Catalyst-free, facile, and an efficient synthesis of α-aminonitriles employing Zn(CN)2 as an ecofriendly cyanating agent

Article abstract of DOI:10.1016/j.tetlet.2011.10.154

An efficient and eco-friendly method has been developed for the synthesis of α-aminonitriles via one-pot three-component condensation of carbonyl compounds, amines, and Zn(CN)₂ under mild conditions. This protocol has the features of use of inexpensive, ecofriendly readily available, effective cyanide source, high yield, and simple work-up procedure.

Full text of DOI:10.1016/j.tetlet.2011.10.154

Tetrahedron Letters 53 (2012) 151–156
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Tetrahedron Letters
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Catalyst-free, facile, and an efficient synthesis of a-aminonitriles employing
Zn(CN)2 as an ecofriendly cyanating agent
⇑
Sakshi Shah , Baldev Singh
Department of Chemistry, Punjabi University, Patiala 147 002, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and eco-friendly method has been developed for the synthesis of a-aminonitriles via one-pot
Received 27 August 2011
Revised 27 October 2011
Accepted 30 October 2011
Available online 7 November 2011
three-component condensation of carbonyl compounds, amines, and Zn(CN)2 under mild conditions. This
protocol has the features of use of inexpensive, ecofriendly readily available, effective cyanide source,
high yield, and simple work-up procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a-Aminonitriles
Zinc cyanide
Catalyst-free
Multicomponent
Eco-friendly
Synthesis of
a
-aminonitriles1 has been an area of current inter-
amount of toxic waste. There are also a few reports using no
catalyst32,33 but their reaction completion time lies in range of
hours. To overcome these difficulties it is still desirable to search
for an ecofriendly cyanating agent and develop an efficient
est for chemists as well as biologists because these are versatile
precursors for the synthesis of pharmacologically significant mole-
cules such as a-amino acids, amides, diamines, and various nitro-
gen and sulfur containing heterocycles such as thiadiazoles,
imidazoles, etc.2–5 Other biologically significant compounds such
as saframycin A6 a natural product and phthalascidin a synthetic
analogue,7 exhibit potent anti-tumor activity. Bruylants reaction
and its Barbier version further crowned Strecker products as they
serve as intermediate for the production of a variety of potent
short-acting opioid analgesics.8–10
synthetic method for the synthesis of a-aminonitriles and it
becomes necessary to adopt alternative approach of generating
the least possible toxic waste. So, we herein report the simple
method for the synthesis of
a-aminonitriles by using non-toxic
Zn(CN)2, a catalyst-free reaction under mild conditions.
Zn(CN)2 is a well-known cyanating agent employed in the
cyanosilylation of carbonyl compounds34, Gattermann synthesis
of hydroxyl aldehydes35 and other than these it is also frequently
used for cyanation in functional group transformations.36 Very re-
cently, it has been used as cyanide source in the synthesis of ben-
zonitriles,37 phthalonitriles,38 and in cycloaddition reactions such
as in the synthesis of a HIV-1 protease inhibitor.39 Advantage of
using Zn(CN)2 owes to its lower toxicity compared to other con-
ventional cyanide sources, low solubility in organic solvents. The
most interesting feature is that both cyanide ions from zinc cya-
nide can be transformed to the products, and afford higher yields
in several cyanation reaction due to highly covalent nature of zinc
cyanide bond. Therefore, these attractive features of Zn(CN)2
prompted us to explore its utility in one-pot Strecker reaction.
In order to explore the importance of zinc cyanide as an
environment friendly cyanating agent, the treatment of benzalde-
hyde 1a, aniline 2a with Zn(CN)2 3 in EtOH/AcOH (3:1) afforded
2-(N-anilino)-2-phenylacetonitrile 4a in 95% yield in 20 min on
stirring. Similarly, a variety of aldehydes were condensed with
aromatic 2a–c and aliphatic amines 2d–f in the presence of zinc
In search of efficient synthesis that provides high yields in short-
er reaction time in an ecofriendly manner several modifications
have been reported using a variety of cyanating agents such as
HCN,3 KCN,11 TMSCN,12 Bu3SnCN,13 MeCOCN,14 and ethyl cyanofor-
mate,15 etc along with catalysts variant such as InCl3,16 BiCl3,17
montmorillonite KSF clay,18 silica-based scandium(III),19 SO24À
/
ZrO2,20 Cu(OTF)2,21 Fe(Cp)2PF6,22 InI3,23 I2,24 NiCl2,25 RuCl3,26
Fe3O4,27 guanidine hydrochloride,28 xanthan sulfuric acid,29 [bmim]
BF4,30 silica sulfuric acid31 in conventional organic solvents have
been described. However, trimethylsilylcyanide the most com-
monly used cyanide source is expensive, moisture sensitive, and
can easily liberate toxic hydrogen cyanide. Therefore the major
drawback of these methods is the use of expensive reagents such
as metal salts and triflates, strong acidic conditions, extended reac-
tion time, and tedious work-up, leading to the generation of a large
⇑
Corresponding author.
E-mail address: sakshishah29@gmail.com (S. Shah).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.154

