ORGANIC
LETTERS
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004
Vol. 6, No. 4
33-535
Catalytic C−H Functionalization Driven
by CO as a Stoichiometric Reductant:
Application to Carbazole Synthesis
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Jacqueline H. Smitrovich* and Ian W. Davies
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065-0900
Received November 24, 2003
ABSTRACT
A palladium-catalyzed regioselective C−H bond functionalization driven by CO as the stoichiometric reductant is described. Nitrogen heterocycles,
e.g., carbazoles, are accessible in good to excellent yields with use of palladium acetate and 70 psig of carbon monoxide at 140 °C.
The functionalization of unactivated C-H bonds represents
a powerful approach to C-C and C-heteroatom bond
formation and is currently receiving significant attention.
cyclization of o-nitro arenes in refluxing triethyl phosphite
as solvent remains the most common method to effect this
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,9
transformation. The widely accepted mechanism for this
transformation involves exhaustive deoxygenation to a singlet
Palladium-catalyzed processes using stoichiometric Cu(OAc)
or dioxygen have recently been developed for the formation
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nitrene that undergoes a downstream C-H insertion. While
broad in scope, the generation of a large amount of
phosphorus waste detracts from this approach. In recent
years, transition metal catalyzed variants of this reaction with
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2,3
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4
of C-C, C-N, and C-O bonds. Rhodium-catalyzed
formation of C-N bonds with PhI(OAc) as the stoichio-
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metric oxidant has also been reported and exploited in
complex molecule synthesis, e.g. (-)-tetrodotoxin. These
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11,12
CO as the stoichiometric reductant have been developed.
new methods introduce functionality at C-H bonds via a
catalytic cycle driven by a terminal oxidative event.
Deoxygenation of nitroaromatics to give heterocycles was
first realized by Waterman and Vivian in 1940 using
Palladium/phosphine catalysts are effective for the reductive
(7) (a) Waterman, H. C.; Vivian, D. L. U.S. 2,292,808, 1942. (b)
Waterman, H. C.; Vivian, D. L. J. Org. Chem. 1949, 14, 289-297.
(8) (a) Cadogan, J. I. G. Synthesis 1969, 1, 11-17. (b) Cadogan, J. I. G.
Organophosphorus Reagents Org. Synth. 1979, 269-294. (c) Cadogan, J.
I. G. Lect. Heterocycl. Chem. 1978, 4, 17-23. (d) Sundberg, R. J. J. Org.
Chem. 1965, 30, 3604-3610.
(9) For applications in the syntheses of carbazole alkaloids, see: (a)
Lowinger, T. B.; Chu, J.; Spence, P. L. Tetrahedron Lett. 1995, 36, 8383-
8386. (b) Moody, J. C. Synlett 1994, 681-688. (c) Hughes, I.; Nolan, W.
P.; Raphael, R. A. J. Chem. Soc., Perkin Trans. 1 1990, 2475-2477.
(10) S o¨ derberg, B. C. G. Org. Chem. 2000, 4, 727-764.
(11) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375-3380.
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stoichiometric iron oxalate at 200 °C. The deoxygenative
(
1) (a) Sezen, B.; Franz, R.; Sames, D. J. Am. Chem. Soc. 2002, 124,
1
1
3372-13373. (b) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
25, 9578-9579.
(2) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
2
003, 125, 12996-12997. (b) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew.
Chem., Int. Ed. 2002, 41, 164-166. (c) Larock, R. C.; Hightower, T. R.;
Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585.
(3) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892-2895.
4) For a review of Pd(II)-catalyzed reactions, see: Hegedus, L. S.
Tetrahedron 1984, 40, 2415-2434.
5) (a) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003,
25, 2028-2029. (b) Espino, C. G.; When, P. M.; Chow, J.; Du Bois, J. J.
Am. Chem. Soc. 2001, 123, 6935-6936.
6) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510-11511.
(12) For palladium-catalyzed reductive cyclization to indoles, see: (a)
Ragaini, F.; Sportiello, P.; Cenini, S. J. Organomet. Chem. 1999, 577, 283-
291. (b) Tollari, S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal. 1994,
87, 203-214. (c) Scott, T. L.; S o¨ derberg, B. C. G. Tetrahedron Lett. 2002,
43, 1621-1624. (d) S o¨ derberg, B. C.; Rector, S. R.; O’Neil, S. N.
Tetrahedron Lett. 1999, 40, 3657-3660. (e) S o¨ derberg, B. C.; Shriver, J.
A. J. Org. Chem. 1997, 62, 5838-5845.
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0.1021/ol036294l CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004