Microwave-assisted synthesis of amides from various amines and benzoyl chloride under solvent-free conditions: A rapid and efficient method for selective protection of diverse amines

Article abstract of DOI:10.1007/s11178-008-3008-1

A number of structurally diverse amides were synthesized by reaction of the corresponding amines with benzoyl chloride under microwave irradiation. The proposed procedure ensures short reaction time, high yields, and excellent selectivity and considerably broadens the series of amines as compared to the microwave-assisted synthesis of amides directly from carboxylic acids. It can also be used for selective protection of various amines, including aromatic, aliphatic, and heterocyclic.

Full text of DOI:10.1007/s11178-008-3008-1

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 358–361. © Pleiades Publishing, Ltd., 2008.
Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 3, pp. 365–368.
Microwave-Assisted Synthesis of Amides from Various
Amines and Benzoyl Chloride under Solvent-Free Conditions:
A Rapid and Efficient Method for Selective Protection
of Diverse Amines*
Yanqiu Lia, Yulu Wangb, and Jinye Wangc
a College of Chemistry and Environmental Science, Key Laboratory of Environmental Pollution Control Technology
of Henan Province, Henan Normal University, Xinxiang, Henan, 453007, P.R. China
e-mail: wyl@henannu.edu.cn
b Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030 P.R. China
c Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032 P.R. China
Received November 7, 2006
Abstract—A number of structurally diverse amides were synthesized by reaction of the corresponding amines
with benzoyl chloride under microwave irradiation. The proposed procedure ensures short reaction time, high
yields, and excellent selectivity and considerably broadens the series of amines as compared to the microwave-
assisted synthesis of amides directly from carboxylic acids. It can also be used for selective protection of
various amines, including aromatic, aliphatic, and heterocyclic.
DOI: 10.1134/S1070428008030081
Relatively stable amide bond is not only common
in naturally occurring materials (such as peptides and
proteins) but is also present in many synthetic sub-
stances [1, 2]. This makes the amide function impor-
tant to synthetic chemists, especially in peptide [1] and
lactam [2] syntheses, where the formation of amide
bond is crucial. Many methods for the synthesis of car-
boxamides are known. In general, amides are formed
from carboxylic acids and amines in the presence of
coupling reagents [3] or via reaction of acyl chlorides
with amines in a solvent [4]. Although good results are
obtained with both approaches, they are time-con-
suming and are sometimes associated with difficult
separation and poor yields. To improve the efficiency,
mild methods for preparation of amides in the absence
of coupling reagents and solvent are highly desired.
efficient and safe technology conforming to “green
chemistry” requirements [5, 10]. Microwave-assisted
syntheses of amides have already been reported
[11–14]. However, a limited number of amines and
carboxylic acids were involved in these studies.
Furthermore, because of lower reactivity of carboxylic
acids, some reactions between amines and carboxylic
acids are characterized by very low conversions
despite long reaction times. Therefore, there is still
a great demand for methods utilizing acyl chlorides for
the synthesis of amides.
Taking into account limitations of the existing
methods, we now report on an improved protocol for
the synthesis of amides (Scheme 1) from benzoyl chlo-
ride (I) and various amines IIa–IIs under microwave
irradiation in the absence of a solvent, which consider-
ably broadens the series of available amides. The
procedure includes mixing the reactants followed by
exposure to microwave irradiation under solvent-free
conditions. The reaction course was carefully moni-
tored by TLC to regulate the reactant ratio, irradiation
time, and microwave power level to achieve the maxi-
mum yield. An equimolar ratio of benzoyl chloride to
amine (except for adenine, uracil and cytosine) was the
most acceptable in terms of efficiency and safety. All
In the last decade, microwaves (MWs) have been
used to simplify and improve reaction conditions for
many classical organic reactions. Reactions performed
under MW conditions proceed faster, more cleanly,
and in much better yields than do similar reactions
under conventional conditions [5–9]. In combination
with solvent-free conditions, MW methods provide
* The text was submitted by the authors in English.
358