152
R
S. Shah, B. Singh / Tetrahedron Letters 53 (2012) 151–156
R2
cyanide in a one-pot operation to provide a-aminonitriles in good
NC
R
R2
R1
yields (Scheme 1).40 Aromatic aldehydes 1a–g afforded good to
excellent yields in shorter reaction time (Table 1, entries 1–17),
whereas heterocyclic 1h–i, conjugated 1j, and aliphatic 1k–m alde-
hydes gave moderate yields in long reaction time (Table 1, entries
18–26, 4r–4z).
EtOH:AcOH (3:1)
R1
O
Zn(CN)2
N
N
+
+
H
H
1a-m
2a-f
3
4a-z
1h: R= -C-O-(CH)3
1i: R= -C-S-(CH)3
-
-
2a: R1= H, R2= C6H5
1a: R= -C6H5
These three-component coupling reactions proceeded effi-
ciently at ambient temperature and no undesired side product
such as cyanohydrin adduct was observed and zinc cyanide reacted
in the desired way because of the rapid formation of the azome-
thine/imine intermediate. This method is equally effective with
aldehydes bearing electron withdrawing 1c–g as well as electron
donating substituents 1b in the aromatic ring and also with pri-
mary 2a–d and secondary amines 2e–f (Table 1). Moreover, acid
2b: R1= H, R2= 4-OCH3-C6H4
2c: R1= H, R2= 4-Cl-C6H4
2d: R1= H, R2= -CH2-C6H5
2e: R1=R2= -(CH2)2-O-(CH2)2
1b: R=4-OCH3-C6H4
1c: R= 4-Cl-C6H4
1j: R= -CH=CH-C6H5
1d: R=4-F-C6H4
1k: R= -C4H9
1e: R=4-NO2-C6H4
1f: R=3-NO2-C6H4
1g: R=4-CN-C6H4
1l: R= -C6H11
-
2f: R1=R2= -(CH2)4
-
1m: R= -C2H5
Scheme 1. Synthesis of a-aminonitriles employing Zn(CN)2.
Table 1
Catalyst-free synthesis of various
a
-aminonitriles
Entry
Aldehyde
Amines
Producta
Time (min)
20
Yieldb (%)
CN
NH
NH2
CHO
1
95
4a
CN
NH
4b
CHO
CHO
CHO
Cl
NH2
2
3
35
30
94
93
Cl
CN
H3CO
NH2
NH
OCH3
4c
CN
4
5
45
40
89
87
HN
HN
N
4d
CN
CHO
CHO
O
N
O
4e
CN
NH
6
7
35
45
93
88
NH2
4f
CN
NH
H3CO
CHO
NH2
H3CO
4g

