P-Toluene sulfonic acid-catalysed microwave synthesis of symmetrical bisamides by reaction between aromatic aldehydes and amides

Article abstract of DOI:10.3184/030823410X12812905400188

Reaction between aldehydes and amides catalysed by p-toluene sulfonic acid in microwave conditions provided a simple and efficient one-pot route for the synthesis of symmetrical bisamide derivatives in excellent yields.

Full text of DOI:10.3184/030823410X12812905400188

478 RESEARCH PAPER
AUGUST, 478–480
JOURNAL OF CHEMICAL RESEARCH 2010
p-Toluene sulfonic acid-catalysed microwave synthesis of symmetrical
bisamides by reaction between aromatic aldehydes and amides
Mohammad Anary-Abbasinejada, Alireza Hassanabadib* and Motahareh Heidari-Barfehc
aYoung Researchers Club, Islamic Azad University, Anar Branch, Anar, Iran
bDepartment of Chemistry, Islamic Azad University, Zahedan Branch, P.O. Box 98135-978, Zahedan, Iran
cDepartment of Chemistry, Islamic Azad University, Yazd Branch, P.O. Box 89195-155, Yazd, Iran
Reaction between aldehydes and amides catalysed by p-toluene sulfonic acid in microwave conditions provided a
simple and efficient one-pot route for the synthesis of symmetrical bisamide derivatives in excellent yields.
Keywords: bisamides, p-toluene sulfonic acid, aldehydes, amides
Bisamides are useful synthetic intermediates. Pyrolysis of
benzylidenebisbenzamides afforded N-benzoylbenzaldimine
derivatives, which has been used for the synthesis of N-(α-alk
oxybenzy1)benzamides.1 Bisamides are also important frag-
ments for the introduction of gem-diaminoalkyl residues in
retro-in verso pseudopeptide derivatives2 by treating the cor-
responding amide with iodobenzene bistrifluoroacetate.3,4 Pre-
viously reported methods to prepare bisamides all applied the
reaction of the corresponding amides with aldehydes in solu-
tion in the presence of strong acidic catalysts such as triflic
acid.5 Recently we reported the reaction of aldehydes with
alkyl nitriles promoted by chlorosulfonic acid6 and the reaction
between aldehydes and amides under solvent-free conditioin
affording symmetrical bisamides7.
Table
1
Acid catalysed one-pot condensation reaction
between 4-chlorobenzaldehyde and acetamide
Entry Catalyst
Catalyst Temperature Time
Yielda
/%
/mol%
/min
/°C
1
2
3
4
5
6
7
8
9
NH4Cl
ZrCl4
FeCl3.3H2O
ZnCl2
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
10
10
10
10
10
1
100
100
100
100
100
100
100
100
70
120
120
120
120
60
120
60
50
65
77
85
95
97
95
85
85
5
20
10
120
120
a Isolated yield.
Results and discussion
and chloroform afforded moderate yields (Table 2, entries 1–
4), while when 1,2-dichloroethane and toluene were used as
solvents, better results were obtained (Table 2, entries 5 and 6).
However, the best result was obtained when the reaction was
carried out under solvent-free conditions at 100 °C (Table 2,
entry 7).
To study the scope of the reaction, a series of aldehydes
and amides were applied. The results are shown in Table 3. In
all cases, aromatic aldehydes substituted with either electron-
donating or electron-withdrawing groups underwent the
reaction smoothly and gave the products in good yields. It
could also be concluded that the aldehydes bearing electron-
withdrawing groups required shorter time and gave higher
yields (Table 3). In addition, aromatic aldehydes reacted
with other amides, such as propionamide (Table 3, entries 8–
14) and benzamide (Table 3, entries 17 and 18) to afford
the corresponding bisamide derivatives in excellent yields.
The reaction is also compatible with aliphatic aldehyde (pos-
sessing α-hydrogen), so that 2-phenyl-propion aldehyde and
3-phenylpropenal reacted with amides affording the related
bisamides in good yields (Table 3, entries 13 and 19)
We describe here a practical and inexpensive method for the
preparation of symmetrical bisamides via a three-component
condensation reaction between aldehydes and amides under
microwave conditioin.
Initially, we studied the reaction of benzaldehyde and ace-
tamide using different catalysts under microwave conditions
at 100 °C, and the results are listed in Table 1 (Scheme 1). p-
TSA was found to show better catalytic activity among these
catalysts. When p-TSA was used, the reaction was completed
after 1min (the reaction progress was monitored by TLC) and
N-[acetylamino phenyl methyl]-acetamide 3a was obtained in
95% yield (Table 1, entry 5). Moreover, we found that the
yields were obviously affected by the amount of p-TSA loaded.
When 1 mol %, 5 mol %, 10 mol %, and 20 mol % of p-TSA
were used, the yields were 20%, 77%, 95%, and 95%, respec-
tively (Table 1, entries 5–8). Therefore, 10 mol % of p-TSA
was sufficient and excessive amount of catalyst did not increase
the yields significantly (Table 1, entry 8). In addition, no pro-
duct was detected in the absence of the catalyst. Furthermore,
it was found that increasing the reaction time over 60 min or
reaction temperature over 100 °C did not improve the yields.
The above reaction was also examined in various solvents
(Table 2). The results indicated that different solvents affected
