A new class of organocatalysts: Sulfenate anions

Article abstract of DOI:10.1002/anie.201405996

Sulfenate anions are known to act as highly reactive species in the organic arena. Now they premiere as organocatalysts. Proof of concept is offered by the sulfoxide/sulfenate-catalyzed (1-10 mol%) coupling of benzyl halides in the presence of base to generate trans-stilbenes in good to excellent yields (up to 99%). Mechanistic studies support the intermediacy of sulfenate anions, and the deprotonated sulfoxide was determined to be the resting state of the catalyst. Sulfenates take center stage: Sulfenate anions are known as highly reactive species in the organic arena. Now they premiere as organocatalysts: A sulfoxide/sulfenate (1-10 mol%) promotes the transformation of benzyl halides into trans-stilbenes under basic conditions (up to 99% yield). CPME=cyclopentyl methyl ether.

Full text of DOI:10.1002/anie.201405996

Angewandte
Chemie
DOI: 10.1002/anie.201405996
Organocatalysis
Hot Paper
A New Class of Organocatalysts: Sulfenate Anions**
Mengnan Zhang, Tiezheng Jia, Haolin Yin, Patrick J. Carroll, Eric J. Schelter, and
Patrick J. Walsh*
Abstract: Sulfenate anions are known to act as highly reactive
species in the organic arena. Now they premiere as organo-
catalysts. Proof of concept is offered by the sulfoxide/sulfenate-
catalyzed (1–10 mol%) coupling of benzyl halides in the
presence of base to generate trans-stilbenes in good to excellent
yields (up to 99%). Mechanistic studies support the interme-
diacy of sulfenate anions, and the deprotonated sulfoxide was
determined to be the resting state of the catalyst.
Scheme 1. Palladium promotes the conversion of aryl benzyl sulfoxides
into diaryl sulfoxides, which proceeds through three catalytic cycles;
a sulfenate anion acts as the leaving group in cycle B and as a nu-
cleophile in cycle C.
I
n recent years, sulfenic acids and their conjugate bases,
sulfenate anions (Figure 1), have gone from chemical curi-
osities to important intermediates in biological and synthetic
chemistry.[1–5] Small-molecule sulfenic acids are highly reac-
tive and difficult to isolate unless they are sterically protected
or stabilized by hydrogen bonds.[6] Likewise, the conjugate
bases of sulfenic acids, sulfenate anions, are highly reactive
intermediates,[7] which have been generated and trapped in
a number of organic and metal-catalyzed processes.[8] Despite
their versatility, we are unaware of prior examples of small-
molecule sulfenate anions that were employed as catalysts.
Herein, we introduce sulfenate anions as organocatalysts and
demonstrate their catalytic ability in the conversion of benzyl
halides into trans-stilbenes.[9]
to behave as nucleophiles and leaving groups in this process,
we hypothesized that sulfenate anions could be organocata-
lysts and set out to test this hypothesis. We proposed the
sulfenate-anion-catalyzed coupling of benzyl halides to form
symmetric stilbenes, which is depicted in Scheme 2.
Figure 1. Sulfenic acid and its conjugate base, the sulfenate anion.
Scheme 2. Proposed mechanism of the sulfenate-anion-catalyzed cou-
pling of benzyl halides to form symmetric stilbenes.
For the present work, we were inspired by our recent
development of a palladium-catalyzed conversion of aryl
benzyl sulfoxides into diaryl sulfoxides, wherein the palla-
dium species drives three distinct catalytic cycles
(Scheme 1).[10] The key intermediate in this process was the
sulfenate anion ArSOÀ, which was the leaving group in
cycle B and underwent transmetalation in cycle C, ultimately
The starting point for our proof-of-concept reaction is
benzylic sulfoxide A (Scheme 2). Under basic conditions,
benzylic sulfoxides can be deprotonated at the a-position, and
the resulting sulfoxide anion B reacts with the benzyl halide to
generate sulfoxide D. Deprotonation at the b-position of D
was envisioned to promote an E2 elimination generating
trans-stilbene while expelling the sulfenate anion catalyst.
Sulfenate anions are known to undergo nucleophilic substi-
tution with benzyl halides,[11] regenerating sulfoxide A and
completing the catalytic cycle. The sulfenate anion F is the
smallest structural unit carried through this catalytic cycle.
We initiated a search for conditions for the sulfenate-
anion-catalyzed synthesis of trans-stilbene from benzyl chlo-
ride by screening six bases, namely, LiOtBu, NaOtBu, KOtBu,
LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2, in the presence
of benzyl phenyl sulfoxide (10 mol%) in cyclopentyl methyl
ether (CPME) as the solvent at 808C (Table 1, entries 1–6).