S. Shah, B. Singh / Tetrahedron Letters 53 (2012) 151–156
153
Table 1 (continued)
Entry
Aldehyde
Amines
Producta
Time (min)
40
Yieldb (%)
CN
NH
H3CO
CHO
CHO
H3C
NH2
8
90
H3CO
CH3
4h
CN
H3CO
H3CO
9
35
91
NH
NH2
4i
CN
C l
CHO
NH2
10
11
30
25
92
94
Cl
NH
4j
CN
NH
Cl
CHO
H3C
NH2
Cl
CH3
4k
CN
NH
Cl
CHO
Cl
12
30
95
NH2
4l
CN
NH
NH2
F
F
CHO
CHO
13
14
15
50
40
70
84
84
82
F
F
4m
CN
H3C
NH2
NH
CH3
4n
CN
NH
O2N
CHO
NH2
O2N
O2N
4o
O2N
NH2
CN
NH
16
17
65
55
85
CHO
4p
CN
NH
NH2
NC
CHO
87
NC
4q
(continued on next page)

154
S. Shah, B. Singh / Tetrahedron Letters 53 (2012) 151–156
Table 1 (continued)
Entry
Aldehyde
Amines
Producta
Time (min)
40
Yieldb (%)
CN
NH2
O
18
83
O
HN
CHO
CHO
4r
CN
NH2
19
50
78
O
O
NH
4s
NH2
CN
S
S
20
45
81
CHO
HN
4t
NH2
CN
NH
21
22
45
40
85
87
CHO
4u
H3C
NH2
CN
NH
CHO
CHO
CH3
4v
H3CO
NH2
CN
NH
23
40
95
88
78
OCH
4w
NH2
NH2
NH2
CN
NH
24
25
CHO
4x
CN
CHO
75
82
75
NH
4y
CN
NH
CHO
26
110
4z
a
Reaction conditions: aldehyde (1 mmol), amine(1 mmol), Zn(CN)2 (1 mmol), stirred in ethanol/acetic acid (3:1). The products were characterized by spectral techniques
like IR, 1H NMR, 13CNMR, mass.
b
Isolated yields after recrystallization.

