; Lutz, M.; Spek, A. L.; van Koten, G. Helv. Chim. Acta 2001, 84,
3519.
39 Calligaris, M.; Carugo, O. Coord. Chem. Rev. 1996, 153, 83.
40 Fernández, I.; Khiar, N. Chem. Rev. 2003, 103, 3651.
41 Riley, D. P.; Oliver, J. D. Inorg. Chem. 1986, 25, 1821.
42 Riley, D. P.; Oliver, J. D. Inorg. Chem. 1986, 25, 1825.
43 Evans, D. R.; Huang, M.; Seganish, W. M.; Fettinger, J. C.; Williams, T. L. Organometallics
2002, 21, 893.
44 Schaub, T.; Radius, U.; Diskin-Posner, Y.; Leitus, G.; Shimon, L. J. W.; Milstein, D.
Organometallics 2008, 27, 1892.
45 Eapen, K. C.; Saba, C. S.; Tamborski, C. J. Fluorine Chem. 1987, 35, 571.
46 Mariz, R.; Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172.
47 Bürgi, J. J.; Mariz, R.; Gatti, M.; Drinkel, E.; Luan, X.; Blumentritt, S.; Linden, A.; Dorta, R.
Angew. Chem. Int. Ed. 2009, 48, 2768.
48 Hennrich, G.; Lynch, V. M.; Anslyn, E. V. Chem. Eur. J. 2002, 8, 2274.
49 Wang, Y.; Parkin, S. R.; Gierschner, J.; Watson, M. D. Org. Lett. 2008, 10, 3307.
74
50 Gingras, M.; Placide, V.; Raimundo, J.-M.; Bergamini, G.; Ceroni, P.; Balzani, V. Chem. Eur.
J. 2008, 14, 10357.
51 Holmes, K. E.; Gilby, L. M.; Stonehouse, J. M.; Kelly, P. F.; Elsegood, M. R. J.
CrystEngComm 2004, 6, 34.
52 Pelotier, B.; Anson, M. S.; Campbell, I. B.; Macdonald, S. J. F.; Priem, G.; Jackson, R. F. W.
Synlett 2002, 1055.
53 Bolm, C.; Bienewald, F. Angew. Chem. Int. Ed. Engl. 1995, 34, 2640.
54 García-Flores, F.; Flores-Michel, L. S.; Juaristi, E. Tetrahedron Lett. 2006, 47, 8235.
55 Padwa, A.; Wong, G.S.K. J. Org. Chem. 1986, 51, 3125.