An efficient and facile synthesis of vinyl sulfones via microwave-assisted copper triflate catalyzed hydrosulfonylation of alkynes

Article abstract of DOI:10.1055/s-0034-1378546

An efficient method has been described for the synthesis of vinyl sulfones via hydrosulfonylation of alkynes using sodium arene sulfinates catalyzed by Cu(OTf)₂ under microwave irradiation. A variety of vinyl sulfones was obtained in good to ex

Full text of DOI:10.1055/s-0034-1378546

LETTER
▌A
lAettner Efficient and Facile Synthesis of Vinyl Sulfones via Microwave-Assisted
Copper Triflate Catalyzed Hydrosulfonylation of Alkynes
Microwave-Assisted Synthesis of Vinyl Sulfones
Ganesh M. Shelke, V. Kameswara Rao, Kasiviswanadharaju Pericherla, Anil Kumar*
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India
Fax +91(1596)244183; E-mail: anilkumar@pilani.bits-pilani.ac.in
Received: 19.05.2014; Accepted after revision: 29.06.2014
or copper-catalyzed cross-coupling and addition reactions
of sulfinate salts.16 Despite this range of available meth-
odologies, these methods suffer from one or more draw-
backs in terms of sensitive functional group tolerance,
Abstract: An efficient method has been described for the synthesis
of vinyl sulfones via hydrosulfonylation of alkynes using sodium
arene sulfinates catalyzed by Cu(OTf)2 under microwave irradia-
tion. A variety of vinyl sulfones was obtained in good to excellent
(71–89%) yields and with high regio- and stereoselectivity. Short- formation of isomer mixtures and side products, or need
ened reaction times, simple reaction conditions and low catalyst
loading are the salient features of this protocol.
for inaccessible starting materials, relatively harsh reac-
tion conditions or tedious procedures. Therefore, there re-
Key words: microwave, vinyl sulfones, copper triflate, alkynes, so-
dium arene sulfinates
mains the need to develop facile, highly selective and
resource-efficient protocols to construct vinyl sulfones.
Owing to our interest in developing simple and efficient
synthetic methods using metal triflates;17 we report herein
an efficient copper triflate catalyzed hydrosulfonylation
of alkynes using sodium arene sulfinates under micro-
wave irradiation to give β-vinyl sulfones in good to excel-
lent yields with high regio- and stereoselectivity (Scheme
1). To the best of our knowledge this is first report on the
synthesis of vinyl sulfones under microwave irradiation in
the presence of copper triflate.18
Vinyl sulfones and their derivatives have been extensively
used as versatile building blocks and valuable intermedi-
ates in organic synthesis1 and medicinal chemistry.2 They
are excellent Michael acceptors3 and 2π-partners in cyc-
loaddition reactions.4 Vinyl sulfones are well known to
act as irreversible inhibitors of many types of cysteine
proteases5 through conjugate addition of the thiol of the
active site cysteine residue. In addition to cysteine prote-
ase inhibition, vinyl sulfones also serve as key structural
motifs in several other biologically active molecules pos-
sessing anticancer,6 carcinogenesis suppression7 and anti-
trypanosomal activity.8
Initially, we investigated the catalytic activity of various
metal salts in acetic acid at 110 °C under microwave irra-
diation (Table 1, entries 1–9) for the addition of sodium
benzene sulfinate (2a) to phenylacetylene (1a) to give
[2-(phenylsulfonyl)vinyl]benzene (3a). Among all the
screened catalysts, copper salts were found to be more ef-
fective for this reaction. Notably, Cu(OTf)2 was found to
be the best catalyst to afford 3a in 80% yield. Other cata-
lysts such as Pd(OAc)2, Yb(OTf)3, and Zn(OTf)2 either
did not promote or sluggishly promoted this reaction. We
further proceeded to optimize the catalyst loading and sol-
vent screening. It was found that there was no significant
change in the yield of 3a on increasing the amount of
Cu(OTf)2 from 5 mol% to 10 mol% (Table 1, entries 9 and
10) but a slight increase in yield was observed when the
amount of Cu(OTf)2 was reduced to 2.5 mol% (Table 1,
entries 9 and 11). In the absence of Cu(OTf)2, 3a was not
