C O M M U N I C A T I O N S
Table 2. Catalytic Synthesis of R-Substituted Ketonesa
copper, zinc, or magnesium to the R-carbon of the ketone substrate
(Scheme 2, path c). Metal coordination to the chloride or carbonyl
may occur, although no evidence currently implicates these modes
of activation. The copper-catalyzed substitution of R-chloroketones
thus appears mechanistically distinct from copper-catalyzed allylic
substitution reactions.13
The copper-catalyzed cross-coupling of organozinc halides with
R-chloroketones represents a general strategy for the synthesis of
R-branched ketones. Furthermore, the use of optically active
chloroketones has enabled the preparation of enantiomerically
enriched substituted ketones. Notably, the products derived from
addition of secondary alkyl zinc reagents would be difficult to access
using conventional enolate alkylation. Current efforts are directed
toward expanding this reaction manifold to include other classes
of nucleophiles and electrophiles.
Acknowledgment. We acknowledge assistance from Dr. Carlos
A. Amezcua and Dr. Sanjay C. Panchal (UT Southwestern) with
NMR experiments. J.M.R. is a Southwestern Medical Foundation
Scholar in Biomedical Research.
Supporting Information Available: Experimental procedures for
cross-coupling reactions and eqs 1-2; spectral data for all new
compounds. This material is available free of charge via the Internet
References
(1) Cain, D. In Carbon-Carbon Bond Formation; Augustine, R. L., Ed.; M.
Dekker: New York, 1979; Vol. 1, pp 86-249.
(2) (a) Inoue, Y.; Toyofuku, M.; Taguchi, M.; Okada, S.; Hashimoto, H. Bull.
Chem. Soc. Jpn. 1986, 59, 885-891. (b) Imai, M.; Hagihara, A.; Kawasaki,
H.; Manabe, K.; Koga, K. Tetrahedron 2000, 56, 179-185. (c) Cho, C.
S.; Kim, B. T.; Kim, T.-J.; Sim, S. C. Tetrahedron Lett. 2002, 43, 7987-
7989. (d) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
Int. Ed. 2002, 41, 3492-3495. (e) Vignola, N.; List, B. J. Am. Chem.
Soc. 2004, 126, 450-451.
(3) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry; HarperCollins: New York, 1987; pp 376-379.
(4) Cross-couplings of R-halo carbonyl compounds: (a) Amano, T.; Yoshika-
wa, K.; Sano, T.; Ohuchi, Y.; Shiono, M.; Ishiguro, M.; Fujita, Y. Synth.
Comm. 1986, 16, 499-507. (b)Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.;
Baba, A. J. Am. Chem. Soc. 2002, 124, 7440-7447. (c) See also Hennessy,
E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084-12085.
(5) Copper-catalyzed reactions of alkyl zinc reagents: (a) Fujii, N.; Nakai,
K.; Habashita, H.; Yoshizawa, H.; Ibuka, T.; Garrido, F.; Mann, A.;
Chounan, Y.; Yamamoto, Y. Tetrahedron Lett. 1993, 34, 4227-4230.
(b) Dubner, F.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 379-381.
(c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley: New York, 2002; pp
224-258. (d) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 5680-5681.
a Reactions were carried out under N2 for 14 h at 25 °C. See Supporting
Information for complete experimental details. b Alkyl zinc halide reagents
were prepared as suspensions in Et2O ([RZnX] ) 0.2 M) via treatment of
ZnX2 with RMgX. c Isolated yields.
) Cu, Zn, or Mg) would occur with inversion of stereochemistry.
To distinguish between the latter two mechanistic possibilities, the
stereochemical course of the reaction was investigated. Cross-
coupling with optically active chloroketone 2j indicated that the
substitution reaction occurs with inversion of stereochemistry (eq
2).11
(6) Reactions of lithium dialkyl cuprates with R-bromo ketones: (a) Posner,
G. H.; Sterling, J. J.; Whitten, C. E.; Lentz, C. M.; Brunelle, D. J. J. Am.
Chem. Soc. 1975, 97, 107-118 and references therein. (b) Vaillancourt,
V.; Albizati, K. F. J. Org. Chem. 1992, 57, 3627-3631.
(7) Tertiary alkylzinc reagents and tertiary R-chloro ketones provide negligible
yields of the cross-coupled products.
(8) (a) Bartlett, P. D.; Rosenwald, R. H. J. Am. Chem. Soc. 1934, 56, 1990-
1994. (b) Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K.
Tetrahedron 1981, 37, 3967-3975.
(9) Control experiments verified formation of the zinc alkoxide under the
conditions of eq 1. At elevated temperatures, ring contraction to generate
cyclopentyl isopropyl ketone predominates. See the Supporting Information
for details.
(10) The copper enolate could exist primarily in the η-1 O-bound, η-1 C-bound
or η-3 oxallyl form. For a theoretical study, see: Rosi, M.; Sgamellotti,
A.; Floriani, C. J. Mol. Stuct. (THEOCHEM) 1999, 459, 57-65.
(11) Additional examples can be found in the Supporting Information.
(12) The uncatalyzed reaction occurs with inversion of configuration. See the
Supporting Information for details.
A final observation pertinent to the mechanistic discussion relates
to the reaction of chloroketone 2a with isopropylzinc chloride in
the absence of copper (Table 1, entry 8).12 This unusual example
of an uncatalyzed substitution reaction with an alkyl zinc reagent
indicates that a direct displacement pathway is accessible.5d
Taken together, the data are most simply explained by a
mechanism in which an alkyl group is directly transferred from
(13) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126,
6287-6293 and references therein.
JA0467768
9
J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004 10241