Copper-catalyzed cyanation of benzyl chlorides with non-toxic K 4[Fe(CN)6]

Article abstract of DOI:10.1016/j.tetlet.2012.03.109

Copper-based catalysts were firstly introduced into the cyanation of benzyl chlorides with non-toxic K₄[Fe(CN)₆]. The presented method avoids the use of extremely poisonous alkali cyanides and precious palladium catalysts. No other reagent apart from CuI, K₄[Fe(CN) ₆] and toluene was used in the cyanation, showing that the presented protocol is simple and practical. A series of benzyl chlorides were smoothly cyanated in up to 85% yield under the optimal conditions.

Full text of DOI:10.1016/j.tetlet.2012.03.109

Tetrahedron Letters 53 (2012) 2825–2827
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Tetrahedron Letters
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Copper-catalyzed cyanation of benzyl chlorides with non-toxic K [Fe(CN) ]
4
6
⇑
Yunlai Ren, Chuanhua Dong, Shuang Zhao, Yanpei Sun, Jianji Wang , Junying Ma, Chaodong Hou
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang Henan 471003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper-based catalysts were firstly introduced into the cyanation of benzyl chlorides with non-toxic
[Fe(CN) ]. The presented method avoids the use of extremely poisonous alkali cyanides and precious
palladium catalysts. No other reagent apart from CuI, K [Fe(CN) ] and toluene was used in the cyanation,
showing that the presented protocol is simple and practical. A series of benzyl chlorides were smoothly
cyanated in up to 85% yield under the optimal conditions.
Received 22 November 2011
Revised 21 March 2012
Accepted 27 March 2012
Available online 5 April 2012
K
4
6
4
6
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyanation
Benzyl chlorides
Copper
Potassium hexacyanoferrate(II)
Cyanation of alkyl halides is an important synthetic transforma-
tion as the resulting products are extremely useful synthetic inter-
mediates that have widely been used in the construction of a
variety of compounds such as amines, nitrogen-containing hetero-
N-ligands such as ethylenediamine, 1,2-diaminobenzene, triphenyl-
phosphine, 2,2 -bipyridine, and 1,10-phenanthroline did not result
in satisfactory results (Table 1, entries 2–7). However, it was delight
that the desired product was obtained in a high yield in the absence of
ligand (Table 1, entry 8). Surprisingly, an addition of 1.5 mmol
0
1
cycles, carboxylic acids, and carboxylic acid derivatives. NaCN and
KCN are generally used as the cyanating agents for cyanation of al-
kyl halides. However, an extremely poisonous character of these
cyanide salts seriously restricts their application from environ-
mental perspectives. Recently, several methods for cyanation of al-
2 3
Na CO led to a significant decrease in yield (Table 1, entry 9), while
2
our previous investigations revealed that the cyanations with Pd cat-
alysts were highly dependent on the amount and type of inorganic
7
base. The cyanation reactions proceeded efficiently with as low as
kyl halides with lower poisonous trimethylsilyl cyanide (Me
as the cyanating agent have been developed.3 Unfortunately, the
use of Me SiCN has some inconvenience, it is expensive, sensitive
to moisture, and easily liberates highly poisonous hydrogen
cyanide.
3
SiCN)
20 mol % ligand-free CuI catalyst. We tried to reduce the catalyst
loading to 10 mol %, but found that this was not possible without sac-
rificing the product yield even if the reaction time was prolonged to
30 h. The same was true when we tried to decrease the reaction tem-
3
4 6
perature or the ratio of K [Fe(CN) ] to benzyl chloride. Our experi-
More recently, we introduced non-toxic and inexpensive K
4
[Fe
mental results indicated that the presence of oxygen badly
prevented benzyl chloride from being cyanated, which possibly re-
sulted from the oxidation destruction of catalytically active Cu(I) spe-
cies by oxygen. Thus the reactions were required to be performed in
an inert ambiance to avoid or suppress the deactivation of the
catalysts.
4
–6
(
6
CN) ]
as the cyanating agent for the cyanation of alkyl halides
7
catalyzed by palladium compounds. Considering the fact that cop-
per salts are less expensive than palladium compounds, our atten-
tion was drawn to developing a copper-catalyzed procedure. Here,
we report a simple and practical copper-catalyzed method for the
8
b
cyanation of benzyl chlorides with K
agent.
At the start of our investigations, the cyanation of benzyl chloride
was chosen as a model reaction to demonstrate the catalytic effec-
tiveness of various copper compounds. As shown in Table 1, the cya-
nation using CuI in combination with DMEDA, a typical and effective
4
[Fe(CN)
6
] as the cyanating
Subsequently, various ligand-free copper salts were examined
to understand the effect of the metal precursors on the reaction.
Among the screened copper salts, CuI turned out to be the most
effective one (Table 1, entries 8–19). CuCN had comparable cata-
lytic effectiveness with CuI, while most of the tested Cu(II) salts
were less effective. A considerable amount of 1,2-diphenylethane
and benzylacetate products were respectively observed in the case
8
catalyst system for the cyanation of aryl halides, afforded the desired
product in 6% yield (Table 1, entry 1). Changing DMEDA to other
of using CuBr
2
and Cu(OAc)
2
ꢀH
2
O as the catalysts (Table 1, entries
[Fe(CN) ] as the
1
4, 15). According to the literatures related to K
4
6
8
,9
cyanating agents as well as our previous investigations on Pd-
catalyzed cyanation of benzyl chloride, high-boiling, and polar
solvents were preferred in order to ensure sufficient solubility.
7
⇑
Corresponding author. Tel.: +86 379 64232156; fax: +86 379 64210415.
E-mail address: jwang@mail.haust.edu.cn (J. Wang).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.109

