Copper-catalyzed cyanation of arenes using benzyl nitrile as a cyanide anion surrogate

Article abstract of DOI:10.1039/c2cc35046g

The copper-catalyzed cyanation of arenes using benzyl nitrile as a cyanide anion surrogate furnishes aromatic nitriles in moderate to good yields. The cascade process involves a copper-catalyzed aerobic C-H oxidation, a retro-cyanohydrination, and a copper-catalyzed aerobic oxidative C-H functionalization. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35046g

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COMMUNICATION
Copper-catalyzed cyanation of arenes using benzyl nitrile as a
cyanide anion surrogatew
Jisong Jin, Qiaodong Wen, Ping Lu* and Yanguang Wang*
Received 14th July 2012, Accepted 17th August 2012
DOI: 10.1039/c2cc35046g
The copper-catalyzed cyanation of arenes using benzyl nitrile as
a cyanide anion surrogate furnishes aromatic nitriles in moderate
to good yields. The cascade process involves a copper-catalyzed
aerobic C–H oxidation, a retro-cyanohydrination, and a copper-
catalyzed aerobic oxidative C–H functionalization.
method for the cyanation of arenes. Herein, we report the
results of this effort.
During the screening of reaction conditions (Table S1,
ESIw), we discovered that the reaction of 2-phenylpyridine
(1a) with 1.5 equiv. of benzyl cyanide (2a) in DMF under
1
.2 equiv. of CuBr and air atmosphere at 130 1C for 18 h gave
aryl nitrile 3a in 83% yield (Scheme 1). For the electron-
withdrawing group substituted benzyl cyanides 2b and 2c, the
yield of 3a was decreased apparently. For the electron-donating
group substituted benzyl cyanide 2d, we obtained 3a (55% yield)
along with dicyanated product 4a (39% yield).
The C–H bond functionalizations have attracted much atten-
tion because they could directly convert a C–H bond into a
C–C or C–FG bond without the assistance of transfer groups,
such as halogens. In this blooming field, the palladium-
1
catalyzed C–H bond activation/C–C bond-forming reactions,
2
With our optimized reaction conditions in hand, we next
explored the substrate scope and the limitation of this reaction
the copper-catalyzed cross-dehydrogenative coupling (CDC),
and the copper-catalyzed aerobic oxidative C–H bond func-
3
tionalization are the most popular perspectives. On the other
(
Scheme 2). The substituent effect on the phenyl ring of
-phenylpyridines was not apparent. Products 3b–h were
4
hand, aryl nitriles are the subunits or the key intermediates
5
2
obtained in yields ranging from 52% to 73%. Steric hindrance
was high when the methyl group occupied the ortho position of
the phenyl ring of 2-phenylpyridine. As a result, 3i was
obtained in lower yield (31%). 2-(Naphthalen-1-yl)pyridine
afforded 3m in 66% yield, while 2-(naphthalen-2-yl)pyridine
gave a mixture of 3na and 3nb in a 1 : 2 ratio (63% yield)
along with a dicyanated product 4b (21% yield). With other
directing groups, such as pyrimidine, pyrazole, and 3-methyl-
pyrazole, 3o, 3p, and 3q were prepared in 42%, 43%, and 39%
yields, respectively. Benzo[h]quinoline, in which the free rota-
tion of the C–C bond between phenyl and pyridinyl was
blocked by a covalent CQC bond, could proceed the reaction
to afford the desired product 3r in 51% yield.
of a number of important drugs. They are also versatile
building blocks in organic synthesis and can be transformed
into various compounds such as imines, amines, aldehydes,
6
carboxylic acids, amides, and tetrazoles. Consequently, the
transition metal-catalyzed cyanation of aryl halides and the
cyanation through C–H bond functionalization of arenes have
been significantly developed in the last few decades. The
cyanation reagents used in these processes are metal cyanides,
7
8
9
10
11
such as CuCN, KCN, NaCN, Zn(CN) , TMSCN, and
2
1
2
K Fe(CN) . Organoreagents are seldom reported. A few
2
4
1
3
11
examples include acetone cyanohydrin,
nitromethane,
1
4
15
malononitrile, and N,N-dimethylformamide. More recently,
the combination of ammonium salts and DMF or DMSO as
1
6
We also examined the sterically hindered substrates, such as
the surrogate of cyanide anions was reported, which could
effectively convert Ar–H with directing groups or Ar–X into
the corresponding aryl nitriles. Enlightened by these results
and our recent finding that benzyl cyanide could work as a
cyanide anion surrogate for the palladium-catalyzed cyanation
2
,6-diphenylpyridine (1s), 2-methyl-6-phenylpyridine (1t) and
1
7
of aryl halides, we envisaged that the combination of benzyl
cyanide with a copper-catalyzed aerobic oxidative C–H func-
tionalization might lead to the development of a practical
Department of Chemistry, Zhejiang University, Hangzhou 310027,
P. R. China. E-mail: pinglu@zju.edu.cn, orgwyg@zju.edu.cn;
Fax: +86 571-87952543; Tel: +86 571-87952543
w Electronic supplementary information (ESI) available: Experimental
details, optimization of reaction conditions, characterization data, and
1
13
copies of H and C NMR spectra for all products. See DOI: 10.1039/
c2cc35046g
Scheme 1 Substituent effect of benzyl cyanides.
Chem. Commun., 2012, 48, 9933–9935 9933
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Scheme 2 Preparation of aromatic nitriles 3a–r and 4b from arenes using benzyl cyanide.
Scheme 3 Structures of substrates 1s–v.
-methoxy-6-phenylpyridine (1u) (Scheme 3). It was found
2
that these reactions did not proceed because the substituent
at the 6-position of pyridine inhibited the coordination of the
nitrogen of pyridine to copper. Furthermore, 2-(anthracen-9-yl)-
pyridine (1v) did not react due to the inappropriate ring size for
the copper-catalyzed C–H activation.
Scheme 4 Reaction of cyanation reagents 5 and 6.
À
Since cyanide anion (CN ), 2-hydroxy-2-phenylacetonitrile
(
5) and several by-products, such as benzaldehyde, benzoic
acid, N,N-dimethylbenzamide and cis-/trans-2,3-diphenylfumaro-
nitrile, were detected from the reaction mixture (see ESIw), we
speculated that the cyanide reagent 2a might undergo a
1
8
copper-catalyzed aerobic C–H oxidation to form cyanohydrin
and benzoyl cyanide (6), which could release free cyanide
5
anions. In order to demonstrate this process, we utilized 5 and 6
as cyanation reagents to carry out the reaction with 1a
Scheme 5 Reaction of cyanation reagent 7 with 1a.
(
Scheme 4). In the presence of CuBr, 5 and 6 afforded 3a in
5% and 16% yields, respectively. Cu(OAc) could also cata-
lyze these reactions to give improved yields (22% and 39%).
-Phenylpropanenitrile (7), which can be oxidized into
À
16,17
1
2
With the CN indicator strip,
we monitored the in situ
generated cyanide anion from the cyanation reagents 2a and
5–7 in DMF (Table S2, ESIw). For 2a and 7, both Cu(I) and air
were found to be necessary for the formation of free cyanide
anions. However, 5 and 6 could release cyanide anions without
the copper catalyst.
2
a-cyanohydrin 8, but cannot be further oxidized into ketone,
was also examined (Scheme 5). We found that CuBr could
efficiently catalyze the reaction between 7 and 1a. These results
suggested that a-cyanohydrins can provide cyanide anions via
a retro-cyanohydrination.
In the reaction kinetics investigations, we observed that 1a
consumed steadily along with a steady formation of 3a in the
9
934 Chem. Commun., 2012, 48, 9933–9935
This journal is c The Royal Society of Chemistry 2012

