ORGANIC
LETTERS
2010
Vol. 12, No. 10
2430-2433
One-Pot Synthesis of Amine-Substituted
Aryl Sulfides and Benzo[b]thiophene
Derivatives
Zhongyu Duan, Sadananda Ranjit, and Xiaogang Liu*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
Received April 9, 2010
ABSTRACT
A series of amine-substituted aryl sulfides have been synthesized from nitroaryl halides via a simple one-pot procedure involving metal-free
C-S cross-coupling and in situ nitro group reduction. Various nitroaryl halides were reacted with thiols in recyclable poly(ethylene glycol) to
afford the amine-substituted aryl sulfides in high yield. Additionally, the cross-coupling reactions of nitro- and aldehyde-substituted aryl
halides with benzyl thiols under the same reaction conditions were demonstrated to afford benzothiazole and phenylbenzo[b]thiophene derivatives.
Amine-substituted aryl sulfides are pivotal intermediates
for the synthesis of biologically and pharmaceutically
active molecules. A number of amine-substituted aryl
sulfides have shown potential clinical applications as
antitumor, antifungal, and anti-inflammatory agents.1 In
general, there are three approaches to synthesizing amine-
substituted aryl sulfides. One is to directly couple ami-
noaryl halides with thiols to form the desired compounds.2
The second approach is based on a two-step procedure
involving synthesis of nitroaryl sulfides and subsequent
reduction of the nitro group.3 The third major approach
relies on the cross-coupling of boronic acid derivatives
with aminoaryl disulfides.4 Despite their wide application
in the synthesis of amine-substituted aryl sulfides, these
approaches have limitations with regard to the need of
either costly metal catalysts or multistep reactions. Adapa
and co-workers have reported a one-step synthesis of
aminoaryl sulfides in moderate yields by reacting ami-
noaryl halides with thiols in the absence of the metal
catalyst, but this method requires relatively expensive
iodide or bromide precursors and cesium hydroxide.5 Here,
(1) (a) Marcincal-Letebvre, A.; Gesquiere, C.; Lemer, C.; Dupuis, B.
J. Med. Chem. 1981, 24, 889. (b) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.;
Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; von Geldem, T. W.;
Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025. (c)
Gangjee, A.; Zeng, Y.; Talreja, T.; McGuire, J. J.; Kisliuk, R. L.; Queener,
S. F. J. Med. Chem. 2007, 50, 3046. (d) Jarkas, N.; McConathy, J.; Voll,
R. J.; Goodman, M. M. J. Med. Chem. 2005, 48, 4254.
(3) (a) Jarkas, N.; McConathy, J.; Voll, R. J.; Goodman, M. M. J. Med.
Chem. 2005, 48, 4254. (b) Wrobel, Z. Tetrahedron 2003, 59, 101.
(4) (a) Taniguchi, N. J. Org. Chem. 2007, 72, 1241. (b) Taniguchi, N.
Synlett 2006, 9, 1351.
(2) (a) Carril, M.; SanMartin, R; Dominguez, E.; Tellitu, I. Chem.sEur.
J. 2007, 13, 5100. (b) Zhang, H.; Cao, W.; Ma, D. Synth. Commun. 2007,
37, 25. (c) Wong, Y. C.; Jayanth, T. T.; Cheng, C.H. Org. Lett. 2006, 8,
5613. (d) Fernandez-Rodrıguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 2180. (e) Ham, J.; Cho, S. J.; Ko, J.; Chin, J.; Kang,
H. J. Org. Chem. 2006, 71, 5781. (f) Reddy, V. P.; Swapna, K.; Kumar,
A. V.; Rao, K. R. J. Org. Chem. 2009, 74, 3189. (g) Fernandez-Rodrıguez,
M. A.; Hartwig, J. F. J. Org. Chem. 2009, 74, 1163. (h) Feng, Y.; Wang,
H.; Sun, F.; Li, Y.; Fu, X.; Jin, K. Tetrahedron 2009, 65, 9737. (i) Taniguchi,
N. J. Org. Chem. 2004, 69, 6904. (j) Sperotto, E.; Klink, G. P. M. V.;
Vries, J. G. D.; Koten, G. V. J. Org. Chem. 2008, 73, 5625.
(5) Varala, R.; Ramu, E.; Alam, M. M.; Adapa, S. R. Chem. Lett. 2004,
33, 1614.
(6) (a) Heldebrant, D.; Jessop, P. G. J. Am. Chem. Soc. 2003, 125, 5600.
(b) Perrier, S.; Gemici, H.; Li, S. Chem. Commun. 2004, 604. (c) Zhang,
Z.-H.; Yin, L.; Wang, Y.-M.; Liu, J.-Y.; Li, Y. Green Chem. 2004, 6, 563.
(d) Chandrasekhar, S.; Narsihmulu, Ch.; Shameem Sultana, S.; Ramakrishna
Redd, N. Org. Lett. 2002, 4, 4399. (e) Wang, L.; Zhang, Y.; Liu, L.; Wang,
Y. J. Org. Chem. 2006, 71, 1284. (f) Tzitzios, V.; Basina, G.; Gjoka, M.;
Alexandrakis, V.; Georgakilas, V.; Niarchos, D.; Boukos, N.; Petridis, D.
Nanotechnology 2006, 17, 3750.
10.1021/ol100816g 2010 American Chemical Society
Published on Web 04/26/2010