An efficient protocol for the preparation of amides by copper-catalyzed reactions between nitriles and amines in water

Article abstract of DOI:10.1016/j.tetlet.2013.02.058

The reactions between nitriles and amines catalyzed by Cu(OAc)₂ and 2-piperidinecarboxylic acid were carried out in pure water without any other additives. A variety of substituted amides can be obtained in moderate to good yields up to 90%.

Full text of DOI:10.1016/j.tetlet.2013.02.058

Tetrahedron Letters 54 (2013) 2212–2216
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An efficient protocol for the preparation of amides by copper-catalyzed
reactions between nitriles and amines in water
⇑
Xiaoya Li, Zhengkai Li, Hang Deng, Xiangge Zhou
Institute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu 610064, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions between nitriles and amines catalyzed by Cu(OAc)2 and 2-piperidinecarboxylic acid were
carried out in pure water without any other additives. A variety of substituted amides can be obtained
in moderate to good yields up to 90%.
Received 6 November 2012
Revised 26 January 2013
Accepted 19 February 2013
Available online 27 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Catalysis
Water
Nitrile
Amide
Amides represent an important class of compounds found in
numerous bioactive products, such as Sorafenib 1,1 Lipitor 2, and
Vyvanse 3 (Scheme 1), which have been widely used for the treat-
ment of cancer, hypercholesterolemia, and juvenile hyperactivity,
respectively.
out in organic solvents such as DME. In continuation of our work
on copper-catalyzed hydrolysis of nitrile to amide20a and other
coupling reactions in water,20 herein is reported the reaction of
nitrile and amine catalyzed by copper to form amide in water.
The initial studies were focused on the optimization of catalytic
conditions based on phenylacetonitrile 1a and aniline 2a as model
substrates. As shown in Table 1, control experiments indicated the
catalyst to be essential for the reaction, and only a trace of product
was detected in the absence of ligand or metal (Table 1, entries 1
and 2). Seven different ligands L1–L7 were tested, and 2-piperidin-
ecarboxylic acid L7 seemed to be superior to others in yield of 71%
(Table 1, entries 3–9). It is worthy to note that ammonia L5 gave
only 39% yield, which was reported by us to form high catalytic
species with CuI during catalytic nitrile hydrolysis (entry 7).20a
Comparison of different metal sources indicated Cu(OAc)2 to be
better than others including CuCl2, CuO, CuI, NiCl2, and FeCl3 (Table
1, entries 9–14). Reaction temperature was another important
factor to affect the results. For example, when the reaction temper-
ature was decreased from 100 to 80 °C, the yields of the desired
product dropped from 71% to 50% (Table 1, entries 9 and 15).
Meanwhile, when the reaction temperature was increased to
120 °C, the yield of the desired product remained quite stable at
70% (Table 1, entry 16). Finally, the catalyst loading was investi-
gated and 10 mol % was found to be fitful for the catalysis (Table
1, entries 17–19). Thus, the optimal catalytic conditions consist
of Cu(OAc)2 (10 mol %) and L7 (20 mol %) in water (5 mL) at
100 °C for 18 h.
Normally, the classical synthetic protocol to obtain amide is the
substitution reaction between carboxylic acid and amine,2 which
usually results in the formation of ammonium salt and generally
requires a temperature above 160 °C.3 Further studies revealed
that the reaction temperature could be significantly lowered by
using specially designed areneboronic acids4 or heterogeneous sil-
ica catalysts.5 On the other hand, one of the most common meth-
ods for amide synthesis employs activated derivatives of the
carboxylic acid, such as esters6 together with carbodiimides, phos-
phonium, or uronium salts as additives.7 Other general procedures
for amide synthesis include the well-established name reactions
such as Ritter,8 Schmidt,9 Beckmann,10 Ugi,11 Wolff et al.12 Besides,
catalytic procedures have been developed including oxidative ami-
dation of aldehydes13 or alcohols,14 aminocarbonylation of aryl
halides15 or terminal alkynes,16 rearrangement of oximes and
coupling with amines,13a cross coupling of amides with aryl and
alkenyl halides,17 and transamidation of amides with amines.18
Besides these protocols, a less frequently reported synthetic
method is the coupling of nitrile with amine, which has been
reported to be performed in the presence of ruthenium19a or plat-
inum19b catalysts. These reactions were unexceptionally carried
Next, the scope and limitation of this protocol were examined
by using other substrates under the optimized reaction conditions.
⇑
Corresponding author. Fax: +86 2885412904.
E-mail address: zhouxiangge@scu.edu.cn (X. Zhou).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.058

