Palladium-catalyzed cyanation of aryl bromides with malononitrile via acarbon-nitrile bond cleavage mediated by copper

Article abstract of DOI:10.1055/s-0033-1340176

An efficient palladium catalytic system is developed for the cyanation of aryl bromides using malononitrile as a cheap, less toxic, stable and easy-to-handle 'nonmetallic' cyanide source, which proceeds via copper-catalyzed cleavage of carbon-nitrile (C-CN) bonds. The approach provides a novel and alternative route leading to aryl nitriles. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340176

LETTER
▌547
letter
Palladium-Catalyzed Cyanation of Aryl Bromides with Malononitrile via
Carbon–Nitrile Bond Cleavage Mediated by Copper
A Cyano Group Transfer Process from C(sp3) to C(sp2
)
Guo-ping Lu, Mei-jie Bu, Chun Cai*
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. of China
E-mail: c.cai@mail.njust.edu.cn
Received: 17.10.2013; Accepted after revision: 21.11.2013
form aryl nitriles via cleavage of the C–CN bonds.4a De-
spite the fact that a series of aryl iodides could be em-
ployed utilizing this catalytic system, the cyanation of the
less reactive aryl bromides and aryl chlorides proved un-
Abstract: An efficient palladium catalytic system is developed for
the cyanation of aryl bromides using malononitrile as a cheap, less
toxic, stable and easy-to-handle ‘nonmetallic’ cyanide source,
which proceeds via copper-catalyzed cleavage of carbon–nitrile
(C–CN) bonds. The approach provides a novel and alternative route successful.
leading to aryl nitriles.
The palladium-catalyzed cyanation of aryl halides (espe-
Key words: aryl nitriles, cyanation, malononitrile, aryl bromides,
palladium
cially aryl bromides and aryl chlorides) is a common and
powerful tool to obtain substituted benzonitriles.1c,2b,5
Along these lines, we envisaged the use of palladium cat-
alysts for the synthesis of aryl nitriles employing malono-
nitrile as the cyanide source, such that the cheaper and
more widely available aryl bromides and aryl chlorides
could be employed in the procedure. Herein, we describe
a novel and efficient palladium catalytic system for the
cyanation of aryl bromides with malononitrile, which in-
volves a cyano group transfer process from C(sp3) to
C(sp2) (Scheme 1).
Procedures for the introduction of a cyano group to aro-
matic rings for the preparation of aryl nitriles are of signif-
icant interest to organic chemists due to the importance of
these compounds in chemistry and biology.1 Typically,
aromatic nitriles are prepared efficiently through transi-
tion-metal-catalyzed cyanation of aryl (pseudo)halides
with metallic cyano-group sources, such as copper(I) cya-
nide (CuCN), potassium cyanide (KCN), sodium cyanide
(NaCN), zinc cyanide [Zn(CN)2], trimethylsilyl cyanide
As a representative example, the reaction of bromoben-
zene (1a) and malononitrile was selected to optimize the
reaction conditions (Table 1). During the screening of
copper sources, copper(I) proved to be a better choice than
copper(II), and copper(I) iodide provided the best result
(Table 1, entry 6). No reaction took place in the absence
of a copper source (Table 1, entry 7). Control experiments
indicated the necessity for both sodium tert-butoxide and
potassium fluoride, and only a trace amount of product
was detected in the absence of either of them (Table 1, en-
tries 8–10). Compared with other bases (NaOH, K2CO3,
Cs2CO3, K3PO4) and additives (NaF, CsF, KI), the combi-
nation of sodium tert-butoxide and potassium fluoride
was the best selection for this reaction. The use of two
equivalents of malononitrile proved to be optimum for the
cyanation process (Table 1, entry 11). To further improve
the modest yields, different palladium catalysts were em-
ployed in the reaction (Table 1, entries 11 and 13–15).
