Ligand-free Cu-catalyzed cyanation of aryl halides with K 4[Fe(Cn)6] in water

Article abstract of DOI:10.2174/157017809789869573

A simple methodology for Cu-catalyzed cyanation of aryl halides with K ₄[Fe(CN)₆] was developed with water as the solvent in conjunction with ligand-free Cu(OAc)₂·H₂O as the catalyst. The suggested methodology i

Full text of DOI:10.2174/157017809789869573

564
Letters in Organic Chemistry, 2009, 6, 564-567
Ligand-Free Cu-Catalyzed Cyanation of Aryl Halides with K4[Fe(CN)6] in
Water
Yunlai Ren, Shuang Zhao, Xinzhe Tian, Zhifei Liu, Jianji Wang* and Weiping Yin
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang, Henan 471003,
P. R. China
Received March 30, 2009: Revised August 11, 2009: Accepted August 11, 2009
Abstract: A simple methodology for Cu-catalyzed cyanation of aryl halides with K4[Fe(CN)6] was developed with water
as the solvent in conjunction with ligand-free Cu(OAc)2·H2O as the catalyst. The suggested methodology is applicable to
cyanation of a wide range of aryl iodides and activated aryl bromides, and allows the catalyst to be reused six times with a
very slight change in the catalytic activity.
Keywords: Cyanation, aryl halide, ligand-free catalyst, water solvent.
Aromatic nitriles represent an important class of
compounds since they not only constitute key components of
a range of pharmaceuticals, agrochemicals, dyes and so on
[1], but also can easily be transformed into various classes of
compounds such as nitrogen-containing heterocycles,
aldehydes, amines, amidines, acids, and acid derivatives [2].
One of the most convenient methods for the synthesis of aryl
nitriles is the direct reaction between aryl halides and copper
cyanide (the Rosenmund-von Braun reaction) [3]. However,
such a strategy does not meet today’s criteria of sustainable
synthesis owing to stoichiometric amounts of metal waste,
which has prompted chemists to develop some transition
metal-catalyzed methods by using palladium [4], nickel [5]
or copper [6] compounds as the catalysts, and KCN [7],
Me3SiCN [8], Zn(CN)2 [4b,c] or K4[Fe(CN)6] [9] as the
cyanating agents.
developing a more economical and environmentally benign
procedure for Cu-catalyzed cyanation of aryl halides using
water as the solvent, ligand-free copper salt as the catalyst,
and nontoxic K4[Fe(CN)6] as the cyanide source under
microwave heating [16h]. We found that the reactions could
proceed effectively without an assistance of microwave, and
report our results here.
In our initial study, cyanation of iodobenzene was chosen
as a model reaction to demonstrate the catalytic effectiveness
of ligand-free Cu(OAc)2·H2O with water as the solvent under
argon (Table 1, entries 1-9). According to a related report
[12], the use of Na2CO3 was necessary for facilitating
copper-catalyzed cyanation. However, in the case of using
Na2CO3 as the base, the desired cyanation product was
herein obtained in only 21% yield, accompanied by a
considerable amount of phenolic and benzoic acid products
(Table 1, entry 1). The replacement of Na2CO3 by some
bases such as K2CO3, K3PO4·3H2O and KF, did not improve
the cyanation to a satisfactory extent (Table 1, entries 2-4).
These disappointing results prompted us to use
tetrabutylammonium bromide (TBAB) as an additive to
improve the reaction. To our delight, such a modification to
this procedure allowed the cyanation reaction to proceed in
high yields in the case of using KF as the base (Table 1,
entry 8). We tried eliminating toxic KF from the reaction
system and this modification did not cause a decrease in the
yield of benzonitrile, revealing that the use of the base was
unnecessary (Table 1, entry 9). In order to further improve
this cyanation protocol to allow it more easy-handling, the
reaction was carried out without any inert gas protection
(Table 1, entries 10-12). The results showed that the
presence of oxygen had a negative effect on the reaction
(Table 1, entry 10).
Clearly so far, palladium complexes have dominated as
catalysts in the transition metal-catalyzed cyanation of aryl
halides [4], whereas inexpensive copper catalysts always
receive scanter attention. As was described in previous
literatures [6,10], the first case for copper-catalyzed
cyanation of aryl halides was reported by Buchwald and co-
workers [11], who used 10 mol % CuI and 100 mol %
expensive N,N'-dimethylethylenediamine (DMEDA) as the
catalyst system. Subsequently, only a few catalyst systems
have been developed such as DMEDA/Cu(BF4)2·6H2O [12],
1,10-phenanthroline/ CuI or Cu2O [13], 1-alkylimidazoles/
CuI or Cu(BF4)2·6H2O [6,14], ethylenediamine/Cu(OAc)2·
H2O [15].
All the above-mentioned methods for Cu-catalyzed
cyanation of aryl halides require the use of ligands and
hazardous organic solvents. From environmental and
economic perspectives, both the use of ligand-free catalyst
systems and the replacement of organic solvent by water are
still desirable [16]. Thus our attention has been drawn to
Subsequently, our investigation was focused on the
quantitative recovery and recycling of the catalyst. At the
end of the reaction, 0.5 mL n-pentane was added to the
reaction mixture, and a two-phase mixture is obtained. After
the organic layer containing benzonitrile product was
separated, the recovered aqueous phase containing the
*Address correspondence to this author at the School of Chemical
Engineering
& Pharmaceutics, Henan University of Science and
Technology, Luoyang, Henan 471003, P. R. China; Fax: 86-379-64210415;
E-mail: jwang@henannu.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Ligand-Free Cu-Catalyzed Cyanation of Aryl Halides
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
565
Table 1. Cyanation of Iodobenzene Catalyzed by Cu(OAc)2·H2Oa
Cu(OAc)2 H2O
K4[Fe(CN)6]
I
CN
OH
+
+
H2O, 18 h
Entry
Base
TBAB (mmol)
Conversion (%)b
Yield of Benzonitrile (%)b
Yield of Phenol (%)b
1
2
Na2CO3
-
-
49
73
69
46
68
82
52
91
93
81
94
96
21
9
16
60
38
0
K2CO3
3
K3PO4·3H2O
-
16
45
41
9
4
KF
-
5
Na2CO3
1
1
1
1
1
1
1
1
11
68
25
0
6
K2CO3
7
K3PO4·3H2O
16
90
92
80
92
95
8
KF
9
-
-
-
-
0
10c
11c,d
12c,e
0
0
0
aReaction conditions: the reactions were performed under argon, other reaction conditions were shown in Reference [17]. bDetermined by GC analysis using n-tetradecane as an
internal standard (average of two runs). cThe reactions were performed without inert gas protection. dReaction time: 22 h. e DMEDA (50 mol %) was additionally added.
conjunction with ligand-free Cu(OAc)2·H2O as the catalyst
and K4[Fe(CN)6] as the cyanide source. Although a protocol
using Cu(OAc)2·H2O in combination with DMEDA as the
catalyst system was also effective (Table 1, entry 12), we
preferred the methodology employing no additional ligand
for economic reasons (Table 1, entry 11). Considering the
fact that the procedure without inert gas protection is more
easy-handling, we carried out the reaction without any inert
gas protection regardless of the slight negative effect of
oxygen on the reaction. As shown in Table 2, the cyanation
reactions were able to tolerate a wide range of functional
groups such as ketone carbonyl, ester, nitryl, nitrile,
methoxy, hydroxy groups and so on. Primary amido group
was even well tolerated and did not suffer from N-arylation
(Table 2, entry 8), which possibly resulted from the high
affinity of the cyanide nucleophile towards the copper
catalyst [11]. Both electron-poor and electron-rich aryl
iodides reacted well and gave moderate to high yields (Table
2, entries 1-16). Heteroaryl iodides are also suitable
substrates for the cyanation reaction (Table 2, entries 13, 14).
catalyst could be reused five times with a very slight change
in the catalytic activity (Fig. 1).
Fig. (1). Recycle of the catalyst for Cu(OAc)2·H2O-catalyzed
cyanation of iodobenzene with K4[Fe(CN)6] under the reaction
conditions as shown in entry 11, Table 1.
With the above results in mind, we decided to examine
the scope and limitation of this cyanation protocol by testing
a variety of representative aryl halides. In all cases the
reactions were performed using water as the solvent in
Table 2. Cu(OAc)2·H2O-Catalyzed Cyanation of Various Aryl Halidesa
Cu(OAc)2 H2O
K4[Fe(CN)6]
R
CN
R
X
+
H2O, 22 h
No inert gas protection
Yield(%)c Entry
Yield(%)c
Substrate
Productb
Substrate
Productb
Entry
I
CN
1
I
CN
92d
14
86d
S
S
CN
I
2
85
15
Me
I
Me
CN
83d