X. Li et al. / Tetrahedron Letters 54 (2013) 2212–2216
2213
HO
COOH
OH
H
N
H
N
F3C
Cl
NH2
NH2
N
O
H
N
O
F
H
N
H
N
O
O
O
1
2
3
Scheme 1. Selected examples of biologically and therapeutically active amides.
Table 2
Cu-catalyzed reactions between phenylacetonitrile and different aminesa
Table 1
Optimization of reaction conditionsa
H
N
Cu(OAc)2 / L7
CN
R'
+
R' NH2
H
N
100 °C, 18h, H2O
O
NH2
CN
10 mol% [M] / L
H2O
+
2
1
3
O
Entry Nitrile
Aniline
Product
Yieldb
(%)
1a
2a
3a
NH2
H
N
CN
COOH
N
H
N
COOH
1
71
86
N
N
O
L1
L2
L3
a
NH2
CN
H
N
NH3.H2O
NH HN
2
N
H
COOH
O
b
L5
L7
L4
NH2
H
N
CN
CN
3
4
83
85
O
O
c
N
N
NH2
H
N
NaO3S
OH HO
SO3Na
L6
d
NH2
NH2
H
CN
CN
CN
Entry
[M]
Ligand
Yieldb (%)
N
5
6
7
56
69
52
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2
—
—
4
Br
Cl
F
O
O
Br
L7
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
Trace
16
31
e
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
CuO
CuI
NiCl2
FeCl3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
H
N
27
22
39c
29d
71
Cl
f
NH2
H
N
55
29
40
23
O
O
O
O
F
g
NH2
NH2
H
CN
CN
CN
N
18
50e
70f
40g
56h
73i
8
71
75
73
h
H
N
9
a
All reactions were carried out by using phenylacetonitrile (1.0 mmol), phenyl-
amine (1.3 mmol), [M] (0.1 mmol), and ligand (0.2 mmol) in H2O (5 mL) at 100 °C
i
for 18 h.
H
b
NH2
Isolated yields.
[Cu]/Ligand = 1:4.
[Cu]/Ligand = 1:1.
N
c
10
d
e
The reaction temperature was 80 °C.
The reaction temperature was 120 °C.
j
f
a
g
Reaction conditions:
1 (1 mmol), 2 (1.3 mmol), Cu(OAc)2 (0.1 mmol) and
2-piperidinecarboxylic acid (0.2 mmol) in H2O (5 mL) at 100 °C for 18 h.
2.5 mol % catalyst.
5 mol % catalyst.
20 mol % catalyst.
h
b
i
Isolated yields.

2214
X. Li et al. / Tetrahedron Letters 54 (2013) 2212–2216
Table 3
Cu-catalyzed coupling reactions between different nitriles and anilinesa
NH2
Cu(OAc)2 / L7
O
R''
R' CN
+
R''
100 °C, 18h, H2O
R'
N
H
1
3
2
Entry
1
Nitrile
Amine
Product
Yieldb
86
%
NH2
H
N
CN
O
k
NH2
NH2
H
N
CN
2
3
83
80
O
l
H
CN
N
O
m
NH2
NH2
NH2
H
N
CN
4
5
82
51
H3CO
Br
O
H3CO
Br
n
H
N
CN
O
o
H
CN
N
6
7
8
9
Cl
64
50
90
67
O
Cl
p
F3C
NH2
NH2
H
CN
F3C
N
O
q
H
CN
N
O
r
H3C
H3C
C
N
NH2
NH2
H
N
H3C
O
s
C
N
H
N
H3C
10
11
12
71
50
53
O
t
O
CN
NH2
N
H
u
CN
NH2
O
N
H
v
a
Reaction conditions: 1 (1 mmol), 2 (1.3 mmol), Cu(OAc)2 (0.1 mmol) and 2-piperidinecarboxylic acid (0.2 mmol) in H2O (5 mL) at 100 °C for 18 h.
Isolated yields.
b
R'R''NH
-NH3
H2O
RCNH2
O
As shown in Table 2, the reactions of phenylacetonitrile (1a) with a
variety of substituted amines could be effectively conducted in
yields ranging from 52% to 86%. Anilines bearing electron donating
groups resulted in better results than those bearing electron with-
drawing groups. For example, 4-methyl and ethylaniline gave the
desired products in 83% and 86% yields, while 4-chloro and fluoro-
aniline resulted in 69% and 52% yields, respectively (Table 2,
Path (A)
Path (B)
RCNR'R''
O
RCN
NH
H2O
R'R''NH
R''
R
N
-NH3
R'
Scheme 2. Proposed pathways for amide formation.

