An Efficient Synthesis of Symmetrical N,N′-Alkylidene bis-Amides Catalyzed by a Heteropolyacid

Full text of DOI:10.1080/00304948.2015.1066646

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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An Efficient Synthesis of Symmetrical
N,N′-Alkylidene bis-Amides Catalyzed by a
Heteropolyacid
Behrooz Maleki, Farrokhzad Mohammadi Zonoz & Hossien Ali Akhlaghi
To cite this article: Behrooz Maleki, Farrokhzad Mohammadi Zonoz & Hossien Ali Akhlaghi
(2015) An Efficient Synthesis of Symmetrical N,N′-Alkylidene bis-Amides Catalyzed by a
Heteropolyacid, Organic Preparations and Procedures International, 47:5, 361-367, DOI:
10.1080/00304948.2015.1066646
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Date: 11 September 2015, At: 21:33

Organic Preparations and Procedures International, 47:361–367, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1066646
An Efficient Synthesis of Symmetrical
N,N0-Alkylidene bis-Amides Catalyzed
by a Heteropolyacid
Behrooz Maleki, Farrokhzad Mohammadi Zonoz,
and Hossien Ali Akhlaghi
Department of Chemistry, Hakim Sabzevari University, Sabzevar, 96179-76487,
Iran
Amides and polyamides have been found as a key component of many biologically active
and pharmaceutically useful compounds. In particular, symmetrical and unsymmetrical
N,N0-alkylidene bis-amides and their derivatives are key structural sub-units for the con-
struction of peptido-mimetic frameworks.1–2
A literature survey revealed that, for the preparation of bis-amides from aldehydes and
primary amides, several methods have been reported using different homogeneous or het-
erogeneous catalysts and catalytic systems, such as aqueous sulfuric acid,3 trifluorometha-
nesulfonic acid (CF3SO3H),4 sulfamic acid (NH2SO3H),5 p-toluenesulfonic acid (p-TSA),6
silica-supported barium chloride (SiO2-BaCl2),7 boric acid [B(OH)3],8 phosphotungstic
acid (PWA),9 silica-supported perchloric acid (HClO4-SiO2),10 silica-supported polyphos-
phoric acid (SiO2-PPA),11 silica-supported magnesium chloride (SiO2-MgCl2),12 and tris
(hydrogensulfato)boron [B(HSO4)3],13 and nano-SnCl4.SiO2.14 However, several of these
methods suffer from some drawbacks such as prolonged reactions times, utilization of haz-
ardous organic solvents, tedious work-up conditions, use of microwave irradiation,8
employment of large amounts of catalyst. The present work reports the use of
H14[NaP5W29MoO110] as a catalyst for the preparation of symmetrical N,N0-alkylidene bis-
amides (Scheme 1). Recently, heteropolyacids (HPAs), such as H14[NaP5W29MoO110], H5[
a- SiMo2VW9O40].xH2O, and H5[PW10V2O40] have gained importance as environmentally
friendly and economically viable solid acids because of their ready availability, high ther-
mal stability, low cost, ease of handling, and recyclability. In comparison with liquid min-
eral acids, heteropolyacids (HPAs), can be separated easily from the reaction mixture by
simple filtration with high recovery. These features lead to decreasing equipment cauteriza-
tion and environment pollution; these catalysts exhibit high activities and unique selectiv-
ities thus allowing for cleaner reactions than conventional ones and hence may be regarded
as green reagents. They also act as bifunctional catalysts under homogeneous as well as het-
erogeneous conditions.15–17 HPAs are stronger than some mineral acids such as H2SO4,
HCl, and HNO3.18
Received February 8, 2015; in final form February 26, 2015.
Address correspondence to Behrooz Maleki, Department of Chemistry, Hakim Sabzevari Uni-
versity, Sabzevar, 96179-76487, Iran. E-mail: malekibehrooz@gmail.com
361

