ORGANIC
LETTERS
2004
Vol. 6, No. 10
1665-1667
Selective Functionalization in Positions
2 and 3 of Indole via an Iodine−Copper
Exchange Reaction
Xiaoyin Yang, Andreas Althammer, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
Received March 17, 2004
ABSTRACT
Two selectively successive I/Cu exchange reactions performed with (Nphyl)CuLi allow the functionalization of indoles in positions 2 and 3.
The 2,3-diketones prepared by this method can readily be converted to tricyclic heterocycles by standard methods.
The indole system occurs in numerous natural products as
well as in many therapeutic agents.1 The preparation of
polyfunctional indoles is therefore an important research
field, and numerous methods have been developed.2 The
direct lithiation of indoles in positions 2 and 3 has been
described;3 however, the resulting lithiated indoles are
compatible with only weakly electrophilic functional groups
at the indole ring.4 Recently, we have shown that mild
conditions are required for performing an iodine-copper
exchange. The excellent functional group tolerance of
organocopper compounds allows the preparation of new
polyfunctional arylcopper species bearing even an aldehyde
group.5 Herein, we wish to report an application of the
iodine-copper exchange reaction for performing a selective
metalation of the 2,3-diiodoindole derivative 1.6 Thus, the
treatment of 1 with the lithium cuprate (PhMe2CCH2)2CuLi
((Nphyl)2CuLi (2); 25 °C, 0.5 h) in a mixture of THF and
diethyl ether (THF/Et2O ) 3:1) provides the cuprate 3. Its
treatment with various electrophiles (E1) furnishes polyfunc-
tional indoles of type 4. The reactions of the 3-iodoindoles
4 with (Nphyl)2CuLi in a 3:1 THF/Et2O mixture at -78 °C
for 30 min lead to the highly functionalized copper species
of type 5, which react with electrophiles (E2) leading to the
indole derivatives of type 6 (Scheme 1, Tables 1 and 2).
(1) Joule, J. A. Sci. Synth. 2001, 10, 361-652.
(2) For some recent methods, see: (a) Gribble, G. W. J. Chem. Soc.,
Perkin Trans 1. 2000, 1045-1048. (b) Battistuzzi, G.; Cacchi, S.; Fabrizi,
G. Eur. J. Org. Chem. 2002, 2671-2681. (c) Battistuzzi, G.; Cacchi, S.;
Fabrizi, G. Marinelli, F.; Parisi, L. M. Org. Lett. 2002, 4, 1355-1358. (d)
Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-704. (e) Beller, M.;
Breinde, C.; Riermeier, T. H.; Eichberger, M; Tranlhwein, H Angew. Chem.,
Int. Ed. 1998, 37, 3389-3391. (f) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. 1999, 38, 2426-2430. (g) Kondo, Y.; Kojima, S.; Sakamoto, T. J.
Org. Chem. 1997, 62, 6507-6511. (h) Coleman, R. S.; Chen, W. Org. Lett.
2001, 3, 1141-1144. (i) Watanabe, M.; Yamamoto, T.; Nishiyama, M.
Angew. Chem., Int. Ed. 2000, 39, 2501-2504. (j) Takeda, A.; Kamijo, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662-5663. (k) Wagaw, S.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251-10263.
(l) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571-1578. (m) Ko¨hling, P.; Schmidt, A. M.;
Eilbracht, P. Org. Lett. 2003, 5, 3213-3216. (n) Knepper, K.; Bra¨se, S.
Org. Lett. 2003, 5, 2829-2832. (o) Barluenga, J. Pure Appl. Chem. 2002,
74, 1317-1326.
(4) (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615-
5616. (b) Knodo, Y.; Matsudaira, T.; Salo, J.; Musata, N.; Sakamolo, T.
Angew. Chem., Int. Ed. Engl. 1996, 35, 736-738.
(3) (a) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26,
5935-5938. (b) Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett.
2001, 42, 7621-7623. (c) Saulnier, M. G.; Gribble, G. W. J. Org. Chem.
1982, 47, 757-761. (d) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000,
41, 8717-8721.
(5) (a) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 3263-
3265. (b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5,
1229-1231. (c) Yang, X.; Knochel, P. Synlett 2004, 1, 81-84.
(6) Witulski, B.; Buschmann, N.; Bergstra¨âer, U. Tetrahedron 2000, 56,
8473-8480. See also ref 3c.
10.1021/ol049498q CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004