Copper-catalyzed cyanations of aromatic bromides with benzoyl cyanide

Article abstract of DOI:10.1002/cjoc.201400637

Aromatic nitriles were synthesized through copper-catalyzed cyanations of aromatic bromides using benzoyl cyanide as the cyanide source. A series of functional groups were tolerated under the reaction conditions to provide the products in good yields. Moreover, this protocol avoids using of highly toxic alkali cyanides and expensive palladium catalysts.

Full text of DOI:10.1002/cjoc.201400637

COMMUNICATION
DOI: 10.1002/cjoc.201400637
Copper-Catalyzed Cyanations of Aromatic Bromides with
Benzoyl Cyanide
Liang Wang,* Liang Pan, Qun Chen, and Mingyang He*
School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213164, China
Aromatic nitriles were synthesized through copper-catalyzed cyanations of aromatic bromides using benzoyl
cyanide as the cyanide source. A series of functional groups were tolerated under the reaction conditions to provide
the products in good yields. Moreover, this protocol avoids using of highly toxic alkali cyanides and expensive pal-
ladium catalysts.
Keywords nitriles, aromatic bromides, benzoyl cyanide, copper-catalysis, cyanation
Introduction
eral advantages in cyanation reactions since they are
cheap and readily available. Various cyanation reactions
were also realized by using a copper catalyst.[8a,20]
Enlightened by the literature, and in order to further
improve and expand the tools for cyanation of aryl hal-
ides, here, we report a copper-catalyzed cyanation of
aryl bromides using benzoyl cyanide as the cyanide
source (Eq. 1).
Aromatic nitriles are a class of significant com-
pounds in organic synthesis. They are widely present as
key motifs in numerous products including dyes, herbi-
cides, agrochemicals, pharmaceuticals, and materials.[1]
The cyano-group also serves as a versatile precursor for
various functional groups, such as amines, tetrazoles,
aldehydes, amides, or other carboxy derivatives. More-
over, the cyano-group can be employed as a leaving
group, and some transformations thus can be achieved
via the cleavage of C－CN bonds.[2] Therefore, the in-
troduction of cyano-group into aromatic rings is of
long-standing interest to organic chemists.[3]
O
Cu(OAc)2
(1)
Ar Br
Ar CN
+
Ph
CN
KI, TMEDA,
DMF, 130 oC
Experimental
Generally, aromatic nitriles are prepared via the
transition metal-catalyzed cyanation reaction of aryl
halides with metal cyanides, such as CuCN,[4] NaCN,[5]
KCN,[6] Zn(CN)2,[7] K4Fe(CN)6.[8] Recently, the use of
non-metallic cyano-group sources to overcome the dis-
advantages of the metal- or metalloid-bound cyanide
sources, has attracted great attention.[9] A series of or-
ganoreagents, for example, nitromethane,[10] acetone
cyanohydrin,[11] malononitrile,[12] benzyl cyanide,[13]
All chemical reagents are obtained from commercial
suppliers and used without further purification. 1H NMR
and 13C NMR spectra are recorded on an AVANCE 500
Bruker spectrometer operating at 500 MHz and 125
MHz in CDCl3, respectively.
General procedure for the cyanation of aromatic
bromides with benzoyl cyanide
N-cyano-N-phenyl-p-toluenesulfonamide,[14]
2,3-di-
A mixture of aromatic bromides 1 (0.5 mmol), ben-
zoyl cyanide (0.75 mmol), TMEDA (0.5 mmol), KI (0.1
mmol), Cu(OAc)2 (0.05 mmol), Na2CO3 (0.1 mmol) and
1 mL DMF was stirred at 130 ℃ for 16 h. After the
reaction, the mixture was then diluted with EtOAc (4
mL), filtered through a bed of silica gel layered over
Celite. The volatiles were removed in vacuo to afford
the crude product, which was subjected to column chro-
matography (silica, hexane/ethyl acetate) to afford the
pure products. All prepared benzonitriles are identified
by comparison with commercially available materials
and the literature. Caution! Benzoyl cyanide is sensi-
chloro-5,6-dicyano-p-benzoquinone (DDQ),[15] azo-
bisisobutyronitrile (AIBN),[16] acetonitrile,[17] and
ICN[18] have been successfully utilized in cyanation re-
actions. More recently, the combination of ammonium
salt and DMF or DMSO was also reported as a green
cyanide surrogate.[19]
In another aspect, catalysts applied in cyanation re-
actions are based primarily on the palladium catalysts.