362
Maleki et al.
Scheme 1
The development of methodologies that involve the use of inexpensive and re-usable
catalysts under mild and environmentally friendly conditions is one of the major goals in
green and sustainable chemistry. Methodologies leading to various organic compounds
are in high demand for both academic and industrial applications.19–23 As a continuation
Table 1
Various Conditions Used for the Synthesis of N,N0-(Phenylmethylene)dibenzamide
Entry
Solvent
Temperature(ꢀC)
Time (min)
Yield (%)
1
Ethanol
Methanol
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100
90
90
90
90
90
90
90
90
90
90
90
90
180
80
86
46
80
80
28
82
54
78
88
45
72
2
3
Ethyl acetate
Acetonitrile
Toluene
4
5
6
Dichloromethane
1,4-Dioxane
Solvent-free
Methanola)
Methanolb)
Methanolc)
Methanold)
Methanole)
7
8
9
Reflux
Reflux
Reflux
Reflux
Reflux
10
11
12
13
f)
–
a)H14[NaP5W29MoO110] (0.08 g) used in model reaction. b)H14[NaP5W29MoO110] (0.25 g)
used in model reaction; c)H5[ a- SiMo2VW9O40].xH2O (0.15 g) used in model reaction;
d)H5[PW10V2O40] (0.15 g) used in model reaction; e)In the absence of any catalyst. f)No reaction.

Symmetrical N,N0-Alkylidene bis-Amides
363
of our work on the development of efficient and environmentally benign reagents and cat-
alysts,24–30 we now report that H14[NaP5W29MoO110] is an excellent catalyst for the syn-
thesis of symmetrical N,N0-alkyli-dene bis-amide derivatives.
In order to explore the catalytic activity of H14[NaP5W29MoO110], prepared accord-
ing to the literature procedure,17 the condensation of benzaldehyde (1 mmol) with benza-
mide (2 mmol) in the presence of the catalyst (0.15 g) was initially carried out as a model
reaction by heating in different solvents (1 ml) to examine its effect on the yield and rate
of the reaction to give N,N0-(phenylmethylene)dibenzamide (3a) (Table 1, Entries 1–7).
While the yield and the rate of reaction were quite good when methanol was used as sol-
vent (Entry 2), only a 54% yield of the product was obtained under solvent-free condi-
tions, at 100ꢀC and after 100 min (Entry 8). To optimize the amount of catalyst required,
the reaction was performed using various catalyst loadings (Entries 9 and 10).
In comparison with H14[NaP5W29MoO110], the use of H5[a-SiMo2VW9O40].xH2O
and of H5[PW10V2O40] as catalysts afforded lower yields in the model reaction under the
same condi-tions (Entries 11 and 12); in the absence of catalyst, the reaction did not pro-
ceed at all even upon prolonged reaction times (Entry 13). This success led us to apply
these conditions to the condensation of a wide variety of aromatic aldehydes containing
both electron-withdrawing and electron-donating groups and of aliphatic aldehydes.
The corresponding symmetrical N,N0-alkylidene bis-amides were obtained; aromatic
aldehydes bearing electron-withdrawing groups reacted more rapidly than those with
electron-donating substituents. The reaction of formaldehyde (3n) and cinnamaldehyde
(3o) proceeded more slowly and gave lower yields while 4-nitroacetophenone and
Table 2
Synthesis of Symmetrical N,N0-Alkylidene bis-Amide Derivatives
mp (ꢀC)
Products (3a–r)
R
R1 Yield (%) Time (min) Found
Lit.
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
C6H5
C6H5
86
94
95
92
83
82
79
80
90
82
74
77
87
72
42
90
80
82
90
50
217–219 214–21614
255–257 259–26113
234–236 230–2348
226–228 232–23513
259–261 257–25912
252–254 251–25412
199–200 195–19713
4-NO2C6H4 C6H5
4-CNC6H4 C6H5
50
60
3-NO2C6H4 C6H5
2-NO2C6H4 C6H5
80
70
4-ClC6H4
2,4-ClC6H3 C6H5
C6H5
80
90
3-ClC6H4
4-BrC6H4
3-BrC6H4
2-MeC6H4
4-MeC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
221–222
–
70
90
256–258 252–25413
226–228
223–225
–
–
120
100
60
244–246 242–24313
3-PhOC6H4 C6H5
C6H5
194–196
–
H
100
150
60
219–220 216–21810
198-200 199–20114
272–274 270–27210
245–247 244–24610
232–234 231–2336
C6H5CHDCH C6H5
4-NO2C6H4
4-BrC6H4
3-NO2C6H4
CH3
CH3
CH3
90
70

