A mild hydration of nitriles catalysed by copper(ii) acetate

Article abstract of DOI:10.1039/c5cc08714g

A simple, mild and general procedure for the hydration of nitriles to amides using copper as catalyst and promoted by N,N-diethylhydroxylamine is described. The reaction can be conducted in water at low temperature in short reaction times. This new procedure allows amides to be obtained from a wide range of substrates in excellent yields.

Full text of DOI:10.1039/c5cc08714g

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COMMUNICATION
A Mild Hydration of Nitriles Catalysed by Copper(II) Acetate
Patricia Marcé,a James Lynch,a A. John Blackerb and Jonathan M. J. Williamsa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple, mild and general procedure for the hydration of the in situ formation of a nitrile by dehydration of the
nitriles to amides using copper as catalyst and promoted by aldoxime. In a second step this nitrile is transformed into an
N,N-diethylhydroxylamine is described. The reaction can be amide by reaction with another molecule of aldoxime.1b,2,11,12
conducted in water at low temperature in short reaction times. Based on these results and our earlier work using
This new procedure allows amides to be obtained from a wide hydroxylamine hydrochloride to catalyse transamidation,2 as
range of substrates in excellent yields.
well as the conversion of nitriles into secondary amides using
hydroxylamine,13 we decided to explore this reactivity for the
synthesis of primary amides.
The availability of efficient processes to obtain amides is of
great interest due to their many applications in organic
chemistry. Amides can be found in a large variety of drugs,
fabrics, fertilizers, plastics and lubricants. Additionally, amides
are key intermediates in organic synthesis. Among all the
methods reported for the synthesis of amides,1,2 hydration of
nitriles has become one of the most widely used methods to
obtain primary amides in both, academia and industry.3
Conventional procedures involve the use of strong acids and
bases which can cause the formation of by-products in
sensitive substrates along with the formation of carboxylic
acids.4 In the last decade an important advance/progress of
this transformation has been achieved. In that sense, the use
of metal catalysts such as Ru,5 Au,6 Rh,7 Mn8 have been crucial
for the development of milder and more efficient
transformations.9 Recent work has reported the use of metal
nanoparticles for the hydration of nitriles.10 Despite all the
efforts, most of the methods reported to date require high
temperatures, long reaction times, large excess of reagents or
the use of expensive catalysts. We therefore decided to
explore a new methodology to obtain amides from nitriles
which would require milder conditions than those previously
reported.
Table 1 Optimization of the Hydration of Nitriles
OH
O
N
Catalyst
Additive
CN
NH2
NH2
+
MeO
H2O, T, time
MeO
MeO
1
2
3
Entry
Additive
NH2OH
Catalyst
T (oC)
Time (h)
Conv (%)a
100
1
--
r.t.
24
(16 equiv.)
NH2OH
2:3 1:1
100
[Ir Cp*I2]2
(1 mol%)
Cu(OAc)2
(2 mol%)
Zn(OAc)2
(5 mol%)
2
3
4
5
6
7
8
9
r.t.
r.t.
r.t.
25
35
35
35
35
24
24
24
24
24
24
3
(16 equiv.)
NH2OH
2:3 1:1
100
(16 equiv.)
NH2OH
2:3 1:1
100
(16 equiv.)
NEt2OH
2:3 1:1
--
--
--
82
(10 equiv.)
NEt2OH
100
100
100
100
(10 equiv.)
NEt2OH
(3 equiv.)
NEt2OH
[Ir Cp*I2]2
(2 mol%)
Cu(OAc)2
(2 mol%)
Mechanistic studies carried out in the transformation of
aldoximes to amides have shown that the first step involves
(3 equiv.)
NEt2OH
3
(3 equiv.)
a Conversions were determined by analysis of the 1H-NMR of the reaction mixture
In a first approach, p-methoxybenzonitrile (1) was treated with
16 equivalents of hydroxylamine. The reaction proceeded at
room temperature and no starting material was observed after
24 h. Analysis of the reaction crude by 1H-NMR showed the
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Table 2. Scope of the hydration of nitrilesa
formation of two products in the same ratio which were
assigned to the desired amide ( ) and the amidoxime ( ) (table
2
3
1, entry 1).14 In order to reduce the amount of amidoxime
different catalysts were tested but none of them seemed to
play any role in the formation of the by-product (table 1,
entries 2 - 4, see ESI).
Several reaction conditions were tested to transform the
amidoxime (3) into the desired amide (2). Treatment of the
reaction mixture with HCl and NaOH provided different ratios
of products (see ESI). The addition of NaOH after 24 h to the
2, 97%
6, 92%
4, 98%
7, 93%
5, 98%
8, 96%
reaction mixture led to the formation of
2 as the sole product.
