Practical synthesis of aromatic nitriles via gallium-catalysed electrophilic cyanation of aromatic C-H bonds

Article abstract of DOI:10.1039/c2cc18008a

A gallium-catalysed, direct cyanation reaction of aromatic and heteroaromatic C-H bonds with cyanogen bromide was developed as a practical synthetic method for the preparation of aromatic nitriles. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc18008a

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COMMUNICATION
Practical synthesis of aromatic nitriles via gallium-catalysed electrophilic
cyanation of aromatic C–H bondsw
Kazuhiro Okamoto, Masahito Watanabe, Masahito Murai, Ryo Hatano and Kouichi Ohe*
Received 22nd December 2011, Accepted 2nd February 2012
DOI: 10.1039/c2cc18008a
A gallium-catalysed, direct cyanation reaction of aromatic and
heteroaromatic C–H bonds with cyanogen bromide was developed as
a practical synthetic method for the preparation of aromatic nitriles.
gallium-catalysed direct cyanation reaction of aromatic
C–H bonds with cyanogen bromide.
In the first set of experiments, we employed 1,3-dimethoxy-
benzene as a model substrate. The reaction was performed
with 1.2 equiv. of cyanogen bromide and 10 mol% of gallium
chloride in 1,2-dichloroethane at 30 1C. At full conversion of
the starting arene, the usual work-up of the reaction mixture
afforded the expected cyanation product 2a in 40% yield
(Table 1, entry 1). 4-Bromoarene 3a and 2,4-dibromoarene
4a were also obtained as by-products (17% and 32% yield,
respectively).10 We were pleased to find that, by raising the
reaction temperature, the competing bromination reactions were
suppressed. The yield of 2a was improved up to 82%, involving
the 2-CN isomer (4%), under optimised conditions (120 1C, 1 h;
entry 5). Gallium bromide also catalysed this reaction to afford
the product in slightly lower yield (70%; entry 6). The chloride
salts of homologous elements, such as AlCl3 and InCl3, were not
effective in this reaction (entries 7 and 8).
Aromatic cyanation reactions are one of the most fundamental
organic transformation reactions. Of the various methods used to
date, nucleophilic cyanation of aryl halides or aryl diazonium salts
with copper(I) cyanide (Rosenmund–von Braun reaction or
Sandmeyer reaction) has been most widely applied (Scheme 1a).1
Nickel-2 or palladium-catalysed3 cyanation reactions of aryl halides
with alkali metal cyanides4 have been intensively studied since the
early 1970s (Scheme 1b).1b,5 Recently, much attention has been
paid to direct cyanation reactions of aromatic C–H bonds because
of the synthetic generality of C–H bond functionalisation. This
type of transformation has been achieved with a stoichiometric
amount of various oxidants (Scheme 1c).6,7 Moreover, the electro-
philic cyanation reaction of aromatic compounds with cyanogen
halides activated by Lewis acids (Friedel–Crafts–Karrer cyanation),
which was originally discovered in 1878, is also classified as a direct
C–H cyanation reaction (Scheme 1d).8 However, this reaction has
not been extensively studied because of the requirement for a
stoichiometric amount of Lewis acids.
The present catalytic electrophilic cyanation reaction with
cyanogen bromide was applicable to various aromatic
compounds, including those containing electron-donating
groups and polycyclic structures (Table 2). m-Dimethoxyarenes
are highly electron-rich aromatic compounds and two ortho/para
During the course of our study on the catalytic electrophilic
cyanation of unsaturated compounds, we found the gallium(III)
chloride-catalysed regio- and stereoselective bromocyanation
of alkynes with cyanogen bromide.9 Herein, we report a
Table 1 Gallium-catalysed cyanation of 1,3-dimethoxybenzene (1a)
with cyanogen bromidea
Entry LA
Conditions Yieldb 2a (%) Yieldb 3a (%) Yieldb 4a (%)
1
2
3
4
5
6
7
8
GaCl3 30 1C, 70 h
40
53
47
74
17
14
48
15
12
11
0
32
29
0
0
1
0
0
0
GaCl3 50 1C, 70 h
GaCl3 70 1C, 21 h
GaCl3 100 1C, 1 h
GaCl3 120 1C, 1 h
GaBr3 120 1C, 1 h
AlCl3 120 1C, 1 h
InCl3 120 1C, 1 h
83 (82)c
70
20
Scheme 1 Aromatic cyanation reactions.
