ORGANIC
LETTERS
2009
Vol. 11, No. 1
173-176
A Novel Synthetic Route to 3-Sulfenyl-
and 3-Selenylindoles by n-Bu4NI-Induced
Electrophilic Cyclization
Yu Chen, Chul-Hee Cho, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received September 10, 2008
ABSTRACT
3-Sulfenyl- and 3-selenylindoles are prepared in excellent yields by the palladium/copper-catalyzed crossing coupling of N,N-dialkyl-o-iodoanilines
and terminal alkynes, followed by electrophilic cyclization with arylsulfenyl chlorides and arylselenyl chlorides in the presence of a stoichiometric
amount of n-Bu4NI.
The indole ring is a ubiquitous heterocycle in a wide variety
of biologically important compounds as well as pharmaceuti-
cal agents.1 Among the numerous indole derivatives, 3-thio-
indoles have recently attracted considerable interest from the
pharmaceutical industry due to their therapeutic value in
diseases, such as HIV,2 cancer,3 obesity,4 heart disease,5 and
allergies.6 A number of synthetic routes to 3-sulfenylindoles
have been demonstrated in the literature, including the direct
sulfenylation of indoles by disulfides7 and quinone mono-
O,S-acetals;8 halide-catalyzed sulfenylation by N-thioalkyl-
(aryl)phthalimides;9 sulfenylation using thiols activated in
situ by N-chlorosuccinimide,10 phenyliodine(III) bis(trifluo-
roacetate),11 Selectfluor,12 or transition-metal catalysts;13
oxidant-promoted thiocyanation with ammonium thiocyan-
ate;14 and treatment of 3,3′-dithiobisindoles with metalated
aromatics or heterocycles.15 In general, all these protocols
have focused on direct sulfenylation at the 3-position of the
indole nucleus using different sulfenylating agents.
Recently, our group has shown that the palladium/copper-
catalyzed coupling of functionally substituted aryl halides
and terminal alkynes provides aromatic acetylenes, which
readily undergo electrophilic cyclization in the presence of
halogen, sulfur, and selenium electrophiles to produce an
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(4) Ramakrishna, V. S. N.; Shirsath, V. S.; Kambhampati, R. S.;
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(14) (a) Pezzella, A.; Palma, A.; Iadonisi, A.; Napolitano, A.; d’Ischia,
M. Tetrahedron Lett. 2007, 48, 3883. (b) Wu, G.; Liu, Q.; Shen, Y.; Wu,
W.; Wu, L. Tetrahedron Lett. 2005, 46, 5831. (c) Yadav, J. S.; Reddy,
B. V. S.; Krishna, A. D.; Reddy, C. S.; Narsaiah, A. V. Synthesis 2005,
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10.1021/ol8021287 CCC: $40.75
Published on Web 12/01/2008
2009 American Chemical Society