Monohydrocyanation of symmetrical azines using potassium hexacyanoferrate(II) as an environmentally friendly cyanide source

Article abstract of DOI:10.1055/s-0033-1339133

The monohydrocyanation of symmetrical azines to synthesize α-hydrazinonitriles using potassium hexacyanoferrate(II) as cyanide source and benzoyl chloride as a promoter under catalyst-free conditions is described. The advantages of this protocol are the environmentally friendly cyanide source, high yield, and simple work-up procedure. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339133

1786▌
LETTER
lMetteor nohydrocyanation of Symmetrical Azines Using Potassium Hexacyano-
ferrate(II) as an Environmentally Friendly Cyanide Source
Monohydrocyanation of Symmetrical Azines
Xiaochun Hu,a,b Hongbo Li,a Jingya Yang,a Zheng Li*a
a
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, P. R. of China
Fax +86(931)7971183; E-mail: lizheng@nwnu.edu.cn
b
Editorial Department of the University Journal, Northwest Normal University, Lanzhou, Gansu, 730070, P. R. of China
Received: 21.03.2014; Accepted after revision: 25.04.2014
pounds by nucleophilic addition reactions using
Abstract: The monohydrocyanation of symmetrical azines to syn-
K4[Fe(CN)6] as an environmentally friendly cyanide
thesize α-hydrazinonitriles using potassium hexacyanoferrate(II) as
source, which included the cyanation of aldehydes and ke-
cyanide source and benzoyl chloride as a promoter under catalyst-
free conditions is described. The advantages of this protocol are the
tones to cyanohydrins,15 the cyanation of aldimines, keti-
environmentally friendly cyanide source, high yield, and simple mines, and sulfonylimines to α-aminonitriles,16 and the
work-up procedure.
cyanation of α,β-unsaturated ketones and esters to the cor-
responding β-cyano compounds.17 As an extension of
Key words: green chemistry, hydrocyanation, nucleophilic addi-
tion, synthetic methods, azines
such research, in this work, we report the selective mono-
hydrocyanation of substrates including the C=N–N=C
fragment, azines, to synthesize α-hydrazinonitriles by us-
ing K4[Fe(CN)6] as an environmentally friendly cyanide
source under catalyst-free conditions.
α-Hydrazinonitriles are important organic intermediates
that can be easily transformed into α-hydrazino acids,1
and further into α-hydrazino peptides, α-amino acids, and
even nitrogen-containing heterocycles.2 Although α-hy-
drazinonitriles have been synthesized by substitution of
cyanohydrin with phenylhydrazine in ethanol3 and reduc-
tion of N-(cyanomethyl)-N-phenylnitrous amide with zinc
in acetic acid,4 a more general route is the hydrocyanation
of substances containing the C=N–N fragment, such as
N,N-dialkylhydrazones5 and N-acylhydrazones.6 Howev-
er, these hydrocyanation reactions usually use HCN7 or
KCN8 as cyanide sources. Clearly, these compounds are
highly toxic, unfriendly and unsafe for the environment.
Recently, the use of TMSCN as a cyanide source for hy-
drocyanation reactions has been investigated because of
the lower toxicity of this reagent compared to the alterna-
tives.6 However, TMSCN is sensitive to moisture and can
easily liberate highly toxic hydrogen cyanide. Therefore,
there remains a need to develop an environmentally
friendly cyanide source for the synthesis of α-hydrazino-
nitriles.
Initially, the hydrocyanation of azines was attempted by
using benzalazine 1a (R1 = Ph, R2 = H; Scheme 1)18 as
substrate and K4[Fe(CN)6] as an environmentally friendly
cyanide source. The reaction was conducted under differ-
ent conditions including the use of Lewis acids, Lewis
bases, and organometallic compounds as catalysts or cat-
alyst-free conditions at different temperature in various
solvents. Unfortunately, no products were observed for
this reaction because of the stability of K4[Fe(CN)6].
However, in subsequent research, it was found that benzo-
yl chloride could react with K4[Fe(CN)6] to liberate CN–
and form benzoyl cyanide as an intermediate, which sub-
sequently reacted with 1a to give monohydrocyanation
product, α-hydrazinonitrile, in high yield. It was found
that for 1 mol of 1a, only 0.2 equiv of K4[Fe(CN)6] was
required, which indicated that all six CN– groups in
K4[Fe(CN)6] could be readily utilized in this reaction.
However, the dihydrocyanation product was not observed
under the studied conditions including the use of an ex-
cess amount of K4[Fe(CN)6], prolonged reaction time, and
elevated reaction temperature.
Potassium hexacyanoferrate(II), K4[Fe(CN)6], is mainly
used as a carburizing agent in the iron and steel industry,
however, it is also used in the food industry for metal pre-
cipitation and as an anticoagulant for table salt (NaCl).
K4[Fe(CN)6] is a byproduct of the coal chemical industry
and is commercially available on a ton scale. Furthermore,
it is even cheaper than KCN. Recently, K4[Fe(CN)6] has
been used as a cyanide source in substitution reactions to
synthesize benzonitriles,9 aroyl cyanides,10 benzyl cya-
nides,11 cinnamonitriles,12 dihaloacrylonitriles,13 and cya-
no-substituted heterocycles.14 Our recent research
interests focused on the cyanation of unsaturated com-
R2
N
R1
R1
N
R2
R1
R2
PhCOCl
160 °C
N
R1
K4[Fe(CN)6]
PhCOCN
NC
N
H
MeOH, 60 °C
R2
Scheme 1 The monohydrocyanation of symmetrical azines using
K4[Fe(CN)6] as an environmentally friendly cyanide source
It was also confirmed that the solvent played a key role in
the reaction (Table 1). It was found that no α-hydrazino-
nitriles were obtained in solvents such as N,N-dimethyl-
formamide, dimethyl sulfoxide, or toluene (Table 1,
SYNLETT 2014, 25, 1786–1790
Advanced online publication: 28.05.2014
DOI: 10.1055/s-0033-1339133; Art ID: st-2014-w0246-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Monohydrocyanation of Symmetrical Azines
1787
Table 1 Effect of Solvent on the Yield of Monohydrocyanation of 1a with K4[Fe(CN)6] as Cyanide Sourcea
N
N
CN
1a
PhCOCl
160 °C
N
N
PhCOCN
K4[Fe(CN)6]
H
solvent, 60 °C
2a
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
DMF
16
16
16
6
0
0
DMSO
toluene
MeOH
EtOH
THF
0
85
73
50
60
16
18
16
MeCN
a Reaction conditions: 1a (1 mmol), K4[Fe(CN)6] (0.2 mmol), benzoyl chloride (1.2 mmol), solvent (20 mL).
b Isolated yield.
entries 1–3). However, the reaction in methanol, ethanol, withdrawing groups on the aromatic rings of R1 gave
acetonitrile or tetrahydrofuran afforded the desired prod- slightly lower yield and required longer reaction time (Ta-
uct in moderate to high yield (Table 1, entries 4–7), with ble 2, entries 6–10). The substituents in the ortho- and
the best result being obtained in methanol (Table 1, entry para-position of the aromatic rings had no clear effect on
4).
the product yield. For symmetrical azines with R2 = Me,
the reactions slowed down significantly because of the
steric hindrance imparted by the methyl group, and the
yield was also lower than their analogues with R2 = H (Ta-
ble 2, entries 11 and 12).
Based on the above findings, a series of symmetrical
azines were employed in the monohydrocyanation using
K4[Fe(CN)6] in MeOH as an environmentally friendly cy-
anide source and benzoyl chloride as a promoter under
catalyst-free conditions (Table 2).19 It was found that sym- A symmetrical azine with an aliphatic ring, 5,6-dihydro-
metrical azines with electron-donating groups on the aro- 4H-1,2-diazepine (1m), reacted more rapidly and afforded
matic rings of R1 gave the products in high yield (Table 2, the monohydrocyanation product in 93% yield (Scheme
entries 2–5). Whereas, symmetrical azines with electron- 2).
The monohydrocyanation of unsymmetrical azines
(Scheme 3), such as azine 1n (R = 2-Cl) and 1o (R = 4-Cl),
was also investigated under similar conditions. However,
mixtures of two kinds of monohydrocyanation products
were obtained in almost 1:1 ratio for each substrate in
79% (for 2n1 and 2n2) and 83% (for 2o1 and 2o2) overall
yield. This indicated that R groups on the aromatic rings
had no clear effect on the monohydrocyanation.
N
1m
N
PhCOCl
160 °C
K4[Fe(CN)6]
PhCOCN
CN
MeOH, 60 °C
N
NH
2m
Scheme 2 The monohydrocyanation of 5,6-dihydro-4H-1,2-di-
azepine using K4[Fe(CN)6] as an environmentally friendly cyanide
source
R
N
N
CN
H
R
R
1n, R = 2-Cl
1o, R = 4-Cl
N
N
PhCOCl
160 °C
N
N
H
+
PhCOCN
K4[Fe(CN)6]
CN
MeOH, 60 °C
2n1, R = 2-Cl, 48%
2o1, R = 4-Cl, 46%
2n2, R = 2-Cl, 52%
2o2, R = 4-Cl, 54%
Scheme 3 The monohydrocyanation of unsymmetrical azines using K4[Fe(CN)6] as an environmentally friendly cyanide source
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1786–1790

