Sulfonium Ylides by (3+2) Cycloaddition of Arynes with Vinyl Sulfides: Stereoselective Synthesis of Highly Substituted Alkenes

Article abstract of DOI:10.1002/anie.201608144

The reaction of in situ generated arynes with vinyl sulfides provides benzannulated sulfonium ylides in a (3+2) cycloaddition. Trapping of the intermediate ylides with electrophiles (proton transfer or a second aryne addition) and subsequent β-elimination give rise to di-, tri-, or tetrasubstituted alkenes with high stereoselectivity. Experimental studies and DFT calculations provide insight into the mechanisms of these cascade reactions.

Full text of DOI:10.1002/anie.201608144

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608144
German Edition: DOI: 10.1002/ange.201608144
Sulfur Ylides
Sulfonium Ylides by (3+2) Cycloaddition of Arynes with Vinyl
Sulfides: Stereoselective Synthesis of Highly Substituted Alkenes
Yuanming Li, Christian Mꢀck-Lichtenfeld, and Armido Studer*
Abstract: The reaction of in situ generated arynes with vinyl
sulfides provides benzannulated sulfonium ylides in
a (3+2) cycloaddition. Trapping of the intermediate ylides
with electrophiles (proton transfer or a second aryne addition)
and subsequent b-elimination give rise to di-, tri-, or tetrasub-
stituted alkenes with high stereoselectivity. Experimental
studies and DFT calculations provide insight into the mech-
anisms of these cascade reactions.
We herein report that vinyl thioethers lacking a-CH
protons react with benzyne through direct (3+2) cycloaddi-
tion to give sulfonium ylides, which, upon proton transfer and
b-elimination, afford the corresponding trisubstituted alkenes
with high stereoselectivity (Scheme 1c). We will also discuss
mechanistic experiments and computational studies on this
sequence (see Scheme 6 and Figure 1). The herein reported
cycloaddition represents a conceptually novel approach to the
direct generation of sulfonium ylides. Furthermore, depend-
ing on the vinyl substituents in the starting sulfide, the
intermediate sulfonium ylide can react with a second aryne to
eventually give, after proton transfer and b-elimination,
tetrasubstituted alkenes[12] with high stereocontrol.
We commenced our studies with (Z)-3-(phenylthio)acry-
late 2a and ortho-silyl aryl triflate 1a[3a] as the aryne precursor
(Scheme 2). After an intensive screening of reaction condi-
tions (see the Supporting Information), we found that the best
result was achieved upon reacting 1a (1.2 equiv) with 2a
(1 equiv) in the presence of CsF (2.4 equiv) and H2O
(2 equiv) in CH3CN at 808C for 14 h. Product 3a was isolated
in 63% yield, and 27% of unreacted 2a could be recovered.
Interestingly, in the absence of water, the yield significantly
decreased (43%),[13] and a larger-scale synthesis (4 mmol)
gave 3a in 63% yield.
Arynes have recently gained great attention in organic
synthesis,[1,2] also because reliable procedures for clean aryne
generation have been introduced.[3] Valuable synthetic meth-
ods that utilize arynes have been developed,[4,5] and aryne
chemistry has also found application in natural product
synthesis.[6] Owing to their low-lying LUMO, arynes react
with various anionic and neutral nucleophiles. Moreover, they
are known to insert into various s-bonds to afford ortho-
disubstituted arenes (Scheme 1a).[7] Surprisingly, the reaction
of arynes with thioethers as nucleophiles has not been well
investigated.[8,9] For example, it has been shown that for alkyl
thioethers bearing a-CH protons, the initial aryne adduct
zwitterions undergo fast intramolecular 1,4-proton transfer to
generate sulfonium ylides[10] (Scheme 1b), which further react
to yield valuable products.[9a,11]
Scheme 2. Reaction of 1a with various vinyl sulfides. Tf=trifluorome-
thanesulfonyl, TMS=trimethylsilyl.
Scheme 1. Benzyne s-bond insertion and reactions with thioethers.
[*] Y. Li, Dr. C. Mꢀck-Lichtenfeld, Prof. Dr. A. Studer
Westfꢁlische Wilhelms-Universitꢁt
Under the optimized reaction conditions, the vinyl sulfide
was varied while still using 1a as the benzyne precursor. The
stereochemistry of the vinyl sulfide did not influence the
reaction outcome, and sulfides 2b–o were used either as the
pure Z isomer, as an E/Z mixture, or as the pure E isomer (see
the Supporting Information). Varying the ester substituent
did not change the reaction outcome to a large extent, and the
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢀnster (Germany)
E-mail: studer@uni-muenster.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201608144.
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targeted products 3b (ethyl ester) and 3c (tert-butyl ester)
were obtained in yields of 50% and 60%, respectively.
Slightly lower yields were achieved with amide- and ketone-
functionalized sulfides (3d–f), and a trifluoromethylated vinyl
sulfide provided the desired product 3g in 55% yield.
However, with the phenyl-substituted congener, only small
quantities of thioether 3h were formed, and PhSPh was
obtained as the major product (see the Supporting Informa-
tion).