formed (Table 1, entry 18). Subsequently it was estab-
In view of the importance of vinyl sulfones in synthetic
chemistry and medicinal chemistry, various methods have
been developed for their synthesis.2e,f Classical protocols
for the synthesis of vinyl sulfones include olefination re-
actions,9 manipulation of acetylenic sulfones,10 and addi-
tion of sulfonyl halides to alkenes followed by elimination
reactions.11 Recent methods for synthesizing vinyl sul-
fones include hydrozirconation of 1-alkynyl sulfones,12
cerium(IV) ammonium nitrate mediated oxidative addi-
tion of sodium arene sulfinate and sodium iodide with
alkenes,13 boron trifluoride or AIBN-catalyzed addition of
polystyrene-supported selenosulfonates to alkenes,14 re-
action of sulfinate salts with dibromides,15 and palladium-
R3
O
Cu(OTf)2 (2.5 mol%)
AcOH, MW, 110 °C
O
S
ONa
R1
R2
+
S
R1
O
R3
1
5–7 min
R2
2
3a–p
Scheme 1 Synthesis of vinyl sulfones
SYNLETT 2014, 25, 000A–000E
Advanced online publication: 26.08.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378546; Art ID: st-2014-d0437-l
© Georg Thieme Verlag Stuttgart · New York

B
G. M. Shelke et al.
LETTER
lished that solvent has a significant role (Table 1, entries eroaromatic alkynes such as 2-ethynylpyridine reacted ef-
11–17). Very poor yields of 3a were observed in THF, ficiently with both sodium p-toluene sulfinate and sodium
water and methanol while only a trace was observed in di- benzene sulfinate providing the corresponding vinyl sul-
methoxyethane and no product was formed in acetonitrile. fones (3o and 3p) in excellent yields (Table 2, entries 15
and 16). The structures of all the synthesized vinyl sul-
fones were elucidated by IR and NMR analysis (see sup-
plementary data). Based on the spectroscopic analysis it
Lowering the reaction temperature to 80 °C and 60 °C un-
der microwave irradiation decreased the yield of 3a to
40% and 25%, respectively. Thus, the optimum condi-
can be concluded that the reaction is regio- and stereose-
tions for this transformation were established to be micro-
lective giving (E)-vinyl sulfones. Furthermore it is worthy
wave heating at 110 °C in the presence of Cu(OTf)2 (2.5
of note that β-keto sulfones, which have been reported to
mol%) in acetic acid.
be formed by oxidative addition of sulfinic acids to
alkynes in the presence of copper catalysts,16f,19 were not
detected under these conditions.
Table 1 Optimization of the Reaction Conditiona
Entry
Catalyst (mol%)
Solvent
Yield (%) of 3aa
To gain insight into the reaction mechanism, 1a and 2a
were reacted in the presence of one equivalent of TEMPO
as a radical scavenger when only a 15% yield of 3a was
observed, suggesting that the reaction might involve a
radical process. Based on the literature reports18 and our
own experimental observations, a plausible mechanism is
proposed as shown in Scheme 2. It is believed that initial-
ly radical 4 is generated from sulfinyl anion 2 via single
electron transfer involving Cu(II).20 The radical 4 adds to
alkyne 1 affording vinyl radical 5 which further reacts
with the Cu(I) species to yield vinyl sulfone copper(II)
complex 6. Finally, demetallation–protonation of 6 results
in the formation of adduct 3a.21
1
2
Pd(OAc)2 (5)
Yb(OTf)3 (5)
Zn(OTf)2 (5)
CuI (5)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
HCOOH
THF
0
trace
trace
18
3
4
5
CuCl2·H2O (5)
CuBr2 (5)
62
6
60
7
CuSO4·5H2O (5)
Cu(OAc)2·H2O (5)
Cu(OTf)2 (5)
Cu(OTf)2 (10)
Cu(OTf)2 (2.5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
–
74
8
68
9
80
In conclusion, we have developed a very efficient method
for the synthesis of vinyl sulfones via hydrosulfonylation
of alkynes using sodium arene sulfinates catalyzed by
Cu(OTf)2 under microwave irradiation.22 The method
provides a variety of vinyl sulfones in good to excellent
yields and high regio- and stereoselectivity. In addition,
this method exploits the use of microwaves and is faster
than the conventional heating process. The advantages of
this methodology include its experimental simplicity,
short reaction time, simple conditions, low catalyst load-
ing and ready availability of the starting materials.
