Pd-catalyzed cyanation of benzyl chlorides with nontoxic K 4[Fe(CN)6]

Article abstract of DOI:10.1016/j.tetlet.2011.07.112

Non-toxic K₄[Fe(CN)₆] was demonstrated to be effective as a green cyanating agent for the cyanation of alkyl halides using PPh₃/Pd(OAc)₂ as a catalyst system. The presented method allowed a series of benzyl chlorides to be smoothly cyanated in up to 88% yield. In order to avoid or suppress the deactivation of the catalyst, the reaction was required to be performed in a stringent inert ambiance.

Full text of DOI:10.1016/j.tetlet.2011.07.112

Tetrahedron Letters 52 (2011) 5107–5109
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Tetrahedron Letters
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Pd-catalyzed cyanation of benzyl chlorides with nontoxic K4[Fe(CN)6]
⇑
Yunlai Ren, Mengjie Yan, Shuang Zhao, Yanpei Sun, Jianji Wang , Weiping Yin, Zhifei Liu
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang 471003, Henan, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Non-toxic K4[Fe(CN)6] was demonstrated to be effective as a green cyanating agent for the cyanation of
alkyl halides using PPh3/Pd(OAc)2 as a catalyst system. The presented method allowed a series of benzyl
chlorides to be smoothly cyanated in up to 88% yield. In order to avoid or suppress the deactivation of the
catalyst, the reaction was required to be performed in a stringent inert ambiance.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 May 2011
Revised 23 July 2011
Accepted 25 July 2011
Available online 31 July 2011
Keywords:
Cyanation
Benzyl chlorides
Palladium
Potassium hexacyanoferrate(II)
Cyanation of alkyl halides plays a crucial role in synthetic or-
ganic chemistry since the resulting products can be further trans-
formed into a wide range of important synthetic intermediates
including amines, nitrogen-containing heterocycles, carboxylic
acids, and carboxylic acid derivatives.1 The most classic method
for the cyanation of alkyl halides is the direct reaction between
alkyl halides and cyanide salts (NaCN and KCN) by nucleophilic
substitution.2 However, an extremely poisonous character of KCN
and NaCN seriously restricts their application from environmental
perspectives. Therefore, several methods for the cyanation of alkyl
halides with lower poisonous trimethylsilyl cyanide (Me3SiCN) as
the cyanating agent were developed.3 Unfortunately, the use of
Me3SiCN has some inconveniences, it is expensive, sensitive to
moisture, and easily liberates highly poisonous hydrogen cyanide.
K4[Fe(CN)6] has significant advantages over the above-men-
tioned cyanide sources.4 It is non-toxic, commercially available
on ton scale, and even cheaper than KCN. However, classic cyana-
tion of alkyl halides is a non-catalytic reaction, and the CNꢀ in
K4[Fe(CN)6] can not exert its nucleophilic efficacy in the absence
of a transition metal catalyst, so that there was no successful
example of the reaction between alkyl halides and K4[Fe(CN)6].
So our attention was drawn to developing a catalytic procedure
for the cyanation of alkyl halides with non-toxic K4[Fe(CN)6] as
the cyanating agent, and the results are reported here.
1). The addition of triphenylphosphine afforded benzyl cyanide in
84% yield (Table 1, entry 4). The ratio of the ligand to Pd(OAc)2
was found to have a significant effect on the reaction, and the
experimental results revealed that a ratio of 2–4 was optimal.
DPPE, DDPPI, and BINAP (see Fig. 1) were also effective as the
ligands, while nitrogen ligands including 2,20-bipyridine, o-phenyl-
enediamine, N,N0-dimethyl ethylenediamine, and ethylenediamine
were almost ineffective (Table 1, entries 6–14). The reaction was
highly dependent on the reaction temperature. Under the reaction
condition of 120–140 °C, the desired cyanation product was affor-
ded in high yields. It was worthy to note that the reaction temper-
atures of both 160 °C and 100 °C possibly allowed the cyanation to
proceed in high yields, but the resulting experimental results were
less reproducible, as was true for a reaction time of 1 h. Our
investigation showed that the experimental results were more
reproducible in the case of 140 °C and 10 h, which prompted us
to perform all the following reactions under such a condition.
The results in Table 2 revealed that Na2CO3 played an important
role in the reaction, and it was necessary to add more than
50 mol % Na2CO3 to allow the cyanation to proceed smoothly.
According to some literature on palladium-catalyzed cross-cou-
pling reactions,5 the real catalytically active species was possibly
the Pd(0) intermediate, and the role of the base was to facilitate
the reduction of Pd(II) intermediate to catalytically active Pd(0)
species. Among the screened bases, Na2CO3 turned out to be the
most effective one (Table 2, entries 5–9). K2CO3 was less effective
than Na2CO3 although they have similar basicity. The cyanation
reactions proceeded efficiently with as low as 1 mol % catalyst.
We tried to reduce the catalyst loading to 0.5 mol % but found that
this was not possible without sacrificing the product yield even if
the reaction time was prolonged to 30 h. In addition, decreasing
the ratio of K4[Fe(CN)6] to benzyl cyanide to 0.2:1 allowed the
Our investigation began with the cyanation of benzyl chloride
with Pd(OAc)2 as the catalyst. In the case of 140 °C, a small amount
of the desired cyanation product and a considerable amount of
benzyl alcohol (41% yield) were obtained after 10 h (Table 1, entry
⇑
Corresponding author. Tel.: +86 379 64232156; fax: +86 379 64210415.
E-mail address: jwang@mail.haust.edu.cn (J. Wang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.112

