Copper(II)-catalyzed hydration of nitriles with the aid of acetaldoxime

Article abstract of DOI:10.1016/j.tetlet.2011.11.075

An efficient method for the selective hydration of nitrile to amide by employing inexpensive copper salt catalyst and commercially available acetaldoxime in environmentally friendly water is described. Under this protocol, nitriles including aromatic nitriles, heterocyclic nitriles and aliphatic nitriles were converted into the corresponding amides in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.11.075

Tetrahedron Letters 53 (2012) 449–452
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(II)-catalyzed hydration of nitriles with the aid of acetaldoxime
⇑
Xiao-Yun Ma, Ying He, Yu-Lin Hu, Ming Lu
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the selective hydration of nitrile to amide by employing inexpensive copper salt
catalyst and commercially available acetaldoxime in environmentally friendly water is described. Under
this protocol, nitriles including aromatic nitriles, heterocyclic nitriles and aliphatic nitriles were con-
verted into the corresponding amides in good to excellent yields.
Received 20 September 2011
Revised 7 November 2011
Accepted 15 November 2011
Available online 19 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Hydration
Nitriles
Amides
Copper oxide
Acetaldoxime
Hydration of nitriles to the corresponding amides is an impor-
tant transformation from both academic and industrial points of
view.1 Classically the reaction was carried out in the presence of
a strong acid or base catalyst, methods which usually cause over-
hydrolysis of the amides into the corresponding carboxylic acids,
system, the reaction yield was increased significantly. At the same
time, we have also noticed that the hydration of nitriles promoted
by the combination of oxime and metal compounds, such as
9
10
11
RhCl(PPh
3
)
3
, Pd(OAc)
2
,
3
InCl ,
etc. have been reported. In these
literatures, the hydration of nitrile to amide was catalyzed by
metal compounds with an excess of oxime (2–5 equiv) and the
reactions were carried out in organic media. Compared with these
methods, our method for the conversion of nitriles into their corre-
sponding amides is relatively simple and environmentally friendly.
For instance, 100% of benzonitrile could be converted into benzam-
ide after 12 h of reflux in water with the aid of 0.1 equiv copper
oxide and 1.5 equiv acetaldoxime. In addition, to our knowledge
an efficient Cu-catalyzed hydration of nitriles to amides with the
aid of oxime has not been reported.
To further understand the roles of copper salt and acetaldoxime,
a comprehensive study of the hydrolysis of nitriles was carried out.
In the first stage of the study we focused on the hydrolysis of
benzonitrile with the aid of copper salt and acetaldoxime. We
examined the effects of copper salt, acetaldoxime, reaction temper-
atures, and reaction times on the yields of the hydration reaction.
The detailed results are listed in Table 1.
As shown in Table 1, we found that benzonitrile was easily
hydrated to benzamide by the action of copper salt and acet-
aldoxime in water. The yield of benzamide is very low when acet-
aldoxime was used alone (Table 1, entry 1). Similarly, the use of
copper salt alone resulted in no product (Table 1, entry 2). In this
reaction, various copper salts listed in Table 1 appear to be efficient
to catalyze the reaction (Table 1, entries 3 and 8–11), and it was
shown that copper oxide (CuO) and copper(II) chloride dihydrate
2
a faster reaction specially under basic conditions. Although under
acidic conditions it is possible to stop the process at the amide
stage, in these cases it is necessary to control carefully the temper-
ature and stoichiometry employed in order to avoid the formation
3
of polymeric side products. It is also important to note that, from
an industrial perspective, the final neutralization step required
either in the acid- or base-catalyzed reactions leads to extensive
salt formation with inconvenient product contamination and pol-
4
lution effects. To overcome these limitations, several protocols
using enzymes, heterogeneous catalysts,6 and transition-metal
5
7
complexes have been developed. During our recent studies of
conversion of nitrile to amide, we disclosed an improved method
for the preparation of amides from nitriles by the use of N,N-disub-
stituted hydroxylamine.8 Under this protocol, nitriles were
smoothly hydrated to amides using water as a reaction medium
at refluxing temperature. In view of the similar molecular structure
of N,N-disubstituted hydroxylamine and oxime, we decided to
explore the possibility that acetaldoxime could be used in place
of N,N-diethylhydroxylamine in this reaction. As expected, acet-
aldoxime can promote the nitrile hydration. However, the conver-
sion rate was found to be relatively lower, especially when nitrile
has no electron-withdrawing substituents. To our surprise, when
a catalytic amount of copper oxide was added into the reaction
(
CuCl
2
Á2H
2
O) were much more efficient than copper sulfate
Á5H O), cupric acetate (Cu(OAc) ) and cupric
⇑
Corresponding author. Tel.: +86 025 84315514; fax: +86 025 84315030.
E-mail address: lumingnjust@163.com (M. Lu).
pentahydrate (CuSO
4
2
2
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.075