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X. Hu et al.
LETTER
Table 2 Monohydrocyanation of Symmetrical Azines with K4[Fe(CN)6] as Cyanide Sourcea
R2
N
R1
R1
N
R2
R1
R2
PhCOCl
160 °C
N
R1
K4[Fe(CN)6]
PhCOCN
NC
N
H
MeOH, 60 °C
R2
2
Entry
R1
Ph
R2
H
Product
Time (h)
Yield (%)b
Mp (°C)
100–102
CN
N
N
H
1
6
85
2a
2b
2c
CN
N
N
H
2
3
2-MeC6H4
4-MeC6H4
H
H
4
6
86
87
108–110
104–106
CN
N
N
H
t-Bu
CN
N
N
H
4
4-t-BuC6H4
H
8
80
98–100
t-Bu
2d
OMe
CN
N
N
5
6
7
4-MeOC6H4
2-ClC6H4
4-ClC6H4
H
H
H
10
16
18
85
76
77
93–95
H
MeO
2e
Cl
CN
N
N
H
112–114
103–105
Cl
2f
Cl
CN
N
N
H
Cl
2g
CF3
CN
N
N
H
8
4-F3CC6H4
H
16
73
77–79
F3C
2h
Synlett 2014, 25, 1786–1790
© Georg Thieme Verlag Stuttgart · New York

