Acetohydroxamic acid: A new reagent for efficient synthesis of nitriles directly from aldehydes using Bi(OTf)3 as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.04.057

An efficient method for the preparation of nitriles directly from aldehydes by reaction with AHA using Bi(OTf)₃ as the catalyst is described. Bi(OTf)₃ is shown to be an efficient catalyst also for the conversion of aldoximes into nitriles.

Full text of DOI:10.1016/j.tetlet.2012.04.057

Tetrahedron Letters 53 (2012) 3421–3424
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Acetohydroxamic acid: a new reagent for efficient synthesis of nitriles
directly from aldehydes using Bi(OTf)3 as the catalyst
Madabhushi Sridhar a, , Mallu Kishore Kumar Reddy a, Vangipuram Venkata Sairam a, Jillella Raveendra a,
⇑
Kondal Reddy Godala a, Chinthala Narsaiah a, Beeram China Ramanaiah a, Cirandur Suresh Reddy b
a Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 January 2012
Revised 9 April 2012
Accepted 12 April 2012
Available online 21 April 2012
An efficient method for the preparation of nitriles directly from aldehydes by reaction with AHA using
Bi(OTf)3 as the catalyst is described. Bi(OTf)3 is shown to be an efficient catalyst also for the conversion
of aldoximes into nitriles.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acetohydroxamic acid
Bi(OTf)3
Aldehydes
Aldoximes
Nitriles
Acid catalysis
Nitriles are important starting materials for the preparation of
amines, amides, carboxylic acids, aldehydes, esters, and ketones1
and they are also industrially important for the production of poly-
mers, agrochemicals, pharmaceuticals, and dyes.2 The classical
methods for the preparation of nitriles include Kolbe nitrile syn-
thesis,3 ammoxidation of aldehydes,4 hydrocyanation of alkenes,5
Sandmeyer reaction of diazonium salts,6 and Rosenmund–von
Braun reaction of aryl halides.7 During the past decade, studies
on preparation of nitriles from aldehydes8 and aldoximes9 have re-
ceived more focus and several methods are reported in literature.
Most of the existing methods suffer from one or more of the disad-
vantages such as limited substrate scope, high reaction tempera-
tures, low yields, and use of excess and toxic reagents. Therefore,
development of a mild, efficient, and versatile method is still
strongly desirable.
Acetohydroxamic acid (AHA) is a simple and stable organic
compound, which is widely in use as a drug (LithostatÒ) for treat-
ment of urinary tract infections10 and it also finds application as a
chelating agent for extraction of metals, particularly for recovery of
uranium from spent nuclear fuel by UREX process.11 AHA is easily
prepared by reacting ethyl acetate and hydroxylamine and it is also
commercially available. Since the studies on reactions and applica-
tions of AHA in organic synthesis are scarcely recorded, we
developed interest to study AHA for its applications and recently
we showed that AHA is a useful reagent for conversion of alde-
hydes into aldoximes in high yields under BF3ꢀEt2O catalysis in
methanol as shown in Scheme 1.12
In the above reaction we did not observe the formation of ni-
triles even in trace quantities. However, the literature shows that
some of the Lewis acids such as Ga(OTf)3,9a InCl3,9b TiCl3(OTf),9c
Cu(OAc)2,9d PtCl4(EtCN)2,9e and Pd(OAc)2 promote conversion of
9f
aldoximes into nitriles. Hence, we envisaged the scope for forma-
tion of nitriles by reacting an aldehyde and AHA and modifying
the reaction conditions. Accordingly, we explored the reaction con-
ditions with several acid catalysts and solvents to obtain nitriles
and herein we report for the first time, an efficient method for
the preparation of nitriles in high yields (88–97%) by reaction of
an aldehyde with AHA under reflux in acetonitrile using Bi(OTf)3
as the catalyst as shown in Scheme 2.
In our initial experiments, we studied the reaction of 4-isopro-
pylbenzaldehyde 1a and AHA using a variety of acid catalysts such
as Bi(OTf)3, Zn(OTf)2, Y(OTf)3, Eu(OTf)3, Sc(OTf)3, La(OTf)3,
NOH
H
76-87%
O
BF3.Et2O (10 mol% )
CH3CONHOH
+
R
R
H
reflux
MeOH,
AHA
3.5-8h
R=akyl, aryl or heteroaryl
⇑
Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (M. Sridhar).
Scheme 1. Synthesis of aldoximes by reaction of AHA with aldehydes under
BF3ꢀEt2O catalysis.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.057

