Regioselective hydrothiolation of alkynes by sulfonyl hydrazides using organic ionic base-Br?nsted acid

Article abstract of DOI:10.1021/ol401925u

A practical and novel approach has been developed for the synthesis of vinyl sulfides by the reaction of sulfonyl hydrazides with aryl/ heteroarylacetylenes using a DBU-based ionic liquid. The system offers a new sulfur source for hydrothiolation and is endowed with green credentials.

Full text of DOI:10.1021/ol401925u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Hydrothiolation of Alkynes
by Sulfonyl Hydrazides Using Organic
Ionic BaseÀBrønsted Acid
Rahul Singh, Dushyant Singh Raghuvanshi, and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science,
Banaras Hindu University, Varanasi 221005, India
knsinghbhu@yahoo.co.in
Received July 9, 2013
ABSTRACT
A practical and novel approach has been developed for the synthesis of vinyl sulfides by the reaction of sulfonyl hydrazides with aryl/
heteroarylacetylenes using a DBU-based ionic liquid. The system offers a new sulfur source for hydrothiolation and is endowed with green
credentials.
Regioselective hydrothiolation of terminal alkynes using
thiols is an established strategy.1 The vinyl sulfides, produced
as a result of the anti-Markownikoff addition, serve as
important synthetic intermediates in total syntheses and as
precursors to a wide range of functionalized molecules.2À5
Many natural products and compounds exhibiting re-
markable biological properties contain the vinyl sulfide
moiety.6 These compounds have also found extensive
applications in materials science7 and thus are cherished
targets of contemporary interest. Although lower compat-
ibility of the sulfur compounds to the metal-catalyzed
ꢀ
(1) (a) Giuseppe, A. D.; Castarlenas, R.; Perez-Torrente, J. J.;
Crucianelli, M.; Polo, V.; Sancho, R.; Lahoz, F. J.; Oro, L. A. J. Am.
Chem. Soc. 2012, 134, 8171. (b) Yang, Y.; Rioux, R. M. Chem. Commun.
2011, 47, 6557. (c) Sabarre, A.; Love, J. Org. Lett. 2008, 10, 3941. (d)
Misumi, Y.; Seino, H.; Mizobe, Y. J. Organomet. Chem. 2006, 691, 3157.
(e) Cao, C. S.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127,
17614. (f) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, J. J. Am. Chem. Soc.
1999, 121, 5108. (g) Benati, L.; Capella, L.; Montevecchi, P. C.;
Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1035. (h) Griesbaum,
K. Angew. Chem., Int. Ed. Engl. 1970, 9, 273. (i) Weiss, C. J.; Wobser,
S. D.; Marks, T. J. J. Am. Chem. Soc. 2009, 131, 2062. (j) Weiss, C. J.;
Marks, T. J. J. Am. Chem. Soc. 2010, 132, 10533.
(2) (a) Beletskaya, I. P.; Ananikov, V. P. Eur. J. Org. Chem. 2007,
3431. (b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem.
Rev. 2004, 104, 2239. (c) Zyk, N. V.; Beloglazkina, E. K.; Belova, M. A.;
Dubinina, N. S. Russ. Chem. Rev. 2003, 72, 769. (d) Sizov, A. Y.;
Kovregin, A. N.; Ermolov, A. F. Russ. Chem. Rev. 2003, 72, 357. (e)
Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205. (f) Mangini, A.
Sulfur Rep. 1987, 7, 313. (g) Block, E. Reactions of Organosulfur
Compounds; Academic Press: New York, 1978.
(4) (a) Li, Q.; Dong, T.; Liu, X.; Lei, X. J. Am. Chem. Soc. 2013, 135,
4996. (b) Bodipati, N.; Peddinti, R. K. Org. Biomol. Chem. 2012, 10,
1958. (c) Yamazaki, S. J. Synth. Org. Chem. Jpn. 2000, 58, 50. (d)
€
Bruckner, R.; Huisgen, R. Tetrahedron Lett. 1990, 31, 2561. (e)
Singleton, D. A.; Church, K. M. J. Org. Chem. 1990, 55, 4780. (f)
Sugimura, H.; Osumi, K. Tetrahedron Lett. 1989, 30, 1571. (g) Gupta,
R. B.; Franck, R. W.; Onan, K. D.; Soll, C. E. J. Org. Chem. 1989, 54,
1097. (h) Tsuge, O.; Kanemasa, S.; Sakamoto, K.; Takenaka, S. Bull.
