Published on Web 10/25/2005
Mild Palladium-Catalyzed Selective Monoarylation of Nitriles
Lingyun Wu and John F. Hartwig*
Contribution from the Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06510
Received May 9, 2005; E-mail: john.hartwig@yale.edu
Abstract: Two new palladium-catalyzed procedures for the arylation of nitriles under less basic conditions
than previously reported have been developed. The selective monoarylation of acetonitrile and primary
nitriles has been achieved using R-silyl nitriles in the presence of ZnF2. This procedure is compatible with
a variety of functional groups, including cyano, keto, nitro, and ester groups, on the aryl bromide. The
arylation of secondary nitriles occurred in high yield by conducting reactions with zinc cyanoalkyl reagents.
These reaction conditions tolerated base-sensitive functional groups, such as ketones and esters. The
combination of these two methods, one with R-silyl nitriles and one with zinc cyanoalkyl reagents, provides
a catalytic route to a variety of benzylic nitriles, which have not only biological significance but utility as
synthetic intermediates. The utility of these new coupling reactions has been demonstrated by a synthesis
of verapamil, a clinically used drug for the treatment of heart disease, by a three-step route from commercial
materials that allows convenient variation of the aryl group.
amides.10 However, selective halogenation to form the benzylic
halide is challenging in many cases, and the use of cyanide can
Introduction
R-Aryl nitriles can possess biological activity and are useful
synthetic intermediates. For example, ariflo (cilomilast) 11 and
verapamil 22 are used in the clinic for chronic obstructive
pulmonary disease (COPD) and hypertension. R-Aryl nitriles
lead to R-aryl amides and carboxylic acids by hydrolysis, and
this hydrolysis is part of a commercial route to Ibuprofen.3 They
can also generate â-arylamines by reduction4,5 and can serve
as precursors to ketones by addition of Grignard reagents and
hydrolysis of the resulting imine.6 R-Arylnitriles are also useful
in the synthesis of heterocycles, such as thiozoles, oxazolines,
tetrazoles, imidazoles, and triazoles.7
be undesirable in some settings. Friedel-Crafts reactions have
limited functional group tolerance, and the use of amides diverts
the synthetic problem to the synthesis of R-aryl amides. Thus,
alternative routes to R-aryl nitriles have been sought,11-16 and
a general, catalytic coupling of cyanoalkyl anions with aryl
halides would be a valuable method.
Although palladium-catalyzed R-arylation of carbonyl com-
pounds has been established as a general method for the
synthesis of R-aryl ketones17-19 and R-aryl esters,20-24 the
coupling of nitriles has only been partially addressed.21,25-29
The coupling of nitriles with aryl halides has proven to be
challenging for several reasons. First, nitriles are only weakly
acidic. Therefore, strong bases must be used to generate the
cyanoalkyl anions, and the resulting anions may react faster with
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2000, 122, 1360.
R-Aryl nitriles are traditionally prepared by cyanation of a
benzylic halide,8 Friedel-Crafts reactions,9 or dehydration of
(1) Jeffery, P. Pulm. Pharmacol. Ther. 2005, 18, 9.
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J. AM. CHEM. SOC. 2005, 127, 15824-15832
10.1021/ja053027x CCC: $30.25 © 2005 American Chemical Society