10
11
12
13
14
15
16
17
18
76
82
64
25
H2O
18
MeOH
MeCN
DME
16
0
Trace
0
TfONa
CuOTf
AcOH
Cu(OTf)2
O
O
O
O
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (2.5–10
mol%), solvent (2 mL), at 110 °C under microwave irradiation, 5 min.
Ar
S
Ar
S
Ar
S
O
ONa
2
4
1
Ar = Ph, 4-MeC6H4
With the optimized reaction conditions in hand, we ex-
plored the substrate scope of the reaction using various
arylacetylenes with sodium arene sulfinates. The results
are shown in Table 2. Phenylacetylenes bearing either an
electron-donating substituent or an electron-withdrawing
substituent afforded the corresponding vinyl sulfones in
good to excellent yields under the optimized conditions.
Not only terminal alkynes but also internal alkynes react-
ed to give the corresponding vinyl sulfones (3m and 3n)
in good yield (Table 2, entries 13 and 14). Moreover, het-
R1
R2
Cu(OTf)2
TfOH
Ar
Ar
O
Ar
O
O
O
O
CuOTf
II
S
H
S
(TfO)Cu
AcOH
S
R2
O
or
R1
R2
Cu(OAc)2
R1
R2
R1
3
6
5
Scheme 2 Proposed mechanism for the synthesis of vinyl sulfones
Synlett 2014, 25, A–E
© Georg Thieme Verlag Stuttgart · New York

LETTER
Microwave-Assisted Synthesis of Vinyl Sulfones
C
Table 2 Vinyl Sulfones Derivatives 3a–p Produced via Reaction of Arene Sulfinates and Alkynes in the Presence of Cu(OTf)2 under Micro-
wave Irradiationa
Entry
R1
R2
H
R3
H
Product
Time (min)
Yield (%)b
O
1
Ph
3a
5
82
S
O
O
S
S
2
3
4
4-MeC6H4
3-MeC6H4
4-EtC6H4
H
H
H
H
H
H
3b
3c
3d
5
5
5
84
77
74
O
O
O
O
O
S
S
O
O
5
6
4-t-BuC6H4
H
H
H
H
3e
3f
5
79
71
t-Bu
O
S
4-FC6H4
5.30
O
F
O
S
7
8
9
Ph
H
H
H
Me
Me
Me
3g
3h
3i
5
5
5
84
86
81
O
O
S
4-MeC6H4
3-MeC6H4
O
O
S
O
O
S
10
11
4-t-BuC6H4
H
H
Me
Me
3j
5
5
82
87
O
t-Bu
O
S
4-MeOC6H4
3k
O
MeO
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, A–E

D
G. M. Shelke et al.
LETTER
Table 2 Vinyl Sulfones Derivatives 3a–p Produced via Reaction of Arene Sulfinates and Alkynes in the Presence of Cu(OTf)2 under Micro-
wave Irradiationa (continued)
Entry
R1
R2
H
R3
Product
Time (min)
5.30
Yield (%)b
O
S
12
4-FC6H4
Me
3l
74
O
F
O
O
O
O
S
S
S
S
13
14
15
16
Ph
Me
Me
H
Me
H
3m
3n
3o
6.30
6.30
5
89
81
79
74
O
O
O
O
Ph
N
N
C5H4N
C5H4N
Me
H
H
3p
5
a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), Cu(OTf)2 (2.5 mol%), AcOH (2 mL), MW irradiation (at 110 °C, 250 psi, 200 W).
b Isolated yield.