MICROWAVE-ASSISTED SYNTHESIS OF AMIDES
359
Scheme 1.
O
O
MW
R1
H
N
Cl
N
+
R1
R2
R2
I
IIa–IIs
IIIa–IIIn, IIIq–IIIs
For R1 and R2, see Table 1.
the products were separated into four groups according
to the required power level: amides IIIa–IIId, IIIi–
IIIk, IIIn, IIIr, and IIIs constituted the first group,
IIIe–IIIh and IIIl, the second, IIIm and IIIq, the
third, and IIIo and IIIp, the fourth. A power level of
495 W was the most appropriate for the synthesis of
the first group amides. In general, the reaction times
were fairly short (3–10 min), and the yields were good
to excellent (58–95%). However, the behaviors of
amines IIi, IIr, and IIs were slightly different from the
other amines. An appreciable amount of the amine
remained unchanged, while benzoyl chloride disap-
peared in 15 min, other conditions being equal. Natu-
rally, the conversions were very low. By raising the
amount of benzoyl chloride to a ratio of 2:1 we suc-
ceeded in strongly increasing the yield of the corre-
sponding amides, even though a small amount of un-
reacted amine was detected in the reaction mixture.
The yield did not increase upon further raising the I-to-
II ratio. It should be noted that the benzoylation of
adenine, uracil, and cytosine gave only the correspond-
ing 6-N-, N1-, and 4-N-benzoyl derivatives, respec-
Table 1. Microwave-assisted synthesis of amides under solvent-free conditionsa
Amine no. R1 R2 Product Power, W Time, min Yield,b %
mp, °C
182–184
197–198
154–156
162–163
Liquid
IIa
IIb
IIc
IId
IIe
IIf
H
4-ClC6H4
4-O2NC6H4
4-MeC6H4
Ph
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
495
495
495
495
250
250
250
03
04
93
92
95
85
80
92
94
H
H
03
Ph
04
–CH=CHN=CH– (1H-imidazole)
.001.5
02
H
H
Pyridin-2-yl
Pyridin-4-yl
84–87
IIg
01
207–210
IIh
IIi
H
H
H
Pyrimidin-2-yl
IIIh
IIIic
IIIj
250
495
495
495
250
300
495
03
05
04
03
01
05
05
82
81
89
90
91
87
80
140–142
240–243
245–247
202–204
150–151
Liquid
Purin-6-yl
IIj
9,10-Dioxo-9,10-dihydroanthracen-1-yl
IIk
IIl
H
H
4-PhN=NC6H4
IIIk
IIIl
1,3-Thiazol-2-yl
IIm
IIn
IIo
IIp
Bu
H
Bu
IIIm
IIIn
–
PhCO
149–151
o-C(O)C6H4C(O) (phthalimide)
495
495
30
30
–
–
–
–
H
1,5-Dimethyl-2-phenyl-3-oxo-1,2-di-
–
hydro-3H-pyrazol-4-yl
IIq
IIr
IIs
H
C7H15
IIIq
IIIr
IIIs
300
495
495
04
08
10
93
63
58
Liquid
165–168
347–349
–C(O)NHCH2CH2C(O)– (uracil)
H
2-Oxo-1,2-dihydropyrimidin-4-yl
a
b
c
All products were reported previously in the literature; they were characterized by melting points and IR and 1H NMR spectra.
Yield of the isolated product.
Reactant ratio I:II = 2:1.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