S. Shah, B. Singh / Tetrahedron Letters 53 (2012) 151–156
155
sensitive aldehydes such as furfuraldehyde 1h, thiophene-2-carb-
H+
aldehyde 1i, and cinnamaldehyde 1j worked well without any
decomposition or polymerization under these reaction conditions.
The synthetic utility of this reaction lies in the fact that in conju-
gated aldehydes no double bond migration takes place, unlike pre-
viously reported cases where migration of double bond occurs41
which is the one of the utility and advantage of present protocol.
To study the effect of solvent, the above reaction was examined
in different solvent systems (Table 2). Initially, one pot three-com-
ponent reaction of benzaldehyde 1a, aniline 2a, and Zn(CN)2 3 was
carried out in EtOH but after 3 h (Table 2, entry 1) we did not ob-
serve the formation of any end product. The enhanced reaction
rates, improved yields, and high selectivity are the features ob-
tained in ethanol/acetic acid (3:1). For example, the treatment of
benzaldehyde and aniline with zinc cyanide in ethanol/acetic acid
H
N
..
CN
NC
+H
Zn
O
CH3
O
Figure 1. Plausible reaction mechanism via formation of organo zinc complex.
after coordinating with zinc forming tetrahedral complex as shown
in Figure 1.
In this way,
a-aminonitriles were obtained in excellent yields
for 20 min (Table 2, entry 4) afforded the corresponding a-amino-
with high purity along with ecofriendly, environment benign bio-
degradable finish viz Zn(OAc)2 under acidic alcoholic reaction
media without the use of any harsh reaction conditions/catalysts
or formation of hazardous/toxic waste.
nitrile in 95% yield. However, the same reaction in other acidic
media did not give satisfactory results even in longer reaction time
(Table 2, entries 2, 3, 5). Therefore, by employing the optimized
conditions aldehyde (1 mmol), amine (1 mmol), Zn(CN)2 (1 mmol),
It is worth mentioning here that we are the first to use this cya-
nating agent that is, Zn(CN)2 in Strecker reaction which is proven
as good and effective source of cyanide ion. This method is equally
effective with aldehydes bearing electron withdrawing as well as
electron donating substituents in the aromatic ring and also with
primary and secondary amines. Acid sensitive aldehydes worked
well without any migration/decomposition/polymerization. The
advantage of this method is that it involves no additional promoter
or external catalysts. Other attractive features of this protocol are
mild reaction condition, simplicity of the experimental procedure,
avoidance of toxic, moisture sensitive catalysts, and volatile sol-
vents. Also no hazardous by-products are formed during reaction
work-up.
ethanol/acetic acid (3:1) for the synthesis of
one-pot three-component condensation, provide variously substi-
tuted
-aminonitriles in excellent yields.40
a-aminonitriles in this
a
The reaction of benzaldehyde and aniline with Zn(CN)2 was
chosen as a probe to evaluate the impact of previously used Lewis
acid catalyst such as NiCl2, RuCl3, LiBr, I2 on the reaction rate and
yields of obtained products, but it was found that the difference
was minimal when the reaction was carried out in the presence
of catalysts or without catalysts (Table 3). The results showed that
the impact of Lewis acid catalysts on the reaction rate and yields
was nearly superfluous so the use of these catalysts should be
avoided as they require tedious work-up and leading to the gener-
ation of large amount of toxic waste.
Reaction seems to proceed through the formation of organo zinc
complex with the in situ formed azomethines where in zinc first
coordinates with N-atom and displacing cyanide ion and facilitate
its attack on the azomethinic carbon. Acetic acid available in reac-
tion media releases H+ which seems to catalyze the reaction also,
Acknowledgments
The authors are thankful to the University Grant Commission
(UGC) New Delhi, for the financial assistance and Sophisticated
Analytical Instrumentation Facility (SAIF) Punjab University, Chan-
digarh for spectral analysis.
References and notes
Table 2
Condensation of benzaldehyde, aniline and Zn(CN)2 in different solventsa
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Entry
Solvent
Time (min)
Yieldb
1
2
3
4
5
EtOH
180
180
120
20
—
CH2Cl2/AcOH
THF/AcOH
EtOH/AcOH
MeCN/AcOH
70
75
95
85
90
a
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2208.
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b
Isolated yield.
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Table 3
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Entry
Catalyst
Catalyst
Yieldb
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1767–1771.
1
2
3
4
5
No catalyst
NiCl2
RuCl3
LiBr
—
95
83
95
90
88
5 mol %
5 mol %
5 mol %
5 mol %
I2
a
Reaction conditions: benzaldehyde (1 mmol), aniline(1 mmol), Zn(CN)2
(1 mmol), stirred in ethanol/acetic acid (3:1) for 20 min.
b
Isolated yield.
19. Karimi, B.; Safari, A. A. J. Organomet. Chem. 2008, 693, 2967–2970.

