Ultrasound-promoted synthesis of symmetrical bisamides by reaction between aromatic aldehydes and amides catalysed by p-toluenesulfonic acid

Article abstract of DOI:10.3184/174751916X14495888748571

Reaction between aldehydes and amides catalysed by p-toluenesulfonic acid (p-TSA), under ultrasound irradiation and ambient conditions, gives symmetrical bisamide derivatives in excellent yield and in short time.

Full text of DOI:10.3184/174751916X14495888748571

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 JANUARY, 35–37
RESEARCH PAPER 35
Ultrasound-promoted synthesis of symmetrical bisamides by reaction
between aromatic aldehydes and amides catalysed by p-toluenesulfonic acid
Raziyeh Pyrzehi-Bakhshani and Alireza Hassanabadi*
Department of Chemistry, Zahedan Branch, Islamic Azad University, PO Box 98135-978, Zahedan, Iran
Reaction between aldehydes and amides catalysed by p-toluenesulfonic acid (p-TSA), under ultrasound irradiation and ambient conditions,
gives symmetrical bisamide derivatives in excellent yield and in short time.
Keywords: ultrasound, bisamides, p-toluene sulfonic acid, aldehydes, amides
Bisamides are useful synthetic intermediates. Pyrolysis of
benzylidenebisbenzamides afforded N-benzoylbenzaldimine
derivatives, which have been used for the synthesis of N-(α-
alkoxybenzy1)benzamides.1 Bisamides are also important
fragments for the introduction of gem-diaminoalkyl residues
in retro-in verso pseudopeptide derivatives2 by treating the
corresponding amide with iodobenzene bistrifluoroacetate.3,4
Previously reported methods to prepare bisamides all applied
the reaction of corresponding amides with aldehydes in solution
in the presence of strong acidic catalysts such as triflic acid.5 We
reported the reaction of aldehydes with alkyl nitriles promoted
by chlorosulfonic acid.6 We also reported reaction between
aldehydes and amides under solvent-free conditions giving
symmetrical bisamides.7 These observations gave impetus to
attempt reaction of aryl aldehydes and amides catalysed by
p-toluene sulfonic acid (p-TSA), under sonication.
found that increasing the reaction time over 120 min did not
improve the yields.
The above reaction was also examined in various solvents
(Table 2).
The results indicate that different solvents affect the efficiency
of the reaction. Acetone, dichloromethane, THF, chloroform
and toluene afforded moderate yields (Table 2, entries 1–5),
while when the reaction was carried out under sonication and
solvent-free condition at 28–30 ºC better results were obtained
(Table 2, entry 6).
Table 1 Acid catalysed one-pot condensation reaction between
benzaldehyde and acetamide under sonication
Catalyst
/mol%
Temperature
/°C
Entry
Catalyst
Time /min Yield/%a
1
2
3
4
5
6
7
8
NH4Cl
ZrCl4
FeCl3.3H2O 10
10
10
28–30
28–30
28–30
28–30
28–30
28–30
28–30
28–30
20
20
20
20
20
60
60
120
50
65
77
85
96
90
92
95
Results and discussion
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
sonication.
ZnCl2
10
10
1
5
20
p-TSA
p-TSA
p-TSA
p-TSA
Initially, we studied the reaction of benzaldehyde and
acetamide using different catalysts under ultrasound at 20 ºC
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 20
min (the reaction progress was monitored by TLC) and N,N′-
[(phenyl)methylene]bis(acetamide) 3q was obtained in 96%
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 90%, 92%, 96%, and 95%, respectively (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 product was
detected in the absence of the catalyst. Furthermore, it was
aIsolated yield.
Table 2 Solvent effect on the reaction between benzaldehyde (1
equiv.) and acetamide(1.1 equiv.) catalysed by p-TSA (0.1 equiv.) under
sonication
Entry
Solvent
Temperature/°C Time /min
Yield/%a
1
2
3
4
5
6
Acetone
Dichloromethane
THF
Chloroform
Toluene
28–30
28–30
28–30
28–30
28–30
28–30
20
20
20
20
20
20
25
28
30
18
55
96
Neat
aIsolated yield.