(TMSCN),
and
potassium
hexacyanoferrate(II)
{K4[Fe(CN)6]}.2 These methods, however, suffer from
limitations which include the formation of stoichiometric
amounts of metal waste, poisoning of the metal catalysts,
or the generation of toxic hydrogen cyanide (HCN) gas. In
order to eliminate these problems, a range of ‘nonmetal-
lic’ organic cyano group sources have been explored for
the cyanation of aryl halides and arene C–H bonds.3
Compared with commonly employed metallic cyanation
reagents, malononitrile as an alternative organic cyanide
source has the distinct advantages of being relatively
cheap, less toxic, stable and easy-to-handle. Recently, at-
tempts have been made to utilize malononitrile as the
source of cyanide in several cyanation reactions (Scheme
1).4 Zhou and co-workers reported the copper-catalyzed
coupling reactions of aryl iodides with malononitrile to
Ar
Ar
I
CN
Cu(OAc)2/phen
ref. 4a
O
CN
O
base
ref. 4b
NC
CN
R1
R2
R1
R2
this work
cat. Pd, CuI/phen
Ar
Ar
Br
CN
Scheme 1 Cyanation reactions using malononitrile as the cyanide source via C–CN bond cleavage
SYNLETT 2014, 25, 0547–0550
Advanced online publication: 08.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340176; Art ID: ST-2013-W0974-L
© Georg Thieme Verlag Stuttgart · New York

548
G.-p. Lu et al.
LETTER
Pd(Amphos)2Cl2 emerged as the best option for this pro- A satisfactory 73% yield was obtained when the reaction
cess (Table 1, entry 11). Additionally, only a trace of was carried out under a nitrogen atmosphere, thereby cer-
product 2a was obtained without a palladium catalyst (Ta- tifying that air did not participate in the protocol (Table 1,
ble 1, entry 16).
entries 11 vs 12). The use of 1,10-phenanthroline (phen)
as the ligand in combination with copper failed to improve
the results of the model reaction. On the other hand, in the
cyanation of 1-bromo-4-methoxybenzene (1b) with malo-
nonitrile, the yield of product 2b was enhanced by adding
1,10-phenanthroline as the ligand (Table 1, entries 20 and
21). The amounts of copper(I) iodide and 1,10-phenanth-
roline were also optimized [CuI (0.50 equiv) and phen
(0.25 equiv)] (Table 1, entry 21). Compared with other or-
ganic cyanide sources such as ethyl cyanoacetate and 2-
cyanoacetic acid, malononitrile was the better cyanide re-
agent for this catalytic system.
Table 1 Optimization of the Reaction Conditionsa
Br
CN
cat. Pd, Cu source
+
NC
CN
t-BuONa, KF
130 °C, DMF, 24 h
1a
2a
Entry
Catalyst
Cu source
Yield (%)b
1
2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(Amphos)2Cl2
Pd(Amphos)2Cl2
Pd(dppf)2Cl2
Pd(OAc)2
Cu(OAc)2
Cu
9
n.r.
3
CuBr2
CuBr
CuCl
CuI
n.r.
In order to ascertain the scope and generality of the proto-
col, a series of aryl bromides was employed in the cyana-
tion with malononitrile under the optimized conditions
(Table 2). Typically, electron-rich aryl bromides gave
moderate to good yields of the desired products. Further-
more, aryl nitriles containing active groups (such as OH
and NH2) could also be prepared from the corresponding
aryl bromides via this process, without the need for any
protection–deprotection steps (2i,j,l). In some cases,
N-methyl-2-pyrrolidinone (NMP) proved to be a better
solvent than N,N-dimethylformamide (2h–j). In contrast,
electron-deficient aromatic bromides provided unsatisfac-
tory results (2m,o,p), due to dehalogenation and the for-
mation of undesired side products (aromatic carboxylic
acids).6 Although the cyanation of 2-bromoaniline with
malononitrile proceeded smoothly (2l), 1-bromo-
2-methoxybenzene afforded only a poor yield of the cor-
responding product 2n. It can be concluded that the cya-
nation will be inhibited when the aryl bromide substrate
contains a sterically hindered group at the ortho position.
4
25
5
52
6
54
7
–
n.r.