5108
Y. Ren et al. / Tetrahedron Letters 52 (2011) 5107–5109
Table 1
Table 3
Palladium-catalyzed cyanation of benzyl chloridea
Effect of water on the cyanation of benzyl chloridea
K4[Fe(CN)6], Na2CO3
Entry Concentration of
water (vol %)
Conversionb Yield of
(%)
Yield of
cyanideb (%)
alcoholb (%)
Catalyst, 10 h, 140 oC
Cl
CN
Entry
Ligand
Ligand/Pd(OAc)2
Conversionb (%)
Yieldb (%)
1
2
3
4
5
6
0
2.4
5.9
11.3
27.3
38.5
100
99
99
100
99
100
79
81
81
58
60
53
3
3
6
23
31
45
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
PPh3
DPPE
DPPE
DPPE
0/1
1/1
2/1
3/1
4/1
1/1
2/1
3/1
4/1
1/1
2/1
2/1
2/1
2/1
51
8
ꢁ100
72
84
84
81
86
79
72
74
77
71
2
99
ꢁ100
ꢁ100
99
a
Reaction conditions were shown in the Ref. 7.
Determined by GC.
b
ꢁ100
99
9
DPPE
DDPPI
98
99
98
80
33
29
Table 4
10
11
12
13
14
a
Cyanation of various benzyl chloride catalyzed by Ph3P/Pd(OAc)2
( )-BINAP
2,20-Bipyridine
Ethylenediamine
DMEDA
Entry
Substrate
Productb
Yieldc (%)
88
5
9
1
a
Reaction conditions were shown in the Ref. 7.
Determined by GC.
Cl
Cl
CN
CN
b
2
3
72
70
CH3
CH3
PPh2
O
PPh2
PPh2
Cl
Cl
CN
MeHN
NHMe
H
O
PPh2
Ph2P
H3C
H3C
H3C
H3C
H
Ph2P
DPPE
DDPPI
( )-BINAP
DMEDA
4
5
6
7
8
71
68
70
60
41
Cl
CN
Figure 1. Several ligands used in the reactions.
CN
CN
Table 2
Palladium-catalyzed cyanation of benzyl chloridea
Cl
Cl
Cl
Entry Base
Amount of base (mol %) Conversionb (%) Yieldb (%)
F
F
CN
CN
1
2
3
4
5
6
7
8
9
Na2CO3
0
20
50
100
150
150
150
150
8
58
ꢁ100
ꢁ100
ꢁ100
97
1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
KF
40
88
84
85
46
22
47
3
Cl
Cl
CN
Cl
9
22
72
Cl
Cl
NaOH
ꢁ100
K3PO4ꢂ3H2O 100
ꢁ100
a
10
11
40
2
Reaction conditions were shown in the Ref. 7.
Determined by GC.
Cl
CN
b
Cl
Cl
CN
CN
cyanation to retain an 80% yield, revealing that basically all the
cyanide ions bound to Fe can be transferred to the benzyl group.
In some cases, the formation of a small amount of 1,2-diphenyl-
ethane by-product was observed. In addition, the cyanation reac-
tion suffered from competing nucleophilic substitution of benzyl
chloride by trace amounts of H2O in the solvent. The experimental
results (Table 3) revealed that the outcome of the competition
between the cyanation and the hydroxylation is highly dependent
on the concentration of H2O, and the cyanation product was
predominant in the case of less than 5.9 vol % H2O. Attempts to
developing a procedure for the cyanation with environmentally
benign water as the solvent were not successful.
Our experimental results revealed that the presence of oxygen
badly prevented benzyl chloride from being cyanated, which
possibly resulted from the oxidation destruction of catalytically
active Pd(0) species by oxygen.6 Thus the reactions were required
to be performed in an inert ambiance to avoid or suppress the
deactivation of the catalysts.
12
5
a
b
c
Reaction conditions were shown in the Ref. 7.
Identified by 1H NMR, 13C NMR or MS data.
Determined by GC with acetophenone as an internal standard.
evaluated to optimize the preparation process of the catalyst.
Surprisingly, whether the addition of Na2CO3 was prior to coordi-
nation of PPh3 to Pd2+ or not, the cyanation product was obtained
in similar yields. Even in the case of the successive addition of
Na2CO3, PPh3, K4[Fe(CN)6], and benzyl chloride to a solution of
Pd(OAc)2 in NMP, the formed catalytically active species could
drive the reaction to near completion.
With the optimized results in hand, we set out to evaluate the
scope of our novel protocol for the cyanation of benzyl chlorides.
It can be seen from Table 4 that several benzyl chlorides with alkyl
substituents in the benzene ring were smoothly converted into the
desired products. The reactions were able to tolerate several
As a general rule, the activity of the in situ catalyst was depen-
dent on its preparation process. Thus, several experiments were
conducted where different addition orders of the reagents were