O
O
HN
CH3
CH3
O
p-TSA (0.1 mmol)
)))), 28-30
H
NH
+
2
C, 20 min
H3C
NH2
O
Scheme 1 Reaction between benzaldehyde and acetamide catalysed by p-TSA under sonication.
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

36 JOURNAL OF CHEMICAL RESEARCH 2016
band at 3262 cm-1 for the NH group. The carbonyl stretching
vibration was observed as a strong absorption band at 1676 cm-1.
In conclusion, we have developed a highly efficient synthesis
of symmetrical bisamide derivatives from aldehydes and amides
under ultrasound conditions. The advantages of the reported
method are inexpensive and easily available starting materials,
simple reaction conditions, high yields, single-product reaction
and simple work-up procedure.
Table 3 Three-component reaction of aldehydes and amides catalysed
by p-TSA under sonication
O
O
O
R
R
HN
p-TSA (0.1 mmol)
2
+
R
NH2
Ar
H
NH
Ar
)))), 28-30 C, 20 min
1
2
3
O
M.p.
Lit.5,7
Experimental
Entry Ar
R
Yield/%a
Found
Melting points were determined with an Electrothermal 9100
apparatus and were uncorrected. Elemental analyses were performed
using a Heraeus CHN-O-Rapid analyser. Mass spectra were recorded
on a FINNIGAN-MAT 8430 mass spectrometer operating at an
ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu
IR-470 spectrometer. Sonication was done using a KMH1 ultrasonic
cleaner (120 W). The reaction flask was placed in the zone of
maximum cavitation, while the surface of the reaction mixture was
kept at a slightly lower level than the level of the water in the bath.
Addition/removal of water was used to control the temperature of the
water bath (28–30 ºC). 1H and 13C NMR spectra were recorded on a
Bruker DRX-400 Avance spectrometer using DMSO-d6 as solvent and
using TMS as internal standard. The chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
3a
3b
3c
3d
3e
3f
4-BrC6H4
Me
Me
Me
Me
Me
Me
92
95
98
93
93
87
92
94
95
96
93
92
93
91
92
93
96
84
92
95
96
94
93
95
91
90
243–246
230–232
271–273
260–262
236–238
270–272
267–269
245–247
156–158
144–146
161–163
176–178
227–229
222–224
185–187
192–194
239–241
227–229
232–234
245–247
221–223
157–159
201–203
150–152
164–166
183–185
246–248
231–233
270–272
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
2-NO2C6H4
4-CH3C6H4
258–260
237–239
269–271
266–268
244–246
155–157
143–145
162–164
178–180
225–228
221–223
188–190
190–192
242–244
230–231
234–236
246–248
–
3g
3h
3i
2-Cl-5-NO2C6H3 Me
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
Et
Et
Et
Et
3j
3k
3l
4-BrC6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-NO2C6H4
pH
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
Et
3m
3n
3o
3p
3q
3r
3s
3t
Me
Me
Ph
Ph
Me
Me
Ph
pH
Me
Et
General procedure
A mixture of amide (2.2 mmol), a liquid aldehyde (1.0 mmol) and
p-TSA (0.1 mmol) in a flat bottom flask (25 mL) was irradiated in the
ultrasonic cleaner at 28–30 ºC for 25 min. The progress of the reaction
was monitored by TLC. After complete consumption of the aldehyde,
the reaction mixture was washed with water (5 mL) and the residue was
crystallised from ethanol. In the case of solid aldehydes, the reaction
was carried out in dichloroethane (10 mL). After completion of the
reaction, the precipitated product was filtered off, washed with water (5
mL) and crystallised from ethanol.
