P-toluene sulfonic acid-catalyzed, solvent-free synthesis of symmetrical bisamides by reaction between aldehydes and amides

Article abstract of DOI:10.1080/00397910903219617

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

Full text of DOI:10.1080/00397910903219617

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p-Toluene Sulfonic Acid–Catalyzed,
Solvent-Free Synthesis of Symmetrical
Bisamides by Reaction Between
Aldehydes and Amides
Mohammad Anary-Abbasinejad a , Mohammad H. Mosslemin b
Alireza Hassanabadi b & Safiyeh Tajik Safa b
,
a Young Research Club , Islamic Azad University , Anar Branch, Anar,
Iran
b Department of Chemistry , Islamic Azad University , Yazd Branch,
Yazd, Iran
Published online: 07 Jul 2010.
To cite this article: Mohammad Anary-Abbasinejad , Mohammad H. Mosslemin , Alireza Hassanabadi
& Safiyeh Tajik Safa (2010) p-Toluene Sulfonic Acid–Catalyzed, Solvent-Free Synthesis of Symmetrical
Bisamides by Reaction Between Aldehydes and Amides, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:15, 2209-2214, DOI:
10.1080/00397910903219617
To link to this article: http://dx.doi.org/10.1080/00397910903219617
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Synthetic Communications1, 40: 2209–2214, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219617
p-TOLUENE SULFONIC ACID–CATALYZED, SOLVENT-
FREE SYNTHESIS OF SYMMETRICAL BISAMIDES BY
REACTION BETWEEN ALDEHYDES AND AMIDES
Mohammad Anary-Abbasinejad,1 Mohammad H. Mosslemin,2
Alireza Hassanabadi,2 and Safiyeh Tajik Safa2
1Young Research Club, Islamic Azad University, Anar Branch, Anar, Iran
2Department of Chemistry, Islamic Azad University, Yazd Branch, Yazd, Iran
Reaction between aldehydes and amides catalyzed by p-toluene sulfonic acid in solvent-free
conditions provided a simple and efficient one-pot route for the synthesis of symmetrical
bisamide derivatives in excellent yields.
Keywords: Aldehydes; amides; bisamides; p-toluene sulfonic acid; solvent-free reaction
Bisamides are important fragments for the introduction of gem-diaminoalkyl
residues in retro-inverso pseudo-peptide derivatives[1] by treating the corresponding
amide with iodobenzene bistrifluoroacetate.[2,3] Bisamides are also useful synthetic
intermediates. Pyrolysis of benzylidenebisbenzamides afforded N-benzoylbenzaldi-
mine derivatives, which have been used for the synthesis of N-(a-alkoxybenzy1)ben-
zamides.[4] Previously reported methods to prepare bisamides all applied the reaction
of the corresponding amides with aldehydes in solution 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 acid, which afforded symmetrical
bisamides.[6] This reaction can only be applied for electron-deficient aldehydes. We
herein describe a practical and inexpensive method for the preparation of symmetri-
cal bisamides via a three-component condensation reaction between aldehydes
and amides under solvent-free conditions.
Initially, we studied the reaction of 4-bromobenzaldehyde and acetamide using
different catalysts under solvent-free condition at 100 ꢀC (Scheme 1), and the results
are listed in Table 1. p-Toluene sulfonic acid (p-TSA) showed the best catalytic
activity among these catalysts. When p-TSA was used, the reaction was completed
after 1 h (the reaction progress was monitored by thin-layer chromatography,
TLC), and N-[acetylamino (4-bromophenyl) 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, 5, 10, and 20 mol% of p-TSA
Received June 2, 2009.
Address correspondence to Mohammad Anary-Abbasinejad, Young Research Club, Islamic Azad
University, Anar Branch, P.O. Box 89195-155, Anar, Iran. E-mail: mohammadanary@yahoo.com
2209

