A mild and efficient procedure for the conversion of aromatic carboxylic esters to secondary amides

Article abstract of DOI:10.1139/v05-134

A mild and efficient procedure has been developed for the conversion of aromatic carboxylic esters to secondary amides using reusable Zn dust with microwave heating in the presence of N,N-dimethylformamide or conventional heating by stirring in an oil bath using THF as solvent. Zn dust can be reused several times after simple washing with dil. HC1 and distilled water.

Full text of DOI:10.1139/v05-134

1137
A mild and efficient procedure for the conversion
of aromatic carboxylic esters to secondary amides
Revika Arora, Satya Paul, and Rajive Gupta
Abstract: A mild and efficient procedure has been developed for the conversion of aromatic carboxylic esters to sec-
ondary amides using reusable Zn dust with microwave heating in the presence of N,N-dimethylformamide or conven-
tional heating by stirring in an oil bath using THF as solvent. Zn dust can be reused several times after simple
washing with dil. HCl and distilled water.
Key words: aromatic carboxylic esters, aromatic primary amines, secondary amides, Zn dust, microwave activation.
Résumé : On a mis au point une méthode douce et efficace de transformer des esters d’acides carboxyliques aromati-
ques en amides secondaires en faisant appel à un catalyseur de Zn en poudre réutilisable, avec chauffage microonde en
présence de N,N-diméthylformamide ou par chauffage conventionnel à l’aide d’un bain d’huile en utilisant du THF
comme solvant. La poudre de Zn peut être réutilisée plusieurs fois après simple lavage avec de l’acide chlorhydrique
dilué et de l’eau distillée.
Mots clés : esters d’acides carboxyliques aromatiques, amines primaires aromatiques, amides secondaires, poudre de
Zn, activation par micro-ondes.
[Traduit par la Rédaction] Arora et al. 1140
Introduction
toxicity of the reagent, particularly those involving tin com-
pounds (10b, 10c), operational simplicity and efficiency. Thus,
in recent times other approaches involving N-acylimidazoles
(11), N-acylbenzotriazoles (12), and indium triiodide (13)
have been demonstrated that also are not very simple and
cost effective. Thus, there is a need to develop a simple,
mild, cost-effective, and environment friendly procedure for
the preparation of secondary amides. Some microwave-
assisted synthesis of amides in the presence of strong bases
has been reported (14–16).
In recent years, metal- or metal-salt-catalyzed reactions
(17) are finding considerable attention because metals can be
removed by simple filtration and be reused several times
only by washing with suitable solvents. Among various met-
als, Zn dust (18) is attracting great attention because of its
easy availability, inexpensiveness, and nontoxic nature. Re-
cently, we have reported the use of reusable Zn powder for
the Friedel–Crafts acylation (19), the Fries rearrangement
(20), and the Williamson ether synthesis (21), and here we
wish to report another successful application of Zn dust for
the conversion of aromatic carboxylic esters to secondary
amides by treatment with primary amines with microwave
heating in the presence of N,N-dimethylformamide or con-
ventional heating by stirring in an oil bath using THF as a
solvent (Scheme 1).
The amide unit (1) is one of the most widely occurring
functional groups as it represents a key feature in many bio-
logically important natural and synthetic products. Numer-
ous methods are available for the preparation of amides.
These include ammonolysis of carboxylic acids and deriva-
tives, thermal decomposition of ammonium salts of
carboxylic acids, partial hydrolysis of cyanides, etc. The re-
action of carboxylic acids with ammonia or amines to pro-
vide the corresponding amides is not a mild, efficient, and
cost-effective method (2) as it requires the use of expensive
reagents like DCC (3), Fe3+-K10 montmorillonite clay (4),
molecular sieves (5), silicon tetrachloride in pyridine (6),
polymer-supported HOBT (7), chlorosulfonyl isocyanate (8),
PCl3 (9), etc. The other derivatives of carboxylic acids, par-
ticularly acyl halides, acid anhydrides and esters, are most
commonly used. However, limitations are associated with
the use of acyl halides and acid anhydrides and thus esters
are preferred. Reactions of ammonia or amines with acyl
halides are highly exothermic. Acid anhydrides, especially
cyclic anhydrides, easily form imides with ammonia and pri-
mary amines.
Usually, reactions with esters require strongly basic cata-
lysts and (or) high pressure. Although quite a number of
methods are reported for the conversion of esters to amides
(10), most of these have serious drawbacks with regard to
Results and discussion
Received 28 March 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 21 September
2005.
To demonstrate the applicability of this method, a series
of secondary amides were prepared in good to excellent
yields by taking various substituted methyl benzoates and ar-
omatic primary amines using Zn dust with both microwave
(MW) heating (70%–91%) or stirring in an oil bath at 70 °C
using THF as the solvent (70%–84%).
R. Arora, S. Paul,1 and R. Gupta. Department of
Chemistry, University of Jammu, Jammu-180 006, India.
1Corresponding author (e-mail: paul7@rediffmail.com).
Can. J. Chem. 83: 1137–1140 (2005)
doi: 10.1139/V05-134
© 2005 NRC Canada