N,N′-[(2-Chlorophenyl)methylene]bis(acetamide) (3u): White
powder; m.p. 221–223 oC; IR (KBr) (νmax cm-1): 3262 (NH), 1676
(C=O). Anal. calcd for C11H13ClN2O2: C, 54.89; H, 5.44; N, 11.64;
found: C, 54.70; H, 5.29; N, 11.78; MS (m/z, %): 240 (7); 1H NMR
(400 MHz, DMSO-d6): δ 1.83 (6H, s, 2CH3), 6.56 (1H, t, 3JHH=8 Hz,
CH), 7.17–7.68 (4H, m, 4CH of C6H4Cl), 8.43 (2H, d, 3JHH=8 Hz, 2NH)
ppm; 13C NMR (100.6 MHz, DMSO-d6): δ 23.51 (2CH3), 57.60 (CH),
125.92, 127.90, 131.05, 133.04, 140.25, 142.11 (phenyl moiety), 169.57
(2C=O) ppm.
3u
3v
3w
3x
3y
3z
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-HOC6H4
2-HOC6H4
2-HOC6H4
–
–
–
–
Ph
Me
ET
PH
–
aIsolated yield
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 excellent yields. In
addition, aromatic aldehydes reacted with other amides, such
as propionamide and benzamide to afford the corresponding
bisamide derivatives in excellent yields.
N,N′-[(2-Chlorophenyl)methylene]bis(propionamide) (3v): White
powder; m.p. 157–159 oC; IR (KBr) (νmax cm-1): 3284 (NH), 1693
(C=O). Anal. calcd for C13H17ClN2O2: C, 58.10; H, 6.38; N, 10.42;
found: C, 58.22; H, 6.51; N, 10.54%; MS (m/z, %): 268 (5); 1H NMR
3
(400.1 MHz, DMSO-d6): δ 1.06 (6H, t, JHH=8 Hz, 2CH3), 2.08–2.17
(4H, m, 2CH2), 6.46 (1H, t, 3JHH=8 Hz, CH), 7.13–7.67 (4H, m, 4CH of
C6H4Cl), 8.46 (2 H, d, 3JHH=8 Hz, 2NH) ppm; 13C NMR (100.6 MHz,
DMSO-d6): δ 10.63 (2CH3), 29.14 (2CH2), 57.52 (CH), 125.83, 127.79,
131.05, 133.16, 140.21, 142.11 (phenyl moiety), 173.02 (2C=O) ppm.
The compounds 3a–t were characterised by 1H, 13C-NMR and
IR spectroscopy and elemental analyses.5–7 Compounds 3u–z
were new and their structures were deduced by elemental and
spectral analysis. The structure of these products was proved
N,N′-[(2-Chlorophenyl)methylene]bis(benzamide) (3w):
White
1
powder; m.p. 201–203 ˚C; IR (KBr) (νmax, cm-1): 3251 (NH), 1653
on the basis of the mass spectrometry and H and 13C NMR
(C=O). Anal. calcd for C21H17ClN2O2: C, 69.14; H, 4.70; N, 7.68; found:
C, 69.24; H, 4.89; N, 7.53%. MS (m/z, %): 364 (8); H NMR (400
spectra. For example, the 1H NMR spectrum of 3u exhibited a
sharp line at δ=1.83 ppm for the protons of two methyl groups
and also exhibited a triplet (3JHH=8 HZ) at 6.56 ppm for the
methine group proton, a multiplet at 7.17–7.68 ppm for aromatic
protons and a doublet (3JHH=8 Hz) at 8.43 ppm for NH protons.
1
MHz, DMSO-d6): δ 6.86 (1H, t, 3JHH=8 Hz, CH), 8.93 (2H, d, 3JHH=8
HZ, 2NH). 7.15–7.94 (14H, m, 14CH aromatic) ppm; 13C NMR (100.6
MHz, DMSO-d6): δ 59.22 (CH), 125.87, 127.90, 131.09, 133.03, 140.35,
142.17 (aromatic carbons of aldehyde moiety), 129.14, 129.33, 132.12,
132.56, 133.19, 134.62, 135.17, 140.11 (carbons of two phenyl rings),
166.53, 168.92 (2C=O) ppm.
