Published on Web 11/17/2007
A Convergent Synthesis of Polysubstituted Aromatic Nitriles
via Palladium-Catalyzed C-H Functionalization
Brian Mariampillai, Julien Alliot, Mengzhou Li, and Mark Lautens*
Contribution from DaVenport Research Laboratories, Department of Chemistry,
UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
Received July 26, 2007; E-mail: mlautens@chem.utoronto.ca
Abstract: A palladium-catalyzed C-H functionalization reaction for the synthesis of highly substituted
aromatic nitriles is reported. The modularity of the reaction is demonstrated by the broad range of aryl
iodides which can be coupled with metal cyanides and alkyl halides or aryl bromides.
Introduction
effort has gone into exploring both the synthetic and mechanistic
potential of this reaction,5 which has led to the elucidation of
We have recently reported a tandem intramolecular ortho
alkylation/cyanation reaction for the synthesis of annulated
heterocycles via a C-H functionalization manifold.1 We now
show that intermolecular alkylation occurs readily between aryl
iodides and alkyl halides, including the much more attractive
alkyl chlorides. In addition we find that cross arylation/cyanation
can be achieved by combining an aryl iodide with an electron-
deficient aryl bromide followed by cyanation. In this way, biaryl
compounds with diverse functionality can be prepared in one
step. Our approach toward developing a tandem reaction relies
on using the inherent reactivity of norbornene to initiate a
competitive C-H functionalization pathway, so that C-C and
C-CN bond formation can occur sequentially. Catalytic C-H
functionalization for the synthesis of carbon-carbon bonds has
many advantages over traditional palladium-catalyzed cross-
couplings, the greatest being the lack of prefunctionalization
of one or both of the coupling partners, which allows for the
simple preparation of substrates. Because of its many advan-
tages, palladium-catalyzed C-H functionalization has recently
undergone significant advancement within the research com-
munity.2 Many recently reported palladium(IV)-based methods
for the functionalization of C-H bonds have relied on oxidative
conditions utilizing hypervalent iodine to oxidize palladium-
(II) to palladium(IV).3 In the late 1990s, Catellani et al. reported
a method that does not use oxidative conditions; rather, it is
based upon the formation of palladacycles and their ability to
react with electrophiles such as alkyl and aryl halides.4 Great
the reaction mechanism.
Mechanism. The proposed mechanism for the palladium-
catalyzed C-H functionalization/cyanation is shown in Figure
1. Initial oxidative addition of palladium(0) into the aryl iodide
followed by carbopalladation of norbornene gives product B.
With no possibility for syn-â-hydride elimination to occur, an
electrophilic metalation occurs, followed by deprotonation at
the ortho position to form palladacycle C. This palladium(II)
intermediate can then undergo reaction with alkyl or aryl halides
to form octahedral palladium(IV) intermediate D. This species
rapidly undergoes reductive elimination to generate palladium-
(II) intermediate E. If the starting aryl iodide has two unsub-
stituted ortho positions, a subsequent C-H functionalization will
take place at the second ortho position of the aryl iodide. If,
however, one of the ortho positions of the aryl iodide is
substituted with an appropriate blocking group, only one C-H
functionalization will occur. With both ortho positions substi-
tuted, extrusion of norbornene via decarbopalladation is favored
because of the increased steric strain. This regenerates the aryl
palladium species H, which can then undergo transmetalation
with a metal cyanide, followed by reductive elimination to
yield the desired product J and regenerate the palladium(0)
catalyst. Although norbornene could theoretically be used in
catalytic amounts, it is often necessary to utilize stoichiometric
amounts to favor the initial carbopalladation and subsequent
insertion processes within the reaction. It is also possible that
the reaction products could be formed by ortho metalation of
an initially formed aryl nitrile; however, when the corresponding
(1) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M. J. Am. Chem. Soc.
2006, 128, 14436-14437.
(2) For recent work and review on palladium-catalyzed C-H functionalization,
see: (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129,
7274-7276. (b) Covell, D. J.; Vermeulen, N. A.; Labenz, N. A.; White,
M. C. Angew. Chem., Int. Ed. 2006, 45, 8217-8220. (c) Delcamp, J. H.;
White, M. C. J. Am. Chem. Soc. 2006, 128, 15076-15077. (d) Stuart, D.
R.; Fagnou, K. Science 2007, 316, 1172-1175. (e) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496-16497. (f) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174-238.
(3) For recent work on Palladium(IV) chemistry, see: (a) Welbes, L. L.; Lyons,
T. W.; Cychosz, K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836-
5837. (b) Tong, X.; Beller, M.; Tse, M. K. J. Am. Chem. Soc. 2007, 129,
4906-4907. (c) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46,
1924-1935.
(4) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. 1997, 36,
119-122.
(5) For recent work on synthesis and mechanistic studies, see: (a) Ferraccioli,
R.; Carenzi, D.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2006, 128,
722-723. (b) Catellani, M.; Motti, E.; Faccini, F.; Ferraccioli, R. Pure
Appl. Chem. 2005, 77, 1243-1248. (c) Rudolph, A.; Rackelmann, N.;
Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485-1488. (d) Martins,
A.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 4827-4829. (e) Cardenas,
D. J.; Martin-Matute, B.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128,
5033-5040. (f) Canty, A. J. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley-
Interscience: New York, 2002; pp 189-211.
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J. AM. CHEM. SOC. 2007, 129, 15372-15379
10.1021/ja075599i CCC: $37.00 © 2007 American Chemical Society