3-tert-butylbenzyne and 3-triethylsilylbenzyne[14] afforded 3u’
and 3v’ as the major isomers with 7:1 regioselectivity.[15]
Next, trisubstituted vinyl sulfides (2p–t) were investigated
in the reaction with benzyne (Scheme 4). Pleasingly, the
reaction of b-phenylthiylcrotonic acid ester 2p with 1a
provided trisubstituted alkene 4a in 50% yield with complete
Z selectivity. Excellent selectivity was also achieved with the
hexyl- and sec-butyl-substituted acrylates 2q and 2r to give 4b
and 4c. The cinnamic acid ester 2s afforded the targeted
product 4d in good yield but with low Z selectivity. A CF3
substituent (2t) is tolerated at the b-position to give 4e in
good yield (71%) with moderate E selectivity under the
optimized reaction conditions.[16]
We then investigated the effect of the R1 substituent by
replacing the phenyl group in 2a with different aryl groups or
a tert-butyl group (2i–o). Aryl substituents bearing electron-
donating groups were tolerated (3i and 3j), and the reaction
also worked with the sterically hindered, electron-poorer
ortho-bromophenyl sulfide 2l, although the product was
obtained in slightly lower yield (3l). However, with vinyl
sulfide 2m, which bears a pentafluorophenyl group, the
targeted product was not detected, and 2m was recovered in
77%. This is likely due to its reduced sulfur nucleophilicity.
The sterically hindered 2,6-dimethylphenyl-substituted sul-
fide 2n provided alkene 3n in 50% yield whereas tert-butyl
sulfide 2o gave the desired product 3o in low yield (19%). As
the major product, 3a was isolated in 31% yield. Obviously,
3o further reacted with benzyne to give 3a through adduct
À
formation, 1,4-proton transfer, and subsequent C S bond
cleavage upon isobutylene release.
We continued our studies by investigating the scope with
respect to the aryne component, also addressing the regio-
chemistry with unsymmetric arynes. All reactions were
conducted with vinyl sulfide 2a (Scheme 3). Symmetric
arynes, such as 2,3-naphthalyne, 2,3-dimethoxybenzyne, and
2,3-dimethylbenzyne, provided the desired products 3p–r in
moderate yields. Reactions with unsymmetric arynes, such as
3-methylbenzyne and 3-methoxybenzyne, occurred with low
regioselectivity to give the corresponding products 3s/3s’ and
3t/3t’ in 76% and 60% yield, respectively (after isolation).
Increasing the size of the 3-substituent in the intermediate
aryne led to significantly improved regioselectivity. Hence,
Scheme 4. Preparation of trisubstituted alkenes.
Surprisingly, we noted a different reaction outcome for
a-ester- and a-acyl-substituted vinyl sulfides 2u–aa
(Scheme 5). Under the optimized reaction conditions, the
reaction of in situ generated benzyne with (Z)-phenylthiyl-
maleic acid dimethyl ester (2u) gave the tetrasubstituted
Z alkene 5a (24%) along with the expected trisubstituted
alkene. Further optimization (see the Supporting Informa-
tion) revealed that this transformation is best conducted in
the absence of water using 2.2 equiv of 1a at 808C for 14 h,
enabling the isolation of 5a in 66% yield. When the S-phenyl
substituent in 2u was replaced with para-methoxy (2v) or
para-fluorophenyl substituents (2w), the corresponding
alkenes 5b and 5c were obtained in good yields (65 and
76%). Vinyl sulfides 2u, 2v, and 2w were used as Z isomers.
To investigate the influence of the substrate stereochemistry
on the reaction outcome, the reaction of benzyne was
repeated with (E)-2v. Alkene 5b was isolated in 77% yield
with complete Z selectivity, showing that the reaction is not
stereospecific. tert-Butyl maleic ester 2x provided 5d in 71%
yield. The vinyl sulfide can also be activated with two benzoyl
groups as shown by the preparation of alkene 5e from 2y, and
the starting maleic esters can bear two different ester groups
to give an alkene with four different substituents with
complete stereocontrol (5 f). Along these lines, ketoester 5g
was stereoselectively prepared. The reaction with (Z)-phenyl-
thiylmaleic acid dimethyl ester (2u) was also conducted with
3,4-dimethoxybenzyne to give 5h, showing that the aryne
component can be readily varied.
Scheme 3. Reaction of 2a with various arynes.
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Scheme 5. Preparation of tetrasubstituted alkenes.