Y. Ren et al. / Tetrahedron Letters 52 (2011) 5107–5109
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functional groups such as alkyl, fluoro, and chloro groups. 2-Meth-
ylbenzyl chloride and 4-methylbenzyl chloride gave 72% and 71%
yields, respectively (Table 4, entries 2 and 4), while 2,4,6-trimeth-
ylbenzyl chloride with two methyl groups in the ortho-position of
chloromethyl gave a lower yield under the same condition (Table
4, entry 10).
In conclusion, non-toxic K4[Fe(CN)6] was demonstrated to be
effective as a cyanating agent for the cyanation of alkyl halides
with PPh3/Pd(OAc)2 as the catalyst. The presented method allowed
a series of benzyl chlorides to be cyanated smoothly. In order to
avoid or suppress the deactivation of the catalyst, the reaction
was required to be performed in an inert ambiance. It is important
that the results provide an idea that facilitate K4[Fe(CN)6] to exert
its efficacy as the cyanating agent by adding metal catalyst in the
case of classic non-catalytic cyanation. Investigation on the cyana-
tion of other alkyl halides with K4[Fe(CN)6] is underway in our
laboratory.
Acknowledgments
The authors would like to thank the financial supports from the
National Natural Science Foundation of China (Grant No.
21002023) and the National Basic Research Program of China
(973 Program, Grant No. 2011CB211702).
7. General experimental procedure for the cyanation of benzyl chlorides: 0.06 mmol
PPh3, 0.02 mmol Pd(OAc)2, and 0.4 mL NMP were added into a dried 20 mL tube
under
a
dry nitrogen atmosphere. After the mixture was stirred at room
homogeneous solution, 0.3 mmol
temperature for about 5 min to give
a
K4[Fe(CN)6], 1.5 mmol Na2CO3, 1 mmol benzyl chloride, and 0.4 mL NMP were
added under a dry nitrogen atmosphere. The reaction tube was sealed with a
septum and placed in a constant-temperature oil bath set at 140( 5) °C to
perform the reaction for 10 h. Once the reaction time was reached, the mixture
was cooled to room temperature, then acetophenone was added as an internal
standard. GC analysis of the mixture provided the yield of the product (note: in
order to decrease the analysis error, the mixture after the reaction was not
purified or concentrated). The cyanation product was purified by column
chromatography and identified by 1H NMR, 13C NMR or GC–MS data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.112.
References and notes
1. Rappoport, Z. Chemistry of the Cyano Group, 1st ed.; John Wiley & Sons: London,
1970.