Hague, J. Med. Res. Rev. 2006, 26, 793. (f) Simpkins, N. S.
Tetrahedron 1990, 46, 6951.
(3) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903.
(4) (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59,
Acknowledgment
We sincerely acknowledge the financial support from the Depart-
ment of Science and Technology (DST), New Delhi for provision
of focused microwave and FTIR facilities under the FIST program-
me. GMS is grateful to BITS Pilani for a Research Fellowship and
VKR & KP are grateful to UGC and CSIR, respectively for Senior
Research Fellowships.
6184. (b) Huang, D. F.; Shen, T. Y. Tetrahedron Lett. 1993,
34, 4477. (c) de Lucchi, O.; Pasquato, L. Tetrahedron 1988,
44, 6755.
(5) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. J. Med.
Chem. 1995, 38, 3193.
(6) Reddy, P. E.; Reddy, R. M. V. PCT Int. Appl W09918068,
Supporting Information for this article is available online
1999.
at
http://www.thieme-connect.com/products/ejournals/journal/
(7) Konopa, J. K.; Konieczny, M. T.; Horowska, B. J.;
Kunikowski, A. J.; Asao, T.; Nishino, H.; Yamada, Y. Jpn.
Patent JP9003037, 1997.
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
(8) Dunny, E.; Doherty, W.; Evans, P.; Malthouse, J. P. G.;
Nolan, D.; Knox, A. J. S. J. Med. Chem. 2013, 56, 6638.
(9) (a) Popoff, I. C.; Dever, J. L.; Leader, G. R. J. Org. Chem.
1969, 34, 1128. (b) Ley, S. V.; Simpkins, N. S. J. Chem.
Soc., Chem. Commun. 1983, 1281.
(10) Ohnuma, T.; Hata, N.; Fujiwara, H.; Ban, Y. J. Org. Chem.
1982, 47, 4713.
(11) (a) Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43,
1208. (b) Sinnreich, J.; Asscher, M. J. Chem. Soc., Perkin
Trans 1 1972, 1543. (c) Gancarz, R. A.; Kice, J. L.
Tetrahedron Lett. 1980, 21, 4155.
References and Notes
(1) (a) Lebrun, M.-E.; Le Marquand, P.; Berthelette, C. J. Org.
Chem. 2006, 71, 2009. (b) Enders, D.; Müller, S. F.; Raabe,
G.; Runsink, J. Eur. J. Org. Chem. 2000, 879. (c) Mauleón,
P.; Alonso, I.; Rivero, M. R.; Carretero, J. C. J. Org. Chem.
2007, 72, 9924. (d) Oishi, S.; Hatano, K.; Tsubouchi, A.;
Takeda, T. Chem. Commun. 2011, 47, 11639. (e) Murphy, J.
J.; Quintard, A.; McArdle, P.; Alexakis, A.; Stephens, J. C.
Angew. Chem. Int. Ed. 2011, 50, 5095.
(2) (a) Schneider, K. C.; Benner, S. A. Tetrahedron Lett. 1990,
31, 335. (b) Freihammer, P. M.; Detty, M. R. J. Org. Chem.
2000, 65, 7203. (c) Katritzky, A. R.; Huang, T.-B.;
(12) Huang, X.; Duan, D.; Zheng, W. J. Org. Chem. 2003, 68,
1958.
