ORGANIC
LETTERS
2009
Vol. 11, No. 8
1773-1775
Selective Monoarylation of Acetate
Esters and Aryl Methyl Ketones Using
Aryl Chlorides
Mark R. Biscoe and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachussetts 02139
Received February 11, 2009
ABSTRACT
Simple, efficient procedures for the monoarylation of acetate esters and aryl methyl ketones using aryl chlorides are presented. Previously,
no general method was available to ensure the highly selective monoarylation of these classes of substrates using aryl chlorides. Using
palladium precatalysts recently reported by our group, these reactions are easily accomplished under mild conditions that tolerate a wide
array of heterocyclic substrates.
It has been well demonstrated that the use of Pd-catalyzed
R-substitution reactions of carbonyl compounds can be an
effective strategy to achieve the arylation and vinylation of
enolates,1,2 often with excellent enantiomeric control.3
However, there are very few reported examples of the
selective monoarylation of enolates from acetate esters and
methyl ketones using aryl halides or sulfonates where the
enolate is not biased toward monoarylation by the presence
of an ortho substituent on the aryl halide or by the presence
of a pre-existing R-substituent on the enolate. Such R-ary-
lation reactions are typically unsuccessful as a result of the
instability of alkali ester enolates2d or the formation of
significant amounts of diarylated side products. To the best
of our knowledge, the few examples of the monoarylation
of tert-butyl acetate that have been demonstrated separately
by Hartwig2b,c and our group2a using aryl bromides constitute
the only examples of the direct monoarylation of acetate
esters. In one recent report, when alkali metal enolates of
acetate esters were employed with aryl chlorides, less than
10% of the desired R-arylated ester was observed (Scheme
1a).2d The corresponding zinc enolates were employed in
an attempt to circumvent this problem, but the only reported
examples utilized chlorobenzene and electron-deficient aryl
(1) For ketones, see: (a) Palucki, M.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Angew. Chem., Int. Ed. 1997, 36, 1740. (d) Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 1473. (e) Fox, J. M.; Huang, X.; Chieffi,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. (f) Nguyen, H. N.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (g) Culkin,
D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (h) Viciu, M. S.;
Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M; Nolan, S. P. Org. Lett.
2003, 5, 1479. (i) Navarro, O.; Marion, N.; Oonishi, Y.; Kelly, R. A.; Nolan,
S. P. J. Org. Chem. 2006, 71, 685. (j) Huang, J.; Bunel, E; Faul, M. M.
Org. Lett. 2007, 9, 4343. (k) Grasa, G. A.; Colacot, T. J. Org. Process Res.
DeV. 2008, 12, 522. (l) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso,
D.; Bell, A.; Nolan, S. P. J. Org. Chem. 2006, 71, 3816. (m) Carril, M.;
SanMartin, R.; Dominguez, E.; Tellitu, I. Tetrahedron 2007, 63, 690
.
(2) For esters, see: (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7996. (b) Lee, S.; Beare, N. A; Hartwig, J. F. J. Am. Chem.
Soc. 2001, 123, 8410. (c) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10,
(3) (a) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald,
S. L. Org. Lett. 2001, 3, 1897. (b) Hamada, T.; Chieffi, A.; Ahman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261. (c) Liao, X.; Weng,
Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.
1545. (d) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549
.
10.1021/ol900295u CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society