À
forming a C S bond. Based on the ability of sulfenate anions
[*] M. Zhang, T. Jia, H. Yin, P. J. Carroll, Prof. E. J. Schelter,
Prof. P. J. Walsh
Roy and Diana Vagelos Laboratories
Penn/Merck Laboratory for High-Throughput Experimentation
Department of Chemistry, University of Pennsylvania
231 S. 34thSt., Philadelphia, PA 19104-6323 (USA)
E-mail: pwalsh@sas.upenn.edu
Homepage: https://sites.google.com/site/titaniumupenn/
[**] We thank the National Science Foundation [CHE-0848460 (GOALI)
and 1152488] for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405996.
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Table 1: Optimization of the formation of stilbene (2a) from benzyl
chloride (1a).[a]
benzyl chlorides and bromides were available, reactions were
performed with both substrates. Benzyl chlorides were more
suitable than benzyl bromides, because the latter substrates
more readily undergo SN2 reactions with the base to generate
benzyl tert-butyl ethers. To favor the catalytic reaction and
diminish the background ether formation, the sulfoxide
loading was increased to 5 mol% in some cases. Benzyl
chloride and bromide gave trans-stilbene 2a in 95% and 81%
yield, respectively. Benzyl halides with alkyl groups on the
arene gave the corresponding products in reasonable to very
good yields (62–92%; products 2b, 2c, and 2k). More
sterically hindered benzyl chloride derivatives, for example
with a methyl substituent in the 2-position (2h, 92%) or with
a naphthyl framework (2i, 80%), also proved to be good
substrates.
Electron-rich 4-methoxybenzyl chloride was found to be
a difficult substrate, providing stilbene 2d in only 31% yield.
This may be due to the decreased acidity of the benzyl
sulfoxide intermediate. In contrast, substrates bearing halides
gave the corresponding products in good to excellent yields
(61–99%). Benzyl chlorides with fluorine substituents in the
2-, 3-, or 4-position underwent the catalytic coupling to afford
stilbenes 2g, 2l, and 2e in 73–89% yield. 4,4’-Dichlorostil-
bene (2 f) was produced from the corresponding benzyl
chloride in 99% yield, and 2,6-dichlorobenzyl chloride gave
tetrachlorostilbene 2j in 88% yield. A benzyl bromide with
a trifluoromethyl substituent in the 3-position led to 2m in
68% yield, when the amount of KOtBu was decreased to
2.0 equivalents.
Entry
Base
Solvent
Catalyst [mol%]
2a[b] [%]
1
2
3
4
5
6
7
8
LiOtBu
NaOtBu
KOtBu
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
Toluene
THF
Dioxane
DME
DCE
CPME
CPME
CPME
CPME
10
10
10
10
10
10
5
2.5
1
1
1
1
1
1
2.5
2.5
2.5
0
0
45
>98
41
51
81
100
100 (95)
74
57
45
33
23
0
88
14
92
0
9
10
11
12
13
14
15[c]
16[d]
17[e]
18
[a] Reactions conditions: 1a (0.1 mmol, 1.0 equiv), base (3.0 equiv),
808C. [b] Yield determined by NMR spectroscopy using CH2Br2 as an
internal standard. Yield of isolated product given in parentheses. [c] Base
(2.0 equiv). [d] 508C. [e] 1a (0.2 mmol). DCE=1,2-dichloroethane,
DME=1,2-dimethoxyethane.