1138
Can. J. Chem. Vol. 83, 2005
Scheme 1.
O
O
MW, Zn/DMF or
R' NH2
+
R
OMe
R
NH R'
∆, Zn/THF
3
2
1
3a. R = C H , R'= C H
6 5
3i. R= CH C H , R' = 3-NO C H
6
5
2
6
5
2
6
4
3b. R= C H , R'= 4-MeOC H
6 4
3j. R= CH C H , R'= 4-NO C H
6
5
2
6
5
2 6
4
3c. R= C H , R'= 2-NO C H
2 6 4
3k. R = 4-ClC H , R'= C H
6 5
6
5
6
4
3d. R= C H , R'= 3-NO C H
3l. R= 4-ClC H , R' = 4-MeOC H
6 4
6
5
2
6
4
4
6
4
3e. R = C H , R'= 4-NO C H
3m. R= 4-ClC H , R' = 2-NO C H
2 6 4
6
5
2 6
6
4
3f. R= CH C H , R'= C H
6 5
3n. R= 4-ClC H , R' = 3-NO C H
2 6 4
2
6
5
6
4
3g. R = CH C H , R'= 4-MeOC H
6 4
3o. R= 4-ClC H , R' = 4-NO C H
2 6 4
2
6
5
6
4
3h. R= CH C H , R'= 2-NO C H
2 6 4
2
6
5
Firstly, with MW heating, experimental conditions were
carefully monitored to regulate the use of Zn dust, irradia-
tion time, and power level to achieve the optimum condi-
tions. The 1:1 ratio of an ester and amine was the most
acceptable one, whereas 0.5 equiv. each of Zn dust and DMF
were required to allow the reaction to proceed efficiently.
The power level of 640 W was found to be the most accept-
able as the low power level gave low yields along with pro-
longed reaction time, whereas, at a high power level,
charring of the reaction mixture was observed. Further, the
addition of DMF along with Zn dust in the ratio of 1:1 was
very important as without DMF, the reaction did take place,
but after 10 s of irradiation, the reaction became violent and
charring of the reaction mixture was observed. So the role of
DMF is possibly to make the reaction medium homogeneous
and absorb some of the extra energy so that the reaction pro-
ceeds safely (every reaction was repeated four times to en-
sure that the reaction proceeds safely). Further, the amount
of Zn dust to be used was examined. If a lesser amount of
Zn dust was used, the product yield was low and with more
amounts, the reaction became violent, which could burn the
reaction mixture. The work-up procedure is simple, involv-
ing dilution with DMF and filtration followed by the addi-
tion of crushed ice.
catalyzes the conversion of carboxylic esters into secondary
amides.
Since the reactions were not carried out under an inert at-
mosphere and unpurified commercially available zinc dust
was used, there may be a possibility of the formation of
ZnO, which may catalyze the reaction. To see whether the
reaction was catalyzed by Zn or ZnO, we carried out the re-
action in the case of product 3a using 0.5 equiv. of ZnO, in-
stead of Zn dust, under the same conditions as described for
the microwave and oil-bath heating experiments. It was
found that we were not able to isolate the desired product af-
ter the final work-up (10 min under MW irradiation and 16 h
using oil-bath heating). This observation clearly indicated
that the formation of secondary amides was catalyzed by Zn
dust.
The Zn powder can be reused six times after simple wash-
ing with diethyl ether and dilute HCl without much loss of
activity, thus rendering the process more economical (Ta-
ble 2).
To check the possibility of specific nonthermal MW ef-
fects for the Zn catalyzed conversion of aromatic carboxylic
esters to secondary amides, we carried out the reaction of
aniline with methyl benzoate (product 3a, Table 1) using a
preheated oil bath at 135 °C (temperature measured at the
end of the reaction in the MW oven) for 2 min, keeping all
other conditions identical as for the MW experiment. It was
found that no reaction took place (TLC), although a yield of
60% was obtained when the reaction time was extended up
to 12.5 h. This observation suggests that the effect of MW
irradiation is not purely thermal. The results are summarized
in Table 3.
With conventional heating (stirring in an oil bath), the op-
timum conditions selected are: for 5 mmol of an ester and
amine each, 2.5 mmol of Zn dust, 10 mL of THF as the sol-
vent, and 70 °C as the reaction temperature. When compared
with MW heating, the yields of the products using oil-bath
heating were lower and also the reaction times were longer
(Table 1).
To see whether the formation of amides was catalyzed by
commercially available Zn dust, the reaction of methyl ben-
zoate (5 mmol) with aniline (5 mmol) was carried out in the
absence of Zn dust with MW heating using DMF
(2.5 mmol) or by stirring in an oil bath at 70 °C using THF
(10 mL) as the solvent (product 3a, Table 1). It was found
that under conditions similar to those described for Zn dust,
no reaction was observed on TLC (2 min under MW irradia-
tion and 16 h in the case of oil-bath heating). Thus, Zn dust
Experimental
Melting points were determined on a Buchi melting point
apparatus and are uncorrected. H NMR spectra were ob-
tained on a Bruker DPX-200 NMR spectrometer (200 MHz)
in CDCl3, with tetramethylsilane as the internal standard,
and IR spectra were recorded using a KBr disc on a FT-
Bruker Vector 22 spectrophotometer. The mass spectral data
1
© 2005 NRC Canada