4
50
X.-Y. Ma et al. / Tetrahedron Letters 53 (2012) 449–452
Table 1
Screen of reaction conditionsa
Table 2
a
Hydration of various nitriles using copper oxide and acetaldoxime
Entry Conditions
Yieldb
Yieldb (%)
Entry Nitrile
Amide
Time (h)
10
(
%)
CN
Cl
O
1
2
3
4
5
6
7
8
9
Acetaldoxime (1.0 equiv), H
CuO (10 mol %), H O, reflux, 16 h
CuO (10 mol %), acetaldoxime (1.0 equiv), H
CuO (10 mol %), acetaldoxime (1.0 equiv), H
CuO (5 mol %), acetaldoxime (1.0 equiv), H
2
O, reflux, 16 h
5
0
2
NH2
O
1
94
2
O, reflux, 16 h
O, reflux, 8 h
O, reflux, 16 h
92
69
75
41
79
Cl
2
2
CN
CuO (10 mol %), acetaldoxime (1.0 equiv), H
CuO (10 mol %), acetaldoxime (1.0 equiv), H
2
O, rt, 24 h
2
NH2
10
12
12
95
93
92
2
O, 50 °C, 16 h
Cl
CuBr
CuCl
6 h
CuSO
6 h
Cu(OAc)
6 h
2
(10 mol %), acetaldoxime (1.0 equiv), H
2
O, reflux, 16 h 78
Cl
2
Á2H O (10 mol %), acetaldoxime (1.0 equiv), H
2
2
O, reflux, 91
H3C
CN
O
1
1
0
1
4
Á5H
2
O (10 mol %), acetaldoxime (1.0 equiv), H
2
O, reflux, 82
H3C
3
NH2
1
1
2
(10 mol %), acetaldoxime (1.0 equiv), H O, reflux,
2
86
1
CN
O
1
1
2
3
CuO (10 mol %), acetaldoxime (0.5 equiv), H
CuO (10 mol %), acetaldoxime (1.5 equiv), H
2
O, reflux, 24 h
O, reflux, 12 h
45
94
4
5
NH2
CH3
2
CH3
a
Reaction conditions: benzonitrile (2.5 mmol), H
Isolated yield.
2
O (10 mL).
b
CN
O
NH2
90c
88c
95
14
14
12
H CO
3
H CO
3
2
bromide (CuBr ) to perform the hydrolysis reaction. At the same
time, we have also compared the catalytic activity of copper oxide
Á2H
CuO) and copper(II) chloride dihydrate (CuCl O). Although
Br
CN
NH2
CN
O
Br
(
2
2
6
NH2
copper(II) chloride dihydrate has superior water-soluble property,
copper oxide exhibits better catalytic performance during the
hydrolysis of nitrile bearing electron-donating groups. In addition,
we found that the conversion and reaction rate were improved sig-
nificantly by increasing the reaction temperature or the reaction
time (Table 1, entries 3, 4, 6, and 7). When we reduced the amounts
of CuO to 5 mol % (Table 1, entry 5), the yield was slightly reduced
NH2
O
7
NH2
HO
HO
CN
O
8
NH2
10
2
95
97
95
95
96
(
75%). When we reduced the amounts of acetaldoxime to 0.5 equiv,
2
O N
the yield was significantly reduced (Table 1, entry 12). Conversely,
when we increased the amounts of acetaldoxime to 1.5 equiv, the
reaction time was reduced from 16 to 12 h and the yield was
slightly increased (Table 1, entry 13). It should be noted that no
benzoic acid was detected in the reaction mixture at high
temperatures.
As show in scheme 1, we have used benzaldoxime in the place
of acetaldoxime to carry out the hydration of nitriles, surprisingly,
most of benzaldoxime reacted with CuO to produce benzonitrile
and benzamide, and a few isonicotinamide was obtained in this
reaction. On the basis of the above results, we can conclude that
both extending of reaction time and increasing the amounts of
acetaldoxime will improve the yield of the product and using
2
O N
CN
CN
O
9
N
NH2
N
O
10
NH2
10
10
10
N
N
CN
O
11
N
NH2
NH2
N
CN
Cl
O
0
.1 equiv CuO and 1.5 equiv acetaldoxime in water at refluxing
temperature is the optimality conditions for benzonitrile
hydrolysis.
This protocol of hydration was subsequently applied to various
aromatic nitriles, heterocyclic nitriles and aliphatic nitriles. As
12
N
N
Cl
Cl
Cl
Cl
Cl
13
2
97
NH2
N
CN
N
O
NH2
CN
1
4
5
12
12
89d
90
O
1
3
CH (CH
2
)
10CN
3 2 2
CH (CH )10CONH
a
Reaction conditions: nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper salt
catalyst (0.25 mmol), H
2
O (10 mL), reflux.
b
Isolated yield.
c
5
mmol acetaldoxime were used.
d
CuCl O was used in place of CuO.
2
Á2H
2
Scheme 1. Use of benzaldoxime in place of acetaldoxime in the hydration reaction.