Chem. Soc. Jpn. 1988, 61, 2513.
(5) (a) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004,
69, 9109. (b) Mizuno, H.; Domon, K.; Masuya, K.; Tanino, K.;
Kuwajima, I. J. Org. Chem. 1999, 64, 2648. (c) Bratz, M.; Bullock,
W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995, 117, 5958.
(d) Trost, B. M.; Lavoie, A. C. J. Am. Chem. Soc. 1983, 105, 5075.
(6) (a) Paris, J. M.; Barriere, J. C.; Smith, C.; Bost, P. E. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lucas, G., Ohno, M.,
Eds.; Springer-Verlag: Berlin, 1990; p 183. (b) Di Giambattista, M.;
Chinali, G.; Cocito, C. J. Antimicrob. Chemother. 1989, 24, 485. (c)
Cocito, C. Microbiol. Rev. 1979, 43, 145.
(7) (a) Lauterbach, C.; Fabian, J. Eur. J. Inorg. Chem. 1999, 1995. (b)
Hope, E. G.; Levason, W. Coord. Chem. Rev. 1993, 122, 109. (c)
Clemenson, P. I. Coord. Chem. Rev. 1990, 106, 171.
(8) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079. (b) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205. (c) Ogawa,
A. J. Organomet. Chem. 2000, 611, 463. (d) Savolainen, M. A.; Wu, J.
Org. Lett. 2013, 15, 3802.
(3) (a) Sarma, R.; Rajesh, N.; Prajapati, D. Chem. Commun. 2012, 48,
4014. (b) Muraoka, N.; Mineno, M.; Itami, K.; Yoshida, J.-I. J. Org.
Chem. 2005, 70, 6933. (c) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P.
J. Org. Chem. 2004, 69, 9109. (d) Farhat, S.; Marek, I. Angew. Chem.
2002, 114, 1468. Angew. Chem., Int. Ed. 2002, 41, 1410. (e) Su, M.; Yu,
W.; Jin, Z. Tetrahedron Lett. 2001, 42, 3771. (f) Mizuno, H.; Domon, K.;
Masuya, K.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1999, 64, 2648. (g)
ꢁ
Andres, D. F.; Dietrich, U.; Laurent, E. G.; Marquet, B. S. Tetrahedron
1997, 53, 647. (h) Baeckvall, J.-E.; Ericsson, A. J. Org. Chem. 1994, 59,
5850.
r
10.1021/ol401925u
XXXX American Chemical Society

reactions has limited their exploration, some reactions
involving thiols have been developed.8aÀc In this regard,
Markovinkov selective hydrothiolation using styrene and
its derivatives with 2-mercaptobenzothiazole is worth
mentioning.8d The use of disulfides has also been made to
some extent,9a,b although the reactions are often endowed
with the formation of bisulfidation products.9cÀe Limited
exploration in this direction with unpleasant smelling thiols
as the prominent source and the use of heavy metals for the
accomplishment of the reaction, has set a considerable
demand for developing a safer alternative for hydrothiola-
tion under practical reaction conditions.
in different permutations. In view of the above and as a
part of our current research program,17 it is a highly
exigent and timely endeavor to report a rapid and useful
alternative for hydrothiolation of alkynes by using a new
S-source (Scheme 1).
Scheme 1
Sulfonyl hydrazides, being stable solids, have beennicely
used as reductants,10 sulfonyl sources11 through the cleav-
age of their sulfurÀnitrogen bonds, and aryl sources12
through the cleavage of their carbonÀsulfur bonds. How-
ever, to the best of our knowledge, there exists no report on
the use of sulfonyl hydrazide as a thiol equivalent.