566 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Ren et al.
(Table 2). Contd…..
Yield(%)c
Yield(%)c Entry
Substrate
Productb
Substrate
Productb
Entry
Me
Me
87d
Ac
CN
3
Ac
I
92
16
I
CN
MeO2C
CN
4
5
MeO2C
I
75
67
17e
18e
CN
6d
Br
NC
CN
11
12
NC
O2N
Cl
I
MeO
Br
MeO
CN
O2N
Cl
MeO
MeO
19e
I
CN
6
7
81
95
MeO
MeO
O2N
Br
MeO
CN
O2N
MeO
O2N
O2N
20e
86
Cl
Br
Cl
CN
MeO
I
I
I
I
MeO
CN
O2N
O2N
H2N
CN
8
9
H2N
MeO
HO
69c
86
21e
22e
79
83
F3C
Br
F3C
CN
MeO
HO
CN
Br
CN
F3C
F3C
MeO
MeO
CN
Br
10
11
MeO
CN
92
77
23e
71
MeO
F
F
MeO
MeO
F
F
CN
I
Br
CN
24e
53
91
Cl
Cl
N
NH
N
NH
S
S
F
F
Br
F
CN
F
AcNH
CN
12
13
AcNH
I
93
25e
Cl
Cl
Cl
Cl
N
I
N
CN
82d
26e
82
F3CO
Br F3CO
CN
c
aReaction conditions were shown in Reference [17]. bAll compounds are known and characterized by comparison of 1H-NMR and 13C-NMR data with that in the literature. Isolated
yield (average of two runs). dDetermined by GC analysis using n-tetradecane as an internal standard (average of two runs). e30 mol % KI was added.

