Zn(OAc)2·2H2O-catalyzed one-pot efficient synthesis of α-amino nitriles

Article abstract of DOI:10.14233/ajchem.2014.17180

A mild, efficient one-pot three component strecker reaction involving electronically and structurally divergent aldehydes, amines and trimethly silyl cyanide in chloroform as solvent at room temperature was accomplished in moderate to excellent yields using an inexpensive and readily available catalyst, Zn(OAc)₂.2H₂O.

Full text of DOI:10.14233/ajchem.2014.17180

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7439-7442
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17180
Zn(OAc)2·2H2O-Catalyzed One-Pot Efficient Synthesis of α-Amino Nitriles
1
2
3
1,*
V. VENKATA RAMI REDDY , B. SARITHA , R. RAMU , RAVI VARALA4,* and A. JAYASHREE
1Centre for Chemical Sciences and Technology, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad-500 085, India
2Department of Chemistry, Vidyajyothi Institute of Technology, Aziznagar Gate C.B Post, Ranga Reddy-500 075, India
3R&D Division, SRC Laboratories Private Limited, Prashant Nagar, Kukatpally, Hyderabad-500 037, India
4Department of Chemistry, AP-IIIT Basara, Rajiv Gandhi University of Knowledge Technologies, Adilabad-504 107, India
*Corresponding authors: E-mail: ravivarala@rgukt.in
Received: 7 February 2014;
Accepted: 30 April 2014;
Published online: 30 September 2014;
AJC-16156
A mild, efficient one-pot three component strecker reaction involving electronically and structurally divergent aldehydes, amines and
trimethly silyl cyanide in chloroform as solvent at room temperature was accomplished in moderate to excellent yields using an inexpensive
and readily available catalyst, Zn(OAc)2.2H2O.
Keywords: Strecker reaction, α-Amino nitriles, Zn(OAc)2.2H2O, Multicomponet reaction.
and also require tedious workup leading to the generation of a
large amount of toxic waste.
INTRODUCTION
Thus, there is a continued need for a simpler, straight forward
and cost effective method for the syntheses of these useful com-
pounds. Earlier, we explored the utility of Zn(OAc)2.2H2O28
in the one-pot synthesis of propargylamines from aldehydes,
amines and phenyl acetylene via three component coupling
reaction. In continuation of our interest in exploring novel
strategies for C-C, C-hetero bond formations29, herein we,
describe the establishment of reaction conditions that enable
the use of readily available, bench stable Zn(OAc)2.2H2O as
inexpensive, high yielding catalyst for the synthesis of α-amino
nitriles.
The synthesis of α-amino nitriles via addition of cyanides
to imines (the strecker reaction) has been subjected to consi-
derable interest, as these molecules are useful intermediates
towards preparation of α-amino acids1 and various nitrogen
containing heterocycle like imidazoles or thiazoles2,3. α-Amino
nitriles are useful intermediates in drugs and other pharma-
ceutical products4-6.
The classical strecker reaction is usually carried out with
alkaline cyanides in aqueous solution and the workup proce-
dure is also tedious. α-Amino nitriles are prepared using imines
or one pot synthesis using carbonyl compounds, amines,
various catalysts and cyanide source substrate such as KCN7,
HCN, trimethly silyl nitriles9, diethyl phosphoro-cyanidate
(EtO)2-P(O)CN10, Bu3SnCN11, Et2AlCN12. Among these,
trimethyl silyl cyanide is a safe and more effective cyanide
anion source for the nucleophilic addition reactions of imines
under mild conditions13. Substantial progress has been made
towards the development of efficient methods for the prepara-
tion of these compounds, using various catalysts like Sc(OTf)314,
EXPERIMENTAL
All melting points were determined on an Electrothermal
Gallenkamp apparatus. 1H and 13C NMR spectra were recorded
on a Varian Gemini Spectrometer 300 and 400 MHz respec-
tively. IR spectra were recorded on Nicolet Fourier Transform
spectrometer. Mass spectra were obtained on a 7070H or VG
Autospec Mass spectrometer using LSIMS technique. Thin-
layer chromatography (TLC) was performed on GF-25U
(Anal. Tech) plates and silica gel glass-backed plates. Routine
column chromatography was conducted using silica gel 100-
200 mesh.
InCl315, BiCl316, RuCl317, NiCl218, Cu(OTf)219, Fe(Cp)2PF620
,
La(NO3)3.6H2O or GdCl3.6H2O21, molecular iodine22, mont-
morillonite KSF clay23, heteropoly acids24, guanidine hydro-
chloride25, lithium perchlorate26, using ionic liquids such as 1-
butyl-3-methylimidazolium tetrafluoroborate [bmim]BF4 and
other catalysts27. However, many of these reagents are not easily
accessible due to their high cost and extended reaction times
and involve the use of expensive reagents, harsh conditions
Typical procedure: A mixture of the amine (1 mmol),
Zn(OAc)2.2H2O (5 mol %) trimethylsilyl cyanide (1.1 mmol)
and the aldehyde (1 mmol) in chloroform (3 mL) was stirred
at ambient temperature for an appropriate time (Tables 1-3).