8c
9d
10e
11
12h
13
14
15
16
17
CuI
12
CuI
10
CuI
trace
CuI
76, 56,f 74g
CuI
73
41
7
CuI
CuI
Pd(OAc)2/2PCy3
–
CuI
68
9
CuI
Pd(Amphos)2Cl2
CuI/pheni
70
Br
CN
Encouraged by these results, we decided to employ the di-
halogenated benzenes 1q and 1r in this procedure in an at-
tempt to produce the desired dicyanobenzenes. However,
instead of the expected dicyanobenzenes, benzonitrile
(2a) was obtained in these reactions, indicating that both
cyanation and dehalogenation occurred in the system
(Scheme 2). To further demonstrate the potential of this
methodology, aromatic nitrile 2s, a crucial intermediate
en route to the tetrazole analogue 3 related to disoxaril,
which displays potent antipicoranvirus activity, was syn-
thesized via the palladium-catalyzed cyanation with
+
NC
CN
MeO
MeO
1b
2b
18
19
20
21
22
Pd(Amphos)2Cl2
Pd(Amphos)2Cl2
Pd(Amphos)2Cl2
Pd(Amphos)2Cl2
Pd(Amphos)2Cl2
CuI
30
28
71
75
36
CuCl
CuI/phenj
CuI/pheni
CuI/phenk
a Reaction conditions: phenyl bromide (0.25 mmol), malononitrile
(0.50 mmol), Pd catalyst (2 mol%), Cu source (1.0 equiv), t-BuONa
(2.0 equiv), KF (2.0 equiv), DMF (1.0 mL), 130 °C, 24 h.
b Yields determined by GC; n.r. = no reaction.
c No KF was used.
I
67%
Br
CN
malononitrile (4.0 equiv)
1q
d No t-BuONa was used.
Pd(Amphos)2Cl2 (2 mol%)
CuI (0.50 equiv), phen (0.25 equiv)
t-BuONa, KF, NMP,130 °C, 24 h
e Neither t-BuONa nor KF was used.
f Malononitrile (0.25 mmol) was used.
Br
2a
g Malononitrile (0.75 mmol) was used.
54%
h Reaction under N2.
Br
i CuI (0.50 equiv) and phen (0.25 equiv) were used.
j CuI (0.50 equiv) and phen (0.50 equiv) were used.
k CuI (0.25 equiv) and phen (0.25 equiv) were used.
1r
Scheme 2 The cyanation of dihalogenated benzenes using the opti-
mized protocol
Synlett 2014, 25, 547–550
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Cyano Group Transfer Process from C(sp3) to C(sp2)
549
malononitrile (Scheme 3). This provides an alternative to
the previously reported methods employing toxic metallic
cyanide sources.7
Table 2 Cyanation of Aryl Bromides with Malononitrile Catalyzed
by Palladiuma
cat. Pd, CuI/phen
Ar CN
+
Ar Br
NC
CN
t-BuONa, KF
Br
Pd(Amphos)2Cl2 (2 mol%)
CuI (0.50 equiv), phen (0.25 equiv)
DMF, 130 °C, 24 h
CN
CN
+
Entry
Product
Ar
Yield (%)b
HO
HO
t-BuONa, KF
NMP,130 °C, 24 h
1
2
2a
2b
2c
2d
2e
2f
Ph
68c
70
1s
CN
n-C3H7
4-MeOC6H4
4-F3CC6H4
4-MeC6H4
2-naphthyl
1-naphthyl
4-PhC6H4
N
N
N
N
(CH)3O
3
73
N
O
4
78
3
2s 72%
5
75
Scheme 3 A potential application of the cyanation to total synthesis
6
60
Finally, a proposed mechanism for the reaction is illustrat-
ed in Scheme 4. The reaction did not take place in the ab-
sence of a copper source, so we believe that copper(I)
iodide performs an important role in the cleavage of
C–CN bonds,8 and 1,10-phenanthroline as the ligand has a
positive effect on the formation of the coordination com-
plex (CuLCN).4a It is more reasonable that cleavage of the
C–CN bonds is promoted by sodium tert-butoxide and po-
tassium fluoride,4a,9 rather than an oxidation process, be-
cause satisfactory results were also obtained in the
absence of an oxidant (Table 1, entries 11 vs 12). Based
on the above results, copper(I) iodide may initially chelate
to the cyanide triple bonds in malononitrile in the pres-
ence of 1,10-phenanthroline. The corresponding carban-
ion intermediate is formed by deprotonation with the base.