In the existing green chemistry scenario, microwave-
assisted organic synthesis (MAOS) has attained the status
of a new and fascinating discipline.13 Ionic liquids (ILs)
have further strengthened the domain owing to their eco-
safe properties.14 1,8-Diazabicycloundec-7-ene (DBU) is
widely used as an organic base,15aÀc and DBU-based ionic
liquids, such as [DBU][HOAc], are particularly useful as a
non-nucleophilic task-specific organic ionic base.15d Ac-
cording to the current synthetic requirements, relevance of
microwave (MW) methodology using ionic liquids is par-
ticularly welcome.16 It is hence imperative to exploit the
combination of MW and IL for organic transformations
with careful assessment of a pair of distinct organo systems
Our studies were indeed initiated to achieve a green
protocol for the preparation of allenes by the reaction of
benzaldehyde tosylhydrazone with phenylacetylene in the
presence of [DBU][HOAc] following the BamfordÀStevens
strategy.18 To our surprise, the spectral data of the isolated
product could not match with the expected allene product.
For that reason, we resorted to the use of single-crystal
X-ray of the molecule so as to finally prove the structure as
vinyl sulfide 3a (Scheme 2, Figure 1), which was also in full
agreement with the spectral data.
Scheme 2
(9) (a) Taniguchi, T.; Fujii, T.; Idota, A.; Ishibashi, H. Org. Lett.
2009, 11, 3298. (b) Wang, Z.-L.; Tang, R.-Y.; Luo, P.-S.; Deng, C.-L.;
Zhong, P.; Li, J.-H. Tetrahedron 2008, 64, 10670. (c) Usugi, S.-i.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 601. (d)
Ananikov, V. P.; Kabeshov, M. A.; Beletskaya, I. P.; Khrustalev, V. N.;
Antipin, M. Y. Organometallics 2005, 24, 1275. (e) Ogawa, A.; Obayashi,
R.; Ine, H.; Tsuboi, Y.; Sonoda, N.; Hirao, T. J. Org. Chem. 1998, 63,
4277.
(10) (a) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91. (b) Pasto,
D. J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 8, p 471.
(11) (a) Li, X.; Xu, X.; Zhou, C. Chem. Commun. 2012, 48, 12240. (b)
Taniguchi, T.; Idota, A.; Ishibashi, H. Org. Biomol. Chem. 2011, 9, 3151.
(c) Ukrainets, I. V.; Tkach, A. A.; Kravtsova, V. V.; Shishkina, S. V.
Chem. Heterocycl. Compd. 2008, 44, 677.(d) Kamijo, S.; Al-Masum, M.;
Yamamoto, Y. Tetrahedron Lett. 1998, 39, 691. (e) Ballini, R.; Marcantoni,
E.; Petrin, M. Tetrahedron 1989, 45, 6791. (f) Deavin, A.; Rees, C. W.
J. Chem. Soc. 1961, 4970.
(12) (a) Yang, F.-L.; Ma, X.-T.; Tian, S.-K. Chem.;Eur. J. 2012, 18,
1582. (b) Liu, B.; Li, J.; Song, F.; You, J. Chem.;Eur. J. 2012, 18, 10830.
(c) Yu, X.; Li, X.; Wan, B. Org. Biomol. Chem. 2012, 10, 7479. (d) Yuen,
O. Y.; So, C. M.; Wong, W. T.; Kwong, F. Y. Synlett 2012, 2714.
(13) (a) Gutmann, B.; Schwan, A. M.; Reichart, B.; Gspan, C.;
Hofer, F.; Kappe, C. O. Angew. Chem., Int. Ed. 2011, 50, 7636. (b)
Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794.
Encouraged by this unique observation, and to further
simplify this new source of sulfur, we undertook the
envisaged reaction employing tosyl hydrazide rather than
tosyl hydrazone, which also served the same cause with
equal readiness facilitating the formation of vinyl sulfide.
But, when tosyl hydrazone/tosyl hydrazide was replaced
by tosyl chloride under the same set of conditions, the
reaction could not succeed. As an outcome, it appears that
the use of organic ionic base reduces the sulfonyl hydrazide
and thus could eventually make it serve as an effective
sulfur source for hydrothiolation. In order to optimize the
reaction conditions for hydrothiolation of terminal
(14) (a) Torimoto, T.; Tsuda, T.; Okazaki, K.ÀI.; Kuwabata, S. Adv.
