Reaction of Arynes with Vinyl Sulfoxides: Highly Stereospecific Synthesis of ortho-Sulfinylaryl Vinyl Ethers

Article abstract of DOI:10.1021/acs.orglett.6b03827

The reaction of in situ generated arynes with aryl vinyl sulfoxides provides ortho-arylsulfinylaryl vinyl ethers via aryne σ-bond insertion into the S-O-bond and concomitant stereospecific S-O-vinyl migration. The cascade allows preparing di- or trisubsti

Full text of DOI:10.1021/acs.orglett.6b03827

Letter
pubs.acs.org/OrgLett
Reaction of Arynes with Vinyl Sulfoxides: Highly Stereospecific
Synthesis of ortho-Sulfinylaryl Vinyl Ethers
Yuanming Li and Armido Studer*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraβe 40, 48149 Munster, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: The reaction of in situ generated arynes with
aryl vinyl sulfoxides provides ortho-arylsulfinylaryl vinyl ethers
via aryne σ-bond insertion into the S−O-bond and
concomitant stereospecific S−O-vinyl migration. The cascade
allows preparing di- or trisubstituted vinyl ethers with excellent
stereospecificity. The reactions proceed under mild conditions,
the substrate scope is broad, and the products obtained are valuable.
rynes have received considerable attention, as readily
Scheme 1. Reaction of Benzyne with Vinyl Thioethers or
Vinyl Sulfoxides
A
generated reactive intermediates over the past few years
and many valuable transformations comprising arynes have
been reported.1−3 Notably, meanwhile over 75 natural products
have been successfully synthesized by using arynes as key
intermediates.4
As part of our ongoing research program on aryne
chemistry,5 we recently disclosed that vinyl thioethers lacking
α-CH protons react with benzyne through direct (3 + 2)
cycloaddition to give cyclic sulfonium ylides. Proton transfer
and β-elimination eventually afford the corresponding trisub-
stituted alkenes with high stereoselectivity (Scheme 1a).5d It is
known that dimethyl sulfoxide, used as a solvent, can react with
benzyne to give the (2 + 2) cycloaddition intermediate,6 which
upon cleavage of the S−O bond leads to the corresponding
zwitterionic sulfonium salt. Subsequent intermolecular trapping
of the phenolate by either an electrophile7 or benzyne8 with
concomitant S-CH3 cleavage of the sulfonium salt moiety
affords ortho-alkoxylated arylmethyl thioethers (Scheme 1b).
Recently, Li et al. found that aryl allyl sulfoxides react with
benzyne to provide 1,2,3-trisubstituted arenes via (2 + 2)
cycloaddition, S−O-allyl migration, and subsequent Claisen
rearrangement (Scheme 1b).9 Based on this precedence and
our own contribution, we decided to investigate the reaction of
aryl vinyl sulfoxides with arynes and assumed that such a
transformation can proceed via either initial (2 + 2) or (3 + 2)
cycloaddition (Scheme 1c). Another point of interest was the
follow-up chemistry of the initially generated cycloadduct. We
herein report first results along those lines and will show that
such reactions proceed via the (2 + 2) pathway to provide
ortho-arylsulfinylaryl vinyl ethers as products.
stereospecificity (Table 1, entry 1). As a side product, vinyl
sulfide 4a derived from deoxygenation of 2a was observed in
17% yield as an E/Z-mixture of isomers. Other fluoride sources
such as tetrabutylammonium fluoride (TBAF) or potassium
fluoride in combination with 18-crown-6 provided significantly
lower yields with similar conversions, and side product 4a was
formed in larger quantities (Table 1, entries 2, 3). Notably,
increasing or decreasing the amount of water led to a lower
yield of target 3a (Table 1, entries 4−6). Other additives such
We commenced the studies using methyl (Z)-3-(phenyl-
sulfinyl) acrylate 2a and ortho-silylaryl triflate 1a as reaction
components (Table 1). Transformations were conducted in
acetonitrile, and various fluoride sources to mediate aryne
generation were tested. Water5d was applied as an additive.