Table 2: Substrate scope of the sulfenate-anion-catalyzed formation of trans-
Yields of stilbene 2a as determined by 1H NMR
spectroscopy ranged from 0% (LiOtBu, entry 1) to
100% (KOtBu, entry 3). The use of amide bases,
such as MN(SiMe3)2, led to decomposition of the
starting materials (entries 4–6). Lowering the cata-
lyst loading to 5 or 2.5 mol% of benzyl phenyl
sulfoxide led to 2a in quantitative NMR yield
(entries 7 and 8). Further reduction of the catalyst
loading to 1 mol% still gave a good yield (74%,
entry 9). The use of five solvents under the con-
ditions described in entry 9 gave 2a in lower yields
than with CPME (entries 10–14). Using 2.5 mol% of
the sulfoxide and decreasing the amount of base to
less than 3.0 equivalents or lowering the reaction
temperature to below 808C resulted in a diminished
NMR yield of 2a (entries 15 and 16). An attempt to
increase the reaction concentration from 0.1m to
0.2m resulted in a slightly decreased yield (92%),
which is due to the formation of benzyl tert-butyl
ether (entry 17).[12] When the reaction was con-
ducted under the conditions of entry 8 in the absence
stilbenes from benzyl halides.[a]
Product
R
X
Yield [%]
Product
R
X
Yield [%]
2a
2a
2b
2b
2c
2d
2e
2e
2 f
H
H
4-Me
4-Me
4-tBu
Cl 95
Br 81
Cl 84
Br 62[b]
Br 70[b]
2g
2h
2i
2j
2k
2l
2-F
2-Me
Cl 73
Cl 92
1-naphthyl Cl 80
2,6-Cl2
3-Me
3-F
3-CF3
2-pyridyl
Cl 88
Br 75[b]
Cl 89
4-OMe Cl 31[b]
4-F
4-F
4-Cl
Cl 81
Br 66[b]
Cl 99
2m
2n
Br 68[c]
Cl 54[d]
[a] Reactions conditions: benzyl halide (0.1 mmol), catalyst (2.5 mol%), KOtBu
(0.3 mmol), CPME (1.0 mL). [b] Catalyst (5 mol%). [c] KOtBu (0.2 mmol). [d] KH as
the base, 1108C for 24 hours.
of the sulfoxide, no stilbene was formed (entry 18). Based on
the results in Table 1, our optimized conditions for sulfenate-
anion-catalyzed trans-stilbene formation from benzyl chloride
entail the use of benzyl phenyl sulfoxide (2.5 mol%) and
KOtBu (3.0 equiv) in CPME at 808C for 12 hours.
Heterocyclic stilbene derivatives exhibit interesting pho-
tophysical properties.[13] Under our standard conditions, 2-
(chloromethyl)pyridine (1n) surprisingly did not react. When
a stronger base, namely KH, was used at a higher reaction
temperature (1108C) for a longer reaction time (24 h),
stilbene derivative 2n was generated in 54% yield. Unfortu-
nately, some base-sensitive electron-withdrawing groups, such
With the optimized reaction conditions in hand, the scope
of the transformation was examined (Table 2). When both the
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as nitro, cyano, and trifluoromethyl substituents, were not
tolerated at the 4-position of the benzyl bromide because of
decomposition of the benzyl halides.
To demonstrate the scalability of this organocatalytic
reaction, we performed the synthesis of 2j on a 7.0 mmol scale
with a sulfoxide loading of 2.5 mol% (Scheme 3). The trans-
Scheme 3. Formation of 2,2’,6,6’-tetrachlorostilbene on gram scale.
Scheme 5. Preliminary mechanistic investigations of the sulfenate-
anion-catalyzed stilbene formation.
configured 2,2’,6,6’-tetrachlorostilbene was isolated in 92%
yield, indicating that the reaction is scalable.
Based on the mechanism proposed in Scheme 2, related
precatalysts could be imagined (Scheme 4). The pKa value of
under the standard reaction conditions, trans-stilbene, 4,4’-
dimethyl-trans-stilbene (2b), and 4-methylbenzyl phenyl
sulfoxide (52%) were generated (Scheme 5c), suggesting
that the phenylsulfenate anion is formed from 4a. These
results support the mechanism proposed in Scheme 2.
To investigate the catalyst resting state, we conducted the
reaction using benzyl chloride (1a) at 508C under otherwise
standard conditions. The reaction was quenched with
30 equivalents of water after 30 minutes. Benzyl phenyl
sulfoxide was isolated in 87% yield, suggesting that the
resting state is benzyl phenyl sulfoxide or its conjugate base.
The reaction was then conducted in [D8]THF and monitored
1
by H NMR spectroscopy. No resonances corresponding to
benzyl phenyl sulfoxide were observed. Furthermore, com-
bining benzyl phenyl sulfoxide with KOtBu and monitoring
the reaction by NMR spectroscopy also indicated sulfoxide
deprotonation (see the Supporting Information). These
results are consistent with the relative pKa values of benzyl
phenyl sulfoxide (pKa 27.2 in DMSO) and tert-butanol
(pKa 32.2 in DMSO).[14] These data indicate that the depro-
tonated sulfoxide is the resting state of the catalyst.
Scheme 4. Application of different sulfoxide catalysts.
To further characterize the catalyst resting state, we
deprotonated benzyl phenyl sulfoxide (3a) with KCH2Ph.
