ORGANIC
LETTERS
2005
Vol. 7, No. 25
5593-5595
Addition of Grignard Reagents to Aryl
Acid Chlorides: An Efficient Synthesis
of Aryl Ketones
Xiao-jun Wang,* Li Zhang, Xiufeng Sun, Yibo Xu,
Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Connecticut 06877
Received September 6, 2005
ABSTRACT
Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide
aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates
the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.
The acylation of organometallic reagents provides one of
the most important synthetic routes to ketones1 and is a
central functionality in a variety of organic transformations,
including regio- and stereospecific C-C bond formation.
Generally, this is accomplished by reaction of an organo-
metallic species with a functional carboxylic acid derivative,
sometimes in the presence of a catalyst. One of the most
attractive classes of organometallic compounds is represented
by Grignard reagents, which have enjoyed an incredibly wide
range of applications during their century-old history.2 These
reagents are typically reacted with a range of active amides,
esters, thioesters, and anhydrides.3 Acid chlorides are by far
the cheapest and industrially most attractive acylating agents,
and ketone syntheses involving these substrates include the
palladium-catalyzed coupling with organostannanes4 and
borates,5 the acylation of organocoppers and zincs reagents,6
as well as derivatives of silicon,7 manganese,8 indium,9
mercury,10 zirconium,11 rhodium,12 and many others.13 Al-
though Ni(II)- and Fe(III)-catalyzed additions of Grignard
reagents to acid chlorides have also been reported,14 to date,
there is no general approach to ketones by the direct, non-
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M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390. (f) Tamaru,
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(g) Sato, F.; Kodama, H.; Tomura, Y.; Sato. M. Chem. Lett. 1979, 623. (h)
Fujisawa, T.; Mori, T.; Higuchi, K.; Sato, T. Chem. Lett. 1983, 1791. (i)
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Whitten, C. E.; McFarland, P. E. J. Am. Chem. Soc. 1972, 94, 5106. (k)
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D. A. In Organic Reactions; Wiley: New York, 1954; Vol. 8, p 28.
(2) (a) Wakefield, B. J. Organomagnesium Methods in Organic Synthesis;
Academic Press: London, 1995. (b) Silverman, G. S.; Rakita, P. E.
Handbook of Grignard Reagents; Marcel Dekker: New York, 1996.
(3) (a) Meyer, A. I.; Comins, D. L. Tetrahedron Lett. 1978, 19, 5179.
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Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 638. (c) Wipf, P.;
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10.1021/ol052150q CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/08/2005