Convenient MW-assisted synthesis of unsymmetrical sulfides using sulfonyl hydrazides as aryl thiol surrogate

Article abstract of DOI:10.1021/ol402948k

An efficient synthesis of unsymmetrical sulfides has been achieved via the cross-coupling reaction of aryl/het-aryl/benzyl halides with stable and easily workable sulfonyl hydrazides as thiol substitutes by means of [DBU][HOAc] and CuI under microwave irr

Full text of DOI:10.1021/ol402948k

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5874–5877
Convenient MW-Assisted Synthesis of
Unsymmetrical Sulfides Using Sulfonyl
Hydrazides as Aryl Thiol Surrogate
Neetu Singh, Rahul Singh, Dushyant S. 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 October 12, 2013
ABSTRACT
An efficient synthesis of unsymmetrical sulfides has been achieved via the cross-coupling reaction of aryl/het-aryl/benzyl halides with stable and
easily workable sulfonyl hydrazides as thiol substitutes by means of [DBU][HOAc] and CuI under microwave irradiation.
One of the current challenges in organic synthesis is to
develop convenient, selective, and energy-efficient syn-
thetic methods. As a part of this effort, the search for more
practical and environmentally benign synthetic methodolo-
gies is of prime importance.1 CarbonÀsulfur (CÀS) bond-
forming reactions comprise a key step in the synthesis of large
variety of molecules of biological and material interest,2
especially via crossÀcoupling reactions.3 Although carbonÀ
nitrogen (CÀN) and carbonÀoxygen (CÀO) bond-forming
processes have been studied extensively, the CÀS bond
formation reactions are yet underdeveloped due to the fact
that thiols are prone to oxidative SÀS coupling leading to the
formation of undesired disulfides and organic sulfur com-
pounds have a propensity to bind to metals thus acting as
metal deactivators.4
Traditional methods for CÀS bond formation employ
harsh reaction conditions such as high temperatures
(∼200 °C) and the use of toxic and high boiling polar
solvents such as quinoline, HMPA, or N,N-dimethylace-
tamide. Alternatively, these sulfides have been synthesized
by the reduction of aryl sulfones or aryl sulfoxides using
strong reducing agents like DIBAL-H or LiAlH4.5 As an
advance, transition-metal-catalyzedcouplingsystems have
been explored. The palladium-catalyzed cross-coupling
reaction of aryl halides with thiols was first developed by
Migita et al.6 followed by other significant reports7 using
ligands such as triphenylphosphine, bidentate phosphine,
or oxo phosphane derivatives. However, the high cost and
air sensitivity of Pd catalysts and often tedious procedure
for the preparation of ligands restrict their applications in
(1) (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
(b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359. (c) Ley, S. V.; Thoma, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (d) Guo, S.-R.; Yuan, Y.-Q.; Xiang, J.-N. Org. Lett.
2013, 15, 4654.
(2) (a) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, F.; Fesik,
S. W.; Von Genldern, T. W. J. Med. Chem. 2001, 44, 1202. (b) Nielsen,
S. F.; Nielsen, E. Ø.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem.
2000, 43, 2217. (c) Gangjee, A.; Zeng, Y.; Talreja, T.; Mc Guire, J. J.;
Kisliuk, R. L.; Queener, S. F. J. Med. Chem. 2007, 50, 3046. (d) Faucher,
A.-M.; White, P. W.; Brochu, C.; Maitre, C. G.; Rancourt, J.; Fazal, G.
J. Med. Chem. 2004, 47, 18. (e) Martino, G. D.; Edler, M. C.; Regina,
G. L.; Coluccia, A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.;
Chiosis, G.; Brancale, A.; Hamel, E.; Artico, M.; Silvestri, R. J. Med.
Chem. 2006, 49, 947. (f) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza,
S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; Von Geldern, T. W.;
Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025.