Mater. 2010, 22, 1196. (b) Lee, J. W.; Shin, J. Y.; Chun, Y. S.; Jang,
H. B.; Song, C. E.; Lee, S. G. Acc. Chem. Res. 2010, 43, 985. (c) Hallett,
J. P.; Welton, T. Chem. Rev. 2011, 111, 3508. (d) Dong, K.; Zhang, S.
Chem.;Eur. J. 2012, 18, 2748.
ꢀ
(15) (a) Larrivee-Aboussafy, C.; Jones, B. P.; Price, K. E.; Hardink,
M. A.; McLaughlin, R. W.; Lillie, B. M.; Hawkins, J. M.; Vaidyanathan,
R. Org. Lett. 2010, 12, 324. (b) Peterson, S. L.; Stucka, S. M.; Dinsmore,
C. J. Org. Lett. 2010, 12, 1340. (c) De Rycke, N.; Couty, F.; David,
O. R. P. Chem.;Eur. J. 2011, 17, 12852. (d) Ying, A. G; Liu, L.; Wu,
G. F.; Chen, G.; Chen, X. Z.; Ye, W. D. Tetrahedron Lett. 2009, 50, 1653.
(16) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629.
(17) (a) Raghuvanshi, D. S.; Gupta, A. K.; Singh, K. N. Org. Lett.
2012, 14, 4326. (b) Singh, N.; Allam, B. K.; Raghuvanshi, D. S.; Singh,
K. N. Adv. Synth. Catal. 2013, 355, 1840. (c) Singh, R.; Allam, B. K.;
Raghuvanshi, D. S.; Singh, K. N. Tetrahedron 2013, 69, 1038. (d)
Vanjari, R.; Allam, B. K.; Singh, K. N. RSC Adv. 2013, 3, 1691.
(18) Adlington, R. M.; Barret, A. G. M. Acc. Chem. Res. 1983, 16, 55.
B
Org. Lett., Vol. XX, No. XX, XXXX

[DBU][HOAc]. The role of an efficient additive was
also examined to look into the effect of cooperative
operation. Different additives namely AcOH, DABCO,
L-proline, and BF3 Et2O (entries 10 and 16À18) were
3
assessed with [DBU][HOAc] under the optimized condi-
tions, and to our delight, the conjugate acid of the counter-
ion (1 equiv, entry 10) appeared to be on the top. In-
creasing or decreasing permutations of the additive AcOH
did not improve the product yields (entries 11 and 12). The
reaction was further probed by varying MW power,
temperature and time (entries 13À15) with the end result
of 60 W power output at 120 °C in 5 min to achieve the
maximum conversion (entry 10). The same reaction under
conventional conditions in a Schlenk tube at 120 °C
required over 24h and ended with muchlower yield (52%).
Figure 1. ORTEP diagram of product 3a.
alkynes, a model reaction between inexpensive and easily
available tosyl hydrazide and phenyacetylene was investi-
gated in detail by varying different parameters, and the
results are given in Table 1.
Table 1. Optimization of Reaction Conditionsa
organic ionic
base
additive
(equiv)
power
(W)
temp
yieldb
(%)
no.
(°C)
1
DBU
60
60
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
120
120
120
8
2
Bmim[BF4]
5
3
Bmim[PF6]
60
0
4
Bmim[Br]
60
0
5
Bmim[OH]
60
15
40
35
20
0
6
[DBU][HOAc]
[DBU][n-Pr]
[DBU][n-Bu]
[DBU][TFA]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
60
7
60
8
60
9
60
10
11
12
13
14
15
16
17
18
AcOH (1)
AcOH (0.5)
AcOH (2)
60
90
65
89
90
90c
78
42
50
20
60
60
AcOH (1)
100
60
AcOH (1)
AcOH (1)
60
DABCO (1)
L-proline (1)
100
100
100
BF3 Et2O (1)
3
a Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), [DBU][HOAc]
(1 mL), additive (0.5À2.0 equiv), 5 min. b Isolated yield based on 1a.
c Reaction carried out at 120 °C for 10 min.