Using 1a (1.2 equiv) with CsF (2.4 equiv) and H2O (2 equiv)
in the presence of 2a (1 equiv) in CH3CN at 80 °C for 3 h
provided the Z-product 3a in 50% yield with complete
Received: December 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03827
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction of 1a with 2a under Different
Conditions
Table 2. Reaction of 1a with Various Vinyl Sulfoxides
ab
,
additive
(equiv)
time
(h)
temp
(°C)
3a
(%)
2a
(%)
4a
(%)
entry
F− source
1
2
3
H2O (2)
H2O (2)
H2O (2)
CsF
3
3
3
80
80
80
50
10
32
0
0
0
17
47
28
TBAF
KF/
18-C-6
4
H2O (1)
H2O (3)
H2O (5)
CsF
CsF
CsF
3
3
80
80
80
80
80
55
55
30
22
<5
27
0
0
68
87
0
23
3
5
6
2
0
7
MeOH (2) CsF
AcOH (2) CsF
3
28
28
8
8
3
0
9
H2O (3)
CsF
24
24
65
10
8
10
−
CsF
0
36
a
Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), and F−source
(0.48 mmol) in acetonitrile (2 mL). Yield was determined by H
NMR spectroscopy.
b
1
as methanol and acetic acid turned out to be less efficient to
mediate the cascade (Table 1, entries 7, 8). The yield of 3a was
improved to 65% upon running the reaction at 55 °C in the
presence of 3 equiv of water (Table 1, entry 9). In the absence
of water under otherwise identical conditions the yield of 3a
significantly decreased (10%) and 4a was formed as the major
product (Table 1, entry 10).10 Water is necessary to suppress
formation of the deoxygenation side product 4a (see discussion
below).
a
Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), H2O (0.6
mmol), and CsF (0.48 mmol) in acetonitrile (2 mL) at 55 °C for 24 h
b
c
under an argon atmosphere. Isolated yield. The reaction was
conducted for 48 h. Larger-scale synthesis 2a (1.0 mmol). The
reaction was conducted with H2O (1.8 mmol).
d
e
provided 3j and 3k in 50% yield each. A slightly lower yield was
achieved using the sterically hindered electron-poorer ortho-
bromophenyl sulfoxide (see 3l). With the vinyl sulfoxide 2m
bearing the pentafluorophenyl group, the desired product 3m
was obtained in only 11% yield. The significantly lower yield is
likely due to the reduced O-nucleophilicity of 2m as compared
to its nonfluorinated congener 2a. The sterically hindered but
electron-rich 2,6-dimethylphenyl-substituted sulfoxide 2n pro-
vided vinyl ether 3n in 87% yield. Using the tert-butyl vinyl
sulfoxide 2o, the target product 3o was not formed.
Next, the trisubstituted vinyl sulfoxides 2p−s were
investigated (Scheme 2). The cinnamic acid ester 2p afforded
in the reaction with benzyne the vinyl ether 3p in 50% yield
with complete stereospecificity. However, an α-CF3-substituent
at the vinyl group of the sulfoxide (see 2q) is not tolerated and
the corresponding product 3q was not formed. α-Methyl-β-
To demonstrate functional group compatibility of the
sulfoxide component, vinyl sulfoxides 2b−o were reacted
with in situ generated benzyne under the optimized conditions,
and the results are illustrated in Table 2. Exchanging the ester
functionality in the acrylate moiety by an amide group does not
alter the reaction outcome, and the target product 3b was
isolated in 63% yield. However, with the ketone functionalized
sulfoxide desired compound 3c was not formed. In this reaction
we isolated the corresponding deoxygenated phenyl vinyl
sulfide as the major product.11 To test the stereospecificity of
the cascade, (E)-3-(phenylsulfinyl) acrylate 2d was reacted with
1a and the trans-vinyl ether was obtained with complete
stereoselectivity showing that this process is highly stereo-
specific. We noted that reaction with the trans-vinyl sulfoxide
2d is far slower as compared to the transformation with its cis-
congener 2a, and therefore the reaction time had to be
extended to 48 h. Product 3d was isolated in 46% yield. A
similar yield and complete stereospecificity were also obtained
with the corresponding ethyl ester. This reaction was
conducted at a larger scale (1.0 mmol) to provide 3e in 48%
yield. The trifluoromethylated vinyl sulfoxide 2f provided the
desired product 3f in 52% yield. Target products (3g−i) were
not formed with the phenylvinyl, methoxyvinyl, and vinyl
sulfoxide 2g−i showing that the activating substituent at the β-
position of the vinyl group in the sulfoxide is of key importance
for a successful reaction outcome.