2210
M. ANARY-ABBASINEJAD ET AL.
Scheme 1. Reaction between 4-bromobenzaldehyde and acetamide catalyzed by p-TSA.
were used, the yields were 20, 77, 95, and 95%, respectively (Table 1, entries 5–8).
Therefore, 10 mol% of p-TSA was sufficient, and an 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 found that increasing
the reaction time over 60 min or reaction temperature over 100 ꢀC did not improve
the yields.
This reaction was also examined in various solvents (Table 2). The results
indicated that different solvents affected the efficiency of the reaction. Acetone,
dichloromethane, tetrahydrofuran (THF), and chloroform afforded moderate yields
(Table 2, entries 1–4), whereas when 1,2-dichloroethane and toluene were used as
solvents, better results were obtained (Table 2, entries 5, 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 substi-
tuted 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 gave greater yields (Table 3).
In addition, aromatic aldehydes reacted with other amides, such as propionamide
(Table 3, entries 13–19) and benzamide (Table 3, entries 20–23) to afford the corre-
sponding bisamide derivatives in excellent yields. The reaction is also compatible
with aliphatic aldehydes (aldehydes possessing a-hydrogen), so that 2-phenylpropio-
naldehyde reacted with amides, affording the related bisamides in good yields
Table 1. Acid-catalyzed one-pot condensation reaction between 4-bromobenzaldehyde and acetamidea
Entry
Catalyst
Catalyst (mol%)
Temperature (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
NH4Cl
ZrCl4
10
10
10
10
1
100
100
100
100
100
100
100
100
70
120
120
120
120
60
50
65
77
85
20
77
95
95
85
FeCl3 ꢁ 3H2O
ZnCl2
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
5
60
60
10
20
10
60
120
aReaction conditions: 4-bromobenzaldehyde (1.0 mmol), acetamide (2.2 mmol), neat, 100 ꢀC.
bIsolated yield.

SOLVENT-FREE SYNTHESIS OF SYMMETRICAL BISAMIDES
2211
Table 2. Solvent effect on the reaction between 4-bromobenzaldehyde (1 eq) and acetamide (2.2 eq) cat-
alyzed by p-TSA (0.1 eq)
Entry
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
Acetone
Dichloromethane
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100
180
180
180
180
180
180
60
60
65
65
43
80
75
95
Chloroform
1,2-Dichloroethane
Toluene
Neat
Table 3. Three-component reaction of aldehydes and amides catalyzed by p-TSA
Mp
Entry
R
R0
Product
Yield%a
Found
Reported (Lit.)
1
2
4-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3f
91
93
95
92
92
85
91
90
91
87
99
90
90
90
92
89
92
93
94
93
90
93
90
90
244–246
230–232
271–273
260–262
238–240
270–272
265–267
225–228
221–223
195–197
202–203
239–240
245–247
160–162
157–159
189–192
178–180
145–147
180–182
247–249
188–190
190–192
265–267
243–245
246–248[6]
231–233[6]
270–272[6]
258–260[6]
237–239[6]
269–271[6]
266–268[6]
—
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
3
4
5
2-NO2C6H4
4-CH3C6H4
2-Cl-5-NO2C6H3
2-MeOC6H4
4-MeOC6H4
C6H4CHCH
PhCH2CH2
Ph
6
7
3g
3h
3i
8
9
221–222[5]
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3j
3k
3l
202–203[5]
239–240[5]
244–246[6]
162–164[6]
155–157[6]
—
4-NO2C6H4
4-BrC6H4
3m
3n
3o
3p
3q
3r
3s
3t
Et
Et
3-NO2C6H4
C6H5CHCH3
3-MeOC6H4
4-ClC6H4
Et
Et
—
Et
Et
143–145[6]
178–179[5]
248–249[5]
—
PhCH2CH2
PhCH2CH2
3-MeOC6H4
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
Ph
Ph
3u
3v
3w
3x
Ph
Ph
—
265–267[5]
241–243[6]
iso-Propyl
aIsolated yield.