Single crystals suitable for a crystallographic study were
obtained after addition of [18]crown-6 and layering with
hexanes.[17] The solid-state structure of the product,
methyl phenyl sulfoxide (3b) is significantly higher than those
of aryl benzyl sulfoxides.[14] A stronger base, such as KH, will
therefore be required to generate the catalyst. The expected
byproduct of catalyst formation, styrene, was observed
(1H NMR spectroscopy). With 5 mol% of methyl phenyl
sulfoxide, stilbene was generated in 92% yield[15a] (Sche-
me 4a). Using 10 mol% of dibenzyl sulfoxide (3c), 2a was
afforded in 92% yield (Scheme 4b). Dimethyl sulfoxide
(DMSO, 3d, 10 mol%), was also a viable precatalyst, afford-
ing 2a in 71% yield[15b] (Scheme 4c).
We next set out to gain insight into the mechanism of the
catalytic coupling. Upon reaction of a stoichiometric amount
of benzyl phenyl sulfoxide (3a) with 1.0 equivalent of benzyl
chloride (1a) under basic conditions, sulfoxide[16] 4a was
observed (2%) along with trans-stilbene (91%, 2a; Sche-
me 5a). When independently synthesized 4a was used as the
catalyst, stilbene (2a) was obtained in 98% yield (Sche-
me 5b), suggesting that sulfoxide 4a is an intermediate of the
catalytic reaction. Furthermore, when 4a was combined with
a stoichiometric amount of 4-methylbenzyl chloride (1b)
=
K([18]crown-6)(THF)[PhS( O)CHPh], was determined to
be monomeric with a potassium cation coordinated to both
the a-carbon and oxygen atoms of the anion (Figure 2). The
sp2 nature of the benzylic carbon atom was evident from the
À
À
short S C bond of 1.691(2) ꢀ, compared to the C S bond
length of 1.837(2) ꢀ that was reported for the benzylic
[18]
=
sulfoxide {2-[(NMe2)CHMe]C6H4}S( O)CH2Ph.
A gas-
phase DFT calculation at the B3LYP/6-31G* level of theory
was performed on the [PhS(O)CHPh]À anion and the
corresponding neutral sulfoxide, PhS(O)CH2Ph (see the
Supporting Information for details). The computed models
À
showed a shortening of the S C(Bn) bond by 0.166 ꢀ and
À
a lengthening of the S O bond by 0.029 ꢀ upon deprotona-
tion. This result, together with the X-ray structure, is
À
supportive of a multiple-bond character of the S C(Bn)
bond in the deprotonated sulfoxide anion.[19]
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[8] For reviews, see: a) J. S. OꢁDonnell, A. L. Schwan, J. Sulfur
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below).
=
Figure 2. Crystal structure of K(18-crown-6)(THF)[PhS( O)CHPh].
Thermal ellipsoids set at 30% probability.
In summary, we hypothesized that sulfenate anions could
act as catalytic intermediates in organocatalytic reactions.
This hypothesis was founded upon their ability to act as both
leaving groups and nucleophiles. As a proof-of-concept
reaction, we developed the base-promoted conversion of
benzyl halides into trans-stilbenes catalyzed by sulfenate
anions. Furthermore, we have shown that a variety of
sulfoxide precatalysts, including DMSO, can promote this
reaction at loadings of 1–10 mol%. Reactivity studies support
the intermediacy of sulfenate anions and provide strong
evidence that the catalyst resting state is the deprotonated
sulfoxide. Based on these studies, we believe that sulfenate
anions have significant potential in organocatalysis. Related
reactions that are catalyzed by this novel class of catalysts are
currently under investigation.
[10] T. Jia, A. Bellomo, S. Montel, M. Zhang, K. El Baina, B. Zheng,
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DMSO, only 80% of the benzyl chloride enters the catalytic
cycle.
Received: June 6, 2014
Published online: && &&, &&&&
Keywords: benzyl halides · organocatalysis · stilbenes ·
.
sulfenate anions · sulfoxides
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=
[19] CCDC 1007043 (K([18]crown-6)(THF)[PhS( O)CHPh]; ex-
cluding structure factors) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4
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Angewandte
Chemie
Communications
Organocatalysis
M. Zhang, T. Jia, H. Yin, P. J. Carroll,
E. J. Schelter, P. J. Walsh*
&&&& — &&&&
A New Class of Organocatalysts:
Sulfenate Anions
Sulfenates take center stage: Sulfenate
anions are known as highly reactive
species in the organic arena. Now they
premiere as organocatalysts: A sulfoxide/
sulfenate (1–10 mol%) promotes the
transformation of benzyl halides into
trans-stilbenes under basic conditions
(up to 99% yield). CPME=cyclopentyl
methyl ether.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!