One-Pot Three-Component Solvent-Free Cyanoaroylation of Aldehydes Using Potassium Hexacyanoferrate(II) as an Environmentally Benign Cyanide Source

Article abstract of DOI:10.1055/s-0030-1258495

An efficient method for one-pot three-component solvent-free cyanoaroylation of aldehydes using potassium hexacyanoferrate(II) as an environmentally benign cyanide source and triethylamine as a catalyst has been described. This method has advantages of not using strongly toxic cyanating agents and volatile organic solvents. In addition, the product was obtained in high yield using a simple workup procedure.

Full text of DOI:10.1055/s-0030-1258495

2164
LETTER
One-Pot Three-Component Solvent-Free Cyanoaroylation of Aldehydes Using
Potassium Hexacyanoferrate(II) as an Environmentally Benign Cyanide
Source
C
yanoaroylation
h
of Aldehyd
e
esUsingP
n
otassium
H
ex
g
acyanoferrate(II) Li,* Guoqiang Tian, Yuanhong Ma
Key Laboratory of Polymer Materials of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, P. R. of China
Fax +86(931)7971989; E-mail: lizheng@nwnu.edu.cn
Received 17 March 2010
cyanide source and as a nucleophilic addition reagent un-
Abstract: An efficient method for one-pot three-component sol-
der solvent-free conditions.
vent-free cyanoaroylation of aldehydes using potassium hexacy-
anoferrate(II) as an environmentally benign cyanide source and
triethylamine as a catalyst has been described. This method has ad-
vantages of not using strongly toxic cyanating agents and volatile
organic solvents. In addition, the product was obtained in high yield
using a simple workup procedure.
In order to explore the application of K4[Fe(CN)6] as an
environmentally friendly cyanating agent for the nucleo-
philic addition reactions, the three-component reaction of
benzoyl chloride, K4[Fe(CN)6] and benzaldehyde was in-
vestigated. Various reaction conditions, including the cat-
alysts, solvents, reaction temperature and the reactant
mole ratios, were studied. Firstly, many catalytic systems
were tried out for the model reaction (Table 1). It was
found that some metal salts (Table 1, entries 3–11), Lewis
acids (Table 1, entries 12 and 13) and phase-transfer cata-
lysts (Table 1, entries 14–16) had no obvious activities for
the reaction. However, triethylamine was found to be an
efficient catalyst for the reaction (Table 1, entries 17–19).
The reaction was also tested using DMF, NMP, DMSO,
THF, CH2Cl2, CHCl3, or toluene as solvent, and it was
found that DMF and NMP could be used as solvent for the
reaction in the presence of triethylamine as a catalyst.
However, the best yield was obtained under solvent-free
conditions (Table 1, entry 19).
Key words: aldehydes, cyanohydrins, green chemistry, multicom-
ponent reaction, nucleophilic addition
Acylated cyanohydrins are important synthetic targets
due to their use as insecticides1 and as precursors to many
useful classes of organic compounds.2 Acylated cyanohy-
drins are generally synthesized by cyanoacylation of car-
bonyl compounds using HCN,3 NaCN,4 TMSCN,5
(R2N)2BCN,6 cyanoformate,7 acetone cyanohydrin,8 and
acyl cyanide9 as cyanide sources. However, these cyanat-
ing agents are strongly toxic and hazardous which render
the nucleophilic additions of carbonyl compounds unsafe
and environmentally unfriendly. Therefore, there is a need
to explore environmentally friendly cyanating agents for
the addition reactions of carbonyl compounds.
The temperature effect also is an important factor for the
reaction. A suitable temperature should be favored to the
decomposition of K4[Fe(CN)6] and release of cyano
groups from the iron complex because it is quite stable.
Many tests showed that benzoyl chloride first reacted with
K4[Fe(CN)6] at 160 °C, then the mixture further reacted
with benzaldehyde, catalyzed by triethylamine at room
temperature. These were the optimal conditions.
Potassium hexacyanoferrate(II), K4[Fe(CN)6], is nontoxic
and is even used in the food industry for metal precipita-
tion. In addition, it has been described as an antiaggluti-
nating auxiliary for table salt (NaCl). K4[Fe(CN)6] is a by-
product of coal chemical industry, and commercially
available on a ton scale and is even cheaper than KCN.
Very recently, K4[Fe(CN)6] has been shown to be an effi-
cient cyanide source for the cyanation of halogenated are-
nes and aroyl chlorides to prepare benzonitriles10 and
aroyl cyanides.11 However, these reported reactions for
the use of K4[Fe(CN)6] as a cyanating agent were all sub-
stitution reactions. No examples have been reported for
addition reactions, especially for the cyanation addition of
carbonyl compounds.
The effect of reactant ratios on the yield of cyanoaroyla-
tion of benzaldehyde was also examined. It was found that
when the mole ratio of benzoyl chloride, potassium
hexacyanoferrate(II) and benzaldehyde was 5:1:5, the ad-
dition product could be obtained in high yield. This indi-
cated that all cyano groups in K4[Fe(CN)6] could be
readily utilized in this reaction.
In this paper, we would like to report an efficient method
for one-pot three-component cyanoaroylation of alde-
hydes using K4[Fe(CN)6] as an environmentally friendly
O
CN
O
O
Et3N (10 mol%)
solvent-free
Cl
K4[Fe(CN)6]
+
+
R1
H
R1
O
R2
R2
Scheme 1 Cyanoaroylation of aldehydes using K4[Fe(CN)6] as
cyanide source
SYNLETT 2010, No. 14, pp 2164–2168
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258495; Art ID: W04410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyanoaroylation of Aldehydes Using Potassium Hexacyanoferrate(II)
2165
Table 1 The Effect of Catalysts and Solvents on the Yield of Cyanobenzoylation of Benzaldehydea
CN
O
O
O
O
catalyst
solvent
K4[Fe(CN)6]
+
H
+
Cl
Entry
1
Catalyst
none
Solvent
none
Yield (%)b
0
0
2
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMF
NMP
DMF
DMF
NMP
none
3
CuCl
CuI
0
4
10
26
32
34
20
35
40
55
53
47
38
52
33
78
75
89
5
ZnCl2
ZnI2
6
7
NiCl2
NiI2
8
9
AgCl
AgI
10
11
12
13
14
15
16
17
18
19
Pd(OAc)2
BiCl3
AlCl3
18-crown-6
PEG-400
Et4NI
Et3N
Et3N
Et3N
a Reaction conditions: benzoyl chloride (15 mmol), potassium hexacyanoferrate(II) (3 mmol) and benzaldehyde (15 mmol).
b Isolated yield.
To explore the generality and scope of this reaction, rep- aroyl chloride first reacts with K4[Fe(CN)6] to afford aroyl
resentative aldehydes and acyl chlorides as substrates cyanide, which could be isolated and identified,14 then
were examined (Scheme 1, Table 2).12 Not only aromatic aroyl cyanide is activated by a nucleophilic attack by Et3N
aldehydes (Table 2, entries 1–14) but also aliphatic alde- to form the corresponding intermediate A, which reacts
hydes (Table 2, entries 19–23) were smoothly reacted un- with aldehyde to give the cyanoalkoxide intermediate B.
der the reaction conditions to give the corresponding Then, intramolecular nucleophilic attack of the cy-
products. Methoxy, methyl and chloro groups on aromatic anoalkoxide on the carbonyl group in intermediate B pro-
rings of various aromatic aldehydes were tolerated under duces the final O-aroyl cyanohydrin ester C and
this condition. Aromatic heterocyclic aldehyde, furfural- regenerates the Et3N catalyst.
dehyde, was also active for the cyanoaroylation (Table 2,
In conclusion, an efficient method for the one-pot three-
entries 15–18). Various aroyl chlorides, such as chloro-,
component cyanoaroylation of aldehydes using potassium
bromo- and methyl-substituted benzoyl chlorides, were
hexacyanoferrate(II) as an environmentally friendly cya-
good substrates for the reactions to give the corresponding
nide source and triethylamine as catalyst under solvent-
products in high yield. In addition, furoyl chloride was
free conditions has been developed. The major advantages
also converted into the corresponding products without
of this method are no use of strongly toxic cyanating
difficulty.
agents, no use of volatile organic solvents, high yield, and
A plausible mechanism, similar to that proposed by simple workup procedure.
Deng13 and Shi,9b is shown in Scheme 2. We suppose that
Synlett 2010, No. 14, 2164–2168 © Thieme Stuttgart · New York