Figure 2. Synthesis of vinyl sulfides 3aÀu. Reaction conditions:
1 (1.0 mmol), 2 (1.2 mmol), [DBU][HOAc] (1 mL), AcOH (1.0
At the outset, DBU and different ionic liquids such
as Bmim[BF4], Bmim[PF6], Bmim[Br], Bmim[OH], and
[DBU][HOAc] were tested for the reaction (entries 1À6),
which afforded the best results with the non-nucleophilic
ionic base [DBU][HOAc]. Therefore, the studies were direct-
ed to look at the prospective of other DBU based ionic liquids
like [DBU][n-Pr], [DBU][n-Bu], and [DBU][TFA] as well
(entries 7À9), but none of them could match the efficacy of
a
b
equiv), 120 °C, 60 W, 5 min. Isolated yield based on 1. E/Z
ratio determined by 1H NMR analysis.
Intrigued by these observation and with the stipulated
conditions in hand, the scope of this method was extended
to achieve the reaction of a wide range of diverse substrates
including a variety of sulfonyl hydrazides, viz. p-tolyl-,
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3
phenyl-, p-methoxyphenyl-, p-nitrophenyl-, p-tert-
butylphenyl-, and benzylsulfonyl hydrazides with terminal
alkynes like phenylacetylene, p-methylphenylacetylene,
p-tert-butylphenylacetylene, 2-ethynylpyridine, and p-fluoro-
phenylacetylene to afford a diverse range of vinyl sulfides
3aÀu in reasonably good to excellent yields under MW
irradiation in 5 min (Figure 2). Sulfonyl hydrazides con-
taining electron-donating groups and alkynes with elec-
tron-withdrawing groups showed better conversion.
Aliphatic terminal alkynes like 1-octyne as well as internal
alkynes failed to register any product formation. This is the
first report on the use of tosyl hydrazide as thiol equivalent.
While preparing the present manuscript, however, a report
by Tian et al. has appeared for the iodine-catalyzed
sulfenylation of indoles, albeit using sulfonyl hydrazide
as a sulfur electrophile source.19 The recyclability of the
ionic liquid was also checked for the model reaction. Upon
completion of the reaction, the product was isolated via
standard work up procedure and the aqueous layer con-
taining [DBU][HOAc] was dried under vacuum at 60 °C to
remove water and then washed with diethyl ether. The
recovered ionic liquid was recycled up to five times without
any significant loss in its activity. It is worthwhile to
mention that the hydrothiolation is invariably regioselec-
tive adopting anti-Markownikoff addition. Although
some of the products came up with good stereoselctivity
but in many cases different cisÀtrans ratios were observed
as specified in Figure 2.
In order to gain insight of the mechanism, a control
experiment with phenylsulfonyl hydrazide, in the ab-
sence of the alkyne, was carried out, which led to the
formation of the corresponding disulfide under opti-
mized conditions. Further, when the resulting disulfide
was separately made to react with phenylacetylene
under the established conditions, it gave rise to the
final product 3e although with a diminished yield. On
the basis of isolation of products, control experiments
and the existing literature,19,20 a plausible mechanism is
outlined in Scheme 3.
In conclusion, we have developed a novel and efficient
MW-assisted synthetic protocol for regioselective hydro-
thiolation of terminal alkynes using sulfonyl hydrazides as
thiol equivalent. Due to high conversion, excellent regio-
selectivity, short reaction time and use of a recyclable ionic
liquid, the process promises to be a practical and greener
alternative. The study will open a new window to many
other useful transformations in organic synthesis. Further
studies on the application of sulfonylhydrazidesare under-
way in our laboratory.
Acknowledgment. We are thankful to the Department
of Biotechnology, New Delhi, for financial assistance.
Supporting Information Available. Detailed experimen-
tal procedure and spectral data of all products along with
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Yang, F.-L.; Tian, S.-K. Angew. Chem., Int. Ed. 2013, 52, 4929.
(20) Nyoni, D.; Lobb, K. A.; Kaye, P. T.; Caira, M. R. ARKIVOC
2012, No. vi, 245.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX