Convenient and rapid synthesis of α-aminonitriles starting directly from nitro compounds in water

Article abstract of DOI:10.1016/j.tetlet.2009.03.150

A distinct approach for the synthesis of α-aminonitriles has been discovered by three-component reaction of nitroarenes, aldehydes, and TMSCN using indium in dilute aqueous HCl at room temperature. The products were formed in high yields (86-96%) within a

Full text of DOI:10.1016/j.tetlet.2009.03.150

Tetrahedron Letters 50 (2009) 2770–2773
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Convenient and rapid synthesis of a-aminonitriles starting directly
from nitro compounds in water q
*
Biswanath Das , Gandham Satyalakshmi, Kanaparthy Suneel
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A distinct approach for the synthesis of a-aminonitriles has been discovered by three-component reac-
Received 23 January 2009
Revised 16 March 2009
Accepted 23 March 2009
Available online 26 March 2009
tion of nitroarenes, aldehydes, and TMSCN using indium in dilute aqueous HCl at room temperature.
The products were formed in high yields (86–96%) within a short period of time (5–20 min). This one-
pot conversion consists of the following steps: (i) reduction of nitro compounds to amines, (ii) formation
of imines from amines and aldehydes and (iii) addition of cyanide anion to the imines.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
a-Aminonitriles
Nitro compound
In/HCl
TMSCN
Aqueous medium
a
-Aminonitriles are useful intermediates for the preparation of
-aminoacids and different nitrogen-containing heterocycles such
as imidazoles and thiadiazoles.1 The most important route for the
synthesis of
-aminonitriles is the Strecker reaction.2 In the classi-
TMSCN
R'
a
In,HCl, H2O,
RNHCH
+
RNO R'CHO
2
r.t.,
5-20 min
CN
a
1
2
3
cal Strecker reaction carbonyl compounds are treated with alkaline
cyanides and salts of amines in aqueous medium. The experimen-
tal procedure of this reaction is tedious and thus, various modified
protocols have been developed using different cyanide reagents
(such as diethyl phosphorocyanidate, tri-n-butyltin cyanide, diet-
hylaluminium cyanide, trimethylsilyl cyanide (TMSCN, etc.)3 as
well as catalysts (such as Sc(OTf)3, Pr(OTf)3, Vo(OTf)3,
La(NO3)3Á6H2O and GdCl3Á6H2O).4 However, many of these proto-
cols are associated with several drawbacks such as long reaction
times, unsatisfactory yields, application of expensive reagents
and harsh reaction conditions. Herein we report a distinct ap-
86-96%
Scheme 1.
source compared to other cyanide reagents has been employed
here. The conversion took place very rapidly (within 5–20 min)
and the products were formed in excellent yields (86–96%). Differ-
ent derivatives of nitrobenzene were used to prepare the a-amino-
nitriles. However, in the case of 4-nitroacetophenone the carbonyl
group was also reduced (Table 1, entry o).
Aromatic and heteroaromatic aldehydes underwent the conver-
sions smoothly. However aliphatic aldehydes required a little
longer reaction time compared to the aromatic aldehydes. An
acid-sensitive aldehyde such as furfuraldehyde (entry f) and a
sterically hindered aldehyde such as 2-naphthaldehyde (entry e)
proach for the synthesis of
nitroarenes.
a-aminonitriles directly from
In continuation of our work5 on the development of useful syn-
thetic methodologies we have discovered that a-aminonitriles can
be synthesized conveniently through the three-component reac-
tion of nitroarenes, aldehydes, and TMSCN using indium in dilute
aqueous HCl at room temperature (Scheme 1).
afforded the corresponding
a- aminonitriles in high yields. Even
a conjugated aldehyde such as cinnamaldehyde (entry d) also
furnished the desired product rapidly. The alcohols, which are
reduction products of the corresponding aldehydes, were not
obtained. The reaction with nitroanilines produced only mono
A series of
a-aminonitriles were easily prepared following the
above method using various nitro compounds and aldehydes
(Table 1). TMSCN which is a safer and more effective cyanide anion
a
-aminonitriles (entry n) and with nitroalkanes furnished the
products in very low yields (10–14%). In the case of nitroalkanes
the major amount of the substrates, nitro compounds, and alde-
hydes was unreacted even after 0.5 h under the present experi-
mental conditions. Indium, which remained unchanged in air or
q
Part 183 in the series, ‘Studies on novel synthetic methodologies’.
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.150

B. Das et al. / Tetrahedron Letters 50 (2009) 2770–2773
2771
Yield (%)
95
Table 1
Synthesis of a
- aminonitriles using indium in dilute aqueous HCl at room temperaturea
S.no.
Nitro compound 1
Aldehyde 2
Product 3
Time (min)
H
NO2
CHO
N
CN
CN
a
5
H
N
CHO
NO2
b
6
95
Cl
Cl
Cl
H
N
CHO
Cl
CN
NO2
c
8
90
Cl
Cl
H
N
CHO
HC
CN
NO2
d
10
89
H
N
CN
NO2
CHO
e
9
88
H
N
NO2
CN
CN
O
CHO
f
8
8
89
89
O
H
N
NO2
S
CHO
g
S
NO2
NO2
NO2
H
N
CN
CN
CN
h
15
16
19
88
88
CHO
H
N
CHO
i
H
N
CHO
j
86
(continued on next page)

2772
B. Das et al. / Tetrahedron Letters 50 (2009) 2770–2773
Table 1 (continued)
S.no.
Nitro compound 1
Aldehyde 2
Product 3
Time (min)
Yield (%)
NO2
H
N
CHO
CN
CN
k
8
94
H3C
CH3
NO2
H
N
CHO
l
7
9
8
96
90
91
H3C
CH3
Cl
Cl
CH3
H
NO2
CH3
CHO
CN
N
m
H
N
NO2
CHO
CN
H2N
n
NH2
H
NO2
CN
CHO
CH3
N
CH3CH2
o
10
93
CH3
O
CH3
a
The structures of the products were settled from their spectral (IR, 1H and 13C NMR, and MS) and analytical data.
R
R
HN
TMSCN
H2O
R'CHO
N
In/HCl
RNH2
RNO2
Me3SiOH
+
CH
CN
R'
R'
InCl3
Scheme 2.
oxygen at room temperature and does not effect oxygen- and
nitrogen-containing functionalities,6 has been successfully applied
three-component reaction of nitroarenes, aldehydes and TMSCN
using indium in dilute aqueous HCl at room temperature. The di-
rect application of nitroarenes, mild reaction conditions, rapid con-
version (5–20 min) and impressive yields (86–96%) are the
advantages of the method.
here for the preparation of
a-aminonitriles from aromatic nitro
compounds in water.7 The structures of the prepared
a-aminonitr-
iles were determined from their spectral (IR, 1H and 13C NMR, and
MS) and analytical data.8
Acknowledgments
The present synthesis of a-aminonitriles involved three steps in
one-pot. The nitroarenes on treatment with In/HCl reduced6b to
anilines that reacted with aldehydes to form the corresponding
imines. The addition of cyanide anion to these imines resulted in
The authors thank CSIR and UGC, New Delhi, for financial
assistance.
the formation of
carried out with an amine, an aldehyde, and TMSCN under the sim-
ilar reaction conditions the corresponding -aminonitrile was also
formed in high yield and in short reaction time. As for an example,
the treatment of aniline, benzaldehyde, and TMSCN using In/aque-
ous HCl at room temperature afforded the aminonitrile 3a (Table 1)
within 4 min with 95% yield.
a-aminonitriles (Scheme 2). The reaction when
References and notes
a
1. (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539; (b) Dyker, G. Angew. Chem., Int. Ed.
1997, 36, 1700; (c) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1999. p 965.
2. (a) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27; (b) Groger, H. Chem. Rev. 2003,
103, 2795.
3. (a) Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663; (b) Mai,
K.; Patil, G. Tetrahedron Lett. 1984, 25, 4583; (c) Kobayashi, S.; Ishitani, H. Chem.
Rev. 1999, 99, 1069.
In conclusion, we have discovered a convenient and efficient
novel method for one-pot synthesis of
a-aminonitriles through a

