Direct preparation of primary amides from carboxylic acids and urea using imidazole under microwave irradiation

Article abstract of DOI:10.1016/S0040-4039(03)01866-5

A very simple and efficient solvent-free procedure for the preparation of primary amides is described from carboxylic acids and urea using imidazole under microwave irradiation. Various aliphatic and aromatic primary amides were prepared in good yields by this direct amidation method.

Full text of DOI:10.1016/S0040-4039(03)01866-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7325–7328
Direct preparation of primary amides from carboxylic acids and
urea using imidazole under microwave irradiation
Ali Khalafi-Nezhad,* Babak Mokhtari and Mohammad Navid Soltani Rad
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, Iran
Received 24 June 2003; revised 20 July 2003; accepted 31 July 2003
Abstract—A very simple and efficient solvent-free procedure for the preparation of primary amides is described from carboxylic
acids and urea using imidazole under microwave irradiation. Various aliphatic and aromatic primary amides were prepared in
good yields by this direct amidation method.
©
2003 Elsevier Ltd. All rights reserved.
The preparation of primary amides from the corre-
sponding carboxylic acids is an important and well-
amides under microwave assisted solvent free condi-
17–19
tions.
However, there have been no reports of the
1,2
known transformation in organic synthesis.
In
direct synthesis of primary amides from carboxylic
acids by this means, although primary amides have
been prepared by hydrolysis of the corresponding
nitriles under microwave irradiation in the presence or
general, the formation of carboxamides from carboxylic
acids requires activation of the carboxyl group. Car-
boxylic acid activation can be achieved by conversion
of the carboxyl group to a more reactive functional
group such as acyl halide, mixed anhydride, acyl azide,
active ester or in situ activation by coupling reagents,
the most common of which is N,N-dicyclohexylcar-
20,21
absence of solvents.
Herein, as an extension of our previous studies on the
application of microwave irradiation in organic synthe-
3
bodiimide (DCC). Other coupling reagents that have
22
sis, we describe the first procedure for the synthesis of
4
been used for this purpose include TiCl , activated
4
primary amides by direct reaction of carboxylic acid
and urea in the presence of imidazole under microwave
irradiation (Scheme 1).
5
6
phosphate, Sn [N(TMS) ] , equivalent amounts of
2
2
7
triphenylphosphine and N-halosuccinimide, triphenyl-
phosphine and trichloroacetonitrile,
Lawesson’s reagent, tert-butyl-3-(3,4-dihydrobenzotri-
azine-4-on)yl carbonate (Boc-Odhbt), (R N) Mg,
8
9
ArB(OH)2,
1
0
11
12
Imidazole was used in this reaction because previously
it has been demonstrated that this compound shows
2
2
13
and 2-mercaptopyridone-1-oxide based uronium salts.
23
useful promotion ability and forms polar carboxylic
2
4
acid salts for efficient microwave energy absorption.
The application of microwave technology in organic
chemistry has been explored extensively within the last
decade. Microwave irradiation often leads to a remark-
able decrease in reaction time, increased yields, easier
work up matching with green chemistry protocols, and
may enhance the regio- and stereoselectivity of
The promotion ability of imidazole was attributed to
the low melting point of imidazolium carboxylate salts
which melt after heating at low microwave power and
short irradiation time and homogenize the reaction
25
mixture in dry media. Instead of imidazole we used
other bases such as 4-dimethylaminopyridine (DMAP),
1
4–16
reactions.
More recently, there have been some reports in which
are described the preparation of secondary and tertiary
Keywords: primary amide; microwave irradiation; urea; imidazole.
*
Corresponding author: Tel.: +98-711-2282380; fax: +98-711-
280926; e-mail: khalafi@chem.susc.ac.ir
2
Scheme 1.
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01866-5

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A. Khalafi-Nezhad et al. / Tetrahedron Letters 44 (2003) 7325–7328
triethylamine and 1,8-diazabicyclo[5,4,0]undec-7-en
DBU), but none of them acted as well as imidazole.
The results for amidation of various carboxylic acids
are summarized in Table 1.
To investigate the generality and scope of this method,
the reaction was examined with various structurally
diverse carboxylic acids. As is clear from Table 1 the
reactions proceed cleanly, and the desired carboxamides
(
Table 1. Direct preparation of primary amides from carboxylic acids and urea by using imidazole under microwave
irradiation

A. Khalafi-Nezhad et al. / Tetrahedron Letters 44 (2003) 7325–7328
7327
were obtained in good yields but the presence of a
References
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aromatic carboxylic acids, the presence of electron-
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the reaction rate and increasing the reaction yields
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5
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1
We thank Shiraz University research council for the
financial support for this work. We also thank Mr
Sajedian Fard for running the NMR spectra.
28. Selected H NMR data (DMSO-d , 250 MHz) for prod-
6
ucts c, d, k, o. c: l 3.72 (s, 2H, CH ), 6.30 (s, 2H, NH ),
7.13–7.27 (m, 5H, Ar). d: l 1.61 (s, 9H, 3CH ), 3.83 (s,
2
2
3

7
328
A. Khalafi-Nezhad et al. / Tetrahedron Letters 44 (2003) 7325–7328
H, CH ), 6.02 (s, 2H, NH ), 8.01 (s, 1H, NH). k: l 5.97
1H, J=4.5 Hz, Ar), 8.68–8.69 (d, 1H, J=4.5 Hz, Ar),
2
2
2
(
s, 2H, NH ), 6.78–6.80 (d, 1H, J=15.5 Hz, olefinic),
9.06 (s, 1H, Ar).
2
7
1
.15–7.43 (m, 6H, Ar and olefinic). o: l 7.44–7.49 (dd,
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H, J=7.7, 4.8 Hz, Ar), 7.66 (s, 2H, NH ), 8.20–8.23 (d,
2