Ligand-Free Cu-Catalyzed Cyanation of Aryl Halides
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
567
MI
MCN
MI
MBr, Cu catalyst
Br
I
CN
Cu catalyst
More reactive
Scheme 1. Copper-catalyzed domino halide exchange-cyanation of bromobenzene.
[3]
(a) Ellis, G.P.; Romney-Alexander, T. M. Chem. Rev., 1987, 87,
779; (b) Lindley, J. Tetrahedron, 1984, 40, 1433.
The scope of the substrates was limited to aryl iodides. In
order to extend the scope of the suggested protocol, 30 mol
% KI was used as an additive to improve cyanation of aryl
bromides. The KI-acceleration effect resulted possibly from
the conversion of the aryl bromide into the more reactive
aryl iodide followed by the cyanation of the resulting aryl
iodide (Scheme 1). By applying this KI-accelerated protocol,
some aryl bromides bearing strong electron-withdrawing
groups provided the corresponding aromatic nitriles in
[4]
Buono, F.G.; Chidambaram, R.; Mueller, R.H.; Waltermire, R.E.
Org. Lett., 2008, 10, 5325; (b) Ryberg, P. Org. Process Res. Dev.,
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[5]
[6]
moderate to excellent yields (Table 2, entries 20-26),
whereas aryl bromides without electron-withdrawing
[7]
Yang, C.; Williams, J.M. Org. Lett., 2004, 6, 2837.
substituents did not act as effective substrates (Table 2,
entries 17-19). In the case of aryl bromides bearing chloro
groups, bromo group was selectively cyanated (Table 2,
entries 20, 24-26).
[8]
Sundermeier, M.; Mutyala, S.; Zapf, A.; Beller, M. J. Organomet.
Chem., 2003, 684, 50.
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H.J.; Ouali, A.; Spindler, J.F.; Taillefer, M. Chem. Eur. J., 2005,
11, 2483.
Schareina, T.; Zapf, A.; Mägerlein, W.; Müller, N.; Beller, M.
Synlett, 2007, 555.
In conclusion, Cu-catalyzed cyanation of aryl halides
with nontoxic K4[Fe(CN)6] was improved to be more
economical and environmentally friendly by the use of water
solvent and ligand-free catalyst. The reactions can be
performed without any inert gas protection, which makes
them more easy-handling. In addition, the suggested
methodology is applicable to cyanation of a wide range of
aryl iodides and activated aryl bromides, and allows the
catalyst to be reused six times with a very slight change in
the catalytic activity.
[14]
[15]
[16]
Ren, Y.L.; Liu, Z.F.; Zhao, S.; Tian, X.Z.; Wang, J.J.; Yin, W.P.;
He, S.B. Catal. Commun., 2009, 768.
(a) Phan, N.T.S.; Styring, P. Green Chem., 2008, 10, 1055; (b) Jia,
X.J.; Wang, L.L.; Chan, A.S.C.; Li Y.M. Chin. J. Catal., 2007, 28,
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X.L.; Dai, L.X. Tetrahedron: Asymmetry, 2003, 14, 2291; (d) Xu,
Y.F.; Tang, S.C.; Han, J.J.; She, X.G.; Pan, X.F. Tetrahedron Lett.,
2008, 49, 3634; (e) Han, J.J.; Xu, Y.F.; Su, Y.P.; She, X.G.; Pan,
X.F. Catal. Commun., 2008, 9, 2077; (f) Fall, Y.; Doucet, H.;
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ACKNOWLEDGEMENTS
The authors wish to thank the financial supports from the
National High Technology Research and Development
Program of China (863 Program, Grant No.2007AA05Z4
54) and the Innovation Scientists and Technicians Troop
Construction Projects of Henan Province (Grant No.
084200510015).
[17]
General experimental procedure for cyanation reaction of aryl
halides: Copper salt (0.1 mmol), K4[Fe(CN)6]·3H2O (123 mg, 0.3
mmol), TBAB (323 mg, 1 mmol), and aryl iodide (1 mmol) were
added to a flask containing H2O (2 mL) without any inert gas
protection. After being sealed, the flask was placed in an 180 ˚C oil
bath and stirred for 22 h. Then the mixture was cooled to room
temperature and the desired product was extracted with 3 ꢀ 5 mL of
diethyl ether. Evaporation of the solvent was followed by the GC
analysis of corresponding products. Then, the cyanation product
was purified by column chromatography. All the products are
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