3422
M. Sridhar et al. / Tetrahedron Letters 53 (2012) 3421–3424
Bi(OTf)3
CH3CN. reflux
Bi(OTf)3 (5 mol%)
CH3CN, reflux
R-CN
[R-CH=NOH]
R-CHO
CH CONHOH
+
3 AHA
3a-v
2a-v
1a-v
88-97%
R= alkyl, aryl or heteroaryl
Scheme 2. Synthesis of nitriles by reaction of AHA with aldehydes under Bi(OTf)3 catalysis.
Table 1
Reaction of AHA and 4-isopropylbenzaldehyde in the presence of an acid catalyst
CHO
CH=NOH
CN
catalyst (5mol%)
CH3CN, reflux
CH CONHOH
+
3
+
1a
2a
3a
S. No.
Catalyst
Reaction time (h)
% Yielda
S. No.
Catalyst
Reaction time (h)
% Yielda
2a
3a
2a
3a
1
2
3
4
5
6
Bi(OTf)3
Zn(OTf)2
Y(OTf)3
Sc(OTf)3
La(OTf)3
Sm(OTf)3
14
15
15
24
24
24
0
15
33
55
52
46
97
80
65
40
40
50
7
8
9
10
11
12
Eu(OTf)3
InCl3
BF3ꢀEt2O
Cu(OAc)2
H2SO4
24
24
24
24
15
24
60
95
80
60
31
66
0
0
0
0
65
30
PTSA
a
Isolated yields.
Table 2
Study of the solvent effect on the reaction of an aldehyde with AHA under Bi(OTf)3 catalysis
CHO
CH=NOH
CN
Bi(OTf)3 (5mol%)
solvent, reflux
CH CONHOH
+
3
+
1a
2a
3a
S. No.
Solvent
CH3CN
N,N-Dimethylformamide
Toluene
Dichloromethane
MeOH
1,4-Dioxane
Reaction time (h)
% Yielda 2a
% Yielda 3a
1
2
3
4
5
6
7
14
24
24
24
24
24
24
0
12
81
84
97
95
96
97
80
15
10
0
0
0
Tetrahydrofuran
a
Isolated yields.
Sm(OTf)3, Cu(OAc)2, BF3ꢀEt2O, InCl3, H2SO4, and p-toluenesulfonic
acid (PTSA) under reflux in acetonitrile and the results are shown
in Table 1. In this study, we observed the formation of nitrile 3a
(30–97% yields) with catalysts such as Bi(OTf)3, Zn(OTf)2, Y(OTf)3,
Sc(OTf)3, La(OTf)3, Sm(OTf)3, H2SO4, and PTSA. Under similar condi-
tions, catalysts such as BF3ꢀEt2O, InCl3, Eu(OTf)3, and Cu(OAc)2 pro-
duced exclusively aldoxime 2a in 60–95% yields. In this study,
nitrile 3a was obtained in maximum yield (97%) with Bi(OTf)3.
In the present reaction, we observed profound influence of the
solvent on the catalysis of Bi(OTf)3. For example, the reaction of
AHA and 4-isopropylbenzaldehyde 1a under Bi(OTf)3 catalysis pro-
duced nitrile 3a in solvents such as acetonitrile, N,N-dimethylform-
amide, toluene, and dichloromethane and it produced exclusively
aldoxime 2a in solvents such as methanol, 1,4-dioxane, and tetra-
hydrofuran as shown in Table 2. Bi(OTf)3 is a oxophilic and hard Le-
wis acid. Hence, it experiences strong chelating effect in solvents
such as methanol, 1,4-dioxane, and tetrahydrofuran. As a conse-
quence, Lewis acidity of Bi(OTf)3 is possibly not sufficiently strong
in these solvents to promote dehydration of an aldoxime.
Since we observed an efficient formation of nitrile 3a from the
reaction of 1a and AHA using Bi(OTf)3 as the catalyst under reflux
in acetonitrile, we studied a variety of akyl, aryl, and heteroaryl
aldehydes 1a–v under similar conditions to obtain corresponding
nitriles 3a–v in 88–97% yields as shown in Table 3.13
The plausible mechanism for the present transformation of
aldehyde into nitrile using AHA under Bi(OTf)3 catalysis is shown
in Scheme 3. In this mechanism, we believe that Bi(OTf)3 catalyzes
reaction of an aldehyde 1 and AHA producing aldoxime 2 in the ini-
tial step and next it converts aldoxime 2 into nitrile 3 by reacting
with it. In this process, we envisage that the catalyst splits into
transient Bi(OTf)2OH and TfOH and regenerates Bi(OTf)3 under
the reaction conditions as shown in Scheme 3.