the efficiency of the reaction. Acetone, dichloromethane, THF,
Compounds 3a–y were known and their structures were
deduced by comparison of melting points and spectral data
with authentic samples.5–7 The structure of other products were
Scheme 1 Reaction between 4-chlorobenzaldehyde and acetamide catalysed by p-TSA
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010 479
Table 2 Solvent effect on the reaction between 4-
chlorobenzaldehyde (1 equiv) and acetamide(1.1 equiv)
catalysed by p-TSA (0.1 equiv)
reported method are inexpensive and easily available starting
materials, simple reaction conditions, high yields, single-
product reaction and simple workup procedure.
Entry Solvent
Temperature
/°C
Time
/min
Yield*
/%
Experimental
1
2
3
4
5
6
7
Acetone
Dichloromethane
THF
Chloroform
1,2-Dichloroethane Reflux
Toluene
Neat
Reflux
Reflux
Reflux
Reflux
180
180
180
180
180
180
60
60
65
65
43
80
75
95
Melting points were determined with an electrothermal 9100 appara-
tus. Elemental analyses were performed at the analytical laboratory
of Science and Researchs Unite of Islamic Azad University. Mass
spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at an ionisation potential of 70 eV. IR spectra were recorded
Reflux
100
1
on a Shimadzu IR-470 spectrometer. H and 13C NMR spectra were
recorded on Bruker DRX-250 Avance spectrometer at solution in
d6-DMSO using TMS as internal standard. The chemicals used in this
work were purchased from Fluka (Buchs, Switzerland) and were used
without further purification.
proved on the basis of the mass spectrometry and H and 13C
NMR spectra. For example, the H NMR spectrum of com-
1
1
General procedure:
pound 3z exhibited a triplet (3JHH = 8 HZ) at 6.99 ppm for
methine group proton, a multiplet at 7.39–7.91 ppm for aro-
matic protons and a doublet (3JHH = 8 HZ) at 9.05 ppm for NH
protons. The phenyl groups of each amide group are diastereo-
topic and two signals were observed for them at 20.1 and 20.4
ppm in the 13C NMR spectrum of compound 3z. Methine group
carbon resonated at 59.3 ppm. Twelve signals were observed
between 128.3 and 140.1 ppm for aromatic carbons and two
carbonyl carbons were observed at 166.6 and 168.8 ppm.
In conclusion, we have developed a highly efficient syn-
thesis of symetrical bisamide derivatives from aldehydes and
amides under microwave conditions. The advantages of the
To a stirred mixture of the amide (2.2 mmol) and aldehyde (1.0 mmol)
in a round-bottomed flask equipped with condenser at 100 °C was
added p-TSA (0.1 mmol) and the reaction was heated for the given
time. For microwave-assisted reactions the above premixed mixture
was irradiated at 475 W in a domestic microwave oven. The progress
of reaction was followed by TLC. After completion of the reaction,
ethyl acetate (10 mL) was added to the resulting mixture and the
product was filtered off and washed with ethyl acetate (10 mL).
N-[benzoylamino(4-clorophenyl)methyl]-benzamide (3z): White
powder; m.p. 246–248 °C. IR (KBr) (νmax, cm–1): 3255 (NH), 1648
(C=O). MS (m/z, %): 364 (M+,4). 1H NMR (500 MHz, d6-DMSO): δ
6.99 (1 H, t ,3JHH = 8 Hz, CH), 9.05 (2 H, d, 3JHH = 8 HZ, 2 NH). 7.39–
Table 3 Three-component reaction of aldehydes and amides catalysed by p-TSA
Entry
R
R'
Yield/%*
M.p.
Found
Reported
(Lit.)
1
2
4-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Et
90
94
96
91
91
84
90
91
93
94
91
90
88
91
92
90
90
92
86
98
92
91
89
68
91
93
244–247
232–234
272–274
261–262
238–240
271–273
265–267
246–248
157–159
142–144
160–162
244–245
186–188
175–177
226–229
224–226
186–188
193–195
192–194
203–204
195–197
241–243
238–240
226–228
230–232
246–248
246–248
231–233
270–272
258–260
237–239
269–271
266–268
244–246
155–157
143–145
162–164
241–243
189–192
178–180
225–228
221–223
188–190
190–192
195–197
206–207
198–199
244–245
242
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
3
4
5
2-NO2C6H4
4-CH3C6H4
2-Cl-5-NO2C6H3
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
6
7
8
9
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Et
Et
iso-Pro
Et
Et
4-BrC6H4
4-ClC6H4
C6H5CHCH3
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-O2NC6H4
C6H4CHCH
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
Me
Me
Ph
Ph
Me
Me
Et
Ph
Me
Me
Ph
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
230–231
234–236
–
Ph
*Isolated yields

480 JOURNAL OF CHEMICAL RESEARCH 2010
7.91 (1 H, m,14 CH aromatic). 13C NMR (125.75 MHz, d6-DMSO): δ
59.3 (CH), 128.3, 128.4, 129.1, 129.2 (aromatic carbons of aldehyde
moiety), 129.1, 129.3, 132.0, 132.5, 133.1, 134.6, 135.1 and 140.1
(carbons of two phenyl rings), 166.6, 168.8 (2C=O). Analyses: Calcd
for C21H17ClN2O2: C, 69.14; H, 4.70; N, 7.68. Found: C, 69.3; H, 4.6;
N, 7.5%.
References
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2
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Received 18 June 2010; accepted 18 July 2010
Paper 1000211 doi: 10.3184/030823410X12812905400188
Published online: 30 August 2010
7
M.H. Mosslemin, M. Anary-Abbasinejad, A. Hassanabadi and S. Tajic,
Synth. Commun., 2010, 40, 2209.

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