X.-Y. Ma et al. / Tetrahedron Letters 53 (2012) 449–452
451
shown in Table 2,12 various nitriles including aromatic nitriles hav-
ing electron-donating or electron-withdrawing substituents (Table
, entries 1–8), heterocyclic nitriles (Table 2, entries 9–13), and ali-
2
phatic nitriles (Table 2, entries 14 and 15) were converted into the
corresponding amides in good to excellent yields. Substrates bear-
ing strong electron-donating groups (Table 2, entries 5 and 6) ren-
der the nitrile carbon less electrophilic to nucleophilic attack by
acetaldoxime and exhibited slightly lower conversions. When the
amount of acetaldoxime was increased (from 1.5 to 2.0 equiv),
yield of amides was consequently improved. In contrast, the hydra-
tion of nitriles with an electron-withdrawing group proceeds more
effectively (Table 2, entries 1, 2 and 8–13). To our surprise, picoli-
nonitrile (Table 2, entry 9) and 3,4-dichloropicolinonitrile (Table 2,
entry 13) show high reactivity, both picolinonitrile and 3,4-dichlo-
ropicolinonitrile were hydrated to the corresponding amides with
complete conversion by employing 1 equiv acetaldoxime after a
relatively short reaction time of 2 h. We thought that there was a
neighboring group participation in reaction course, the nitrogen
lone pair in pyridine derivatives participated in hydrolyses of ni-
triles and then remarkably accelerated the reaction rate. In the case
of aliphatic nitriles the hydration process was similar to aromatic
nitriles and aliphatic nitriles (Table 2, entries 14 and 15) was
smoothly hydrated to give the corresponding amides in good yields
under the employed reaction conditions. In addition, ortho substit-
uents have only slight effects on nitrile hydrolysis due to the tiny
molecular volume of acetaldoxime (Table 2, entries 1, 4 and 6).
Scheme 2. Proposed mechanism of nitrile hydration via CuO and acetaldoxime.
In the course of the study on hydration of nitriles with electron-
withdrawing groups to the corresponding amides, we found that
the hydrolysis of these nitriles can be achieved in good yields at
1
3
room temperature. As shown in Table 3, treatment of nitriles
with 0.1 equiv copper oxide and 1.5 equiv acetaldoxime in a mixed
solvent of methanol and water at room temperature for 48 h gave
amides in good yield. Methanol was used as a co-solvent in the
reaction, only water used as a reaction medium gives low yield (Ta-
ble 3, entry 5). In addition, we found that picolinamide and 3,4-
dichloropicolinamide did not show high reactivity at room temper-
ature. It is worth noting that increasing the electron-withdrawing
ability of the nitrile enhances the rate of the reaction and improves
the rate of conversion.
Table 3
a
Hydration of nitriles at room temperature
As can be seen from Table 1, we reduced the amounts of acet-
aldoxime from 1 to 0.5 equiv, the yield of the amide was signifi-
cantly reduced from 92% to 45% (Table 1, entry 12). Thus, we are
certain that acetaldoxime did not regenerate in this reaction and
acetaldoxime is not a catalyst for the amide formation. Therefore,
we thought that the reaction mechanism is likely to be similar to
the mechanism reported in literature. The mechanistic rationali-
zation is suggested to account for the formation of amides accord-
ing to Scheme 2.
Initially, coordination of benzonitrile to copper oxide results in
an enhanced electrophilicity of the nitrile carbon, then the nucleo-
philic addition of acetaldoxime yields the intermediate I and the
following disruption of the intermediate I into benzamide and ace-
tonitrile proceeds in a concerted manner.
In conclusion, we disclosed an efficient method for the selective
hydration of nitrile to amide using inexpensive copper salt catalyst
and commercially available acetaldoxime in an environmentally
friendly water. Under this protocol, nitriles including aromatic ni-
triles, heterocyclic nitriles and aliphatic nitriles were converted
into the corresponding amides in good to excellent yields. It is
worthwhile to note that nitriles having electron-withdrawing
groups could be converted into the corresponding amides in good
yields at room temperature. In addition, the further search for sub-
strate generality and improvement of the catalyst efficiency is now
underway in our laboratory.
Entry
1
Nitrile
Amide
Time (h)
48
Yieldb (%)
75
CN
O
1
1
NH2
Cl
Cl
CN
O
2
3
4
5
6
NH2
48
48
48
48
48
76
O2N
O2N
CN
CN
O
O
N
NH2
NH2
84
N
85
N
N
N
CN
O
87 (56)c
NH2
NH2
N
CN
Cl
O
88
N
N
Cl
Cl
Cl
Acknowledgment
Cl
Cl
Financial support from the National Natural Science Foundation
of China-NSAF (Grant No. 11076017) is gratefully acknowledged.
7
48
88
NH2
N
CN
N
O
Supplementary data
a
Reaction conditions: nitrile (2.5 mmol), acetaldoxime (3.75 mmol), CuO
0.25 mmol), H O (5 mL), CH OH (5 mL), rt.
Isolated yield.
(
2
3
b
Supplementary data (detailed experimental procedures and
spectroscopic data for some compounds) associated with this
c
Methanol was not used as a co-solvent.

4
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X.-Y. Ma et al. / Tetrahedron Letters 53 (2012) 449–452
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.11.075.
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.
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2
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.
.
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1
´
´
´
7
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