(3) (a) Malik, P.; Chakraborty, D. Appl. Organometal. Chem. 2012,
26, 557. (b) Duan, Z.; Ranjit, S.; Zhang, P.; Liu, X. Chem.;Eur. J. 2009,
15, 3666. (c) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J.; Zhang, P.;
Huang, K.-W.; Liu, X. J. Org. Chem. 2011, 76, 8999. (b) Herradura,
P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019.
(4) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
(5) (a) Bierbeek, A. V.; Gingras, M. Tetrahedron Lett. 1998, 39, 6283.
(b) Campbell, J. R. J. Org. Chem. 1964, 29, 1830. (c) Ham, J.; Yang, I.;
Kang, H. J. Org. Chem. 2004, 69, 3236. (d) Yamamoto, T.; Sekine, Y.
Can. J. Chem. 1984, 62, 1544. (e) Lindley, J. Tetrahedron 1984, 40, 1433.
(f) Hickman, R. J. S.; Christie, B. J.; Guy, R. W.; White, T. Aust. J.
Chem. 1985, 38, 899.
(6) (a) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385. (b) Kosugi, M.; Ogata,
T.; Terada, M.; Sano, H.; Migita, T. Bull. Chem. Soc. Jpn. 1985, 58, 3657.
r
10.1021/ol402948k
Published on Web 10/30/2013
2013 American Chemical Society

large-scale processes. A variety of Co,8 Ni,9 In,10 Cu,11 and
Fe12 catalysts have been afterward explored for the im-
provement of reaction conditions for S-arylation. How-
ever, all these metal-catalyzed reactions invariably require
foul-smelling, volatile, and expensive arenethiols, which
are rather less available and prone to oxidative homo-
coupling.13 To resolve these problems, disulfides have also
been tried,14 albeit requiring an stoichiometric equivalent
of the reductants. Hartwig has nicely demonstrated the
Scheme 1. Synthesis of Unsymmetrical Sulfides
t
catalytic use of a Pd(OAc)2ÀCyPFÀ Bu complex for a
remarkably improved synthesis of unsymmetrical diaryl
sulfides from TIPSÀSH and two different aryl halides.15
To have a viable alternative to thiols, use of different other
sulfur sources, namely thiourea,16 thiolates,17 potassium
Table 1. Optimization of Reaction Conditionsa
(7) (a) Barbieri, R. S.; Bellato, C. R.; Dias, A. K. C.; Massabni, A. C.
Catal. Lett. 2006, 109, 171. (b) Fernandez-Rodriguez, M. A.; Shen, Q.;
Hartwig, J. F. Chem.;Eur. J. 2006, 12, 7782. (c) Fernandez-Rodrıguez,
M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180. (d)
Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397. (e) Li, G. Y.
Angew. Chem., Int. Ed. 2001, 40, 1513. (f) Jiang, Z.; She, J.; Lin, X. Adv.
Synth. Catal. 2009, 351, 2558. (g) Iranpoor, N.; Firouzabadi, H.;
Rostami, A. Appl. Organometal. Chem. 2013, 27, 501. (h) Bastug, G.;
Nolan, S. P. J. Org. Chem. 2013, 78, 9303. (i) Valente, C.; C-alimsiz, S.;
Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed.
2012, 51, 3314. (j) Wang, L.; Zhou, W.-Y.; Chen, S.-C.; He, M.-Y.;
Chen, Q. Adv. Synth. Catal. 2012, 354, 839.
(8) (a) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8,
5613. (b) Lan, M.-T.; Wu, W.-Y.; Huang, S.-H.; Luo, K.-L.; Tsai, F.-Y.
RSC Adv. 2011, 1, 1751.
(9) (a) Xu, X. ÀB.; Liu, J.; Zhang, J. J.; Wang, Y.-W.; Peng, Y. Org.
Lett. 2013, 15, 550. (b) Zhang, Y.; Ngeow, K. N.; Ying, J. Y. Org. Lett.