In spite of the high activities, the expensive palladium
catalysts as well as the expensive ligands are the major
drawbacks. Recently, copper catalysts have shown sev-
*
E-mail: lwcczu@126.com; hemingyangjpu@yahoo.com. Tel.: 0086-0519-86330263; Fax: 0086-0519-86330251
Received September 21, 2014; accepted October 18, 2014; published online XXXX, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400637 or from the author.
Chin. J. Chem. 2014, XX, 1—4
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Wang et al.
COMMUNICATION
tivity to water and acid by releasing hazardous
HCN.
3a in 82% yield (Table 1, entry 12). Although CuI was
often used in such transformation, a relatively lower
yield was obtained in this procedure (75%, entry 13).
Influence of catalyst amount as well as the addition of
KI was also examined. Reducing the amount of
Cu(OAc)2 to 5 mol% decreased the yield significantly
(52%, entry 14). Only 34% yield of product was ob-
tained in the absence of KI. Moreover, addition of cata-
lytic amount of inorganic bases such as Na2CO3, K2CO3
and K3PO4 was less important (Table 1, entries 15－17).
Increasing the temperature to 140 ℃ also did not im-
prove the yield. Other solvents including N,N-dimethyl-
acetamide (DMA), N-methyl-2-pyrrolidinone (NMP),
toluene and dimethyl sulfoxide (DMSO) were also util-
ized, however, relatively lower yields were obtained
(Table 1, entries 19－22).
Results and Discussion
Initially, bromobenzene 1a and benzoyl cyanide 2a
were chosen as the substrates to optimize the reaction
conditions according to Beller’s procedure (Table 1).[8a]
Table 1 Optimization of reaction conditionsa
Br
CN
O
cat. Cu, ligand
DMF
+
Ph
CN
1a
Entry
1
2a
Copper
Cu2O
Ligandb
－
Solvent
Base
Yieldc/%
19
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
DMF Na2CO3
With optimized conditions in hand, various aryl bro-
mides were applied in the cyanation to ascertain the
scope and generality of the protocol. The results are
summarized in Table 2.
2
Cu(OAc)2
CuI
－
35
3
－
21
4
CuCl
－
13
5
CuBr2
－
trace
36
Table 2 The cyanation of various bromides with benzoyl cya-
nidea,b
6
Cu(OAc)2
NEt3
7
Cu(OAc)2 TMEDA
Cu(OAc)2 1,10-phen
76
O
Cu(OAc)2
+
Ar Br
Ar CN
8
trace
70
Ph
CN
TMEDA, KI, Na2CO3
DMF, 130 oC, 16 h
1
2
9
Cu(OAc)2
Cu(OAc)2
NBu3
DBU
10
11
12
13
14
15
16
17
18
19
20
21
22
62
OMe
CN
2c 80%
CN
CN
Cu(OAc)2 DABCO
Cu(OAc)2 TMEDA
17
82
2a 82%, 11%c
CN
2b 84%
CuI
TMEDA
75
CN
CN
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
Cu(OAc)2 TMEDA
DMF Na2CO3 34d (52)e
MeO
DMF
DMF
DMF
－
74
72
O2N
F
K2CO3
K3PO4
2e 89%
MeO
2d 78%
2f 70%
77
80f
MeO
MeO
CN
CN
DMF Na2CO3
DMA Na2CO3
NMP Na2CO3
MeO
MeO
2h 76%
CN
70
Cl
75
2i 72%
CN
2g 81%
2j 86%
Cu(OAc)2 TMEDA Toluene Na2CO3
Cu(OAc)2 TMEDA DMSO Na2CO3
trace
41
CN
CN
a Reaction conditions: bromobenzene (0.5 mmol), benzoyl cya-
nide (0.75 mmol), solvent (1 mL), copper catalyst (10 mol%),
ligand (0.5 mmol), 20 mol% KI, 20 mol% of base, 130 ℃, 16 h.
N
CN
N
2l 68%
2k 66%
b
CN
TMEDA: N,N,N',N'-tetramethylethylenediamine, 1,10-phen:
O
1,10-phenanthroline, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene,
c
DABCO: 1,4-diazabicyclo[2.2.2]octane. Isolated yields. d With-
BnO
O
Ph
2n 71%
CN
out KI. e 5 mol% Cu(OAc)2 was used. f 140 ℃.
2m 84%
2o 84%
a
A series of copper salts including Cu2O, Cu(OAc)2,
CuI, and CuBr2, were studied. Low yields were ob-
served by using these copper catalysts alone. It was
found that ligands were very important for the reaction.