7440 Reddy et al.
Asian J. Chem.
TABLE-1
SOLVENT STUDIES UNDER DIFFERENT PARAMETERS FOR
THE MODEL REACTION CATALYZED BY Zn(OAc)2·2H2O
Then, the reaction was quenched by addition of a saturated
solution of NH4Cl (5 mL) and the mixture was extracted with
ethyl acetate (10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and the solvents were removed under
reduced pressure to give in many cases the pure α-aminonitrile.
In some cases, the aforementioned residues had to be subjected
to chromatography using silica gel and mixtures of hexane/
ethyl acetate of increasing polarity in order to obtain the pure
α-aminonitrile products.
Entry
Solvent
MeOH
1,4-dioxane
H2O
Time (h)
4.5
Conversion (%)[a]
1
2
79
72
0
5.0
3
8.0
4
Toluene
THF
4.0
72
46
56
85
78
65
92
5
6.0
6
DMF
5.5
7
CH3CN
DCM
3.5
2-Phenyl-2-piperidinoacetonitrile (Entry 4, Table-2):
Viscous oil, 1H NMR (200 MHz, CDCl3): δ (ppm) 1.47-1.59
(m, 6H), 2.49 (m, 4H), 4.75 (s, 1H), 7.29-7.32 (m, 3H), 7.49-
7.52 (m, 2H); MS (ESI): m/z 201 (M + 1).
8
2.5
9
DMSO
CHCl3
4.5
10
[a]Isolated yield
3.5
2-Phenyl-2-(1,4-thiazinan-4-yl) acetonitrile (Entry 6,
Table-2): Pale yellow solid, m.p.: 65-66 °C; 1H NMR (200
MHz, CDCl3): δ (ppm) 2.67 (m, 4H), 2.83 (m, 4H), 4.71 (s,
1H), 7.33-7.41(m, 3H), 7.49-7.52 (m, 2H); MS (ESI): m/z 219
(M + 1).
TABLE-2
CYANATION REACTION CATALYZED BY Zn(OAc)2.2H2O
Entry
Amine
Aldehyde
Product
Time
Yield
(%)a
Ph
HN
HN
NH2
(4-Benzylpiperazino)phenyl methyl cyanide (Entry 7,
1
Table-2): Solid, m.p.: 117-119 °C; H NMR (200 MHz,
1
2
A
A
2.5
8530
7630
N
CDCl3): δ (ppm) 2.51 (brs, 4H), 2.62 (brs, 4H), 3.51 ( s, 2H),
4.8 (s, 1H), 7.22-7.43 (m, 10H); MS (ESI): m/z 292 (M + 1).
2-Phenyl-2-piperazinoacetonitrile (Entry 8, Table-2):
Solid, m.p.: 94-96 °C; 1H NMR (200 MHz, CDCl3): δ (ppm)
1.24 (brs, 4H), 2.63 (brs, 4H), 4.85- (s, 1H), 7.33-7.52 (m,
5H); MS (ESI): m/z 202 (M + 1).
Ph
NH2
4.5
N
N
N
NH2
HN
3
4
5
A
A
A
5.0
4.0
3.5
6831
(4-Chlorophenyl) (4-toluidino) methyl cyanide (Entry
8, Table-3): Colourless Solid, m.p.: 85-88 °C; 1H NMR (200
MHz, CDCl3): δ (ppm) 2.27 (s, 3H), 3.85 (d, J = 8.0 Hz, 1H),
5.28 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 7.0 (d, J =
7.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.3 Hz, 2H),
MS (ESI): m/z 257 (M + 1).
N
85
N
H
O
N
O
9231
N
H
RESULTS AND DISCUSSION
N
N
S
N
Initially, a variety of zinc catalysts were tested (5 mol %
as standard) in chloroform for the effective A3 coupling of
benzaldehyde, morpholine and trimethylsilyl cyanide at
ambient temperature (Scheme-I).
S
6
7
A
A
4.5
4.5
76
78
N
H
Ph
Ph
N
N
O
N
CHO
Zn(OAc)2.2H2O
O
N
H
(5 mol%)
N
N
+
TMSCN
+
CHCl3, RT
H
N
N
H
H
N
N
8
9
A
A
A
N
5.5
5.0
5.5
80
N
H
Scheme-I
N
N
Among the catalysts screened, [ZnCl2 (6.5 h, 45 %), zinc
dust (12 h, 0 %), Zn(OAc)2. 2H2O (3.5 h, 92 %), ZnCO3 (5.5
h, 53 %), zinc granules (5.5 h, 60 %), Zn(OTf)2 (4.5 h, 80 %),
Zn(NO3)2 (5 h, 48 %) and Zn(CN)2 (5 h, 52 %)], Zn(OAc)2.2H2O
found to be effective catalyst both in terms of isolated yield
and reaction time. Among the solvents tested, chloroform
proved to be effective (Table-1). We further carried out our
studies in order to optimize the catalyst ratio with respect to
aldehyde. Using 10 mol %, 0.5 equiv. and 1equiv. of catalyst,
no significant improvement in the yield was observed. 5 mol%
of catalyst was found to be sufficient for maximum yield.
N
8231
N
H
HN
10
6231
NH2
N
aIsolated yield A = Benzaldehyde
Intrigued by these results, we proceeded to apply the catalytic
system (5 mol %, chloroform at ambient temperature) for the