2007, 9, 3495. (c) Zhang, J.; Medley, C. M.; Krause, J. A.; Guan, H.
Organometallics 2010, 29, 6393.
entry
catalyst (mol %)
organic ionic base
yieldb (%)
1
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
[DBU][HOAc]
DBU
nil
25
30
24
35
87
10
12
35
10
30
60
45
nil
2
CoCl2 6H2O (10)
3
3
FeCl3 (10)
CdI2 (10)
4
5
NiCl2 6H2O (10)
3
6
CuI (10)
7
CuBr (10)
8
Cu(OAc)2 H2O (10)
3
9
CuCl2 2H2O (10)
3
10
11
12
13
14
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
Bmim[OH]
[DBU][n-Pr]
[DBU][n-Bu]
[DBU][TFA]
(10) (a) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org.
Lett. 2009, 11, 1697. (b) Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao,
K. R. J. Org. Chem. 2009, 74, 3189.
a Reaction conditions: 1b (1.2 mmol), 2a (1 mmol), CuI (10 mol %),
[DBU][HOAc] (1mL),MW60W,130°C, 10 min. b Isolated yield based on 2a.
(11) (a) Uyeda, C.; Tan, Y.; Fu, G. C.; Peters, J. C. J. Am. Chem. Soc.
2013, 135, 9548. (b) Zhang, S.-L.; Fan, H.-J. Organometallics 2013, 32,
4944. (c) Bahekar, S. S.; Sarkate, A. P.; Wadhai, V. M.; Wakte, P. S.;
Shinde, D. B. Catal. Commun. 2013, 41, 123. (d) Rout, L.; Sen, T. K.;
Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583. (e) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (f) Ku, X.; Huang, H.; Jiang, H.;
Liu, H. J. Comb. Chem. 2009, 11, 338. (g) Bhadra, S.; Sreedhar, B.; Ranu,
B. C. Adv. Synth. Catal. 2009, 351, 2369. (h) Kabir, M. S.; Lorenz, M.;
Van Linn, M. L.; Namjoshi, O. A.; Ara, S.; Cook, J. M. J. Org. Chem.
2010, 75, 3626. (i) Huang, Y.-B.; Yang, C.-T.; Yi, J.; Deng, X.-J.; Fu, Y.;
Liu, L. J. Org. Chem. 2011, 76, 800. (j) Yang, H.; Xi, C.; Miao, Z.; Chen,
R. Eur. J. Org. Chem. 2011, 3353. (k) Carril, M.; SanMartin, R.;
Domınguez, E.; Tellitu, I. Chem.;Eur. J. 2007, 13, 5100. (l) Gonzalez-
Arellano, C.; Luque, R.; Macquarrie, D. J. Chem. Commun. 2009, 1410.
(m) Chen, C.-K.; Chen, Y.-W.; Lin, C.-H.; Lin, H.-P.; Lee, C.-F. Chem.
Commun. 2010, 46, 282. (n) Kamal, A.; Srinivasulu, V.; Murty, N. S. R.
C.; Shankaraiah, N.; Nagesh, N.; Reddy, T. S.; Rao, A. V. S. Adv. Synth.
Catal. 2013, 355, 2297.
(12) (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 2880. (b) Wu, J. R.; Lin, C. H.; Lee, C. F. Chem. Commun. 2009,
4450. (c) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5586. (d) Wu, W.-Y.; Wang, J.-C.; Tsai, F.-Y. Green Chem. 2009, 11,
326.
