4
Facile and Highly Selective Conversion of
Nitriles to Amides via Indirect
based on transition metals such as Co, Pd, Rh, etc. and
heterogeneous catalysts such as KF/Al , resins, MnO
, Na/Fluorapatite, etc.5 have been reported for
O
2 3
2
/
,6
SiO
2
Acid-Catalyzed Hydration Using TFA or
selective conversion of nitriles to amides. Indeed, enzyme-
AcOH-H
2
SO
4
mediated hydrations are also now known.7
In the course of our continuing studies on supra-
molecular self-assembly, we needed to synthesize steri-
Jarugu Narasimha Moorthy* and Nidhi Singhal
8
cally hindered and strategically designed tetraamides
starting from the precursor tetranitrile compounds. The
precipitation of partially converted amides or lack of
reaction using several of the procedures led us to explore
new protocols. Herein, we wish to report that the reagent
Department of Chemistry, Indian Institute of Technology,
Kanpur 208 016, India
system consisting of a CF
3
2 4
COOH-H SO mixture ac-
Received October 6, 2004
complishes the conversion of nitriles to amides in a highly
selective manner, via an indirect hydration mechanism,
in excellent isolated yields (eq 1). In addition to the
simplicity of the procedure, the conversions are found to
occur in significantly short durations.
Both aromatic and aliphatic simple nitrile compounds
were found to react in TFA-H SO medium at room
2 4
Both aliphatic and aromatic nitriles are conveniently and
selectively converted in a single step, via an indirect acid-
catalyzed hydration, into the corresponding amides in 1-8
h using a TFA-H2SO4 mixture as a reagent system.
Although the same reagent did not work for the sterically
hindered nitriles such as mesitonitrile, the transformation
could be accomplished by changing TFA to AcOH at higher
temperatures (>90 °C).
temperature to afford the amides in 70 to >95% isolated
yields (Table 1). The procedure involved simple stirring
of 1-2 mmol of the substrate in a mixture of TFA-H2-
SO for 4-8 h at room temperature, followed by quench-
4
ing of the reaction mixture with ice-cold water. In several
cases, the insoluble amides were isolated by simple
filtration (entries 2, 4-8, and 12). In an attempt to find
the best reaction conditions, a systematic study was
carried out on p-bromobenzonitrile as a representative
case by varying the amount of the mineral acid and the
reaction temperature. As can be seen from Table 1 (entry
The hydration of nitriles constitutes a very important
1
transformation to access amides, whose applications lie
2
), the reaction occurred sluggishly (20 h) at room
at the core of organic synthesis as well as chemical
industry as excellent intermediates and raw materials.
temperature (30 °C) with TFA/H SO 10:1 (v/v) combina-
2
4
1,2
tion, whereas it went to completion within 5-6 h with
1:0.25 equiv; indeed, the reaction was found to be much
Traditionally, the hydration is accomplished by acid or
1
,3
base catalysis. Unfortunately, each of these protocols
is associated with certain debilitating disadvantages that
include (a) formation of unwanted acids as side products,
(
4) (a) Kim, J. H.; Britten, J.; Chin, J. J. Am. Chem. Soc. 1993, 115,
618. (b) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657.
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3
(
(
b) high reaction temperatures, and (c) the failure, most
importantly, with substrates that contain more than two
nitrile groups. Thus, reagent systems that perform the
selective conversion of nitriles to amides still continue
to be hot pursuits. A variety of homogeneous catalysts
4
1, 4845. (e) Murahashi, S.-I.; Sasao, S.; Saito, E.; Naota, T. J. Org.
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M.-H.; Huang, H.-W.; Hu, C.-J. Synthesis 1988, 715. (c) Breuilles, P.;
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A.; Sebti, S.; Macquarrie, D. J. Tetrahedron Lett. 2003, 44, 4031.
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*
To whom correspondence should be addressed. Tel: +91-512-
597438; Fax: +91-512-2597436.
1) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd
2
(
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The Chemistry of Amides: Synthesis of Amides; Zabicky, J., Ed.;
Interscience: New York, 1970; p 73. (c) Schaefer, F. C. In The
Chemistry of the Cyano Group: Nitrile Reactivity; Rappoport, Z., Ed.;
Inter Science: New York, 1970; p 239.
(
2) (a) Sydner, H. R.; Elston, C. T. J. Am. Chem. Soc. 1954, 76, 3039.
(
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(
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1
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10.1021/jo048240a CCC: $30.25 © 2005 American Chemical Society
1926
J. Org. Chem. 2005, 70, 1926-1929
Published on Web 01/29/2005