Journal of the American Chemical Society
COMMUNICATION
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(8) This is true despite some early developments in the field
originating from the observation of R-arylated products when Pd-
catalyzed cross-coupling reactions were conducted in acetone solvent
(see ref 1c).
(9) For the diarylation of acetone en route to oxime esters, see the
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Figure 2. Expanded scope for palladium-catalyzed R-arylation of acet-
one using electron-deficient aryl bromides. Reaction conditions: 0.5 M
ArBr in acetone at 90 °C, ArBr:Cs2CO3 = 1:2, [Pd]/L13 = 1:2. Yields
are of isolated material, and the [Pd(cinnamyl)Cl]2 loading (mol %) is
indicated in parentheses. 2ff and 2hh were isolated as the corresponding
alcohols following reduction using NaBH4.
monoarylation of acetone (Figure 2). The use of sterically
hindered electron-deficient aryl bromides (affording 2ee) as well
as those containing one or more electron-withdrawing groups, such
as fluoride, trifluoromethyl, or acyl (affording 2ffÀii), proceeded
selectively to the R-aryl methyl ketone products in good yield
(64À74%). The reactivity pattern of Pd/L13 mixtures was explo-
ited in the selective cross-coupling of 2-chlorobromobenzene to
generate the corresponding chloro-substituted ketone, thereby
providing an opportunity for subsequent Pd(0)-mediated coupling
chemistry of the remaining aryl chloride (2jj).19
In summary, we have described the first example of the selective,
Pd-catalyzed mono-R-arylation of acetone with aryl chlorides, brom-
ides, iodides, and tosylates. The reaction makes direct use of a simple
and abundant three-carbon feedstock without the requirement of
stoichiometric additives or preformed enolates to generate R-aryl
methyl ketones. In view of the excellent selectivity and functional
group tolerance, the ease of conducting such reactions, and the
relative mildness of the reaction conditions, we expect this protocol
to be widely adapted in synthetic chemistry.
’ ASSOCIATED CONTENT
(13) (a) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M.
Angew. Chem., Int. Ed. 2010, 49, 4071. (b) Lundgren, R. J.; Stradiotto, M.
Angew. Chem., Int. Ed. 2010, 49, 8686.
S
Supporting Information. Full experimental details and
b
characterization data. This material is available free of charge via
(14) K2CO3 and Na2CO3 proved to be unsuccessful in promoting
the reaction, and LiHMDS and NaOtBu provided intractable product
mixtures in which negligible amounts of 2a were observed by use of GC.
(15) In neat acetone, L11 also provided good results for arylation
with 1a (94% conv., 93% yield at 60 °C in 19 h).
(16) The use of 3-(trifluoromethyl)phenyl tosylate resulted in the
formation the corresponding phenol as the major product under the
standard conditions.
’ AUTHOR INFORMATION
Corresponding Author
Author Contributions
†These authors contributed equally.
(17) See the Supporting Information.
(18) (a) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2009, 131, 8141. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176.
(19) Preliminary studies also showed that L13 was capable of cross-
coupling electron-rich aryl bromides (4-bromotoluene and 4-bromo-
anisole) under similar conditions.
’ ACKNOWLEDGMENT
We thank the NSERC of Canada, the Killam Trusts, the
Walter C. Sumner Foundation, and Dalhousie University for
their generous support of this work. Pamela G. Alsabeh is
acknowledged for late-stage experimental contributions.
Dr. Michael Lumsden (NMR-3, Dalhousie) is thanked for
assistance in the acquisition of NMR data.
’ REFERENCES
(1) (a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(b) Johansson, C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,
49, 676. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
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