(13) (a) Prasad, D. J. C.; Sekar, G. Org. Lett. 2011, 13, 1008. (b) Jiang,
Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009, 11,
5250.
ethyl xanthogenate,18 thiocyanate,19 metal sulfides,20 and
carbon disulfide,21 have been recently made to achieve the
formation of diaryl thioethers. The use of thiolates as
sulfur source is however limited to Pd/PÀligand as cata-
lyst, while that of thiourea is confined to the synthesis of
symmetrical disulfides,16a oralkylarylthioethers,16b asthis
method is suitable to generate alkyl thiolates only. Use of
potassium ethyl xanthogenate, thiocyanate, and metal
sulfides necessitates either ligands, highly polar solvents,
or long reaction time. Hence, it is important to find a
practical catalytic protocol to avoid volatile and foul-
smelling thiols and other sulfur sources to achieve highly
useful unsymmetrical aryl sulfides particularly. We have
just developed a new hydrothiolation method to achieve
vinyl sulfides by the reaction of sulfonyl hydrazides with aryl/
heteroarylÀacetylenes in the presence of [DBU][AcOH]/
acetic acid.22 Since the investigation implicated the use of
sulfonyl hydrazide as a new nucleophilic sulfur source, it was
imperative to explore the prospects of this novel thiol
surrogate for other demanding reactions. Considering the
advantages and green credentials of microwave (MW) in
current scenario, it was also thought worthwhile to exploit
(14) (a) Zhang, S.; Qian, P.; Zhang, M.; Hu, M.; Cheng, J. J. Org.
Chem. 2010, 75, 6732. (b) Kumar, S.; Engman, L. J. Org. Chem. 2006, 71,
5400. (c) Taniguchi, N. J. Org. Chem. 2007, 72, 1241.
ꢀ
(15) Fernandez-Rodrıguez, M. A.; Hartwig, J. F. Chem.;Eur. J.
2010, 16, 2355.
(16) (a) Kuhn, M.; Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100.
(b) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. Adv. Synth. Catal.
2010, 352, 119.
(17) Park, N.; Park, K.; Jang, M.; Lee, S. J. Org. Chem. 2011, 76,
4371.
(20) Li, Y.; Nie, C.; Wang, H.; Li, X.; Verpoort, F.; Duan, C. Eur. J.
Org. Chem. 2011, 7331.
(18) Prasad, D. J. C.; Sekar, G. Org. Lett. 2011, 13, 1008.
(19) Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X. Org. Lett.
2011, 13, 454.
(21) Zhao, P.; Yin, H.; Gao, H.; Xi, C. J. Org. Chem. 2013, 78, 5001.
(22) Singh, R.; Raghuvanshi, D. S.; Singh, K. N. Org. Lett. 2013, 15,
4202.
Org. Lett., Vol. 15, No. 22, 2013
5875

Table 2. Synthesis of Unsymmetrical Sulfides Using Sulfonyl Hydrazidesa
a Reaction conditions: 1 (1.2 mmol), 2 (1 mmol), CuI (10 mol %), [DBU][HOAc] (1 mL), MW 60 W, 130 °C, 10 min. b Isolated yield after column
chromatography.
the use of MW irradiation.23 In view of the above and as a
part of our current research program,24 we report herein an
efficient use of stable sulfonyl hydrazides as thiol proxy to
bring about the practical synthesis of highly cherished un-
symmetrical thioethers under microwave irradiation by
means of DBU acetate/CuI (Scheme 1).
To look into the prospects of CÀS cross-coupling, a
model reaction using easily available and reasonably
priced tosylhydrazide and iodobenzene was investigated
(23) (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.
5876
Org. Lett., Vol. 15, No. 22, 2013

in detail by varying different parameters such as catalyst mol
%, MW power, base, additive, solvent, and temperature to
develop the appropriate conditions (Table 1). When the
reaction was carried out in [DBU][HOAc] alone at 130 °C
without the use of a catalyst, it did not provide the desired
unsymmetrical sulfide; rather it gave rise to the disulfide
derived from thiol corresponding to tosyl hydrazide
(Table 1, entry 1). Thereafter, different transition metal
catalysts viz. CoCl2 6H2O, FeCl3, CdI2, NiCl2 6H2O, and
3
3
CuI were added (10 mol %) to the reaction mixture to
determine their catalytic efficacy at 130 °C (entries 2À6).