47
6
a
Department of Energy and Hydrocarbon Chemistry, Graduate School
of Engineering, Kyoto University, Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan. E-mail: ohe@scl.kyoto-u.ac.jp
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc18008a
The reaction was carried out with 1,3-dimethoxybenzene 1a
(0.40 mmol), cyanogen bromide (0.48 mmol), and GaCl3 (10 mol%)
b
in ClCH2CH2Cl (1.6 mL). The yields were determined by H NMR
c
using nitromethane as an internal standard. Isolated yield.
1
c
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directors define the reactive positions towards electrophiles.
As expected, the regioselective cyanation occurred with
m-dimethoxyarenes, affording the cyanation products 2a–d
in moderate to high yields (entries 1–4). Surprisingly, however,
tetramethoxybiaryl 1e was much less reactive, and only the
mono-cyanation product was obtained in 30% yield, even in
the presence of 2.4 equiv. of BrCN (entry 5). Biaryl 1f, bearing
one methoxy group, underwent cyanation at the para position of
the methoxy group (entry 6). Both 1- and 2-methoxynaphthalenes
were fully converted within 2 h under the reaction conditions used,
and the cyanation products 2g and 2h were obtained as single
regioisomers in 63% and 80% yield, respectively (entries 7 and 8).
The low yield of 2g from 1-methoxynaphthalene was due to
the bromination reaction. Furthermore, polycyclic aromatic
compounds such as anthracene and pyrene also afforded the
products 2i–k as single regioisomers in high yields (entries 9–11). A
large-scale reaction of 1.78 g of anthracene (1i; 10 mmol) with
1.27 g of BrCN (12 mmol) in the presence of 176 mg of GaCl3
(10 mol%) proceeded well, and 1.59 g of cyanation product 2i
(7.8 mmol, 78% yield) was isolated without column chromato-
graphy (Table 2, entry 9, in parentheses).
Table 2 (continued )
Entry Cyanation products
BrCN (equiv.) Yieldb (%) Ratioc (2/20)
7f
1.2
63
—
8f
1.2
1.2
80
—
—
9
83 (78)g
10
1.2
2.0
85
88
—
—
11d
Table 2 Gallium-catalysed cyanation of arenes 1 with cyanogen bromidea
a
Reactions were carried out with arenes 1 (0.40 mmol, 1.0 equiv.),
cyanogen bromide (0.48 mmol, 1.2 equiv.), and GaCl3 (10 mol%) in
b
ClCH2CH2Cl (1.6 mL). Isolated yield. The isomeric ratios were
c
Entry Cyanation products
BrCN (equiv.) Yieldb (%) Ratioc (2/20)
determined by 1H NMR of the crude products. Reaction time was 3 h.
d
e
f
Reaction time was 12 h. Reaction time was 2 h. The reaction was
g
carried out with anthracene 1i (10 mmol, 1.0 equiv.), cyanogen bromide
(12 mmol, 1.2 equiv.), and GaCl3 (10 mol%) in ClCH2CH2Cl (40 mL).
Reaction time was 3 h. The product was purified by recrystallisation.
1
1.2
1.2
2.0
82
83
68
95 : 5
The cyanation products of heteroaromatic compounds
are very important because they are fundamental building
blocks for complex molecules containing heteroarenes.11,12 We
successively extended the present cyanation to heteroaromatic
compounds (Table 3). The cyanation of five-membered hetero-
aromatic compounds proceeded at the 2-position selectively
and the yields were moderate to high (entries 1–3 and 5).