Arora et al.
1139
Table 1. Synthesis of secondary amides from aromatic carboxylic esters and aromatic primary amines
in the presence of Zn dust.
MWa
Oil bathb
Time (h)
Product
Time (min)
Yieldc (%)
Yieldc (%)
mp/lit. mp (°C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
2
1
8
2
4
6
4
8
6
4
1
1
5
1
1.25
90
91
78
90
89
88
89
70
89
78
90
88
78
88
84
16
12
26
11
18
15
12
30
20
22
12
6
82
82
70
84
80
80
79
64
82
73
81
80
70
80
80
160–162/162 (22)
152–154/154 (22)
96–98/98 (22)
155–157/158 (22)
195–197/199 (22)
113–115/117 (22)
122–124/124 (23)
81–84/84 (24)
124 to 125d
183 to 184d
193–195/195 (22)
153 to 154/155 (25)
88–90d
130 to 131d
20
7
6
168 to 169/170 (26)
aReactions were carried out with a pulse of 15 s (5 s cooling time) in the presence of DMF.
bReactions were carried out by stirring in an oil bath at 70 °C.
cIsolated yield from three experimental runs.
1
dSpectral data of some compounds. 3i: IR (νmax in cm–1, KBr): 3344 (NH), 1706 (C=O). H NMR (CDCl3) δ: 3.90
(s, 2H, CH2), 6.90–8.30 (m, 9H, Harom), 10.20 (bs, 1H, NH). m/z (%): 256 (0.2), 211 (8.3), 166 (1.7), 132 (4.6), 123
(8.1), 92 (100), 65 (70.9). 3j: IR (νmax in cm–1, KBr): 3340 (NH), 1700 (C=O). H NMR (CDCl3) δ: 3.82 (s, 2H,
1
CH2), 6.92–8.20 (m, 9H, Harom), 10.25 (bs, 1H, NH). m/z (%): 256 (0.4), 211 (7.2), 166 (1.3), 132 (4.2), 123 (8.3), 92
(98), 65 (68.2). 3m: IR (νmax in cm–1, KBr): 3342 (NH), 1701 (C=O). H NMR (CDCl3) δ: 6.80–8.20 (m, 8H, Harom),
1
10.10 (bs, 1H, NH). m/z (%): 279 (1.4), 156 (72.7), 139 (100), 111 (42), 92 (32.5), 65 (34.7). 3n: IR (νmax in cm–1,
1
KBr): 3340 (NH), 1702 (C=O). H NMR (CDCl3) δ: 6.90–8.10 (m, 8H, Harom), 10.00 (bs, 1H, NH). m/z (%): 279
(1.3), 156 (70.2), 139 (99), 111 (44), 92 (36), 65 (32.1).
Table 2. Reuse studies of Zn dust for the synthesis of secondary
amides.
Table 3. Comparison of microwave activation (MW) and thermal
heating (∆) in the case of aniline (5 mmol) and methyl benzoate
(5 mmol) using Zn dust (2.5 mmol) and DMF (2.5 mmol)
(power = 640 W).
MW
Oil bath
No. of
uses
Timea
(min)
Yieldb
(%)
Timea
(h)
Yieldb
(%)
Method
Time (min)
Temp. (°C)a
Yield (%)b
2
2
MW
∆
∆
133–135
135
135
90
1
2
3
4
5
6
2
2.5
3
4.5
5
6
90
89
85
82
78
72
16
16.5
18
19
21.5
22
82
80
78
75
72
64
No reaction
60
12.5c
aThe final temperature was measured by immersing the glass thermome-
ter into the reaction mixture at the end of exposure during the MW exper-
iment and was approximate temperature range.
bIsolated yield from three experimental runs.
aTime at which maximum yield was obtained.