2166
Z. Li et al.
LETTER
Table 2 Cyanoaroylation of Aldehydes Using K4[Fe(CN)6] as Cya-
Table 2 Cyanoaroylation of Aldehydes Using K4[Fe(CN)6] as Cya-
nide Sourcea
nide Sourcea (continued)
O
O
CN
O
O
O
CN
O
Et3N (10 mol%)
solvent-free
Et3N (10 mol%)
solvent-free
K4[Fe(CN)6]
+
+
K4[Fe(CN)6]
+
+
R1
H
R2
Cl
R1
O
R2
R1
H
R2
Cl
R1
O
R2
Entry Product15
Time (h) Yield (%)b
Entry Product15
Time (h) Yield (%)b
CN
O
MeO
Cl
CN
O
1
2
4
5
89
82
13
14
15
16
17
18
19
5
5
4
5
5
5
4
74
72
87
75
78
73
69
O
O
O
O
CN
CN
O
O
CN
CN
O
O
O
3
4
5
6
7
5
6
4
5
6
80
79
86
81
78
O
O
O
O
O
Cl
CN
O
CN
CN
CN
O
O
O
O
O
O
CN
O
O
O
O
O
CN
O
O
Br
Br
CN
CN
O
O
O
O
CN
O
CN
O
O
20
21
22
23
5
6
5
5
66
71
68
61
8
9
4
5
5
83
77
73
O
O
O
O
O
MeO
MeO
MeO
Br
CN
CN
CN
CN
O
O
O
O
O
O
CN
O
O
10
Br
CN
O
O
11
12
6
5
80
70
O
O
a All products were characterized by comparison of their melting
points or boiling points, IR, and 1H NMR spectra with those of au-
thentic samples.
MeO
MeO
CN
b Yields refer to isolated products.
O
Synlett 2010, No. 14, 2164–2168 © Thieme Stuttgart · New York

LETTER
Cyanoaroylation of Aldehydes Using Potassium Hexacyanoferrate(II)
2167
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Lyapkalo, I. M. J. Org. Chem. 2008, 73, 2446.
O
Ar
Cl
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KCl + FeCl2
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O
2002, 1392.
O
CN–
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Ar
Ar
CN
A
O
Et3N
R
H
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O
(9) (a) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C.
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O
–O
Ar
O
CN
CN
R
Et3N+
Ar
H
R
H
C
B
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(12) General Procedure: To a 50-mL round-bottomed flask
equipped with an air condenser, acyl chloride (15 mmol) and
potassium hexacyanoferrate(II) (3 mmol) were added. Then
the mixture was heated at 160 °C for the time indicated in
Table 2. After the resulting mixture was cooled to r.t.,
aldehyde (15 mmol) and Et3N (1.5 mmol) were added. The
mixture was further stirred for 5–8 min at r.t. The progress
of the reaction was monitored by TLC. After completion of
the reaction, CH2Cl2 (20 mL) was added, and the solid was
removed by filtration. The filtrate was then washed with icy
H2O (3 × 30 mL), and dried with anhyd MgSO4. After
removal of the solvent under reduced pressure, the residue
was subjected to silica gel flash column chromatography
(PE–EtOAc, 20:1) to obtain pure product. The analytical
data for the representative products are given below.
Cyano(4-methoxyphenyl)methyl Benzoate (Table 2,
entry 8): white solid. IR (KBr): 3057, 2250, 1731, 1610,
1514, 1250, 1060, 702 cm–1. 1H NMR (400 MHz, CDCl3):
d = 8.05 (d, J = 6.8 Hz, 2 H), 7.56–7.62 (m, 5 H), 7.25 (d,
J = 6.8 Hz, 2 H), 6.65 (s, 1 H), 3.83 (s, 3 H). 13C NMR (100
MHz, CDCl3): d = 164.6, 161.1, 133.9, 130.1, 129.6, 128.6,
128.2, 123.9, 116.4, 114.6, 63.1, 55.4. Anal. Calcd for
Scheme 2 Proposed mechanism of Et3N-catalyzed cyanoaroylation
of aldehydes using K4[Fe(CN)6] as cyanide source
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (20772096), and the Key Laboratory of Eco-Environment-
Related Polymer Materials (Northwest Normal University), and the
Ministry of Education of China for the financial support of this
work.
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Synlett 2010, No. 14, 2164–2168 © Thieme Stuttgart · New York

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Z. Li et al.
LETTER
(15) For reported cyanohydrin esters, see: (a) Watahiki, T.;
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1H NMR (400 MHz, CDCl3): d = 8.13–8.15 (m, 2 H), 7.78–
7.82 (m, 1 H), 7.59–7.63 (m, 2 H). 13C NMR (100 MHz,
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Synlett 2010, No. 14, 2164–2168 © Thieme Stuttgart · New York