Next, the carbon–cyano σ-bond is cleaved to form in situ
the cyanide complex, CuLCN. Finally, the aryl nitrile is
formed via the typical palladium-catalyzed cyanation
mechanism.3a
7
2g
2h
2i
70
8
3,4-(MeO)2C6H4
4-HOC6H4
4-H2NC6H4
4-Me2NC6H4
2-H2NC6H4
4-O2NC6H4
2-MeOC6H4
4-AcC6H4
2-pyridyl
65d
79d
76e
61
9
10
11
12
13
14
15
16
2j
2k
2l
72
2m
2n
2o
2p
40
21f
trace
n.r.
a Reaction conditions: aryl bromide (0.25 mmol), malononitrile (0.50
mmol), Pd(Amphos)2Cl2 (2 mol%), CuI (0.5 equiv), phen (0.25
equiv), t-BuONa (2.0 equiv), KF (2.0 equiv), DMF (1.0 mL), 130 °C,
24 h.
b Yields are those of isolated products. NR = no reaction.
c Reaction conditions: Pd(Amphos)2Cl2 (2 mol%), CuI (1.0 equiv),
t-BuONa (2.0 equiv), KF (2.0 equiv), DMF (1.0 mL), 130 °C, 24 h.
d NMP was used as the solvent.
In conclusion, the cyanation of aryl bromides with malo-
nonitrile was achieved via a C(sp3) to C(sp2) cyano group
transfer process in the presence of copper(I) iodide/1,10-
phenanthroline, sodium tert-butoxide and potassium fluo-
ride.10 The use of palladium as the catalyst resulted in con-
siderable enhancement of the cyanation of aryl bromides.
e The reaction was performed in NMP at 150 °C.
f Yield determined by GC.
NC
t-BuOH
Ar Br
CuILI
N
Pd
Ar
Br
t-BuONa
Pd
CuILI
N
CuILCN
NC
Ar CN
Pd
CuILI
+
Ar
CN
=
NC
CN
L
CuI
L
N
N
Scheme 4 A proposed mechanism for the palladium-catalyzed cyanation of aryl bromides with malononitrile
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 547–550

550
G.-p. Lu et al.
LETTER
2010, 49, 8918. (d) Yeung, P. Y.; Tsang, C. P.; Kwong, F. Y.
Tetrahedron Lett. 2011, 52, 7038.
The protocol avoids the use of a highly toxic cyanide
source, thereby offering considerable potential for appli-
cations in organic synthesis. Further investigations on the
synthesis of aryl nitriles using ‘nonmetallic’ cyano-group
sources are ongoing in our laboratory.
(6) Yang, D.; Yang, H.; Fu, H. Chem. Commun. 2011, 47, 2348.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
(8) (a) Marlin, D. S.; Olmstead, M. M.; Mascharak, P. K.
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X.; Li, Y.; Chen, S. J. Am. Chem. Soc. 2004, 126, 4760.
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(10) Palladium-Catalyzed Cyanation, General Procedure
A mixture of aryl bromide (0.250 mmol), malononitrile
(0.500 mmol), Pd catalyst (0.005 mmol), CuI (0.125 mmol),
1,10-phenanthroline (0.063 mmol), t-BuONa (0.500 mmol)
and KF (0.500 mmol) in DMF or NMP (1 mL) was stirred at
130 °C for 24 h. Upon completion of the reaction, the
mixture was diluted with EtOAc (4.0 mL), and filtered
through a bed of silica gel layered over Celite. The volatiles
were removed in vacuo to afford the crude product. The
extent of conversion was determined by GC. Further
purification by column chromatography on silica gel
afforded the desired product.
References and Notes
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Synlett 2014, 25, 547–550
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