Angewandte
Chemie
DOI: 10.1002/anie.201304188
Cross-Coupling
A General, Practical Palladium-Catalyzed Cyanation of (Hetero)Aryl
Chlorides and Bromides**
Todd D. Senecal, Wei Shu, and Stephen L. Buchwald*
Aromatic nitriles have application in a variety of fields as
both synthetic intermediates and final targets.[1] For example,
the antineoplastic Letrozole, antidepressant Citalopram, and
anti-HIV drug Etravirine all possess an aryl nitrile moiety.
Traditionally, benzonitriles are synthesized by diazotization of
anilines followed by a Sandmeyer reaction with superstoi-
chiometric amounts of copper(I) cyanide.[2] Another common
route to benzonitriles is the Rosenmund–von Braun reaction,
which typically entails heating superstoichiometric amounts
of copper(I) cyanide with an aryl iodide at elevated temper-
ature.[3] Recent advances have allowed for the use of catalytic
quantities of copper; however, these approaches still have
limitations.[4]
The palladium-catalyzed coupling of cyanide with aryl
(pseudo)halides proceeds under milder conditions and dis-
plays increased functional-group tolerance. The first Pd-
catalyzed cyanation method was reported by Takagi et al.
40 years ago.[5] Despite great advances,[1,6] cross-coupling
procedures to form aryl nitriles have obtained a reputation
as being highly irreproducible.[7] Mechanistic studies by
Grushin and co-workers have shown this is due, in part, to
catalyst deactivation by cyanide, which is able to poison all of
the intermediates in the catalytic cycle.[8] Common methods
to avoid catalyst poisoning include the addition of reducing
agents[9] or exploiting the low solubility of NaCN, KCN, and
Zn(CN)2 in organic solvents. The NaCN method by Ushkov
and Grushin,[7] while of high industrial relevance, requires the
use of rigorously anhydrous conditions (glovebox setup),
which renders this chemistry inconvenient or inaccessible to
many synthetic chemists. Furthermore, MCN salts (M = Na or
K) are often milled prior to their use to guarantee solubility
and reproducibility in their application. Milling is problematic
considering the high toxicity in conjunction with the possi-
bility of aerosolizing fine cyanide salts. Zinc cyanide finds the
widest use in Pd-catalyzed cyanations of functionalized
substrates.[10] With a toxicity of approximately 10% that of
its sodium or potassium congeners, Zn(CN)2 is less hazardous,
but still poses a significant risk.
To address safety concerns, several Pd-catalyzed methods
involving alternative cyanide sources have been described.[11]
The research groups of Beller[12] and Weissman[13] discovered
that K4[Fe(CN)6], a nontoxic food additive, could serve as
a cyanide source for Pd-catalyzed coupling reactions. Aque-
ous systems of K4[Fe(CN)6]·3H2O with a phase-transfer
catalyst have been reported, but these still require temper-
atures greater than 1408C.[14] Significant advances were
reported by the research groups of Huang[15] and Kwong,[16]
who employed a 1:1 organic/aqueous solvent mixture to
enable cyanide transfer from K4[Fe(CN)6]·3H2O under
milder conditions. However, the scope is narrow, with
examples of five-membered heterocycles being rare. Thus,
while progress has been made towards a practical benzonitrile
synthesis using nontoxic cyanide sources, a general, efficient
method for the cyanation of (hetero)aryl halides is still
needed. Herein, we disclose a Pd-catalyzed cyanation system
that: 1) is applicable to aryl chlorides at low to modest
catalyst loadings; 2) works well with a wide range of hetero-
cyclic halides, including in many cases five-membered hetero-
cycles bearing free NH groups; and 3) is complete in one hour
at ꢀ 1008C.
Our initial experiments focused on identifying conditions
to prepare benzonitrile 1a from the corresponding aryl
chloride. Using our third generation palladacycle precatalysts
(P1–P3; Scheme 1),[17]
a preliminary survey of ligands
[*] Dr. T. D. Senecal, Dr. W. Shu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Scheme 1. Ligands and precatalysts used in this study. Ms=mesyl.
E-mail: sbuchwal@mit.edu
[**] Research reported in this publication was supported by the National
Institutes of Health under award number GM46059. The content is
solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health. We
thank Dr. Robb DeBergh and Dr. Nathan Jui for help with
preparation of this manuscript. MIT has patents on some of the
ligands and precatalysts used in this work from which S.L.B.
receives royalty payments.
revealed that use of a catalyst based on XPhos (L1) provided
superior yields of benzonitrile 1a, outperforming tBuXPhos
(L2) and tBuBrettPhos (L3), as well as other phosphines
commonly used for aryl cyanation reactions, such as tri-tert-
butylphosphine [(P(tBu)3] and 1,1’-bis(diphenylphosphino)-
ferrocene (dppf; see Supporting Information for details).
Next, we examined the effect of base, temperature, and
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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