2,5-Diphenylthiophene (5d) underwent a cyanation reaction at
the 3-position to afford the product 6d in 73% yield. Bicyclic
and tricyclic heteroaromatic compounds also resulted in high
yields of the single cyanation products 6f and 6g, respectively
(entries 6 and 7). However, N-tosylindole afforded the cyanation
product 6h in only 40% yield (entry 8).
2d
—
3d
—
4
5
1.2
2.4
78
30
—
—
Alkynyl arenes bearing alkoxy groups at the ortho position
are known to undergo dealkylative cyclisation by the electrophilic
attack of iodine to afford benzofuran derivatives.13 The present
electrophilic cyanation system was also applied to such type of
reaction. The gallium-catalysed reaction of o,o0-dimethoxy-
diphenylacetylene 7 with BrCN afforded the demethylated
cyanation product 8 in 55% yield.
6e
2.0
60
6 : 1
ð1Þ
c
3128 Chem. Commun., 2012, 48, 3127–3129
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Table 3 Gallium-catalysed cyanation of heteroarenes 5 with cyanogen
bromidea
In conclusion, we have developed gallium-catalysed electrophilic
cyanation of aromatic C–H bonds with cyanogen bromide.
Compared with previously reported cyanation methods, the
present catalytic system offers one of the simplest cyanation
methods. The reaction was applied to a wide range of aromatic
and heteroaromatic compounds. Further investigations into the
reaction mechanisms and the scope of reactions are underway.
This work was financially supported by Grant-in-Aid for
Scientific Research (B) (Grant No. 22350087) and the Global COE
Program ‘‘Integrated Materials Science’’ of Kyoto University
from MEXT, administrated by JSPS, Japan.
Entry
1
Cyanation products 6
BrCN (equiv.)
1.2
Yieldb (%)
80
Notes and references
2
3
1.0c
1.2
73
83
1 For reviews, see: (a) D. T. Mowry, Chem. Rev., 1948, 42, 189;
(b) G. P. Ellis and T. M. Romney-Alexander, Chem. Rev., 1987,
87, 779.
2 Pioneering work: L. Cassar, J. Organomet. Chem., 1973, 54, C57.
3 Pioneering work: K. Takagi, T. Okamoto, Y. Sakakibara and
S. Oka, Chem. Lett., 1973, 471.
4 Other cyanide sources have been also used for catalytic cyanation
of aryl halides, see: Me3SiCN: (a) N. Chatani and T. Hanafusa,
J. Org. Chem., 1986, 51, 4714; Bu3SnCN; (b) V. Nair, D. F. Purdy
and T. B. Sells, J. Chem. Soc., Chem. Commun., 1989, 878;
Zn(CN)2; (c) D. M. Tschaen, R. Desmond, A. O. King,
M. C. Fortin, B. Pipik, S. King and T. R. Verhoeven, Synth.
Commun., 1994, 24, 887; K4Fe(CN)6; (d) T. Schareina, A. Zapf and
M. Beller, Chem. Commun., 2004, 1388; acetone cyanohydrin;
(e) M. Sundermeier, A. Zapf and M. Beller, Angew. Chem., Int.
Ed., 2003, 42, 1661; (f) E. J. Park, S. Lee and S. Chang, J. Org.
Chem., 2010, 75, 2760.
5 For reviews, see: (a) M. Sundermeier, A. Zapf and M. Beller,
Eur. J. Inorg. Chem., 2003, 3513; (b) P. Anbarasan, T. Schareina
and M. Beller, Chem. Soc. Rev., 2011, 40, 5049.