Out of all the trials, an exceedingly high product yield
(87%) was obtained in the presence of CuI (entry 6). As a
Figure 1. ORTEP diagram of product 3s.
under MW in 10 min (Table 2). However, the reaction
using aliphatic benzyl halides (enties 6, 16, 22, and 25) was
also feasible without the aid of CuI, albeit with lower
product yields. In general, sulfonyl hydrazides containing
electron donating groups and aryl halides with electron
withdrawing group showed better conversion. 1-Chloro-
4-iodobenzene exhibited exclusive chemoselectivity for
the iodo (entry 12). The structure of a representative pro-
duct 3s was conclusively proved by single-crystal X-ray
diffraction (Figure 1). A plausible mechanism rationalizing
the generation of thiolating agent from sulfonyl hydrazide is
outlined in our previous work.22
In summary, we have developed a highly efficient [DBU]-
[HOAc]-promoted and copper-catalyzed cross-coupling
reaction of different sulfonyl hydrazides with aryl/
heteroaryl/benzyl halides under microwave irradiation.
The CÀS bond formation is readily accomplished using
sulfonyl hydrazides as a thiol alternative to afford unsym-
metrical thioethers in high yields under mild conditions.
The versatility, air-stability, operational simplicity, and
environmental friendliness of this method highlights its
potential in organic synthesis.
result, other copper salts such as CuBr, Cu(OAc)2 H2O,
and CuCl2 2H2O were also screened (entries 7À9), but
3
3
none of them could match the value of CuI. The use of
DBU and different ionic liquids such as Bmim[OH],
[DBU][n-Pr], [DBU][n-Bu], and [DBU][TFA] was also
made to check the prospects of reaction (entries 10À14),
but the topmost result was ultimately credited to
[DBU][HOAc] (entry 6). The reaction was further probed
by differing MW power, temperature, and time with the
end result of 60 W power output at 130 °C in 10 min to
achieve the maximum conversion. With regard to the catal-
yst loading, 10 mol % of CuI was found to be optimal as
5 mol % of the catalyst afforded lower yield, and no improve-
ment was observed with 15 mol %. Different additives like
AcOH, DABCO, L-proline, and BF3 Et2O were also as-
3
sessed with [DBU][AcOH] under the optimized conditions but
none of them could better the reaction conditions. Intrigued
by these observations and with the stipulated reaction con-
ditions in hand, the scope and versatility of this method was
extended to the reaction of a variety of sulfonyl hydrazides
viz. benzyl-, phenyl-, p-tolyl-, p-tert-butylphenyl-, p-nitro-
phenyl-, and p-methoxyphenylsulfonyl hydrazides with dif-
ferent benzyl/aryl/heteroaryl halides like benzyl bromide,
benzyl chloride, iodobenzene, bromobenzene, p-iodotoluene,
p-iodoanisole, p-nitroiodobenzene, 2-bromonaphthalene,
2-bromopyridine, 3-bromoquinoline, and 5-bromopyri-
midine to afford a diverse range of unsymmetrical diaryl
or benzyl aryl sulfides 3aÀu in reasonably high yields
Acknowledgment. We are thankful to the Department
of Science and Technology, New Delhi, for providing
financial support (Grant No. SR/S1/OC-78/2012).
Supporting Information Available. General informa-
tion, experimental procedure, spectral data, copies of 1H
and 13C NMR spectra for all products, X-ray data for 3s
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) (a) Vanjari, R.; Guntreddi, T.; Singh, K. N. Org. Lett. 2013, 15,
4908. (b) Singh, N.; Allam, B. K.; Raghuvanshi, D. S.; Singh, K. N. Adv.
Synth. Catal. 2013, 355, 1840. (c) Guntreddi, T.; Allam, B. K.; Singh,
K. N. RSC Adv. 2013, 3, 9875. (d) Raghuvanshi, D. S.; Gupta, A. K.;
Singh, K. N. Org. Lett. 2012, 14, 4326.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5877