Gold-catalyzed intermolecular C-S bond formation: Efficient synthesis of α-substituted vinyl sulfones

Article abstract of DOI:10.1002/anie.201310142

A general method for the synthesis of α-substituted vinyl sulfones makes use of a combination of a triazole gold complex and gallium triflate. This efficient C-S bond formation between simple terminal alkynes and sulfinic acids provides access to various α-substituted vinyl sulfones. Less basic, less hindered: The gold-catalyzed intermolecular Markovnikov addition of sulfinic acids to terminal alkynes has been achieved through the use of a bimetallic gold/gallium catalyst system. Various α-substituted vinyl sulfones were efficiently synthesized. A one-pot synthesis that starts from the bench-stable sodium sulfinates was also developed (DCE=1,2-dichloroethane).

Full text of DOI:10.1002/anie.201310142

Angewandte
Chemie
DOI: 10.1002/anie.201310142
À
C S Bond Formation
Hot Paper
À
Gold-Catalyzed Intermolecular C S Bond Formation: Efficient
Synthesis of a-Substituted Vinyl Sulfones**
Yumeng Xi, Boliang Dong, Edward J. McClain, Qiaoyi Wang, Tesia L. Gregg,
Novruz G. Akhmedov, Jeffrey L. Petersen, and Xiaodong Shi*
Abstract: A general method for the synthesis of a-substituted
vinyl sulfones makes use of a combination of a triazole gold
À
complex and gallium triflate. This efficient C S bond forma-
tion between simple terminal alkynes and sulfinic acids
provides access to various a-substituted vinyl sulfones.
À
T
he formation of C S bonds is one of the fundamental
transformations in organic synthesis.[1] Organosulfur com-
pounds do not only contain fundamental functional groups,
such as thiol, sulfide, or disulfide units, which render them
useful synthetic intermediates, but they also exist abundantly
in biological systems ranging from small natural metabolites
to proteins. Vinyl sulfones represent one particularly inter-
esting sulfur-containing functional group. Vinyl sulfones have
found widespread applications in biological research as
covalent protease inhibitors[2] or as substrates for bioconju-
gation[3] owing to their good ability to act as a Michael
acceptor to trap nucleophiles through the formation of stable
covalent adducts (Scheme 1a). In principle, a-substituted
vinyl sulfones, with a much less hindered b-carbon atom,
should react faster in these transformations and should
therefore be more suitable substrates for Michael addition
reactions. However, in most cases, only trans-b-substituted
vinyl sulfones are used. This is mainly due to the limited
availability of methods for vinyl sulfone synthesis.
Scheme 1. Vinyl sulfones: synthesis and biological applications.
Previously described methods for the synthesis of vinyl
sulfones generally involve 1) the elimination from a- or b-
substituted sulfones, 2) the oxidation of vinyl sulfides, or
3) olefination reactions (e.g., Wittig, Horner–Wadsworth–
Emmons, Julia reaction), which often take several steps from
either toxic or unstable starting materials.[4] For example, the
two-step addition/elimination strategy usually requires toxic
mercury- or selenium-containing starting materials, and the
reactions suffer from poor regioselectivity (Scheme 1b). In
contrast, transition-metal-catalyzed alkyne or alkene addition
However, both the copper-catalyzed sulfonyl radical addition
to alkynes and the palladium-catalyzed Mizoroki–Heck
reaction of vinyl sulfones gave exclusively the trans-config-
ured b-substituted products, as anti-Markovnikov addition is
preferred.[5,6] To the best of our knowledge, procedures for the
efficient synthesis of a-substituted vinyl sulfones have rarely
been described.[7] Most of the reported reactions suffer from
limited substrate scope and poor a/b regioselectivity. Herein,
we report a general synthesis of a-substituted vinyl sulfones
that is enabled by the gold-catalyzed Markovnikov addition
of sulfinic acids to alkynes with exclusive a regioselectivity.
Our general rationale entails that unlike for the radical
reaction and the metal-catalyzed (Mizoroki–Heck) coupling
reaction, the sulfinic acid addition to the p-acid activated
alkyne should favor the formation of Markovnikov product
with high efficiency. The challenge is to identify proper p-acid
catalysts that can tolerate sulfinic acid while remaining active.
Cationic gold species have been identified as one of the most
effective catalysts for alkyne activation.[8] However, gold(I)-
À
À
reactions allow the rapid formation of C S and C C bonds
and have been applied to the synthesis of vinyl sulfones.
[*] Y. Xi, B. Dong, E. J. McClain, Q. Wang, T. L. Gregg,
Dr. N. G. Akhmedov, Prof. J. L. Petersen, Prof. X. Shi
C. Eugene Bennett Department of Chemistry
West Virginia University
Morgantown, WV 26506 (USA)
E-mail: Xiaodong.Shi@mail.wvu.edu
Homepage: http://community.wvu.edu/~xs007/
À
catalyzed C S bond formations have rarely been described in
the literature, with most cases being intramolecular reac-
tions.[9] This could be attributed to the fact that S nucleophiles
could form stable complexes with cationic gold(I) species,
which dampens the reactivity and accelerates the rate of
[**] We are grateful to the NSF (CAREER-CHE-0844602 and CHE-
1228336) and the NSFC (21228204) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310142.
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decomposition.[10] Furthermore, sulfoxides have been used as
the O nucleophile in promoting similar alkyne addition
reactions that involve gold carbenoid intermediates.[11] We
envisioned that the sulfinic acid might be a suitable nucleo-
phile for gold(I)-catalyzed reactions, because 1) the sulfur
atom of sulfinic acid is less basic, so that the sulfinic acid
should not form a stable complex with the cationic gold(I)
species, 2) the pKa (ca. 3)[12] of sulfinic acid is similar to that of
carboxylic acids and phosphoric acids, which are suitable
substrates for such addition processes,[13] and 3) the gold(I)–
alkyne complex will likely prefer S addition over O addition
because of its soft nature. We commenced our investigations
with the evaluation of various p-philic Lewis acids using p-
toluenesulfinic acid (1a) and phenylacetylene (2a) as the
starting materials.
promoted the desired transformation much more efficiently
(60%; entry 11). This strongly implies that the yield is directly
related to the ligand used. We then turned our attention to an
even bulkier and more electron-rich ligand, namely 2-
(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-
1,1’-biphenyl (BrettPhos), which was introduced to homoge-
nous gold catalysis by Zhang and co-workers.[14] An even
higher yield (76%; entry 12) was obtained with [Brett-
PhosAuCl]/AgSbF6. This is presumably due to the fact that
steric congestion, which is imposed by the bulky substituents,
stabilizes the cationic gold center, thus preventing decom-
position. Encouraged by our recent finding that the 1,2,3-
triazole gold complex is thermally stable, yet less reactive, we
synthesized [BrettPhosAu(TA)]OTf (TA = 1H-benzotria-
zole).[15] As expected, it gave a much slower reaction rate
(entry 13). However, the addition of Ga(OTf)3 as an external
additive substantially accelerated the rate of the reaction,[16]
giving the desired product in 80% yield. Increasing the gold/
gallium ratio from 1:1 to 1:2 led to 91% yield. Control
experiments showed that Ga(OTf)3 alone could not catalyze
this reaction, which rules out the possibility that the alkyne
was activated by the GaIII center.
As shown in Table 1, [Ph3PAuCl]/AgX gave the best result
(11%; entry 1); after six hours at room temperature, no
further reaction was observed. Other p acids, such as PtCl2,
AuCl3, Ga(OTf)3, and In(OTf)3, did not promote this reaction
Table 1: Optimization of the reaction conditions.[a]
With the optimized conditions in hand, we embarked on
the evaluation of the substrate scope (Table 2). Distinct
reactivities were observed with different alkynes. First,
various aromatic alkynes were tested and gave the corre-
sponding products in modest to good yields. The electronic
effect of substituents at the para position of the aryl acetylene
was evaluated (entries 1–5). The reaction tolerated both
electron-withdrawing (3bc, 3be) and electron-donating
groups (3bb, 3bd). Aromatic alkynes with substituents at
the meta and ortho positions (3bf–3bh) also gave the vinyl
sulfones in good yields. Heteroaromatic alkynes could also be
used as coupling partners in this transformation (3bi, 3bj).
Impressively, an enyne underwent this transformation to give
the desired diene sulfone 3bk, demonstrating the mildness of
the reaction conditions. Aliphatic alkynes generally led to the
corresponding vinyl sulfones in modest yield (35–45%) at
room temperature. Better yields were obtained by employing
harsher conditions (3al–3ap; see the Supporting Informa-
tion). Unfortunately, internal alkynes were not suitable
substrates for this transformation.[17] Notably, 1-trimethyl-
silyl-1-propyne afforded the corresponding a-methyl vinyl
sulfone 3an, which must otherwise be synthesized from
propyne gas. Moreover, amino acid derivative 3bq, estrone
derivative 3br, and cholesterol derivative 3as were also
successfully prepared, which highlights the good functional
group tolerance and potential applications of this method.
The regioselectivity of the nucleophilic addition was first
confirmed by 1H NMR analysis and later unequivocally
established by X-ray crystallography (3bh).[18] It should be
noted that some products have small amounts of impurities in
the NMR spectra because of their relatively poor stability. In
these cases, NMR yields are given.
Entry
Catalyst
(mol%)
Additive
(mol%)
Time
[h]
Yield[c]
[%]
1
2
3
4
5
6
7
8
[Ph3PAuCl]/AgOTf (5)
PtCl2 (10)
AuCl3 (10)
Ga(OTf)3 (10)
In(OTf)3 (10)
–
–
–
–
–
–
–
–
–
–
–
–
6
18
18
18
18
18
6
6
6
6
6
11
0
0
0
0
AgSbF6 (10)
6
[Ph3PAuCl]/AgBF4 (5)
[Ph3PAuCl]/AgSbF6 (5)
[Ph3PAuNTf2] (5)
[IPrAuCl]/AgX (5)
[XPhosAuCl]/AgX (5)
[BrettPhosAuCl]/AgX (5)
[BrettPhosAu(TA)]OTf (5)
[BrettPhosAu(TA)]OTf (5)
[BrettPhosAu(TA)]OTf (5)
14
18
13
ꢀ25
ꢀ60
ꢀ76
32
80
91
9
10[b]
11[b]
12[b]
13
14
15
6
6
6
6
–
Ga(OTf)3 (5)
Ga(OTf)3 (10)
[a] Reaction conditions: 1a (0.2 mmol), 2a (1.4 equiv), gold catalyst
(5 mol%), and additive (if applicable) in dry DCE (0.8 mL) under argon
atmosphere. [b] XÀ =TfOÀ, Tf2NÀ, SbF6À. [c] The yield was determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal
standard. DCE=1,2-dichloroethane, TA=1H-benzotriazole, Tf=tri-
fluoromethanesulfonyl.
at all (entries 2–5). A small amount of product was formed in
the presence of AgSbF6 (10 mol%) after a prolonged reaction
time (18 h). Encouraged by these results, we then tried to
optimize the reaction by screening silver salts with different
counteranions (entry 7–9). Unfortunately, no significant
changes were observed. When a more strongly electron-
donating N-heterocyclic carbene was employed as the ligand,
the yields improved slightly, but were still unsatisfactory (up
to 25%; entry 10). The bulky and electron-rich ligand 2-
dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (XPhos)
To fully evaluate this method, different sulfinic acids were
tested. In practice, however, the unstable sulfinic acids rapidly
decompose through an undesired oxidation, which largely
limits their synthetic utility. To develop a robust synthetic
method, bench-stable sodium benzenesulfinate was employed
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Table 2: Alkyne scope.[a]
Scheme 2. One-pot synthesis of vinyl sulfone 3ba from bench-stable
sodium benzenesulfinate (4b). [a] Yield determined by 1H NMR spec-
troscopy with 1,3,5-trimethoxybenzene as the internal standard.
Table 3: Sulfinic acid scope.[a]
[a] General reaction conditions: 4 (0.2 mmol), TFA (0.24 mmol), 2a
(0.3 mmol), [BrettPhosAu(TA)]OTf (5 mol%) and Ga(OTf)3 (10 mol%)
in DCE (0.8 mL), argon atmosphere, 458C. Yields of isolated products
are given. [b] Yields determined by 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as the internal standard. [c] 1a was used instead of
sodium sulfinate and TFA; reaction run at RT.
[a] General reaction conditions: 1b (0.2 mmol), 2 (0.4 mmol), [Brett-
PhosAu(TA)]OTf (5 mol%), and Ga(OTf)3 (10 mol%) in DCE (0.8 mL)
under argon atmosphere. Yields of isolated products are given. See the
Supporting Information for detailed conditions. [b] Yields determined by
1H NMR spectroscopy with 1,3,5-trimethoxybenzene as the internal
standard. [c] Contains <5% of an impurity. [d] [BrettPhosAuNTf2] was
used. [e] Ga(OTf)3 (20 mol%) and [BrettPhosAu(TA)]OTf (10 mol%).
[f] Ga(OTf)3 (30 mol%) and [BrettPhosAu(TA)]OTf (15 mol%).
the benzene ring allows for further derivatization through
transition-metal-catalyzed cross-coupling reactions. A heter-
ocyclic sulfinic acid was also a successful substrate for this
transformation (3 fa). Aliphatic sulfinic acids gave the corre-
sponding vinyl sulfones in slightly lower yields (3ga–3ia).
The synthetic utility of a-substituted vinyl sulfones still
remains underexplored because of the paucity of these
compounds. However, their close resemblance to b-substi-
tuted vinyl sulfones and disubstituted vinyl sulfones suggests
potential applications of these compounds in cycloaddition
reactions, Michael addition, and desulfonylation with differ-
ent regioselectivity. Furthermore, this method provides a con-
cise and regioselective synthesis of 2-sulfonyl dienes, a val-
uable synthon in organic synthesis.[19] The Diels–Alder
reaction[20] of 3bk and N-methyl maleimide afforded the
tricyclic ring system with excellent endo selectivity
(Scheme 3). The product stereochemistry was confirmed by
as a suitable precursor to generate the corresponding sulfinic
acid in situ in the presence of a stoichiometric amount of acid.
Bearing this idea in mind, different acids were screened in the
presence of the gold and gallium catalysts (Scheme 2).
Trifluoroacetic acid (TFA) was found to be the best choice
of acid, giving the desired product in 91% yield (determined
by NMR spectroscopy) through this one-pot procedure. The
addition of methanesulfonic acid (MsOH) gave the product in
only modest yield, whereas acetic acid did not promote this
reaction at all.
Therefore, a practical one-pot synthesis of vinyl sulfones
has been developed. We then evaluated the scope of sulfinic
acids. Several commercially available sodium sulfinates were
examined (Table 3). In general, substituted benzenesulfinates
gave promising yields (3aa–3ea). The halogen substituent on
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À
Keywords: C S bond formation · gold · Lewis acids ·
Markovnikov addition · vinyl sulfones
.
À
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Information for details).
As mentioned earlier, our initial impetus to develop this
method was to provide a general method for the synthesis of
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gave the Michael adduct in almost quantitative yield at room
temperature. In sharp contrast, the b-substituted vinyl sulfone
gave no conversion at all under the same set of conditions.
This result suggests that the a-substituted vinyl sulfone may
find applications in biological science as a valuable counter-
part to the widely used b-substituted vinyl sulfones
(Scheme 4).
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À
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Revised: February 5, 2014
Published online: && &&, &&&&
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C S Bond Formation
Y. Xi, B. Dong, E. J. McClain, Q. Wang,
T. L. Gregg, N. G. Akhmedov,
J. L. Petersen, X. Shi*
&&&& — &&&&
À
Gold-Catalyzed Intermolecular C S Bond
Formation: Efficient Synthesis of a-
Substituted Vinyl Sulfones
Less basic, less hindered: The gold-
catalyzed intermolecular Markovnikov
addition of sulfinic acids to terminal
alkynes has been achieved through the
use of a bimetallic gold/gallium catalyst
system. Various a-substituted vinyl sul-
fones were efficiently synthesized. A one-
pot synthesis that starts from the bench-
stable sodium sulfinates was also devel-
oped (DCE=1,2-dichloroethane).
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!