Published on Web 09/06/2002
The Copper-Catalyzed N-Arylation of Indoles
Jon C. Antilla, Artis Klapars, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received June 24, 2002
Abstract: A general method for the N-arylation of indoles using catalysts derived from CuI and trans-1,2-
cyclohexanediamine (1a), trans-N,N′-dimethyl-1,2-cyclohexanediamine (2a), or N,N′-dimethyl-ethylenedi-
amine (3) is reported. N-Arylindoles can be produced in high yield from the coupling of an aryl iodide or
aryl bromide with a variety of indoles.
Introduction
The Ullmann-type1 coupling of aryl halides with indoles
represents a straightforward, inexpensive approach to N-
arylindoles.2 These copper-catalyzed reactions traditionally have
required high temperatures, generally 140 °C or more, and often
the use of two or more equivalents of the aryl halide to obtain
optimal yields. The palladium-catalyzed N-arylation of indoles
is an alternative method that addresses the problems of extreme
reaction temperatures.3 Problems, however, such as C-3 aryla-
tion, and an intolerance of several important functional groups
have also limited this method. Further, because of the relatively
high cost of palladium, mild alternatives using inexpensive
metals are desirable. Copper-catalyzed methods reported for the
arylation of nitrogen heterocycles using mild conditions include
the use of arylboronic acids,4 aryl bismuth,5 and aryl lead6
reagents. These methods using alternative arylating agents,
derived from the corresponding aryl halide, are restricted in
terms of the level of substitution tolerated on either the aryl or
indole substrates. Additionally, the toxicity of bismuth and lead
compounds and the cost of arylboronic acids detracts from their
appeal. The nucleophilic aromatic substitution of aryl halides,
activated by electron-withdrawing substituents, with indole
represent an alternate route to N-arylindoles for some substrate
combinations.7
Figure 1. Diamine ligands used for the N-arylation of indoles.
We have previously found that the use of 1,10-phenanthroline
as a ligand for copper could provide more active catalysts for
the N-arylation of imidazoles.8 Goodbrand also observed a
similar acceleration in the arylation of diarylamines to form
triarylamines.9 To discover a more active and general catalyst
system for the N-arylation of indoles, we explored the use of
simple chelating ligands for copper. We soon found that copper
catalysts derived from copper iodide and simple diamine ligand
1 (Figure 1) could efficiently catalyze the coupling of aryl
halides with amides (Goldberg coupling) and N-H heterocycles
in excellent yields under relatively mild conditions and with
low quantities of copper.10 Moreover, the reaction of a variety
of substituted indoles with aryl iodides was explored. Reactions
of carbazole, 7-azaindole, 5-cyano-, and 5-aminoindole pro-
ceeded in high yield. Hindered indoles (those substituted in the
2- and 7-position) were shown to provide the desired products
in moderate yields. In this paper, we report in full our
investigations of the N-arylation of indoles and disclose an
improved copper catalyst system. Our new protocol employs
ligands 2a and 3, with the latter being commercially available,
for the coupling of a variety of indoles with substituted aryl
iodides and bromides.
(1) For a general review, see Lindley, J. Tetrahedron 1984, 40, 1433.
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1980, 23, 635. (c) Lexy, H.; Kauffmann, T. Chem. Ber. 1980, 113, 2755.
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Heterocyclic Chem. 1987, 24, 811. (e) Kato, Y.; Conn, M. M.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1994, 116, 3279. (f) Murakami, Y.; Watanabe, T.;
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I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
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Results and Discussion
In our initial report, the N-arylation of indoles utilized 1-5
mol % CuI, 10-20 mol % ligand 1a,11 K3PO4 as base and
(7) (a) Smith, W. J., III; Sawyer, J. S. Tetrahedron Lett. 1996, 37, 299. (a)
Maiorana, S.; Baldoli, C.; Del Buttero P.; Di Ciolo, M.; Papagni, A.
Synthesis 1998, 735. (c) Smith, W. J., III; Sawyer, J. S. Heterocycles 1999,
51, 157.
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(9) Goodbrand, H. B.; Hu N.-X. J. Org. Chem. 1999, 64, 670.
(10) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727.
(11) We would like to thank Arran Chemical Company for a generous gift of
ligand 1a.
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J. AM. CHEM. SOC. 2002, 124, 11684-11688
10.1021/ja027433h CCC: $22.00 © 2002 American Chemical Society