Scheme 2. Reaction of Benzyne with Trisubstituted Vinyl
Sulfoxides 2p−s
The effect of the R1-substituent in the sulfoxide component
was examined by replacing the phenyl group in 2a with
different aryl groups or by the tert-butyl group (2j−o). Reaction
of the naphthyl and the p-methoxyphenyl sulfoxide with 1a
B
DOI: 10.1021/acs.orglett.6b03827
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Organic Letters
Letter
deutero-substituted vinyl sulfoxide 2r afforded the desired
product 3r in 45% yield keeping 96% deuterium incorporated.
Importantly, β-alkyl-substituents at the vinyl moiety are
tolerated as documented by the successful transformation of
the β-allylvinyl sulfoxide 2s to give 3s in 44% yield with
complete stereospecificity.
Scheme 5. Mechanistic Experiments and Suggested
Mechanism
We continued the studies by investigating substituted aryne
precursors to address the regiochemistry of the cascade with
respect to the intermediate aryne (Scheme 3). Reaction with
Scheme 3. Reaction of 2a with Various in Situ Generated
Arynes
the unsymmetrical arynes, 3-triethylsilyl benzyne and 3-
methoxybenzyne, occurred with complete regioselectivity to
provide the corresponding products 3t and 3u in 80% and 75%
isolated yield, respectively. The other regioisomers 3t′ and 3u′
were not identified in the mixture. The selectivity can be
understood considering the aryne distortion model which
shows that regioselectivity in the initial cycloaddition is
dominated by inherent distortion present in these two
unsymmetrical arynes.12 Decreasing the size of the 3-
substituent in the intermediate aryne led to a significantly
reduced (2.2:1) regioselectivity (3v/3v′, 70% combined yield).
We also explored whether the vinyl substituent in 2a could
be replaced by a phenyl group and tested the reaction of 1a
with diphenyl sulfoxide (2t) to provide the triarylsulfonium salt
3w in 36% yield (Scheme 4). Notably, such salts have been
absence of 1a was followed by 1H NMR spectroscopy at room
temperature (Scheme 5, middle). When 2a was reacted in
CD3CN with CsF, 2a was consumed within 8 h and the sulfone
5a along with the sulfide 4a resulting from a sulfoxide
disproportionation were formed in equal amounts. Sulfoxide
disproportionation is a known reaction at high temperature;14
however, the fluoride-mediated disproportionation at room
temperature has not been reported. Disproportionation is
slower in the presence of water and also if the amount of CsF is
decreased (see Scheme 5). These results indicate that addition
of water simply suppresses disproportionation of 2a to 5a and
4a. We also found that the sulfone 5a does not undergo a clean
reaction under optimized conditions with in situ generated
benzyne. Based on these studies and previous reports6−9,15 we
suggest the following mechanism (Scheme 5, bottom).
Sulfoxide 2a reacts with benzyne in a concerted (2 + 2)
cycloaddition to intermediate A.7,8 Cleavage of the S−O bond
then leads to zwitterion B. Stereospecific S−O vinyl migration
by intramolecular ionic addition elimination (least motion) via
C eventually affords 3a.16
In summary, we showed that in situ generated arynes react
with aryl vinyl sulfoxides via (2 + 2) cycloaddition, S−O bond
cleavage in the four-membered benzanellated cycloadduct, and
subsequent ionic vinyl migration to ortho-arylsulfinylaryl vinyl
ethers. These cascades proceed with complete stereospecificity
in moderate to good yields. It was found that water as an
additive is important to suppress fluoride-mediated dispropor-
tionation of the sulfoxide to the corresponding sulfide and
sulfone. Reaction of the vinyl sulfone with the aryne leads to
unidentified side products thereby consuming the aryne
Scheme 4. Reaction of Benzyne with Diphenyl Sulfoxide
successfully employed in industry as acid generators in
photolithography and also as photoinitiators in cationic
polymerization.13 In contrast to the efficient S−O-vinyl
migration, obviously S−O-phenyl migration cannot compete
with trapping of the phenolate by benzyne.