1
When the H NMR spectrum was recorded after addition of
some D2O to the DMSO-d6 solution of 3u, the doublet related to
the NH proton was absent and the doublet related to the methine
proton was converted to a singlet. The 13C NMR spectrum of
compound 3u showed nine distinct signals, consistent with the
proposed structure. The IR spectrum showed an absorption
N,N′-[(2-Hydroxyphenyl)methylene]bis(acetamide) (3x): White
powder; m.p. 155–157 oC; IR (KBr) (νmax cm-1): 3435, 3260 (NH and
OH), 1670 (C=O). Anal. calcd for C11H14N2O3: C, 59.45; H, 6.35; N,
12.60; found: C, 59.63; H, 6.48; N, 12.74%. MS (m/z, %): 222 (10).

JOURNAL OF CHEMICAL RESEARCH 2016 37
1H NMR (400 MHz, DMSO-d6): δ 1.81 (6H, s, 2CH3), 6.40 (1 H, t,
3JHH=8 Hz, CH), 7.43–7.85 (4H, m, aromatic), 8.48 (2H, d, 3JHH=8
Hz, 2NH), 8.71 (1 H, s, OH) ppm; 13C NMR (100.6 MHz, DMSO-d6):
δ 23.42 (2CH3), 57.72 (CH), 119.1, 124.6, 126.9, 129.1, 145.5, 156.3
(phenyl moiety), 169.40 (2C=O) ppm.
7.35–7.95 (4H, m, aromatic), 8.62 (2H, d, 3JHH=8 Hz, 2NH), 8.73
(1H, s, OH) ppm ; 13C NMR (125.75 MHz, DMSO-d6): δ 59.42 (CH),
118.9, 124.1, 126.9, 129.3, 145.2, 156.6 (aromatic carbons of aldehyde
moiety), 129.14, 129.34, 132.04, 132.52, 133.14, 134.65, 135.13, 140.12
(carbons of two phenyl rings), 166.65, 168.82 (2C=O) ppm.
N,N′-[(2-Hydroxyphenyl)methylene]bis(propionamide) (3y): White
o
powder; m.p. 164–166 C, IR (KBr) (νmax cm-1): 3417, 3283 (NH and
Received 4 November 2015; accepted 1 December 2015
Paper 1503694 doi: 10.3184/174751916X14495888748571
Published online 1 January 2016
OH), 1690 (C=O). Anal. calcd for C13H18N2O3: C, 62.38; H, 7.25; N,
11.19; found: C, 62.52; H, 7.39; N, 11.34%. MS (m/z, %): 250 (5);
1H NMR (400 MHz, DMSO-d6): δ 1.03 (6H, t, JHH=8 Hz, 2CH3),
3
2.07–2.26 (4H, m, 2CH2), 6.43 (1H, t, 3JHH=8 Hz, CH), 7.40–7.81 (4H,
m, aromatic ), 8.56 (2H, d, 3JHH=8 Hz, 2NH), 8.65 (1H, s, OH) ppm;
13C NMR (100.6 MHz, DMSO-d6): δ 10.73 (2CH3), 29.16 (2CH2), 57.44
(CH), 119.2, 124.4, 126.7, 129.0, 145.3, 156.2 (phenyl moiety), 172.97
(2C=O) ppm.
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1
2
3
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N,N′-[(2-Hydroxyphenyl)methylene]bis(benzamide) (3z): White
powder; m.p. 183–185 ˚C; IR (KBr) (νmax, cm-1): 3430, 3232 (NH
and OH), 1641 (C=O). Anal. calcd for C21H18N2O3: C, 72.82; H,
5.24; N, 8.09; found: C, 72.71; H, 5.43; N, 8.20%. MS (m/z, %): 346
7
M. H. Mosslemin, M. Anary-Abbasinejad, A. Hassanabadi and S. Tajic,
Synth. Commun. 2010, 40, 2209.
(4); H NMR (400 MHz, DMSO-d6): δ 6.93 (1H, t ,3JHH=8 Hz, CH),
1