2
826
Y. Ren et al. / Tetrahedron Letters 53 (2012) 2825–2827
Table 1
Table 2
a
a
Copper-catalyzed cyanation of benzyl chloride
Cyanations of various benzyl chlorides catalyzed by CuI
K4[Fe(CN)6]
Productb
Yieldc (%)
78
Entry
1
Substrate
CuI (mol %)
Cl Catalyst, Toluene
CN
30
Cl
CN
Entry
Ligand
Copper salt
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuCN
Conv.b (%)
Yieldb (%)
2
3
30
20
82
70
1
2
3
4
5
6
DMEDA
ꢁ100
ꢁ100
ꢁ100
100
ꢁ100
ꢁ100
100
ꢁ100
ꢁ100
93
6
0
0
Cl
CH3
CN
CH3
Ethylenediamine
1,2-Diaminobenzene
d
4
5
30
20
76
63
Triphenylphosphine
30
59
50
47
78
69
57
39
70
22
0
28
41
0
44
8
0
Cl
Cl
CN
2,2 -Bipyridine
H3C
H3C
H3C
H3C
1,10-Phenanthroline
1,10-Phenanthroline
c
7
6
7
30
20
82
77
8
9
—
—
—
—
—
—
—
—
—
—
—
—
Cl
CN
c
8
9
30
20
60
57
10
11
12
13
14
15
16
17
18
19
CN
CN
99
100
100
100
90
100
70
10
30
20
58
68
11
Cu
CuBr
Cu(OAc)
CuSO
ꢀ5H
Cu(NO
2
O
Cl
Cl
Cl
2
1
1
2
3
30
20
85
60
F
F
2
ꢀH
2
2
O
CN
CN
4
O
1
1
4
5
30
20
43
48
)
3 2
ꢀ3H
2
O
Cl
Cl
CuCl
CuO
2
ꢀ2H
2
O
100
29
16
30
50
64
66
17
a
Reaction conditions: benzyl chloride (1 mmol), K
0.5 mmol), copper salts (0.3 mmol), toluene (1 mL), N
4
[Fe(CN)
6
] (0.5 mmol), ligand
Cl
CN
(
2
, 180 °C, 20 h.
b
Determined by GC.
MeO
NC
MeO
NC
1
1
8
9
30
30
33
27
c
Cl
Cl
CN
CN
Additional 1.5 mmol Na
2
CO
3
was used.
d
0
.6 mmol PPh was used.
3
O
O
O
O
2
2
0
1
50
30
42
8
Cl
CH3
Cl
CN
CH3
CN
However, the cyanations with polar solvents such as NMP (N-
methyl-2-pyrrolidone) and DMF afforded benzyl cyanide in low
yields, while toluene as solvent was optimal in terms of the yield
a
1
0
4 6
Reaction conditions: benzyl chloride (1 mmol), K [Fe(CN) ] (0.5 mmol), CuI,
and selectivity.
2
toluene (1 mL), N , 180 °C, 20 h. For the detailed experimental procedure see
In some cases, the formation of a small amount of benzyl alco-
hol by-product was observed, resulting from the reaction between
14
reference.
b
Identified by GC–MS data.
Determined by GC.
c
benzyl chloride and trace amounts of H
eral experiments were conducted where different amounts of H
were added into the reaction systems to investigate the effect of
2
O in the solvent. Thus, sev-
2
O
O concentration on the reactions.1 The experimental results
1
H
2
Upon the basis of previous literatures,12 a plausible mecha-
suggested that less than 4.8 vol% H O did not remarkably restrain
2
nism is proposed and presented in Scheme 1, omitting some de-
tails such as ancillary ligands, etc. The catalytic cycle starts with
the oxidative addition of benzyl chloride to the catalytically ac-
tive Cu(I) species. The resulting benzyl copper species, which is
the cyanation. Attempts to developing a procedure for the cyana-
tion with environmentally benign water as the solvent were not
successful. For instance, only 30% yield of benzyl cyanide, accom-
panied by a considerable amount of benzyl alcohol was obtained
1
3
13
possibly
g -benzyl or g -benzyl copper intermediate, undergoes
under the condition of H
80 °C, and 20 h.
Based on these results we chose the following conditions for fur-
ther exploration of substrates: 20–50 mol % CuI, 0.5 equiv
[Fe(CN) ], 1 mL toluene, 180 °C, and 20 h. As shown in Table 2,
2
O as the solvent, CuI as the catalyst,
a transmetallation to afford benzyl copper cyanide intermediate,
followed by a reductive elimination to give the expected nitrile
and regenerate the catalytically active Cu(I) species. The ordering
of oxidative addition and transmetallation steps in such
catalytic cycle is unknown, so another possibility that the trans-
1
a
K
4
6
the reactions were able to tolerate several functional groups such
as fluoro, chloro, and methoxy groups. Several benzyl chlorides with
alkyl substituents in the benzene ring were converted into the de-
sired products in high yields. The cyanations of 4-, 3-, and 2-meth-
ylbenzyl chlorides gave similar yields (Table 2, entries 2–7).
However, two methyl substituents in ortho-position lowered the
yield considerably (Table 2, entry 16). 4-Fluorobenzyl chlorides per-
formed reasonably well (85% yield), whereas 4-chlorobenzyl chlo-
rides were converted in lower yield to 4-chlorobenzyl cyanide
metallation step precedes oxidative addition can take place
12
(Scheme 1b).
In conclusion, copper-based catalysts were firstly demonstrated
to be effective in the cyanation of benzyl chlorides with non-toxic
[Fe(CN) ], meanwhile presenting a simple and practical method
K
4
6
that is ligand-, base-free and avoids the use of extremely poisonous
7
alkali cyanides and precious palladium catalysts. A series of ben-
zyl chlorides were smoothly cyanated in up to 85% yield applying
only CuI as catalyst, K
ene as the solvent.
4 6
[Fe(CN) ] as the cyanating agent, and tolu-
(Table 2, entries 12, 14). By the way, the side coupling reaction did
not occur on the aromatic chloride in the case of using 4-chloroben-
zyl chloride. Conversions of 4-methoxylbenzyl chloride, 4-cyanob-
enzyl chloride, 1-naphthylacetonitrile, and
a-chloroethylbenzene
Acknowledgments
were of poor selectivity under our reaction conditions. We had tried
the reaction with allylic chlorides, but no cyanation product was
observed.
The authors would like to thank the financial supports from the
National Natural Science Foundation of China (Grant No. 21002023)