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completion of the reaction as indicated by TLC, the crude product was purified
by recrystallization from diethyl ether (solid products) or by chromatography
using silica gel and mixtures of hexane/ethyl acetate of increasing polarity. The
physical data (mp, IR, NMR) of known compounds were found to be identical
with those reported in the literature.3,11–25 The Spectral data for selected
products are provided below. phenyl(phenylamino)acetonitrile (Table 1, entry
1):1H NMR (400 MHz, CDCl3): d = 4.32 (s, 1H, NH), 5.61 (s, 1H), 6.89-7.80 (m,
10H); 13C NMR (125 M Hz, CDCl3): d = 48.6, 115.4, 116.9, 128.5, 128.7, 129.3,
132.7, 144.6.
(4-Methoxyphenyl)(phenylamino)acetonitrile (Table 1, entry 6): 1H NMR
(400 MHz, CDCl3): d = 3.43 (d, J = 13.4 Hz, 2H), 3.92 (d, J = 13.4 Hz, 2H), 4.73
(s, 1H), 7.01–7.25 (m, 4H), 7.35–7.42 (m, 9H), 7.53–7.60 (m, 2 H); 13C NMR
(125 MHz, CDCl3): d = 17.7, 54.3, 55.7, 116.5, 126.4, 127.5, 128.6, 129.2, 131.5,
132.3, 134.9, 145.9.
29. Shaabani, A.; Maleki, A.; Soudi, M. R.; Mofakham, H. Catal. Commun. 2009, 10,
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2-(4-Nitrophenyl)-2-(phenylamino)acetonitrile (Table 1, entry 15): 1H NMR
(400 MHz, CDCl3): d = 4.10 (d, J = 8.0 Hz, 1H), 5.35 (d, J = 8.0 Hz, 1H), 6.79 (d,
J = 8.0 Hz, 2H), 6.90 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 7.9 Hz, 2H), 7.67 (d, J = 8.1 Hz,
2H), 8.10 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): d = 49.2, 116.6, 118.5,
126.9, 127.6, 128.0, 128.9, 129.8.
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2-(N-Benzylamino)-2-furfurylacetonitrile (Table I, entry 19) 1H NMR (400 MHz,
CDCl3): d = 1.90 (s, 1H), 3.84 (q, J = 13.0 Hz, 2H), 4.69 (s, 1H), 6.26–6.33 (m, 1H),
7.17–7.52 (m, 7H); 13C NMR (CDCl3, 125 MHz): d = 47.6, 51.8, 109.6, 111.8,
126.9, 127.7, 128. 3, 128.4, 138.5, 143.7, 147.1.
2-(N-Anilino)-2-(2-thienyl)acetonitrile (Table 1, entry 20): 1H NMR (400 MHz,
CDCl3): d = 4.2 (d, J = 8.8 Hz, 1H), 5.6 (d, J = 9.2 Hz, 1H), 6.8 (d, J = 7.6 Hz, 2H),
6.9 (t, J = 7.5 Hz, 1H), 7.1 (q, J = 2.9 Hz, 1H), 7.5–7.6 (m, 4H); 13C NMR
(125 MHz, CDCl3): d = 46.5 113.6, 116.5, 120.4, 127.1, 127.6, 127.9, 129.8.,
136.3, 1, 145.1.
2-[(4-Methylphenyl)amino]-4-phenylbut-3-enenitrile (Table 1, entry 21): 1H
NMR (400 MHz, CDCl3): d = 3.92 (s, 1H, NH), 5.03 (d, J = 4.5 Hz, 2H), 6.32 (dd,
J = 7.8 Hz, 4.5 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.14–6 .86 (m, 5H), 7.12–7. 86 (m,
5H); 13C NMR (125 MHz, CDCl3): d = 46.7, 115.3, 117.3, 118.4, 119.7, 126.4,
127.2, 129.7, 131.5, 132.7, 135.2, 147.2.
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J. Med. Chem. 1999, 42, 3835–3844.
2-Cyclohexexyl-2-(phenylamino)acetonitrile (Table 1, entry 25): 1H NMR
(400 MHz, CDCl3): d = 1.22–1.29 (m, 5H), 1.68–2.64 (m, 5H), 3.77 (s, 1H),
4.07 (d, J = 6 Hz, 1H), 6.69–6.82 (m, 3H), 7.23–7.29 (m, 2H). 13C NMR (125 MHz,
CDCl3): d = 24.7, 25.6, 29.4, 41.2, 51.6, 114.5, 118.3, 119.6, 129.5, 145.7.
41. Yanovskya, L. A.; Shachidayatov, C.; Kutcherav, V. E. Tetrahedron 1967, 23,
1311–1316.
40. General procedure for the synthesis of
a-aminonitriles: A mixture of amine
(1 mmol), aldehyde (1 mmol), zinc cyanide (1 mmol), and ethanol/acetic acid
(3:1) was stirred at ambient temperature for the appropriate time. After