2212
M. ANARY-ABBASINEJAD ET AL.
(Table 3, entries 19, 20). Cinamaldehyde also reacted with acetamide under similar
conditions to afford bisamide 3j in good yield (Table 3, entry 10).
Compounds 3h, 3j, 3p, 3q, 3u, and 3v were new, and their structures were
deduced by elemental and spectral analysis. Other products were known, and their
structures were deduced by comparison of melting points and spectral data with
1
authentic samples.[5,6] The H NMR spectrum of compound 3p exhibited a doublet
at 1.78 ppm (3JHH ¼ 7 Hz) for methyl of aldehyde moiety, a multiplet at 3.14 ppm
and a quartet (3JHH ¼ 7 Hz) at 5.48 ppm for two CH groups, and multiplets at
7.13–7.28 ppm for aromatic protons. Two propionamido groups are diastereotopic
and showed distinct signals at NMR spectra of compound 3p. Two triplets
(3JHH ¼ 7 Hz) at 0.75 and 0.98 ppm and two quartets at 1.82 and 2.09 ppm were
observed for two ethyl groups protons. Two NH protons resonated as two doublets
(3JHH ¼ 8 Hz) at 7.78 and 7.96 ppm. 13C NMR spectrum of compound 3p showed 13
distinct signals, consistent with the proposed structure. The infrared (IR) spectrum
of compound 3p showed strong absorption bands at 3300 and 1658 cmꢂ1 for NH
and carbonyl groups, respectively.
In conclusion, we have developed a highly efficient synthesis of symmetrical
bisamide derivatives from aldehydes and amides under solvent-free conditions.
The advantages of the reported method are inexpensive and easily available starting
materials, simple reaction conditions, excellent yields, single-product reaction, and
simple workup procedure.
EXPERIMENTAL
General
Melting points were determined with an electrothermal 9100 apparatus.
Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyzer
at the analytical laboratory of Islamic Azad University, Yazd Branch. Mass spectra
were recorded on a Finnigan-MAT 8430 mass spectrometer operating at an ioniza-
tion potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spec-
1
trometer. H and 13C NMR spectra were recorded on Bruker DRX-250 Avance
spectrometer at solution in dimethyl sulfoxide (d6-DMSO) using tetramethylsilane
(TMS) as internal standard. The chemicals used in this work purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
General Procedure for the Preparation of Bisamides 3a–x
A mixture of amide (2.2 mmol), aldehyde (1.0 mmol), and p-TSA (0.1 mmol)
was stirred in an oil bath at 100 ꢀC, and the reaction was followed by TLC. After
completion of the reaction, ethyl acetate (10 mL) was added to the reaction mixture
and the product was filtered off and washed with ethyl acetate (10 mL).
Selected Data
N-[Acetylamino(2-methoxyphenyl)methyl]-acetamide (3h). White powder;
mp 225–228 ꢀC. IR (KBr) (nmax, cmꢂ1): 3285 (NH), 1683 (C O). MS (m=z, %): 236
=

SOLVENT-FREE SYNTHESIS OF SYMMETRICAL BISAMIDES
2213
1
(Mþ, 8). H NMR (250 MHz, d6-DMSO): d 1.80 (6 H, s, 2 CH3), 3.77 (3 H, s,
OCH3), 6.66 (1 H, t J ¼ 8 Hz, CH), 6.90–7.34 (4 H, m, aromatic), 8.30 (2 H, d
J ¼ 8 Hz, 2 NH). 13C NMR (62.9 MHz, CDCl3): d 21.9 (2 CH3), 52.8 (OCH3),
=
55.0 (CH), 110.5, 119.4, 126.5, 127.8, 128.4 and 156.0 (aromatic), 167.7 (2 C O).
Analyses: Calcd. for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C, 61.1; H,
6.9; N, 11.7.
N-[Acetylamino(4-methoxyphenyl)methyl]-acetamide (3i). White powder;
mp 221–223 ꢀC. IR (KBr) (nmax, cmꢂ1): 3270 (NH), 1686 (C O). MS (m=z, %): 236
=
(Mþ, 9). H NMR (250 MHz, d6-DMSO): d 1.84 (6 H, s, 2 CH3), 3.73 (3 H, s,
1
OCH3), 6.45 (1 H, t J ¼ 8 Hz, CH), 6.89 and 7.24 (4 H, 2 d J ¼ 8 Hz, aromatic),
8.43 (2 H, d J ¼ 8 Hz, 2 NH). 13C NMR (62.9 MHz, CDCl3): d 21.9 (2 CH3), 54.6
=
(OCH3), 56.3 (CH), 113.0, 127.0, 132.0 and 158.1 (aromatic), 167.9 (2 C O).
Analyses: Calcd. for C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C, 61.1; H,
6.9; N, 11.7.
N-(1-Acetylamino-3-phenyl-allyl)-acetamide (3j). White powder; mp
195–197 ꢀC. IR (KBr) (nmax, cmꢂ1): 3275 (NH), 1666 (C O). MS (m=z, %): 232
=
(Mþ, 7). H NMR (250 MHz, d6-DMSO): d 1.86 (6 H, s, 2 CH3), 6.03 (1 H, m,
1
CH), 6.28 (1 H, dd J ¼ 5 Hz, J ¼ 15 Hz, olefinic CH), 6.56 (1 H, d J ¼ 15 Hz, olefinic
CH), 7.23–7.45 (5 H, m, aromatic), 8.37 (2 H, d J ¼ 8 Hz, 2 NH). 13C NMR
(62.9 MHz, CDCl3): d 22.0 (2 CH3), 55.4 (CH), 125.8, 127.3, 128.1, 129.3 and
=
135.5 (aromatic and olefinic carbons), 167.9 (2 C O). Analyses: Calcd. for
C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.3; H, 6.8; N, 12.1.
N-(3-Phenyl-1-propionylamino-propyl)-propionamide (3p). White powder;
mp 189–192 ꢀC. IR (KBr) (nmax, cmꢂ1): 3300 (NH), 1658 (C O). MS (m=z, %): 262
=
(Mþ, 8). 1H NMR (250 MHz, d6-DMSO): d 0.75 and 0.98 (6 H, 2 t J ¼ 8 Hz, 2 CH3),
1.78 (3 H, d J ¼ 7 Hz, CH3), 1.82 and 2.09 (4 H, 2 p J ¼ 8 Hz, 2 CH2), 3.14 (1 H, m,
CH), 5.48 (1 H, q J ¼ 8 Hz, CH), 7.13–7.28 (5 H, m, aromatic), 7.78 and 7.96 (2 H, 2
d J ¼ 8 Hz, 2 NH). 13C NMR (62.9 MHz, CDCl3): d 9.1, 9.3 and 17.2 (3 CH3), 27.8
and 27.9 (2 CH2), 42.4 and 58.9 (2 CH), 125.6, 127.1, 127.4 and 142.9 (aromatic),
=
171.3 and 171.9 (2 C O). Analyses: Calcd. for C15H22N2O2: C, 68.67; H, 8.45; N,
10.68. Found: C, 68.8; H, 8.5; N, 10.6.
N-[Propionylamino(3-methoxyphenyl)methyl]-propionamide (3q). White
powder; mp 178–180 ꢀC. IR (KBr) (nmax, cmꢂ1): 3280 (NH), 1660 (C O). MS (m=
=
z, %): 618 (Mþ, 9). 1H NMR (250 MHz, d6-DMSO): d 0.99 (3 H, t J ¼ 8 Hz,
CH3), 2.15 (2 H, q J ¼ 8 Hz, CH2), 6.51 (1 H, t J ¼ 8 Hz, CH), 6.86 (1 H, s, CH
aromatic), 7.13 and 7.49 (2 H, 2 d J ¼ 8 Hz, 2 CH aromatic), 7.28 (1 H, t J ¼ 8 Hz,
Hz, CH aromatic), 8.39 (2 H, d, J ¼ 8 Hz, 2 NH). 13C NMR (62.9 MHz, CDCl3): d
9.2 and 9.3 (CH3), 27.9 (CH2), 54.5 (OCH3), 58.1 (CH), 112.1 112.4 119.3, 128.9,
=
132.7, 158.9 (aromatic), 170.1 (C O). Analyses: Calcd. for C14H20N2O3: C, 63.62;
H, 7.63; N, 10.60. Found: C, 63.5; H, 7.7; N, 10.5.
N-[Benzoylamino(3-methoxyphenyl)methyl]-benzamide (3u). White pow-
der; mp 188–190 ꢀC. IR (KBr) (nmax, cmꢂ1): 3280 (NH), 1646 (C O). MS (m=z,
=
%): 360 (Mþ, 5). H NMR (250 MHz, d6-DMSO): d 6.89 (1 H, t J ¼ 8 Hz, CH),
1
7.05 (3 H, m, 3 CH aromatic), 7.31 (1 H, t J ¼ 8 Hz, CH aromatic), 7.53 (6 H, m,

