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.