6 (a) T. Dohi, K. Morimoto, Y. Kiyono, H. Tohma and Y. Kita,
Org. Lett., 2005, 7, 537; (b) G. Yan, C. Kuang, Y. Zhang and
J. Wang, Org. Lett., 2010, 12, 1052; (c) H.-Q. Do and O. Daugulis,
Org. Lett., 2010, 12, 2517.
4d,e
2.0
73
5
1.0c
1.2
50
90
6e
7 For examples of Pd-catalysed oxidative cyanation of aromatic
C–H bonds assisted by ortho-directing groups, see: (a) X. Chen,
X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006,
128, 6790; (b) X. Jia, D. Yang, S. Zhang and J. Cheng, Org. Lett.,
2009, 11, 4716; (c) X. Jia, D. Yang, W. Wang, F. Luo and
J. Cheng, J. Org. Chem., 2009, 74, 9470; (d) J. Kim and
S. Chang, J. Am. Chem. Soc., 2010, 132, 10272.
8 (a) C. Friedel and J. M. Crafts, Bull. Soc. Chim., 1878, 29, 2; (b) C.
Friedel and J. M. Crafts, Ann. Chim., 1884, 1, 523; (c) P. Karrer and
E. Zeller, Helv. Chim. Acta, 1919, 2, 482; (d) P. Karrer, A. Rebmann
and E. Zeller, Helv. Chim. Acta, 1920, 3, 261; (e) P. H. Gore,
F. S. Kamounah and A. Y. Miri, Tetrahedron, 1979, 35, 2927.
9 M. Murai, R. Hatano, S. Kitabata and K. Ohe, Chem. Commun.,
2011, 47, 2375.
10 We hypothesised that the generation of molecular bromine by a
disproportionation reaction of cyanogen bromide and hydrogen
bromide would cause the gallium-catalysed and/or non-catalysed
electrophilic bromination of arenes forming aromatic bromides.
HBr + BrCN ! Br2 + HCN.
11 (a) Z. Rappoport, The Chemistry of the Cyano Group, Interscience
Publishers, London, 1970; (b) R. C. Larock, Comprehensive
Organic Transformations. A Guide to Functional Group Preparations,
VCH Publishers, New York, 1989.
12 Lewis acid-catalysed electrophilic cyanation of indoles and
pyrroles with PhN(Ts)–CN has been recently reported, see:
Y. Yang, Y. Zhang and J. Wang, Org. Lett., 2011, 13, 5608.
13 D. Yue, T. Yao and R. C. Larock, J. Org. Chem., 2005, 70, 10292.
14 Our previous NMR-based experiments indicate that the active species
should be dꢀBr–d+CN–GaCl3 or [CN]+[GaCl3Br]ꢀ, see ref. 9.
15 Friedel–Crafts reactions generally involve the intermediacy of
arene–[CN]+ s-complex generated from the reaction of an arene
with a [CN]+ source, see: F. A. Carey and R. J. Sundberg,
Advanced Organic Chemistry, Springer, Science + Business Media,
New York, 5th edn, 2007, ch. 9.
7e
2.0
3.0
80
40
8
a
Reactions were carried out with heteroarenes 5 (0.40 mmol, 1.0 equiv.),
cyanogen bromide (0.48 mmol, 1.2 equiv.), and GaCl3 (10 mol%) in
b
c
ClCH2CH2Cl (1.6 mL). Isolated yield. 1.2 equiv. of heteroarene 5 was
d
used. GaCl3 (20 mol%) was used. Reaction time was 3 h.
e
Finally, we performed a deuterium-labelling experiment.
The gallium-catalysed reaction of a 1 : 1 : 1 mixture of arenes
1a, 1a-d3, and BrCN afforded the corresponding aromatic
nitriles 2a and 2a-d2 (40% and 33% yield, respectively)
(eqn (2)). The observed modest kinetic isotope effect
(kH/kD = 1.2) implies that the deprotonation is not much
faster than the formation of the arene–[CN+] s-complex.14,15
ð2Þ
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3127–3129 3129