Communications
DOI: 10.1002/anie.201006763
Cross-Coupling
Synthesis of a-Aryl Nitriles through Palladium-Catalyzed
Decarboxylative Coupling of Cyanoacetate Salts with Aryl Halides and
Triflates**
Rui Shang, Dong-Sheng Ji, Ling Chu, Yao Fu, and Lei Liu*
Table 1: Decarboxylative coupling under various reaction conditions.[a]
a-Aryl nitriles are versatile intermediates for the synthesis of
carboxylic acids, amides, primary amines, aldehydes, and
heterocycles.[1] They can also have biological activity as
exemplified by medicinal compounds such as anastrozole.[2]
Traditional methods for the synthesis of a-aryl nitriles include
cyanation of benzylic halides or alcohols,[3] Friedel–Crafts
reactions,[4] and dehydration of a-aryl amides.[5] Recently, the
groups of Hartwig[6] and Verkade[7] developed new methods
that involve palladium-catalyzed a-arylation of nitriles (and
also 2-cyanoacetate esters) with aryl chlorides and bromides.
The requirement of a strong base (e.g., NaN(SiMe3)2) in these
palladium-catalyzed a-arylation reactions limits the func-
tional group tolerance, and monoarylation is difficult to
achieve for acetonitrile and primary nitriles. To solve these
two problems, Hartwig et al. described improved methods
that use relatively expensive a-silyl nitriles and zinc cya-
noalkyl reagents to couple with aryl bromides (but not
chlorides).[8] Herein we report a new synthetic strategy for a-
monoarylated nitriles through palladium-catalyzed decarbox-
ylative coupling of aryl bromides, chlorides, and even triflates
with readily accessible cyanoacetate salts.[9] This new reaction
expands the scope and synthetic utility of the catalytic
decarboxylative coupling reactions previously developed by
the groups of Myers,[10] Forgione,[11] Goossen,[12] and
others.[13–15] This work also shows that for some synthetic
purposes the decarboxylative coupling not only provides a
conceptually alternative method, but also can be practically
favored in terms of both reagent accessibility and reaction
scope.
Entry X, M
[Pd]
Ligand
Solvent
Yield [%]
1
2
1
2
3
4
5
6
7
8
Cl, K
Cl, K
Cl, K
Cl, K
Cl, K
Cl, K
Cl, K
Cl, K
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
P(Cy)3
P(tBu)3
X-Phos
mesitylene trace 16
mesitylene trace trace
mesitylene 10
28
Cy-JohnPhos mesitylene trace 21
DavePhos
Ru-Phos
tBuX-Phos
S-Phos
mesitylene 33
mesitylene 65
mesitylene 18
mesitylene 69
mesitylene 86
18
7
8
10
trace
9[b]
10
11
12
Cl, Na [Pd2Cl2(allyl)2] S-Phos
Cl, Li [Pd2(dba)3]
Cl, Na [Pd2(dba)3]
Cl, Na [Pd2(dba)3]
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
mesitylene trace trace
DMA
diglyme
9
23
6
13
4
80
13[c] Cl, Na Pd(OAc)2
mesitylene 57
mesitylene 63
mesitylene 88
14[c] Cl, Na Pd(TFA)2
15
Br, Na [Pd2Cl2(allyl)2] S-Phos
2
[a] Yields determined by GC methods using benzophenone as the
internal standard (average of two runs). [b] 87% yield of isolated
product. [c] 4 mol% [Pd] used. Cy=cyclohexyl, dba=dibenzylideneace-
tone, DMA=dimethylacetamide, DavePhos=2-dicyclohexylphosphanyl-
2’-(N,N-dimethylamino)biphenyl,
no)biphenyl, RuPhos=2-dicyclohexylphosphanyl-2’,6’-diisopropoxy-1,1’-
biphenyl, S-Phos=2-(2,6-dimethoxybiphenyl)dicyclohexylphosphine,
JohnPhos=2-(di-tert-butylphosphi-
TFA=trifluoroacetic acid, X-Phos=2-(dicyclohexylphosphino)-2’,4’,6’-
triisopropylbiphenyl.
Our study began by testing the coupling of chlorobenzene
with sodium or potassium cyanoacetate (Table 1). A series of
palladium salts, phosphine ligands, and solvents were exam-
ined. Under the optimal reaction conditions and using
[Pd2Cl2(allyl)2]/S-Phos as the catalyst (entry 9), the desired
monoarylated product was selectively obtained in 86% yield
without the use of any extra base. The same conditions can
also be used to achieve the coupling with bromobenzene to
produce the monoarylated product selectively (entry 15).
Notably, without adding chlorobenzene we observed the
formation of acetonitrile as a result of the decarboxylation of
cyanoacetate (see the Supporting Information). Also, in a
control experiment in which palladium was not added, sodium
cyanoacetate did not decompose at 1508C, thus indicating the
essential role of palladium for the decarboxylation process.
Moreover, a competition reaction (Scheme 1) was conducted
in which 2-phenylacetonitrile was added to the reaction
mixture containing 4-bromoanisole and potassium cyanoace-
tate. The major product of the competition reaction corre-
sponds to the decarboxylative monoarylation of cyanoacetate,
[*] R. Shang, D.-S. Ji, Prof. Dr. L. Liu
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
Fax: (+86)10-6277-1149
E-mail: lliu@mail.tsinghua.edu.cn
L. Chu, Prof. Dr. Y. Fu
Department of Chemistry, University of Science and
Technology of China, Hefei 230026 (China)
[**] We acknowledge the support of the national “973” grants from the
Ministry of Science and Technology (No. 2011CB965300). We also
thank The State Key Laboratory of Bio-organic and Natural Products
Chemistry (CAS) and the Knowledge Innovation Program of CAS for
support.
Supporting information for this article is available on the WWW
4470
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4470 –4474