X. Li et al. / Tetrahedron Letters 54 (2013) 2212–2216
2215
NH2
O
Cu(OAc)2 / L7
CN
( C )
( D )
100 °C, 18h, H O
2
trace
H
NH2
N
NH2
Cu(OAc)2 / L7
+
100 °C, 18h, H O
O
2
O
12%
H
N
H
N
NH2
Cu(OAc)2 / L7
100 °C, 18h, DMF
CN
+
H2O
( E )
O
NH
70%
Scheme 3. Control experiments of phenylacetonitrile hydrolysis and transamidation of phenylacetamide with aniline.
entries 3, 4 and 6, 7). Furthermore, the catalytic system could also
Acknowledgments
be applied for aliphatic amine such as cyclohexylamine, propyl-
amine, and ethylamine in moderate yields (Table 2, entries 8, 9,
and 10).
Meanwhile, similar phenomena could also be found in the case
of the reactions between substituted phenylacetonitriles and ani-
line as shown in Table 3, in which electron-donating substituents
also benefited the results.
We appreciate the Natural Science Foundation of China (Nos.
21072132, 21272161), Ministry of Education (NCET-10-0581)
and Sichuan University for financial support.
Supplementary data
Furthermore, the steric hindrance of substituents seemed to
have less effect on the results. For instance, ortho- and para-
methyl aniline gave 86% and 83% yields (Table 2, entries 2 and
3), while ortho- and para-phenylacetonitrile also gave similar
results (Table 3, entries 1 and 2). And the best result was ob-
tained in the reaction between 4-methyl phenylacetonitrile and
2-methyl aniline to give desired product in 90% yield (Table 3,
entry 8). Furthermore, acetonitrile could also be applied for the
reactions in yields around 70% (Table 3, entries 9 and 10). On
the other hand, benzonitrile could also be reacted with 2-methyl
aniline and 4-methyl aniline, affording the corresponding prod-
ucts in 50% and 53% yields, respectively (Table 3, entries 11
and 12).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
058.
References and notes
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The catalytic pathway was then studied,19 and two possible
routes might exist as shown in Scheme 2. In path A, nitrile is firstly
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B might be the true reaction path,
although the direct isolation of amidine failed due to its instabil-
ity in water.22 Actually, amidine was detected in the reaction
between phenylacetonitrile and aniline in DMF, and was hydro-
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(Scheme 3E).
In conclusion, an efficient copper-catalyzed protocol for the for-
mation of amide form nitrile and amine has been disclosed.23 It
exhibited several advantages: copper as catalyst instead of expen-
sive metals; water as reaction media instead of organic solvents;
neutral reaction conditions without any other additives. This ap-
proach represents an important complement to the synthesis of
substituted amides and exhibits potential usage in industry. Fur-
ther work on aqueous catalysis is currently underway in this
laboratory.

2216
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23. General experimental procedure: nitrile (1 mmol), amine (1.3 mmol), Cu(OAc)2
(0.1 mmol), and the ligand 2-piperidinecarboxylic acid (0.2 mmol) in water
(5 mL) were put into a teflon septum screw-capped tube. The reaction mixture
was stirred at 100 °C for 18 h without an inert gas atmosphere, and then cooled
to room temperature and extracted with dichloromethane. The organic layer
was dried over Na2SO4 and the solvent was removed under reduced pressure.
The residue was purified by silica-gel column chromatography to afford the
corresponding product.