SCHEME 1
Con ven ien t P r ep a r a tion of In d olyl
Ma lon a tes via Ca r ben oid In ser tion
Romelo Gibe and Michael A. Kerr*
Department of Chemistry, The University of Western
Ontario, London, Ontario, Canada, N6A 5B7
makerr@uwo.ca
Received April 23, 2002
Abstr a ct: Indoles, when treated with methyldiazomalonate
under catalysis by rhodium(II)acetate, undergo C-H and
N-H insertion reactions regioselectively depending on the
substitution pattern on the indole moiety. In indoles where
the 3-position is unsubstituted, high yields of the C3-H
insertion product were observed. In 3-alkylindoles, 2-sub-
stitution predominated, while N-methyltetrahydrocarbazole
yielded the product resulting from insertion into the C6-H
bond. Indoles in which the nitrogen is unprotected yield
varying degrees of N-H insertion.
SCHEME 2
The indole moiety remains at the forefront of biological
and medicinal chemistry. The most ubiquitous of the
bioactive alkaloids known are based on the indole nucleus.1
Medicinal chemists repeatedly turn to indole-based com-
pounds as a target pharmacophore for the development
of therapeutic agents.2 It should come as no surprise,
then, that there continues to be considerable emphasis
on new methods for the formation and the elaboration of
the benzopyrrole ring system.3 Such methods add to the
palette of the synthetic chemist and aid in the chemical
synthesis of indole alkaloids.4 For some time now, our
group has been keenly interested in the development of
new methods for the formation5 and the elaboration6 of
the indole ring system.
presence of catalytic rhodium acetate (Scheme 1).7 The
only identifiable reaction product was not the desired
cyclopropane but the malonic ester 3. This type of
reaction is not without precedent8 and could proceed via
a cyclopropylindoline,8a which collapses rapidly to the
observed alkylated indole. Most of the reported cases of
this type of reaction are intramolecular, and no reports
appear to exist for the general reaction of diazomalonates
with indoles. Herein we report a useful and high-yielding
method for the installation of a malonate moiety into the
3-position of indoles.
During the course of a study of intramolecular indole/
cyclopropane cyclopentannulations,6b,d we had occasion
to attempt the preparation of cyclopropane 4 via the
treatment of olefin 1 with methyldiazomalonate 2 in the
While Scheme 1 shows an alkylation at the 2-position
of the indole moiety, the putative intermediate 5 could
conceivably collapse to two regioisomeric products giving
either the 2-alkyl or 3-alkyl product (Scheme 2). Loss of
a proton from the benzylic position and dissociation of
the cyclopropane bond leads to 3-alkylation (compound
7 via path a). Loss of a proton R to the nitrogen atom
and dissociation of a cyclopropane bond leads to 2-sub-
stitution (compound 6 via path b). Existing substitution
(1) (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry, 2nd
ed.; Pergammon Press: New York, 1996; Vol. 2, pp 203-257. (b)
Snieckus,V. In The Alkaloids; Academic Press: New York, 1968; Vol.
11, Chapter 1.
(2) Gribble, G. W. In Comprehensive Heterocyclic Chemistry, 2nd ed.;
Pergammon Press: New York, 1996; Vol. 2, pp 211-213.
(3) (a) Gribble, G. W. J . Chem. Soc., Perkin Trans. 1 2000, 1045. (b)
Sundberg, R. J . Indoles; Academic Press: San Diego, 1996. (c) Brown,
R. K. In Heterocyclic Compounds; Wiley: New York, 1972; Vol. 25,
Part 1, Chapter 2.
(4) (a) Rahman, A.; Basha, A. Indole Alkaloids; Harwood Academic
Publishers: Amsterdam, 1998. (b) Saxton, J . E. Heterocyclic Com-
pounds; Wiley: New York, 1994; Vol. 25, Supplement to Part 4. (c)
Saxton, J . E. Heterocyclic Compounds; Wiley: New York, 1983; Vol.
25, Part 4.
(5) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001, 3,
3325. (b) Banfield, S. C.; Kerr, M. A. Synlett 2001, 436.
(6) (a) England, D. B.; Woo, T.; Kerr, M. A. Can. J . Chem. 2002, in
press. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J .
Org. Chem. 2001, 66, 4704. (c) Brown, M. A.; Kerr, M. A. Tetrahedron
Lett. 2001, 42, 983. (d) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett.
1999, 5671. (e) Harrington, P. E.; Kerr, M. A. Can. J . Chem. 1998, 76,
1256. (f) Harrington, P. E.; Kerr, M. A. Tetrahedron Lett. 1997, 5949.
(g) Kerr, M. A.; Harrington, P. E. Synlett 1996, 1047.
(7) (a) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Inter-
science: New York, 1998. (b) Davies, H. M. L. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergammon Press: Oxford, 1991;
Vol. 4, p 1031. (c) Davies, H. M. L.; Clark, T. J .; Church, L. A.
Tetrahedron Lett. 1989, 30, 5057. (d) Doyle, M. P.; van Leusen, D.;
Tamblyn, W. H. Synthesis 1981, 787. (e) Doyle, M. P.; Bagheri, V.;
Wandless, T. J .; Harn, N. K.; Brinker, D. A.; Eagle, C. T.; Ih, K. L. J .
Am. Chem. Soc. 1990, 112, 1906.
(8) (a) Salim, M.; Capretta, F. Tetrahedron 2000, 56, 8063. (b) Wood,
J . L.; Stoltz, B. M.; Dietrich, H.-J .; Pflum, D. A.; Petsch, D. T. J . Am.
Chem. Soc. 1997, 119, 9641. (c) Muthusamy, S.; Gunanathan, C.; Babu,
S. A.; Suresh, E.; Dastidar, P. J . Chem. Soc., Chem. Commun. 2002,
824.
10.1021/jo025851z CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002
J . Org. Chem. 2002, 67, 6247-6249
6247