Screening on a series of N-containing ligands suggested
that TMEDA was crucial, affording the desired product
Reaction conditions: 1 (0.5 mmol), benzoyl cyanide (0.75
mmol), Cu(OAc)2 (0.05 mmol), TMEDA (0.5 mmol), DMF (1
mL), 20 mol% KI, 20 mol% of Na2CO3, 130 ℃, 16 h. Isolated
yields. c Chlorobenzene as starting material.
b
Generally, both electron-poor and electron-rich
2
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, XX, 1—4

Copper-Catalyzed Cyanations of Aromatic Bromides with Benzoyl Cyanide
bromoarenes reacted smoothly to give the products in
moderate to good yields. A series of functional groups
including chloro, fluoro, methyl, methoxyl, and nitro
tolerated the reaction conditions. 1-Bromonaphthalene
and 2-bromonaphthalene showed good activities to-
wards the reaction, furnishing the naphthonitriles in ex-
cellent yields. Cyanation of 2-bromopyridine and
3-bromopyridine could also produce the corresponding
nitriles (2k, 66%; 2l, 68%). No desired product was ob-
tained when the aryl bromide containing active group
(such as －OH, －NH2). Interestingly, 2n was yielded
as the final product using 4-bromobenzyl alcohol as the
substrate. Moreover, replacement of bromobenzene with
chlorobenzene dramatically decreased the yield (11%).
To further highlight the potential of this protocol,
aromatic nitrile 2p, a crucial intermediate for L692, 429
3 (non-peptidyl growth hormone secretagogue),[21] was
synthesized from 1p via this copper-mediated cyanation
using benzoyl cyanide as the cyanide source (Scheme
1).
be rationalized assuming in situ copper-catalyzed con-
version of the aryl bromide into the more reactive aryl
iodide, followed by the cyanation of the resulting aryl
iodide (Eq. 2).[20a]
O
Standard conditions
+
Ar
X
Ar CN
Ph
CN
X= Br, 82%;
X= Br, 34% (without KI)
X = I, 85% (without KI);
Based on the above results, a plausible mechanism
was also proposed. Initially, cyanide anion was gener-
ated by heating benzoyl cyanide in DMF. Meanwhile,
aryl bromides were converted to the more active aryl
iodides catalyzed by the copper salt in the presence of
KI.[22] Then oxidative addition occurred between Cu
catalyst, cyanide anion and aryl iodides to give interme-
diate A. Subsequently, reductive elimination reaction
took place to give the aryl nitriles together with the re-
generation of the Cu(I) catalyst and iodine anion
(Scheme 2).
Scheme 1 A potential application of the protocol in organic
synthesis
Scheme 2 Plausible mechanism
O
O
O
H2O or DMF
CN-
Standard conditions
+
Ph
N
Ph
CN
Ph
OH
CN
Br
1p
2p, 82%
Reductive
elimination
Cu salt,
TMEDA
Cu(I)
ArI
I
ArBr
Ar Cu
ArCN
CN-
O
CN
KI
Cu(I), I-
1
A
2
NH2
NH
N N
NH
N
O
Conclusions
N
In conclusion, we have developed a practical cop-
per-catalyzed cyanation of aryl bromides using benzoyl
cyanide as the cyanation reagent. Benzoyl cyanide
proves to be an efficient and eco-friendly non-metallic
cyanide source. Also, the present method has several
advantages over the conventional protocols due to the
good yields, good substrate compatibilities as well the
using of a cheap copper catalyst.
3
To gain more insight into the mechanism, a series of
tests were carried out to investigate the roles of benzoyl
cyanide and KI. Previously, Lu and Wang reported a
copper-mediated cyanation reaction using benzyl cya-
nide as the CN− source.[13b] It was found that the
CN− anion was generated in the presence of copper
source, benzyl cyanide and air. Also benzoyl cyanide
was found as the intermediate, which was attacked by
water or DMF to form the benzoic acid and
N,N-dimethylbenzamide, respectively, accompanied by
the generation of the cyanide anion. To our delight, the
presence of cyanide anion was also confirmed in our
study by using a picrate paper after heating benzoyl
cyanide in DMF.
Acknowledgement
This project was financially supported by the Na-
tional Natural Science Foundation of China (No.
21302014), the Natural Science Foundation for Colleges
and Universities of Jiangsu Province (13KJB150002),
and the Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology (grant No. BM2012110).