Y. Ren et al. / Tetrahedron Letters 53 (2012) 2825–2827
2827
[Fe(CN) ]2
-n
Cu(I)
Cu(I)
n
BnCN
BnCl
Bn
BnCN
Cl
+
-
[Fe(CN)n-1]3-n
Bn
Bn
Cu
Cu
Cl Cu
CuCN
BnCl
CN
Cl
CN
-
3-n
[Fe(CN) ]2-n
n
Cl + [Fe(CN)n-1]
n = 1-6, Bn = benzyl
a
b
Scheme 1. Proposed mechanism, omitting some details such as ancillary ligands, etc.
and the National Basic Research Program of China (973 Program,
Grant No. 2011CB211702).
5. For the cyanation reactions with K
4
[Fe(CN)
6
] or K
3
[Fe(CN)
6
] through transition-
metal catalyzed C–H bond activation, see (a) Yan, G. B.; Kuang, C. X.; Zhang, Y.;
Wang, J. B. Org. Lett. 2010, 12, 1052–1055; (b) Jia, X. F.; Yang, D. P.; Wang, W. H.;
Luo, F.; Cheng, J. J. Org. Chem. 2009, 74, 9470–9474.
6.
For three-component arylcyanation of internal alkynes with K
Cheng, Y. N.; Duan, Z.; Yu, L. J.; Li, Z. X.; Zhu, Y.; Wu, Y. J. Org. Lett. 2008, 10, 901–
04.
4 6
[Fe(CN) ], see
Supplementary data
9
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.109.
7. Ren, Y. L.; Yan, M. J.; Zhao, S.; Sun, Y. P.; Wang, J. J.; Yin, W. P.; Liu, Z. F.
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Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890–2891.
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4 6
1 min, 0.5 mmol K [Fe(CN) ], 1 mmol benzyl chloride, and 0.7 mL toluene were
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septum and placed in a constant-temperature oil bath set at 180(±5) °C to
perform the reaction for 20 h. Once the reaction time was reached, the mixture
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