2214
M. ANARY-ABBASINEJAD ET AL.
6 CH aromatic), 7.91 (4 H, d J ¼ 8 Hz, 4 CH aromatic), 9.04 (2 H, d, J ¼ 8 Hz, 2
NH).. 13C NMR (62.9 MHz, CDCl3): d 54.5 (OCH3), 58.1 (CH), 111.9 112.3
118.3, 128.9, 133.3, 158.8 (aromatic carbons of aldehyde moiety), 127.0, 127.8,
=
131.0 and 141.4 (carbons of two phenyl rings), 165.1 (C O). Analyses: Calcd. for
C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C, 73.4; H, 5.7; N, 7.6.
N-[Benzoylamino(3-nitrophenyl)methyl]-benzamide (3v). White powder;
mp 190–192 ꢀC. IR (KBr) (nmax, cmꢂ1): 3255 (NH), 1645 (C O). MS (m=z, %):
=
375 (Mþ, 8). 1H NMR (250 MHz, d6-DMSO): d 7.09 (1 H, t J ¼ 8 Hz, CH),
7.47–8.34 (14 H, aromatic), 9.23 (2 H, d, J ¼ 8 Hz, 2 NH). 13C NMR (62.9 MHz,
CDCl3): d 58.6 (CH), 121.4, 122.7, 129.9, 133.5, 133.7 and 147.8 (aromatic carbons
of aldehyde moiety), 127.6, 128.3, 131.7 and 142.4 (carbons of two phenyl rings),
=
165.9 (C O). Analyses: Calcd. for C21H17N3O4: C, 67.19; H, 4.56; N, 11.19. Found:
C, 67.1; H, 4.4; N, 11.3.
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