Voronkov, M. V.; Wang, M.; Kolb, H. J. Org. Chem. 2000,
65, 8819. (d) Wang, G.; Mahesh, U.; Chen, G. Y. J.; Yao, S.
Q. Org. Lett. 2003, 5, 737. (e) Meadows, D. C.; Gervay-
(13) (a) Nair, V.; Augustine, A.; George, T. G.; Nair, L. G.
Tetrahedron Lett. 2001, 42, 6763. (b) Nair, V.; Augustine,
A.; Suja, T. D. Synthesis 2002, 2259.
(14) Qian, H.; Huang, X. Synlett 2001, 1913.
Synlett 2014, 25, A–E
© Georg Thieme Verlag Stuttgart · New York

LETTER
Microwave-Assisted Synthesis of Vinyl Sulfones
E
(15) Guan, Z.-H.; Zuo, W.; Zhao, L.-B.; Ren, Z.-H.; Liang, Y.-M.
Synthesis 2007, 1465.
crude product which was purified by passing through a silica
column to give pure 3a (200 mg, 82%) as a white solid.
Selected Spectroscopic Data:
(16) (a) Bian, M.; Xu, F.; Ma, C. Synthesis 2007, 2951.
(b) Huang, F.; Batey, R. A. Tetrahedron 2007, 63, 7667.
(c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M.;
Bernini, R. J. Org. Chem. 2004, 69, 5608. (d) Battace, A.;
Zair, T.; Doucet, H.; Santelli, M. Synthesis 2006, 3495.
(e) Xu, Y.; Zhao, J.; Tang, X.; Wu, W.; Jiang, H. Adv. Synth.
Catal. 2014, in press . (f) Taniguchi, N. Synlett 2012, 1245.
(g) García Ruano, J. L.; Alemán, J.; Paredes, C. G. Org. Lett.
2006, 8, 2683.
(17) (a) Khedar, P.; Pericherla, K.; Kumar, A. Synlett 2014, 25,
515. (b) Shelke, G. M.; Rao, V. K.; Tiwari, R. K.; Chhikara,
B. S.; Parang, K.; Kumar, A. RSC Adv. 2013, 3, 22346.
(c) Rao, V. K.; Tiwari, R.; Chhikara, B. S.; Shirazi, A. N.;
Parang, K.; Kumar, A. RSC Adv. 2013, 3, 15396.
(d) Pericherla, K.; Khungar, B.; Kumar, A. Tetrahedron
Lett. 2012, 53, 1253.
(E)-1-Methyl-3-[2-(phenylsulfonyl)vinyl]benzene (3c):
yellow solid; mp 74–76 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.95–7.99 (m, 2 H), 7.68 (d, J = 15.4 Hz, 1 H), 7.61–7.65
(m, 1 H), 7.54–7.60 (m, 2 H), 7.29–7.33 (m, 3 H), 7.23–7.26
(m, 1 H), 6.87 (d, J = 15.4 Hz, 1 H), 2.37 (s, 3 H). 13C NMR
(101 MHz, CDCl3): δ = 142.71, 140.81, 138.87, 133.35,
132.31, 132.08, 129.34, 129.16, 128.99, 127.65, 127.00,
125.85, 21.28. IR (KBr): 3047, 2916, 1612, 1443, 1296,
1142 cm–1. HRMS: m/z [M + H]+ calcd for C15H15O2S:
259.0787; found: 259.0765.
(E)-1-Ethyl-4-[2-(phenylsulfonyl)vinyl]benzene (3d):
yellow solid; mp 95–96 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.95–7.99 (m, 2 H), 7.69 (d, J = 15.4 Hz, 1 H), 7.61–7.66
(m, 1 H), 7.54–7.59 (m, 2 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.24
(d, J = 8.1 Hz, 2 H), 6.84 (d, J = 15.4 Hz, 1 H), 2.68 (q, J =
7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 148.19, 142.63, 140.94, 133.31, 129.85, 129.33,
128.74, 128.67, 127.61, 126.10, 28.86, 15.31. IR (KBr):
3055, 2962, 1612, 1512, 1450, 1311, 1149 cm–1. HRMS: m/z
[M + H]+ calcd for C16H17O2S: 273.0944; found: 273.0958.