To gain insight into the mechanism, the reactions of
benzyne with 2p and 2v were repeated using the correspond-
ing deuterated sulfides 2p-D and 2v-D (Scheme 6). When
2p-D was employed under the optimized conditions (2 equiv
of H2O), product 4a was isolated in 47% yield with only 15%
deuterium incorporation. The deuterium content was close to
zero upon running the same reaction in the presence of
5 equiv water, revealing that H2O is the proton source in this
cascade process and that intramolecular proton transfer can
be ruled out. This was further supported by calculations,
which determined the 1,2-proton transfer to have a high
barrier (35 kcalmolÀ1; see the Supporting Information).[17]
With substrate 2v-D, we obtained product 5b-D with 94%
deuterium incorporation in 66% yield, revealing that intra-
molecular proton transfer had occurred. Based on these
studies, we suggest the following mechanism. As will be
further supported by DFT calculations (see below), the vinyl
sulfide reacts with benzyne in a (3+2) cycloaddition[18] to
yield intermediate A. In the presence of H2O for R = H, alkyl,
or aryl, A is protonated to sulfonium salt B. Protonation
occurs diastereoselectively anti to the CO2Me substituent.[19]
A hydroxide anion then acts as the base in the anti
b-elimination that yields 3 and cis-4. Ylides A bearing ester
or acyl R substituents are trapped by benzyne to give
zwitterionic C. The trapping occurs diastereoselectively anti
to the shielding ester group. This also explains why E and
Z vinyl sulfides or mixtures thereof deliver the same product
isomer. Intramolecular 1,4-proton transfer and subsequent
b-elimination give the tetrasubstituted cis alkenes 5, as
supported by the deuterium labeling experiments.
Scheme 6. Mechanistic experiments and proposed mechanism.
TZVP + COSMO; see the Supporting Information for
details). It was found that the formation of the two bonds
occurs in an asynchronous fashion for both isomers
À
(Figure 1). Despite the initial formation of the C S bond,
the reaction is concerted, that is, no other intermediates were
found along the reaction path. The free energy barrier is very
low (7.3 kcalmolÀ1 for (Z)-2a and 8.9 kcalmolÀ1 for (E)-2a),
and is dominated by entropic contributions. This is in line with
the highly reactive nature of the aryne. Owing to the
pyramidal geometry of the sulfur atom, sulfur ylide A can
be formed as the cis or trans isomer, and the isomers have
a free energy barrier of interconversion that is too high for
isomerization (35 kcalmolÀ1, see the Supporting Informa-
tion).
The selectivity of the initial cycloaddition with (E)-2a is
À
controlled by the conformation around the C SPh s-bond.
Overall, we found four conformers of (E)-2a with similar
energies leading to similar transition-state energies, with two
transition states leading to cis S-ylide A and the two other
The suggested initial (3+2) cycloaddition of benzyne with
vinyl sulfide 2a (E and Z isomers) was also studied
theoretically by DFT calculations (PW6B95-D3/def2-
Figure 1. Transition states of the (3+2) cycloaddition of 1,2-benzyne
with (E)-2a (left) and (Z)-2a (right).
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energy TS leading to cis S-ylide A is depicted; see the
Supporting Information for all other transition states). Hence,
the initial cycloaddition is not stereoselective.[19] In contrast,
for substrate (Z)-2a, we found a major conformer reacting via
the lowest-energy TS that leads stereoselectively to trans
S-ylide A (Figure 1).
In summary, we have introduced a new approach for the
direct generation of sulfonium ylides from in situ generated
arynes and aryl vinyl sulfides. The sulfonium ylides can either
be protonated or trapped with a second equivalent of the
aryne, which results in highly substituted alkenes. In our eyes,
the chemistry presented herein is not only interesting in terms
of the new reactivity (a new approach to the direct generation
of sulfur ylides), but it is also valuable for the preparation of
highly substituted alkenes in stereoisomerically pure form.
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We thank Dr. Klaus Bergander for NMR analysis and Dr.
Shyamal Chakrabarty for providing us with some of the
triflates used. This work was financially supported by the
China Scholarship Council (stipend to Y.L.) and the Deutsche
Forschungsgemeinschaft (DFG).
Keywords: alkenes · arynes · cycloaddition · sulfonium ylides ·
synthetic methods
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[15] Only the major isomer was isolated, and the ratio was
determined by 1H NMR analysis of the crude product. The
selectivity for the silyl derivative can be understood in terms of
the distortion model (Ref. [14]), and the selectivity for the tert-
butylated aryne is controlled by steric effects assuming the SPh
group to be sterically less demanding than the ester moiety.
[16] The E selectivity increased to 14:1 when the 3.4:1 mixture was
stirred under the standard conditions for 12 h, indicating
isomerization of 4e, whereas in the case of 4d, the Z/E
selectivity did not change (see the Supporting Information).
[17] In the absence of H2O, CH3CN might act as a proton donor as
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[19] Protonation or aryne addition always occurs trans to the ester
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À
À
lengths of C C compared to C S bonds, the ester group is much
closer to the reacting carbon atom than the S-phenyl substituent,
and therefore, for trans S-ylide A, the ester group is a much
better shield for the incoming electrophile than the S-phenyl
group.
Received: August 20, 2016
Published online: && &&, &&&&
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Sulfur Ylides
Y. Li, C. Mꢁck-Lichtenfeld,
A. Studer*
&&&& — &&&&
Sulfonium Ylides by (3+2) Cycloaddition
of Arynes with Vinyl Sulfides:
Stereoselective Synthesis of Highly
Substituted Alkenes
A new approach to sulfur ylides: The
(3+2) cycloaddition of arynes and vinyl
sulfides represents a conceptually novel
approach to the direct generation of
sulfonium ylides, which further react to
yield highly substituted alkenes with
excellent stereoselectivity (see scheme).
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www.angewandte.org
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