Vol. 26, No. 21 (2014)
Zn(OAc)2·2H2O-Catalyzed One-Pot Efficient Synthesis of α-Amino Nitriles 7441
TABLE-3
CYANATION REACTION CATALYZED BY Zn(OAc)2.2H2O
Entry
1
Aldehyde
O
Amine Product
Time
2.5
Yield (%)a
8530
NHPh
NH2
C
H
N
Cl
Cl
O
C
NHPh
NH2
H
2
3
3.5
4.5
7611
N
F
F
NHPh
O
NH2
C
H
7132
N
HO
HO
OCH3
NHPh
O
C
NH2
H
4
5
3.5
5.0
5232
N
OH
OH
NHPh
O
C
NH2
H
8631
N
OCH3
OCH3
NHPh
O
NH2
C
H
6
7
3.0
3.0
8130
8130
N
H3CO
H3CO
NHPh
O
C
NH2
H
N
H3C
H3C
CH3
O
C
NH2
HN
H
8
9
3.0
5.0
4.5
83
8230
85
H3C
N
Cl
Cl
O
NH2
OCH3
HN
C
H
OCH3
N
O
CH3
NH2
HN
C
H
10
H3C
N
O
C
HN
Ph
H
NH2
11
N
5.5
7231
OCH3
OCH3
NHPh
NHPh
NH2
NH2
O
C
12
13
4.0
4.5
8230
7811
H
H
O
N
N
O
S
O
C
S
O
NH2
HN
7232
7730
C
H
14
15
5.5
5.5
N
O
NH2
HN
C
H
6
N
NHPh
O
NH2
16
17
5.0
3..00
7531
6231
C
H
N
NHCH2Ph
NHCH2Ph
O
NH2
C
N
N
C
NHPh
CH3
NH
NH22
O
C
18
N
8.0
0
aYield refer to the isolated pure products after column chrome orgraphy

7442 Reddy et al.
Asian J. Chem.
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and 20 amines such as morpholine, diverse functionalized
piperazines were also well tolerated to give the corresponding
products in moderate to excellent isolated yields (52-92 %).
The longer reaction times for aliphatic amines can be attri-
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The present methodology using Zn(OAc)2·2H2O provides
an efficient synthesis of a-aminonitriles by a one-pot three
component coupling of aldehydes, amines and trimethyl silyl
cyanide in moderate to excellent yields with the following
notable features: use of a readily available and inexpensive
catalyst; tolerability of various functional groups and clean
reaction conditions.
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ACKNOWLEDGEMENTS
One of the authors, V.Venkata Rami Reddy thank SRC
Labs Pvt, Ltd. Hyderabad, India for constant encouragement.
Dr. RaviVarala acknowledges the support from Prof. Rajendra
Sahu (Director, IIIT Basara) and Prof. Raja Kumar (Vice-
Chancellor, RGUKT).
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