References
Next, to understand the role of KI, iodobenzene was
employed as the substrate instead of bromobenzene in
the absence of KI. As expected, the reaction proceeded
smoothly to give the product in 85% yield. However,
only 34% yield was obtained when bromobenzene was
used as the substrate (Table 1, entry 14). This result can
[1] (a) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035; (b) Kim,
J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 11948; (c)
Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J.
Med. Chem. 2010, 53, 7902; (d) Kumar, S.; Kumar, P.; Jain, S. L.
RSC Adv. 2013, 3, 24013.
[2] (a) Tobisu, M.; Chatani, N. Chem. Soc. Rev. 2008, 37, 300; (b)
Chin. J. Chem. 2014, XX, 1—4
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Wang et al.
COMMUNICATION
Wang, R.; Falck, J. R. RSC Adv. 2014, 4, 1062.
[3] (a) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003,
3513; (b) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev.
2011, 40, 5049; (c) Senecal, T. D.; Shu, W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2013, 52, 10035; (d) Ellis, G. P.; Romney-Alexander,
T. M. Chem. Rev. 1987, 87, 779; (e) Martínez-Sarti, L.;
Díez-González, S. ChemCatChem 2013, 5, 1722; (e) Shu, Z.; Ye, Y.;
Deng, Y.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2013, 52,
10573; (f) Lu, G.-P.; Lin, Y.-M. J. Chem. Res. 2014, 38, 371.
[4] Do, H.; Daugulis, O. Org. Lett. 2010, 12, 2517.
[5] Cristau, H.; Ouali, A.; Spindler, J.; Taillefer, M. Chem. Eur. J. 2005,
11, 2483.
[6] Murahashi, S.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc.
2008, 130, 11005.
[7] Yu, H.; Richey, R. N.; Miller, W. D.; Xu, J.; May, S. A. J. Org.
Chem. 2011, 76, 665.
[8] (a) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46,
2585; (b) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Org.
Lett. 2011, 13, 648.
2012, 354, 589.
[13] (a) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2012, 48,
9933; (b) Wen, Q.; Jin, J.; Mei, Y.; Lu, P.; Wang, Y. Eur. J. Org.
Chem. 2013, 4032; (c) Luo, Y.; Wen, Q.; Wu, Z.; Jin, J.; Lu, P.;
Wang, Y. Tetrahedron 2013, 69, 8400; (d) Zhang, L.; Wen, Q.; Jin,
J.; Wang, C.; Lu, P.; Wang, Y. Tetrahedron 2013, 69, 4236.
[14] Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu,
L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630.
[15] (a) Zhang, G.; Chen, S.; Fei, H.; Cheng, J.; Chen, F. Synlett 2012,
2247; (b) Zheng, K.; Yu, P.; Chen, S.; Chen, F.; Cheng, J. Chin. J.
Chem. 2013, 31, 449.
[16] Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett. 2013, 15, 3354.
[17] Wen, Q.; Jin, J.; Hu, B.; Lu, P.; Wang, Y. RSC Adv. 2012, 2, 6167.
[18] Okamoto, K.; Watanabe, M.; Sakata, N.; Murai, M.; Ohe, K. Org.
Lett. 2013, 15, 5810.
[19] (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272; (b)
Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett. 2011, 13,
5004; (c) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun.
2011, 47, 6725; (d) Kim, J.; Choi, J.; Shin, K.; Chang, S. J. Am.
Chem. Soc. 2012, 134, 2528.
[9] (a) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51,
11948; (b) Pawar, A. B.; Chang, S. Chem. Commun. 2014, 50, 448;
(c) Lu, G.-p.; Bu, M.-j.; Cai, C. Synlett 2014, 547.
[10] Chen, X.; Hao, X.; Goodhue, C. E.; Yu, J. J. Am. Chem. Soc. 2006,
128, 6790.
[20] (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 2890; (b) Wu, J. X.; Beck, B.; Ren, R. X. Tetrahedron Lett.
2002, 43, 387; (c) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.; Wang,
Y. Tetrahedron Lett. 2014, 55, 1271.
[11] Schareina, T.; Zapf, A.; Cott, A.; Gotta, M.; Beller, M. Adv. Synth.
Catal. 2011, 353, 777.
[21] Bhupathy, M.; Bergan, J. J.; McNamara, J. M.; Volante, R. P.; Rei-
der, P. J. Tetrahedron Lett. 1995, 36, 9445.
[12] Jiang, Z.; Huang, Q.; Chen, S.; Long, L.; Zhou, X. Adv. Synth. Catal.
[22] Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
(Zhao, X.)
4
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, XX, 1—4