To study the effect of water on the reaction outcome, we
repeated the experiment of 1a with 2a using D2O (2 equiv) as
an additive and obtained vinyl ether 3a without any deuterium
incorporation (Scheme 5, top). This transformation revealed
that water is likely not involved in any protonation/
deprotonation steps in this cascade. To gain further under-
standing of the beneficial water effect, the reaction of 2a in the
C
DOI: 10.1021/acs.orglett.6b03827
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
155. (c) Okuma, K.; Okada, A.; Koga, Y.; Yokomori, Y. J. Am. Chem.
Soc. 2001, 123, 7166.
(7) Liu, F.-L.; Chen, J.-R.; Zou, Y.-Q.; Wei, Q.; Xiao, W.-J. Org. Lett.
component. The chemistry presented is valuable for the
stereoselective preparation of highly substituted vinyl ethers.
In contrast to the vinyl migration, the analogous sequence
comprising a phenyl migration starting with diphenyl sulfoxide
was not observed and reaction of diphenyl sulfoxide with
benzyne provided the corresponding triarylsulfonium salt as a
result of initial (2 + 2) cycloaddition, S−O bond cleavage, and
trapping of the zwitterionic phenolate with benzyne.
2014, 16, 3768.
(8) (a) Li, H.-Y.; Xing, L.-J.; Lou, M.-M.; Wang, H.; Liu, R.-H.;
Wang, B. Org. Lett. 2015, 17, 1098. (b) Lou, M.-M.; Wang, H.; Song,
L.; Liu, H.-Y.; Li, Z.-Q.; Guo, X.-S.; Zhang, F.-G.; Wang, B. J. Org.
Chem. 2016, 81, 5915.
(9) Li, Y.; Qiu, D.; Gu, R.; Wang, J.; Shi, J.; Li, Y. J. Am. Chem. Soc.
2016, 138, 10814.
(10) Szmant, H. H. Chemistry of the sulfoxide group. In Organic
Sulfur Compounds; Kharasch, N., Ed.; Pergamon: 1961; Chapter 16, p
154.
(11) A 39% yield of 4b was obtained by using CsF (2.4 equiv) and
H2O (3 equiv) in the presence of 2c (1 equiv) in CH3CN at 55 °C for
1 h.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03827.
■
S
1
Experimental procedures, characterization data, and H
and 13C NMR spectra (PDF)
(12) Bronner, S. M.; Mackey, J. L.; Houk, K. N.; Garg, N. K. J. Am.
Chem. Soc. 2012, 134, 13966.
AUTHOR INFORMATION
■
(13) (a) Imazeki, S.; Sumino, M.; Fukasawa, K.; Ishihara, M.;
Akiyama, T. Synthesis 2004, 2004, 1648. (b) DeVoe, R. J.; Olofson, P.
M.; Sahyun, M. R. V. Photochemistry and Photophysics of ’Onium
Salts. In Advances in Photochemistry; John Wiley & Sons, Inc.: 2007, p
313. (c) Racicot, L.; Kasahara, T.; Ciufolini, M. A. Org. Lett. 2014, 16,
6382.
(14) Bates, D. K.; Xia, M. J. Org. Chem. 1998, 63, 9190.
(15) Yoshida, S.; Yano, T.; Misawa, Y.; Sugimura, Y.; Igawa, K.;
Shimizu, S.; Tomooka, K.; Hosoya, T. J. Am. Chem. Soc. 2015, 137,
14071.
Corresponding Author
*E-mail: studer@uni-muenster.de.
ORCID
Armido Studer: 0000-0002-1706-513X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006, 8,
3853.
We thank Dr. Klaus Bergander (University of Munster) for
NMR analysis and Dr. Shyamal Chakrabarty (University of
̈
Munster) for providing some triflates. This work was financially
̈
supported by the China Scholarship Council (stipend to Y.L.)
and the Deutsche Forschungsgemeinschaft (DFG).
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