YANQIU LI et al.
360
tively, while no N9-benzoyladenine, N3-benzoyluracil,
or N1-benzoylcytosine was detected by TLC. These
results are consistent with the microwave irradiation
power-to-selectivity merit. We also presumed that our
procedure can be used as a method for selective pro-
tection of amino group.
with 2 equiv of benzoyl chloride. The products were
only the corresponding monobenzoyl derivatives,
while no N,N-disubstituted products were detected.
Obviously, conjugation between the carbonyl group
and lone electron pair on the nitrogen atom in the
resulting amide strongly reduces nucleophilicity of
the nitrogen atom, thus hampering its subsequent ben-
zoylation; in addition, the second benzoylation is hin-
dered for steric reasons. These factors are responsible
for the failure of benzoyl chloride to react with imide
IIo and heterocyclic amine IIp.
Next we selected 4-aminopyridine as a model for
the preparation of second group amides. When the re-
action was performed under the above conditions, the
mixture turned black in less than 1 min. Presumably,
tarring occurred due to high temperature; therefore, we
tried to reduce the power level and found that an ir-
radiation power of 250 W was the most suitable. These
conditions were used to synthesize compounds IIIe,
IIIf, IIIh, and IIIl. In the synthesis of amides IIIm
and IIIq, the reactions were complete in 4–5 min at
an MW power of 300 W, and the yields were higher.
4-Amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyr-
azol-3-one (IIp) and phthalimide (IIo) failed to react
with benzoyl chloride despite variation of the power
level and reactant ratio. The results are collected in
Table 1.
To conclude, the proposed solvent-free procedure
for the synthesis of benzamides under microwave irra-
diation is applicable to structurally diverse amines. It is
superior to the existing methods in terms of yield,
reaction time, selectivity, and experimental simplicity.
The procedure provides a powerful tool for peptide
synthesis.
EXPERIMENTAL
The IR spectra were recorded on a FTS-40 spec-
1
trophotometer in KBr. The H NMR spectra were
In order to elucidate chemoselectivity of the proc-
ess we performed reactions of benzoyl chloride with
mixtures of equimolar amounts of two different
amines. The reaction mixture was exposed to micro-
wave irradiation for a few minutes, and the product
ratio was calculated. As follows from the data in
Table 2, significant differences in the reactivities of
amines are observed: (1) primary amines are more re-
active than secondary amines; (2) aliphatic amines are
more reactive than aromatic amines; and (3) aromatic
amines bearing electron-donating groups are more re-
active than those having electron-withdrawing groups.
Thus, the proposed procedure ensures selective protec-
tion of amines.
measured on a Bruker DPX-400M spectrometer using
TMS as internal reference. The melting points were
not corrected.
N-(4-Nitrophenyl)benzamide (typical procedure).
4-Nitroaniline, 276 mg (2 mmol), and benzoyl chloride,
280 mg (2 mmol), were thoroughly mixed in a crucible,
and the mixture was exposed to microwave irradiation
in a domestic microwave oven at 495 W for 4 min.
When the reaction was complete (TLC), the crude
product (a powder) was recrystallized from 95% alco-
hol and dried.
This study was supported by the National Program
on Key Basic Research Projects of China (973 Pro-
gram, 2005 CB724306).
We also examined reactions of p-chloroaniline
(IIa), p-nitroaniline (IIb), and p-methylaniline (IIc)
REFERENCES
Table 2. Competing microwave-assisted solvent-free ben-
zoylation of different amines
1. Albericio, F., Curr. Opin. Chem. Biol., 2004, vol. 8,
p. 211.
Major product
Amine no. Power, W Time, min
(fraction, mol %)
2. Singh, G.S., Tetrahedron, 2003, vol. 59, p. 7631.
3. Sheehan, J.C. and Hess, G P., J. Am. Chem. Soc., 1955,
vol. 77, p. 1067.
IIb + IIc
IIb + IId
IIm + IIq
IIb + IIq
IIc + IIq
495
495
300
300
300
4
4
5
5
5
IIIc (98)
IIIb (97)
IIIq (100)
IIIq (98)
IIIq (96)
4. Vago, I. and Greiner, I., Tetrahedron Lett., 2002, vol. 43,
p. 6039; Girard, C., Tranchant, I., Nioré, P.-A., and
Herscoviei, J., Synlett, 2000, p. 1577; Jang, D.O.,
Park, D.J., and Kim, J., Tetrahedron Lett., 1999, vol. 40,
p. 5323; Cho, D.H. and Jang, D.O., Tetrahedron Lett.,
2004, vol. 45, p. 2285.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

MICROWAVE-ASSISTED SYNTHESIS OF AMIDES
361
5. Loupy, A., Petit, A., Hamelin, J., Texier-Boullet, F.,
10. Varma, R.S., Green Chem., 1999, vol. 1, p. 43.
11. Vasquez-Tato, M.P., Synlett, 1993, p. 506.
Jacquault, P., and Mathé, D., Synthesis, 1998, p. 1213.
6. Kappe, C.O., Angew. Chem., Int. Ed., 2004, vol. 43,
12. Perreux, L., Loupy, A., and Volatron, F., Tetrahedron,
p. 6250.
2002, vol. 58, p. 2155.
7. Lidstrom, P., Tierney, J., Wathey, B., and Westman, J.,
13. Goretski, C., Krlej, A., Steffens, C., and Ritter, H.,
Tetrahedron, 2001, vol. 57, p. 9225.
Macromol. Rapid Commun., 2004, vol. 25, p. 513.
8. Caddik, S., Tetrahedron, 1995, vol. 51, p. 10403.
9. Kuhnert, N., Angew. Chem., Int. Ed., 2002, vol. 41,
14. Gelens, E., Smeets, L., Sliedregt, L.A.J.M., Van-
Steen, B.J., Kruse, R.L., and Orru, R.V.A., Tetrahedron
Lett., 2005, vol. 46, p. 3751.
p. 1863.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008