ORGANIC
LETTERS
2006
Vol. 8, No. 20
4517-4520
Novel and Efficient Synthesis of
Iminocoumarins via Copper-Catalyzed
Multicomponent Reaction
Sun-Liang Cui, Xu-Feng Lin, and Yan-Guang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P. R. China
Received July 9, 2006
ABSTRACT
A variety of substituted iminocoumarins are prepared in good to excellent yields via a copper-catalyzed multicomponenet reaction of sulfonyl
azides, terminal alkynes, and salicylaldehydes or o-hydroxylacetophenones. The method is general, mild, versatile, and efficient. A plausible
mechanism for the domino process is proposed.
Coumarins are an important class of compounds that exist
widely in nature and have numerous applications in medi-
cine1 and perfumery,2 as dyes in laser technology,3 and as
fluorescent indicators.4 A number of coumarins possess
interesting biological activity, including anticancer, antifun-
gal, and anti-HIV activities.5 Coumarin derivatives, imi-
nocoumarins have been reported to be a type of protein
tyrosine kinase (PTK) inhibitors that are most valuable for
the treatment of diseases involving excess cell proliferation
as well as the antitumor process.6 Classic methods for the
synthesis of iminocoumarins, such as Knoevenagel reaction
and derivation from coumarins, suffer from major shortcom-
ings such as limited substituents and troublesome chemical
managing processes.7 Thus general and efficient approaches
to iminocoumarin are attractive and challenging.
Multicomponent reactions (MCRs) involving a domino
process with at least three different simple substrates have
emerged as a powerful strategy.8 This methodology allows
molecular complexity and diversity to be created by the facile
formation of several new covalent bonds in a one-pot
transformation quite closely approaching the concept of an
ideal synthesis and is particularly well-adapted for combi-
natorial synthesis.9
(1) (a) Coumarins: Biology, Applications, and Mode of Action; O’Kennedy,
R., Thomas, R. D., Eds.; Wiley: Chichester, UK, 1997. (b) Yu, D.; Suzuki,
M.; Xie, L.; Morris-Natschke, S. L.; Lee, K.-H. Med. Res. ReV. 2003, 23,
322-345. (c) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins; Wiley: Chichester, U.K., 1982.
(7) (a) Volmajer, j.; Toplak, R.; bittner, S.; Leban, I.; Le Marechal, A.
M. Tetrahedron Lett. 2003, 44, 2363-2366. (b) EI-Emary, T. I.; Khalil,
A.; EI-Hag Ali, G. A. M.; EI-Adasy, A. A. A. M. Phosphrous, Sulfur Silicon
the Relat. Elem. 2005, 180, 19-30.
(8) (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E.
Org. Lett. 2004, 6, 4223-4225. (b) Lie´by-Muller, F.; Constantieux, T.;
Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176-17177. (c) Byk, G.;
Kabahn, E. J. Comb. Chem. 2004, 6, 596-603. (d) Marcaccini, S.; Miguel,
D.; Torroba, T.; Garcia-Valverge, M. J. Org. Chem. 2003, 68, 3315-3318.
For some recent reviews of MCRs, see: (e) Ramon, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602-1634. (f) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.-Eur. J. 2000, 6, 3321-3329. (g) Domling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (h) Zhu, J. Eur. J. Org.
Chem. 2003, 1133-1144.
(2) Clark, G. S. Perfum. FlaVor. 1995, 20, 23-34.
(3) Sekar, N. Colourage 2003, 50, 55-56.
(4) Brun, M.-P.; Bischoff, L.; Garbay, C. Angew. Chem., Int. Ed. 2004,
43, 3432-3436.
(5) (a) Hariprassad, V.; Talele, T. T.; Kulkarni, V. M. Pharm. Pharmacol.
Commun. 1998, 4, 365-372. (b) Sardari, S.; Nishibe, S.; Daneshtalab, M.
Stud. Nat. Prod. Chem. 2000, 23, 335-393. (c) Lacy, A.; O’Kennedy, R.
Curr. Pharm. Des. 2004, 10, 3797-3811.
(6) (a) Burke, T. R.; Lim, B.; Marquez, V. E.; Li, Z.-H.; Bolen, J. B.;
Stefanova, I.; Horak, I. D. J. Med. Chem. 1993, 36, 425-432. (b)
O’Callaghan, C. N.; Conalty, M. L. Proc. R. Ir. Acad., Sect. B 1979, 6,
87-98.
10.1021/ol061685w CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006