(E)-1-Fluoro-4-(2-tosylvinyl)benzene (3l): white solid; mp
95–96 °C. 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.3
Hz, 2 H), 7.64 (d, J = 15.4 Hz, 1 H), 7.46–7.52 (m, 2 H), 7.36
(d, J = 8.0 Hz, 2 H), 7.09 (t, J = 8.6 Hz, 2 H), 6.81 (d, J =
15.4 Hz, 1 H), 2.45 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ
= 164.30 (d, JC–F = 252.8 Hz), 144.49, 140.61, 137.65,
130.56 (d, JC–F = 8.7 Hz), 130.02, 128.72 (d, JC–F = 3.4 Hz),
127.72, 127.41 (d, JC–F = 2.4 Hz), 116.31 (d, JC–F = 22.1 Hz),
21.64. IR (KBr): 3055, 1597, 1504, 1450, 1304, 1234, 1142
cm–1. HRMS: m/z [M + H]+ calcd for C15H14FO2S: 277.0693;
found: 277.0685.
(18) After our work had been completed, a completely
independent report on Cu(OAc)2-catalyzed addition of
sulfinates to alkynes appeared. See: Wei, W.; Li, J.; Yang,
D.; Wen, J.; Jiao, Y.; You, J.; Wang, H. Org. Biomol. Chem.
2014, 12, 1861.
(19) (a) Taniguchi, N. Tetrahedron 2014, 70, 1984.
(b) Taniguchi, N. Synlett 2011, 1308.
(20) (a) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei,
A. Angew. Chem. Int. Ed. 2013, 52, 7156. (b) Lu, Q.; Zhang,
J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc.
2013, 135, 11481. (c) Barun, O.; Ila, H.; Junjappa, H.; Singh,
O. M. J. Org. Chem. 2000, 65, 1583.
(21) (a) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2007, 129, 4099. (b) Kim, S.; Lee, P. H. J. Org. Chem.
2011, 77, 215.
(22) Representative Procedure: Phenylacetylene (102 mg, 1
mmol), sodium benzene sulfinate (164 mg, 1 mmol), and
Cu(OTf)2 (16 mg, 2.5 mol%) were added to a 10-mL
microwave tube containing AcOH (2 mL) and a magnetic
stirrer bar. The reaction mixture was placed in a CEM
Discover BenchMate. The reaction parameters were set to
200 W, 250 psi, 110 °C for 5 min with stirring. After
completion of the reaction, the reaction mixture was diluted
with H2O (10 mL) and extracted with EtOAc (2 × 10 mL).
The organic layer was dried with anhyd Na2SO4, filtered and
the solvent evaporated on a rotary evaporator to give the
(E)-2-(2-Tosylvinyl)pyridine (3o): yellow solid; mp 98–99
°C. 1H NMR (400 MHz, CDCl3): δ = 8.62 (d, J = 3.9 Hz, 1
H), 7.85 (d, J = 8.3 Hz, 2 H), 7.74 (td, J = 7.7, 1.8 Hz, 1 H),
7.64 (d, J = 14.9 Hz, 1 H), 7.43 (dd, J = 13.5, 11.4 Hz, 2 H),
7.35 (d, J = 8.0 Hz, 2 H), 7.28–7.32 (m, 1 H), 2.44 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 151.11, 150.29, 144.61,
140.03, 137.25, 137.04, 132.15, 130.00, 127.94, 125.39,
124.94, 21.65. IR (KBr): 3040, 1620, 1589, 1435, 1311,
1142 cm–1. HRMS: m/z [M + H]+ calcd for C14H14NO2S:
260.0740; found: 260.0725.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, A–E