LETTER
Monohydrocyanation of Symmetrical Azines
1789
Table 2 Monohydrocyanation of Symmetrical Azines with K4[Fe(CN)6] as Cyanide Sourcea (continued)
R2
N
R1
R1
N
R2
R1
R2
PhCOCl
160 °C
N
R1
K4[Fe(CN)6]
PhCOCN
NC
N
H
MeOH, 60 °C
R2
2
Entry
R1
R2
H
Product
Time (h)
19
Yield (%)b
Mp (°C)
F
CN
N
N
9
2-FC6H4
66
42–44
H
F
2i
F
CN
N
N
10
4-FC6H4
H
20
70
139–141
H
F
2j
CN
N
N
H
11
12
Ph
Ph
Me
Me
24
24
60
63
110–112
140–142
2k
2l
CN
N
N
H
a Reaction conditions: azine (1 mmol), K4[Fe(CN)6] (0.2 mmol), benzoyl chloride (1.2 mmol), MeOH (20 mL).
b Isolated yield.
A plausible mechanism for the monohydrocyanation of
KCl, FeCl2
Ph
O
OMe
CN
azines using K4[Fe(CN)6] as a cyanide source is shown in
Scheme 4. First, K4[Fe(CN)6] reacts with benzoyl chlo-
ride to form benzoyl cyanide as an intermediate, which
was confirmed by its isolation and identification.15a Ben-
zoyl cyanide is attacked by methanol to yield nucleophilic
addition intermediate A. Intermediate A undergoes the
loss of methyl benzoate to produce hydrogen cyanide in
situ. Nucleophilic addition of hydrogen cyanide to azines
1 then yields α-hydrazinonitriles 2 as final products.
K4[Fe(CN)6]
Ph
CN
OH
O
MeOH
A
Ph
Cl
O
Ph
OMe
R1
HCN
R2
N
R1
N
In summary, an environmentally friendly method has
been developed for the monohydrocyanation of symmet-
rical azines to synthesize α-hydrazinonitriles using
K4[Fe(CN)]6 as a cyanide source and benzoyl chloride as
a promoter. The advantages for this protocol are the use of
nontoxic, inexpensive cyanide source, simple work-up
procedures, and catalyst-free conditions.
R2
1
R2
R1
N
N
R1
NC
H
R2
2
Scheme 4 Proposed mechanism for monohydrocyanation of azines
using K4[Fe(CN)6] as a cyanide source
Acknowledgment
Environment-Related Polymer Materials for the Ministry of Educa-
tion for financial support of this work.
The authors thank the National Natural Science Foundation of
China (21162024, 21362034) and the Key Laboratory of Eco-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1786–1790

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X. Hu et al.
LETTER
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o
o
nr
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(19) Monohydrocyanation of Azines; General Procedure: A
mixture of K4[Fe(CN)6] (0.2 mmol) and benzoyl chloride
(1.2 mmol) was heated at 160 °C for 3 h. After the reaction
system was cooled to room temperature, azine (1 mmol) in
methanol (20 mL) was added. The resulting mixture was
further stirred at 60 °C for the appropriate time indicated in
Table 2. After completion of the reaction, monitored by
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representative products are given.
(E)-2-(2-Benzylidenehydrazinyl)-2-phenylacetonitrile
(2a): White solid; mp 100–102 °C. IR (KBr): 3241 (NH),
2226 (CN) cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.77 (s,
1 H, CH), 7.60–7.63 (m, 4 H, ArH), 7.44–7.46 (m, 3 H,
ArH), 7.36–7.38 (m, 3 H, ArH), 5.53 (s, 1 H, CH). 13C NMR
(CDCl3, 100 MHz): δ = 143.4, 134.2, 132.6, 129.5, 129.4,
129.1, 128.6, 127.7, 126.7, 118.5, 55.8 ppm.
(Z)-3,4,5,6-Tetrahydro-2H-1,2-diazepine-3-carbonitrile
(2m): White solid; mp 240–242 °C. IR (KBr): 3176 (NH),
2226 (CN) cm–1. 1H NMR (CDCl3, 400 MHz): δ = 4.04–4.06
(m, 1 H, CH), 3.58–3.60 (m, 1 H, CH), 2.97 (s, 1 H, NH),
1.69–1.99 (m, 6 H, CH2). 13C NMR (CDCl3, 100 MHz,): δ =
115.9, 75.2, 53.8, 28.6, 28.0, 19.4.
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Synlett 2014, 25, 1786–1790
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