B. Das et al. / Tetrahedron Letters 50 (2009) 2770–2773
2773
1H
4. (a) Heydari, A.; Fatemi, P.; Alizadeh, A.-A. Tetrahedron Lett. 1998, 39, 3049; (b)
Compound 3b: IR (KBr): 3370, 2238, 1601, 1504, 1431, 1309,1246 cmÀ1
;
Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529; (c) Yadav, J. S.; Reddy,
B. V. S.; Easwaraiah, B.; Srinivas, N. Tetrahedron 2004, 60, 1769; (d) De, S. K.
Synth. Commun. 2005, 35, 653; (e) Royer, L.; De, S. K.; Gibbo, R. A. Tetrahedron
Lett. 2005, 46, 4595; (f) Prakash, G. K. S.; Panja, C.; Do, C.; Mathew, T.; Olah, G. A.
Synlett 2007, 2395; (g) Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.; Reddy, S.
M.; Reddy, A. V.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2007, 264, 288.
5. (a) Das, B.; Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu, B.; Kumar, D.
N. Tetrahedron Lett. 2008, 49, 2225; (b) Das, B.; Damodar, K.; Chowdary, N.;
Saritha, D.; Ravikanth, B.; Krishnaiah, M. Tetrahedron 2008, 64, 9396; (c) Das, B.;
Krishnaiah, M.; Laxminarayana, K.; Suneel, K.; Kumar, D. N. Chem. Lett. 2009, 38, 42.
6. (a) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347; (b) Lee, J. G.; Choi, K., II.; Koh, H. Y.;
Kang, Y.; Kim, Y.; Kang, Y.; Cho, Y. S. Synthesis 2001, 81.
NMR (CDCl3, 200 MHz): d 7.62 (1H, d, J = 2.0 Hz), 7.53 (1H, m), 7.42–7.35 (2H,
m), 7.25 (2H, t, J = 8.0 Hz), 6.90 (1H, t, J = 8.0 Hz), 6.72 (2H, d, J = 8.0 Hz), 5.40
(1H, d, J = 7.0 Hz), 4.02 (1H, d, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 144.2,
136.0, 135.2, 130.8, 130.0, 129.9, 127.5, 125.2, 120.9, 117.8, 114.1, 49.8; ESIMS:
m/z 216 [MÀCN]+. Anal. Calcd for C14H11ClN2: C, 69.28; H, 4.54; N, 11.55. Found:
C, 69.43; H, 4.48; N, 11.62.
Compound 3c: IR (KBr): 3368, 2247, 1601, 1503, 1473, 1250 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): d 7.71 (1H, d, J = 8.0 Hz), 7.52 (1H, d, J = 1.5 Hz), 7.35 (1H, dd,
J = 8.0, 1.5 Hz), 7.29–7.20 (2H, m), 6.89 (1H, t, J = 8.0 Hz), 6.71 (2H, d, J = 8.0 Hz),
5.62 (1H, d, J = 7.0 Hz), 3.96 (1H, d, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d
144.6, 136.8, 130.9, 130.0, 129.8, 128.1, 120.8, 114.2, 47.3; ESIMS: m/z 250, 252,
254 [MÀCN]+. Anal. Calcd for C14H10Cl2N2: C: 60.65; H, 3.61; N, 10.11. Found: C,
60.78; H, 3.58; N, 10.21.
7. Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and Professional:
London, 1998.
Compound 3k: IR (KBr): 3328, 2241, 1651, 1519, 1449, 1280 cmÀ1
(CDCl3, 200 MHz): d
;
1H NMR
7.65–7.57 (2H, m), 7.49–7.38 (3H, m), 7.06 (2H, d,
J = 8.0 Hz), 6.66 (1H, d, J = 8.0 Hz), 5.37 (1H, d, J = 7.0 Hz), 3.82 (1H, d,
8. General experimental procedure: To a mixture of a nitroarene (1 mmol), indium
(325 mesh, 2 mmol) and 1 N aqueous HCl (1 mL) in water (5 mL) an aldehyde
(1 mmol) was added followed by addition of TMSCN (1 mmol). The mixture was
stirred at room temperature and the reaction was monitored by TLC. After
completion, the mixture was washed with saturated NaHCO3 solution
(3 Â 5 mL) and water (3 Â 5 mL) and subsequently extracted with EtOAc
(3 Â 5 mL). The extract was concentrated under reduced pressure and the
crude product was purified by column chromatography (silica gel, hexane–
J = 7.0 Hz), 2.29 (3H, s); 13C NMR (50 MHz, CDCl3):
d 142.1, 133.9, 129.9,
129.5, 129.0, 128.8, 127.0, 118.2, 114.1, 50.2, 20.0; ESIMS: m/z 196 [MÀCN]+.
Anal. Calcd for C15H14N2: C, 81.08; H, 6.31; N, 12.61. Found: C, 81.21; H, 6.38; N,
12.56.
Compound 3o: IR (KBr): 3363, 2234, 1615, 1467, 1264 cmÀ1 1H NMR (CDCl3,
;
200 MHz):
d 7.49 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz), 7.07 (2H, d,
EtOAc) to obtain pure
When the above reaction was carried out with 4-nitroacetophenone (1 mmol)
using In (2 mmol) a mixture of products was formed. However, using excess In
a
- aminonitrile.
J = 8.0 Hz), 6.67 (2H, d, J = 8.0 Hz), 5.30 (1H, d, J = 7.0 Hz), 3.81 (1H, d, J = 7.0 Hz),
2.59 (2H, q, J = 7.0 Hz), 2.40 (3H, s), 1.22 (3H, t, J = 7.0 Hz) 13C NMR (50 MHz,
CDCl3): d 142.8, 139.2, 135.5, 130.9, 129.4, 128.2, 127.0, 118.6, 113.8, 50.0, 27.8,
20.9, 15.2; ESIMS: m/z 224 [MÀCN]+. Anal. Calcd for C17H18N2: C, 81.60; H, 7.20;
N, 11.20. Found: C, 81.72; H, 7.14; N, 11.28.
(6 mmol) the
a- aminonitrile 3o was obtained in high yield (93%) in 10 min.
The spectral and analytical data of the novel products are given below.