W. Wang et al. / Tetrahedron Letters 48 (2007) 3647–3649
3649
4. For examples, see: (a) Flynn, B. L.; Verdier-Pinard, P.;
Hamel, E. Org. Lett. 2001, 3, 651, and references cited
therein; (b) Zhang, T. Y.; O’Toole, J.; Proctor, C. S. Sulfur
Rep. 1999, 22, 1; (c) Zlotin, S. G.; Kislitsin, P. G.; Samet,
A. V.; Serebryakov, E. A.; Konyushkin, L. D.; Semenov,
V. V.; Buchanan, A. C., III; Gakh, A. A. J. Org. Chem.
2000, 65, 8430, and references cited therein.
5. Silvestri, M. G.; Wong, C.-H. J. Org. Chem. 2001, 66, 910,
and references cited therein.
6. (a) Wu, J.; Yang, Z.; Fathi, R.; Zhu, Q.; Wang, L. U.S.
Patent 6,703,514; (b) Wu, J.; Yang, Z.; Fathi, R.; Zhu, Q.
U.S. Pat. Appl. Publ., 2004, 43 pp.
7. (a) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66,
3642; (b) Wu, J.; Wang, L.; Fathi, R.; Yang, Z. Tetra-
hedron Lett. 2002, 43, 4395; (c) Wu, J.; Sun, X.; Zhang, L.
Chem. Lett. 2005, 34, 797; (d) Wu, J.; Zhang, L.; Luo, Y.
Tetrahedron Lett. 2006, 47, 6747; (e) Wu, J.; Zhang, L.;
Xia, H.-G. Tetrahedron Lett. 2006, 47, 1525.
ent electronic demands on aromatic rings involving
electron-donating and electron-withdrawing groups.
Synthetically, all these amination reactions illustrated
in Table 1 went to completion at 80 °C within 24 h,
and the desired products were afforded in good to excel-
lent yields. Better results were generated when anilines
with electron-donating group attached on the aromatic
ring were employed as substrates. For example, com-
pound 2b reacted with p-anisidine leading to the corre-
sponding product 3d in 96% yield, while only 77%
yield of product 3f was obtained when 4-fluoroaniline
was utilized in the reaction (Table 1, entries 4 and 6).
Benzylamine was also a suitable partner in this transfor-
mation. For instance, the reaction of compound 2c with
benzylamine furnished the desired product in 62% yield
(entry 10).
8. For examples, see: (a) Fu, X.; Zhang, S.; Yin, J.;
McAllister, T. L.; Jiang, S. A.; Tann, C.-H.; Thiruvenga-
dam, T. K.; Zhang, F. Tetrahedron Lett. 2002, 43, 573; (b)
Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P. Tetra-
hedron Lett. 2002, 43, 6673; (c) Lei, J.-G.; Xu,
M.-H.; Lin, G.-Q. Synlett 2004, 2364; (d) Tang, Z. Y.;
Hu, Q.-S. Adv. Synth. Catal. 2004, 346, 1635; (e) Schio, L.;
Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543.
9. Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67,
7429.
In summary, the reaction described here represents a
highly efficient and practical route to 3-amino-4-sulfan-
yl-coumarins. The synthesis of the focused library of this
type biological activity screening of these small mole-
cules are under investigation in our laboratory.
Acknowledgements
10. For reviews, see: (a) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125; (b) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805; (c) Hartwig, J. F. Angew. Chem., Int.
Ed. 1998, 37, 2046.
We thank Professors Xue-Long Hou and Zhen Yang
for their invaluable advice during the course of this
research. Financial support from National Natural
Science Foundation of China (20502004, 20642006) and
the Science and Technology Commission of Shanghai
Municipality (05ZR14013) is gratefully acknowledged.
11. General procedure for the synthesis of 3-amino-4-sul-
fanylcoumarins via substitution and palladium-catalyzed
amination reaction. Reaction of 3-bromo-4-tosyloxy-cou-
marin 1 with thiols: Triethylamine (1.1 mmol) was added to
a solution of 3-bromo-4-tosyloxy-coumarin 1 (1.0 mmol)
and thiol (1.0 mmol) in dichloromethane (2.0 mL) at room
temperature. After the reaction was complete monitored
by TLC, the mixture was directly purified by flash column
chromatography on silica gel to afford the desired 3-
bromo-4-sulfanylcoumarin 2. Palladium-catalyzed reaction
of 3-bromo-4-sulfanyl-coumarin 2 with amine: A mixture of
3-bromo-4-sulfanyl-coumarin 2 (0.25 mmol), potassium
carbonate (2.0 equiv), Pd2(dba)3 (5 mol %), and Xantphos
(10 mol %) was added into a reaction tube under nitrogen
atmosphere. Then toluene (2.0 mL) and amine (1.2 equiv)
was added subsequently. The reaction mixture was stirred
at 80 °C overnight. Following completion of the reaction
as monitored by TLC, the reaction mixture was cooled,
diluted with ethyl acetate (10 mL), washed with water
(3.0 mL), brine (3.0 mL) and dried over Na2SO4. The
solvent was removed under vacuum and the residue was
purified by flash chromatography to give the correspond-
ing 3-amino-4-sulfanylcoumarin 3.
References and notes
1. For examples, see: (a) Santana, L.; Uriarte, E.; Gonzalez-
Diaz, H.; Zagotto, G.; Soto-Otero, R.; Mendez-Alvarez,
E. J. Med. Chem. 2006, 49, 1149; (b) Rivkin, A.; Adams,
B. Tetrahedron Lett. 2006, 47, 2395; (c) Yamaguchi, T.;
Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett.
2006, 47, 3755, and references cited therein; (d) Burlison,
J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S.
J. J. Am. Chem. Soc. 2006, 128, 15529.
2. (a) Gellert, M.; O’Dea, M. H.; Itoh, T.; Tomizawa, J. I.
Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474; (b) Pereira,
N. A.; Pereira, B. M. R.; Celia do Nascimento, M.;
Parente, J. P.; Mors, W. B. Planta Med. 1994, 60, 99; (c)
Levine, C.; Hiasa, H.; Marians, K. J. Biochim. Biophys.
Acta 1998, 1400, 29.
3. Witczak, Z. J. Curr. Med. Chem. 1999, 6, 165.