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and a copper-catalyzed aerobic oxidative C–H functionaliza-
tion. We believe that matching two copper-catalyzed reaction
rates is the key for the success of this transformation. Further
investigations on the reaction mechanism and synthetic appli-
cations of the present method are currently underway in our
laboratory.
The authors thank the national nature science foundation
of China (20972137, 21032005) for the financial support of
this work.
Notes and references
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Scheme 6 Possible mechanism for the Cu-catalyzed reaction between
a and 2a.
1
CuBr-catalyzed cyanation of 1a with 2a (Fig. S2, ESIw). The
half conversion of 1a was determined at 12 h, while the
reaction completed at 18 h. However, for the CuBr-catalyzed
cyanation of 1a with 6, a rapid increment of 3a and a rapid
decrement of 1a appeared after the reaction took place for
3 For a recent review, see: A. E. Wendlandt, A. M. Suess and
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hours (Fig. S3, ESIw). In this case, there was an initiation
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to Cu(II) for the C–H functionalization of 2-phenylpyridine.
6
¨
For the Cu(OAc) catalyzed reaction, a steady increment of
2
8
H. Cristau, A. Ouali, J. Spindler and M. Taillefer, Chem.–Eur. J.,
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a was observed (Fig. S4, ESIw). These results suggest that
2
Cu(I) is responsible for the oxidation of benzyl cyanide,
while Cu(II) is responsible for the C–H functionalization
of 2-phenylpyridine. The activated Cu(II) could be in situ
generated from the Cu(I) salt in our reaction system. More-
over, the copper catalyzed oxidation step from 2a to 5 is
critical for a high yield of 3a. Both 5 and 6 could rapidly
release cyanide anions without the oxidation step, but
they gave the cyanated product in poor yields (Scheme 4). In
these cases, the formation of cyanide anions might be so fast
9
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À
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1
9
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Scheme 6. Firstly, 2a undergoes a copper-catalyzed oxidation
(
b) J. Kim, J. Choi, K. Shin and S. Chang, J. Am. Chem. Soc.,
1
8
with air to generate 5 and 6, accompanying the generation of
Cu(II) species. Then, a cyanide anion is formed through a
retro-cyanohydrination of 5 and hydrolysis of 6. Finally, the
cyanide anion participates in the copper-catalyzed-cyanation
cycle. This cycle is initiated with the coordination of Cu(II) to
the pyridine, which forms Cu(II) complex A. Subsequently, a
single electron transfer (SET) from the aryl ring to the
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11
coordinated Cu(II) leads to the cation-radical intermediate B,
which coordinates with the in situ generated cyanide anion to
form Cu(I) complex C. Then, C undergoes an intramolecular
anion transfer to form radical D. Finally, D is oxidized by O
to 3a and Cu(II).
2
In conclusion, we demonstrated an efficient transformation
from arenes to aryl cyanides using benzyl cyanide as the cyanide
anion surrogate. The cascade cyanation involves a copper-catalyzed
aerobic oxidation of benzyl cyanide, a retro-cyanohydrination,
1
34, 7025.
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4
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9933–9935 9935