cTime reported in hours.
bIsolated yield from three experimental runs.
glass rod (10 s) and then irradiated in a microwave oven for
an appropriate time (Table 1) at 640 W. After cooling, DMF
(5 mL) was added and the reaction mixture was filtered. To
the filtrate, ice-cold water (100 mL) was added and the
product extracted with ethyl acetate (3 × 15 mL). The com-
bined extracts were washed with water and dried over anhy-
drous sodium sulfate. The product was obtained after the
removal of the solvent under reduced pressure followed by
crystallization from EtOAc – petroleum ether or by passing
through a column of neutral alumina and elution with petro-
leum ether.
was obtained on a JEOL JMS-D 300 spectrometer. The reac-
tions were monitored by TLC. For the microwave irradiation
experiments described in the following, a conventional (un-
modified) household microwave oven equipped with a turn-
table was used (LG Little Chef MS 194 W operating at
2450 MHz having a maximum output of 800 W).
General procedure for the synthesis of secondary
amides in the presence of Zn dust
Microwave heating approach
To a mixture of the aromatic carboxylic ester (5 mmol),
the appropriate aromatic amine (5 mmol), and Zn dust
(2.5 mmol) in a 50 mL borosil beaker, DMF (2.5 mmol) was
added. The reaction mixture was mixed thoroughly with a
Oil-bath heating approach
To a mixture of the aromatic carboxylic ester (5 mmol),
the appropriate aromatic amine (5 mmol), and Zn dust
© 2005 NRC Canada

1140
Can. J. Chem. Vol. 83, 2005
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duced pressure and the product was obtained by the same
procedure as described for the MW experiment.
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Conclusion
In conclusion, we have developed an efficient procedure
for the synthesis of secondary amides using Zn dust
with MW heating in the presence of DMF or by stirring in
an oil bath using THF as a solvent. The salient features of
our method is that it is simple, rapid, economic, general, and
environment friendly, and Zn dust can be reused several
times without much loss of activity. This method could be a
very efficient alternative to other existing methods.
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Acknowledgements
The authors thank the Jammu and Kashmir State Council,
the Department of Science and Technology, and the Jammu
and Kashmir Government for providing financial assistance
and awarding a project fellowship to Revika Arora.
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