Published on Web 05/09/2002
Mechanistic Study of â-Substituent Effects on the Mechanism
of Ketone Reduction by SmI2
Edamana Prasad and Robert A. Flowers, II*
Department of Chemistry and Biochemistry, Texas Tech UniVersity, Box 41061,
Lubbock, Texas 79409-1061
Received January 9, 2002
Abstract: The rate constants for the reduction of 2-butanone, methylacetoacetate, N, N-dimethylacetoac-
etamide, and a series of 4′- and 2′-substituted acetophenone derivatives by SmI2 were determined in dry
THF using stopped-flow absorption decay experiments. Activation parameters for the electron-transfer
processes in each series of compounds were determined by a temperature-dependence study over a range
of 30 to 50 °C. Two types of reaction pathways are possible for these electron-transfer processes. One
proceeds through coordination (Scheme 1) while the other involves chelation (Scheme 2). The results
described herein unequivocally show that both coordination and chelation provide highly ordered transition
states for the electron-transfer process but the presence of a chelation pathway dramatically increases the
rate of the reduction of these substrates by SmI2. The ability of various functional groups to promote a
chelated reaction pathway plays a crucial role in determining the rate of the reaction. Among the
2′-substituted acetophenone series, the presence of a fluoro, amino, or methoxy substituent enhances the
rate of reduction compared to the 4′-analogues. In particular, the presence of a 2′-fluoro substituent on
acetophenone provides a highly ordered transition state and considerably enhances the rate of ketone
reduction.
Introduction
reaction with the equilibrium lying to the side of unreacted
dialkyl ketone and SmI2 (1).12
Since Kagan’s pioneering work in 1980,1 Samarium diiodide
(SmI2) has become a powerful tool in the arsenal of synthetic
chemists. There are essentially three classes of transformations
mediated by SmI2 that are discussed in Kagan’s seminal paper:
functional group reductions, reductive coupling of two Π bonds,
and reductive coupling between halides and Π bonds. In
particular, the reduction of ketones to alcohols and the reductive
coupling of carbonyls with olefins provide entry into a diverse
range of natural products2 including, (()-muscone,3 upial,4
paeoniflorigenin,5 (-)-grayanotoxin,6 and (-)-steganone.7 Al-
though SmI2 is clearly a useful reagent in organic synthesis, its
mode of action in the reduction of carbonyls is only beginning
to be understood at a basic level.
While additives can increase the rate of ketone reduction,
the presence of an amide or ester in close proximity to a ketone
also enhances the rate of reduction to a ketyl. In fact, Molander
has reported that â-ketoamides can be reduced preferentially
in the presence of a pendant alkyl iodide.13 This is surprising
because the redox potentials of alkyl iodides are typically 1 V
less negative than dialkyl ketones, and this indicates that
chelation may enhance the rate of reduction of ketones
significantly.
In the realm of enantioselective reactions, chelation is the
predominant feature of most transition-state models that are used
to explain the stereochemical outcome of reactions mediated
by SmI2. Molander,14 Keck,15 and Matsuda16 have utilized chiral
The reduction of dialkyl ketones to alcohols or pinacols by
SmI2 tends to be a slow process in the absence of additives
such as HMPA,8 alcohols,9 or inorganic salts.10 Conversely, the
intramolecular reductive coupling of ketones containing pendant
olefins is a fast reaction.11 On the basis of this evidence, Curran
postulated that the reductions of ketones is a fast reversible
(8) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485.
(9) (a) Kagan, H. B.; Namy, J. L.; Girard, P. Tetrahedron 1981, 37, 175; (b)
Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2001, 42, 5565.
(10) (a) Kamochi, Y.; Kudo, T. Tetrahedron Lett. 1991, 32, 3511; (b) Fuchs, J.
R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett.
1997, 38, 8157.
(11) Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60, 872.
(12) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.; Totleben, M. J. Synlett 1992,
943.
(13) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109,
453.
To whom correspondence should be addressed. E-mail: robert.flowers@
ttu.edu.
(1) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693.
(2) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307.
(3) Suginome, H.; Yamada, S. Tetrahedron Lett. 1987, 28, 3963.
(4) Nagaoka, H.; Shibuya, K.; Yamada, Y. Tetrahedron Lett. 1993, 34, 1501.
(5) Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871.
(6) Kan, T.; Hosokawa, S.; Nara, S.; Oikawa, M.; Ito, S.; Matsuda, F.;
Shirahama, H. J. Org. Chem. 1994, 59, 5532.
(14) Molander, G. A.; Harris, C. R. J. Org. Chem. 1998, 63, 812.
(15) Keck, G. E.; Wager, C. A.; Sell, T.; Wager, T. T. J. Org. Chem. 1999, 64,
2172.
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Soc. 2000, 122, 52.
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10.1021/ja020051r CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 6357-6361
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