M. Sridhar et al. / Tetrahedron Letters 53 (2012) 3421–3424
3423
Table 3
Synthesis of nitriles by reaction of an aldehyde with AHA under Bi(OTf)3 catalysis
O
Bi(OTf)3 (5mol%)
reflux
CH3CONHOH
R-CN
+
R
H
CH3CN,
14-24h
3a-v
1a-v
Entry
Aldehyde 1
Nitrile 3
Reaction time (h)
% Yielda
3
mp (°C) 3
Liquid
mp (°C) 3 (L)
CHO
CN
a
b
c
14
15
17
16
17
97
CHO
CN
93
Liquid
96
91–93
92–9314a
14814b
Cl
CHO
CHO
CHO
CHO
Cl
CN
CN
CN
CN
O2N
MeO
MeO
d
e
O2N
MeO
MeO
95
146–148
58–60
95
57–5814a
f
16
16
15
93
94
94
69–71
Liquid
87–89
67–6814c
MeO
MeO
CHO
CN
g
h
MeO
MeO
HO
CHO
HO
CN
87–8814d
MeO
MeO
HO
F
CHO
CHO
HO
F
CN
CN
i
j
16
18
90
90
111–112
35–36
11014a
35–3614a
k
l
18
16
16
93
95
90
Liquid
Liquid
Liquid
CN
CHO
CHO
CN
m
CHO
CHO
CN
CN
n
o
24
16
88
97
Liquid
Liquid
CHO
CN
p
14
90
Liquid
CHO
CN
CHO
CHO
CHO
CN
q
r
15
15
92
94
Liquid
Liquid
CN
CN
S
S
s
t
16
15
91
89
Liquid
77–78
O
N
O
N
CHO
CN
75–7714a
N
N
u
v
14
15
89
92
175–177
181–182
176–17714f
CHO
CHO
CN
CN
N
H
N
H
183–18414e
N
N
H
H
Isolated yields. All products gave satisfactory 1H & 13C NMR, IR, and mass spectral data.
a
Since we proposed that aldehyde gets converted into nitrile via
In conclusion, this work describes an efficient one-step method
for the preparation of nitriles directly from aldehydes using aceto-
hydroxamic acid as a novel reagent, which was reacted with a vari-
ety of aliphatic, aromatic, and heteroaromatic aldehydes under
Bi(OTf)3 catalysis to obtain corresponding nitriles in high yields.
In this study, we screened several acid catalysts and solvents, and
optimized the reaction conditions to obtain nitriles in high yields.
aldoxime in the above mechanism, we verified the scope for con-
version of aldoximes into nitrile using Bi(OTf)3 as the catalyst.
In this study, we prepared a variety of aldoximes using our
method (Scheme 1) and refluxed in acetonitrile in the presence
of Bi(OTf)3 to obtain corresponding nitriles 83–97% as shown in
Table 4.15

3424
M. Sridhar et al. / Tetrahedron Letters 53 (2012) 3421–3424
O
F3C
S
O
N
O
H
Bi(OTf)2
OH
H
R
OH
H
R
Bi(OTf)3
AHA
N
O
R-CN
Bi(OTf)3
2
3
1
R
[Bi(OTf)2OH + TfOH]
Bi(OTf)3 + H2O
Regeneration of the catalyst
Scheme 3. Plausible mechanism for formation of a nitrile from the reaction of an aldehyde with AHA under Bi(OTf)3 catalysis.
Table 4
Formation of a nitrile from an aldoxime under Bi(OTf)3 catalysis
NOH
Bi(OTf)3 (5 mol%)
CH3CN, reflux
R-CN
3
R
H
2
S. No.
Oxime 2
Reaction time (h)
Nitrile 3
% Yielda
3
S. No.
Oxime 2
Reaction time (h)
Nitrile 3
% Yielda
3
1
2
3
4
5
2a
2b
2c
2d
2k
6
8
6
6
8
3a
3b
3c
3d
3k
97
93
93
95
87
6
7
8
9
10
2n
2o
2s
2t
10
8
8
10
8
3n
3o
3s
3t
83
96
86
86
91
2v
3v
a
Isolated yields.
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Acknowledgements
K.K.R.M., R.J., C.R.B., K.R.G. are thankful to the CSIR, New Delhi
and N.C. is thankful to the UGC, New Delhi for the financial support
in the form of research fellowship.
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A typical method for preparation of nitrile from aldehyde using AHA: 4-
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liquid and it was characterized by the following spectral data: 1H NMR
(300 MHz, CDCl3): d = 7.60–7.56 (d, J = 8.5 Hz, 2H), 7.33–7.30 (d, J = 8.7 Hz, 2H),
3.00–2.91 (q, J = 6.9 Hz, 1H), 1.27–1.25 (d, J = 6.8 Hz, 6H); 13C NMR (75 MHz,
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15. A typical method for preparation of a nitrile from an aldoxime using Bi(OTf)3 as the
catalyst: 4-Isopropylbenzaldoxime 2a (0.5 g, 3 mmol), Bi(OTf)3 (60 mg,
0.09 mmol) and acetonitrile (5 ml) were taken into a 25 ml round bottomed
flask fitted with a condenser and CaCl2 guard tube. The mixture was refluxed
and when reaction was complete (GC), the reaction mixture was cooled to
room temperature, concentrated under reduced pressure and the crude
product was purified by normal column chromatography (silica gel 100–200
mesh, EtOAc/hexane = 1:20) to obtain 4-isopropylbenzonitrile 3a (0.43 g, 97%),
which gave the spectral data identical to that given above.