a
Table 3 The catalytic behaviour of the recycling filtrates
b
Yield (%) for each
cycle
Entry
Nitrile
K
2
CO
3
(mol%)
Amide
1st
2nd
3rd
1
2
1a
1o
5
50
2a
2o
85
89
84
90
82
83
a
b
Microwave-assisted hydration with 1 mmol scale. Isolated yield.
Fig. 1 A proposal mechanism for hydration of organonitriles in water.
extraction by EtOAc, less than 10% yield of p-chlorobenzoic
acid was isolated, which suggested a part of p-chlorobenzamide
2a was further converted to acid under the basic conditions after
a long time of microwave irradiation. Due to only catalytic
were usually less-active substrates than their m- and p-analogues,
however, sterically more-demanding substrates like o-chloroben-
zonitrile 1c and o-tolunitrile 1i afford better results than their
p-analogues (1a and 1k). The substrates bearing electron-with-
drawing groups were more reactive than those with electron-
donating groups; for most electron-donating substituted sub-
strates, 20 mol% K CO was required to achieve satisfied con-
amount of K CO being applied and high solubility of the corre-
2 3
sponding potassium benzoate in water, a satisfactory isolated
yield of amides was still afforded by simply filtration even after
the 3rd recycle, which further indicated the protocol practicabil-
ity and efficiency. In addition, with this negative charge mechan-
ism, it is easy for us to understand that the organonitriles with
electron-withdrawing groups show better reactivity than the elec-
tron-donating analogues in Table 2.
2
3
versions and yields (Table 2, entries 8–13). With 50 mol%
K CO , sterically more demanding substrates like 1-naphthoni-
2
3
trile 1o were also tolerated (Table 2, entry 14). To our delight,
di-ortho-substituted benzonitriles converted to the corresponding
amides 2p and 2q even with 20 mol% K CO , indicating a
In summary, K CO can act as an efficient catalyst for the
2 3
2
3
broad substrate scope of the protocol (Table 2, entries 15 and
6). In addition, our protocol tolerated heterocyclic substrates
such as 3-thiophenecarbonitrile 1r and 4-cyanopyridine 1s
Table 2, entries 17 and 18). For less soluble organonitriles,
additional organic solvents such as i-PrOH or EtOH have to be
involved to increase their solubility in water. With the help of
i-PrOH, double hydration of dinitrile underwent conversion to
diamides 2t within 15 minutes (76%, Table 2, entry 19). Under
similar conditions, the protocol can successfully be extended for
the hydration of 2-phenylacetonitrile 1u and 2-(naphthalen-1-yl)
acetonitrile 1v to the corresponding amides 2u and 2v in 72%
and 94% yields, respectively (Table 2, entries 20 and 21). Cinna-
mamide 2w was readily obtained with similar procedure in a
hydration of organonitriles in aqueous conditions assisted by
microwave irradiation, which represents an inexpensive, practi-
cal, atom-economical, and straightforward transition metal-free
protocol to various amides. Besides various mono-, di- and even
tri-substituted benzonitriles, heterocyclic and aliphatic substrates
were also facilely converted to the corresponding amides in high
selectivity, which demonstrated the broad substrate scope of the
newly developed catalytic hydration system. In addition, a
simple product separation procedure and recyclability of the
filtrate as the catalyst highlight the applicability of the protocol.
Financial support from National Science Foundation of China
(No. 20902001 and 21172045) and Shanghai Leading Academic
Discipline Project (B108) is gratefully acknowledged.
1
(
9
2% isolated yield (Table 2, entry 22), and a small amount
EtOH was required in this case. Furthermore, hydration of ali-
phatic nitriles like octanenitrile 1x resulted in a 67% yield for 2x
with 25 mol% K CO , even when prolonging the reaction time
Notes and references
2
3
1
(a) The Amide Linkage: Structural Significance in Chemistry, Biochemis-
try and Materials Science, ed. A. Greenberg, C. M. Breneman and
J. F. Liebman, Wiley, New York, 2002; (b) The Chemistry of Amides, ed.
J. Zabicky, Wiley-Interscience, New York, 1970.
to 40 minutes in the aqueous i-PrOH (Table 2, entry 23).
As a practical protocol with broad substrate scope, the possi-
bility of catalyst recycling is considered as another important
issue. With 5 mol% K CO , almost constant isolated yields for
2 (a) S. Rivara, A. Lodola, M. Mor, A. Bedini, G. Spadoni, V. Lucini,
M. Pannacci, F. Fraschini, F. Scaglione, R. O. Sanchez, G. Gobbi and
G. Tarzia, J. Med. Chem., 2007, 50, 6618; (b) A. Bhattacharya, B.
P. Scott, N. Nasser, H. Ao, M. P. Maher, A. E. Dubin, D. M. Swanson, N.
P. Shankley, A. D. Wickenden and S. R. Chaplan, J. Pharmacol. Exp.
Ther., 2007, 323, 665.
2
3
2
a were obtained by the hydration with the first three recycling
filtrates (82–85%, Table 3, entry 1). Only trace amide 2a along
with a big amount of starting material was obtained with the 4th
filtrate. Similarly, the filtrate can also be recycled for another
three times in the hydration of 1o with 50 mol% K CO ;
3
Kirk-Othmer Encyclopedia of Chemical Technology, ed. I. Johansson,
Wiley, New York, 5th edn, 2004, vol. 2.
2
3
8
2–90% yields were observed (Table 3, entry 2). The pH value
4
(a) R. Opsahl, in Encyclopedia of Chemical Technology, ed.
J. I. Kroschwitz, Wiley, New York, 1991, vol. 2, p. 346;
of the 3rd filtrate of hydration of 1a is ca. 7.5, which is much
(b) K. Ingvosersen and J. Kamphuis, in Enzyme Catalysis in Organic
lower than the pH value of solution of 5 mol% K CO in water
2
3
−
Synthesis, ed. K. Drauz and H. Waldmann, VCH, Weinheim, 1995, vol.
(
pH = 8.5) and suggests that OH plays a crucial role in the
1.
hydration of organonitriles. Therefore, a possible weak base cata-
lytic hydration mechanism is proposed in Fig. 1. However, if the
catalytic route went along this mechanism, theoretically the
filtrate should be recycled more than three times. By carefully
acidification of the 3rd filtrate of the reaction mixture of 1a and
5 S. Sato, R. Takahashi, T. Sodesawa, K. Matsumoto and Y. Kamimura, J.
Catal., 1999, 184, 180.
6
(a) T. J. Ahmed, S. M. M. Knapp and D. R. Tyler, Coord. Chem. Rev.,
2
2
011, 255, 949; (b) V. Y. Kukushkin and A. J. L. Pombeiro, Chem. Rev.,
002, 102, 1771; (c) P. K. Mascharak, Coord. Chem. Rev., 2002, 225,
201.
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