Although the hydrolysis of the amidoxime could be
accomplished, the use of NaOH increased the harshness and
the number of steps of the reaction making this approach
impractical for synthetic purposes. In order to overcome this
problem, the use of other additives was further investigated.
The synthesis and the mechanistic study of the formation of
amidoximes suggests that it would be possible to regulate the
formation of amidoxime by using N,N-disubstituted
9, 81%
10, 93%
13, 92%
11, 94%
14, 85%
hydroxylamine.14 Indeed the treatment of
equivalents of NEt2OH at room temperature provided the
desired amide in 82% conversion (table 1, entry 5).
1 with 10
2
Increasing the temperature to 35 oC afforded the amide in
100% conversion (table 1, entry 6). Further optimisation of the
reaction conditions allowed us to reduce the amount of
NEt2OH to three equivalents. The introduction of a Lewis acid
such as [IrCp*I2]2 permitted the decrease in reaction times to 3
h (see ESI). Interestingly, the replacement of [IrCp*I2]2 with
Cu(OAc)2 did not show any drop in the reaction conversions.
The use of Cu(OAc)2 makes this reaction more sustainable and
economical. To the best of our knowledge these are the
mildest reactions conditions reported until now for the
hydrolysis of nitriles.15,16,17
12, 95%
Cl
O
NH2
Cl
15, 50%
16, 92%
19, 78%
22, 96%
17, 79%
20, 85%
23, 98%
O
NH2
18, 80%
With the optimal conditions in hand the scope of the reaction
was subjected to study. We were pleased to find that a broad
range of nitriles could be hydrolysed under these reaction
conditions (table 2).
21, 88%
Electron-withdrawing and electron-donating groups in the
ortho, meta and para positions are very well tolerated as well
as the use of aliphatic nitriles. Vinylic nitriles and nitriles
containing heteroaromatic groups such as 2-furonitriles and 2-
24, 80%
a Isolated yields
thiophenecarbonitriles
as
well
as
the
use
of
ethylphenylcyanoacetate gave the corresponding amides in
excellent isolated yields. The general applicability of our
hydrolysis conditions was proved in a variety of substrates
affording the corresponding amides in excellent yields,
showing the potential of this reaction.
The most accepted mechanism for the hydration of nitriles
involves the coordination of the nitrile to the metal centre.
Through this coordination, the CN group increases its
electrophilicity being more susceptible to nucleophilic attack
by water.18 The subsequent rearrangement of the
corresponding iminolate species leads to the formation of the
desired amide (scheme 2).
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Notes and references
1
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Scheme 2 Plausible mechanisms for the hydration of nitriles
5804; (f) H. Fujiwara, Y. Ogasawara, K. Yamaguchi and N.
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When NEt2OH is employed, the oxygen could act as
nucleophile and in subsequent steps the reaction could follow
a radical pathway15,16 or a rearrangement facilitated by the
metal (scheme 2).2
2
3
C. L. Allen, R. Lawrence, L. Emmett and J. M. J. Williams, Adv.
Synth. Catal., 2011, 353, 3262
Intrigued by the nature of this transformation NMR
experiments were carried out to attempt to detect
intermediates which could give some information about the
mechanism. Unfortunately, only the rapid appearance of the
final amide was observed (see ESI). In order to study if water
was indeed acting as nucleophile, the reaction was performed
in the presence of H2O18 (scheme 3).
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Scheme 3 Hydration of benzonitrile using H2O18
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The analysis of the reaction crude by mass spectrometry did
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ESI). This evidence indicates that in the hydration pathway
water is not acting as nucleophile. These results will support
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or rearrangement pathway facilitated by the Lewis acid.2,14
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In summary, we report a new methodology for the hydration
of nitriles. The use of copper as Lewis acid allows the synthesis
of amides in water as a solvent at low temperatures and short
reaction times. The amides were obtained in excellent yields
for a broad range of nitriles making this methodology very
efficient and general, solving the main problems associated to
the methods reported until now.
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Acknowledgements
5
We are grateful to the EPSRC for funding through the UK
Catalysis Hub.
3
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