364
Maleki et al.
crotonaldehyde failed to react with benzamide under the same conditions even after
200 min, only starting material being recovered.
In order to illustrate the efficiency of our procedure, results for the preparation of N,
N0-alkylidene bis-amides previously reported are compared with our data (Table 3). The
present method using H14[NaP5W29MoO110] as catalyst offers several advantages such as
excellent yields, a simple procedure, short reaction times, facile work-up and greener con-
ditions. The green aspect of HPA catalysts has been discussed in terms of being non-corro-
sive, presenting fewer disposals problem, facile isolation of the products, and recyclability.
The recycling of H14[NaP5W29MoO110] was investigated using the synthesis of 3a.
After completion of the reaction, the solid product was collected and the filtrate was evap-
orated under reduced pressure to give the catalyst which was washed with diethyl ether
and dried at 80ꢀC for 2 h. It was re-used directly in the model reaction to give 3a in yields
of 86%, 80%, 72% for three consecutive runs (Table 4).
In conclusion, we have developed an alternative and simple protocol for the synthesis of
symmetrical N,N0-alkylidene bis-amides using H14[NaP5W29MoO110]. These catalysts based
on HPAs have several advantages over acid catalysts; they are not corrosive, are environme-
tally benign, present fewer disposal problems, are removed easily and are thermally stable.
Experimental Section
All reagents were obtained from commercial sources and were used without purification.
IR spectra were recorded as KBr pellets on a Shimadzu 435-U-04 spectrophotometer. 1H
and 13C NMR spectra were determined on a Bruker DRX-300 Avance spectrometer in
Table 3
Comparison of the Efficiencies of Various Catalysts used in the Synthesis of N,N0-Alkyli-
dene bis-Amides
N,N0-Alkylidene
bis-Amides
Time
(min)
Yield
(%)
Entry
Conditions
SiO2-BaCl2/
3b
90
91
100ꢀC/solvent-free7
B(OH)3/toluene/reflux8
PWA//toluene/reflux9
Present work
1800
1200
50
65
71
94
3f
B(OH)3/toluene/reflux8
SiO2-MgCl2/
100ꢀC/solvent-free12
Present work
2880
120
65
74
70
82
3r
Sulfamic acid/
125ꢀC/Solvent-Free5
Present work
1080
70
68
82

Symmetrical N,N0-Alkylidene bis-Amides
365
DMSO-d6 or CDCl3, and shifts are given in d downfield from tetramethylsilane (TMS) as
an internal standard. Melting points were determined using an Electrothermal 9200 appa-
ratus and are uncorrected.
General Procedure for the Synthesis of Symmetrical N,N0-Alkylidene bis-
Amides
The catalyst, H14[NaP5W29MoO110] (0.5 mol%, 0.15 g), was added to a mixture of the
aldehyde (1 mmol), the amide (2 mmol), and 1 mL of methanol in a 5 mL flask fitted
with a reflux condenser. The resulting mixture was heated to reflux (an oil bath) for the
appropriate time (see Table 2) with stirring (spin bar). After the completion of the reac-
tion as determined by TLC (hexane-ethyl acetate, 4:1), the mixture was cooled to room
temperature. The solid product which separated, was collected and recrystallized from
ethanol (96%, 3 ml) to afford the pure symmetrical N,N0-alkylidene bis-amide (3a–r).
Analytical Data for New Compounds
N,N0-(3-Chlorophenylmethylene)dibenzamide (3h): IR: 3280, 1675, 1540, 1510, 1480,
1330, 1280, 1080, 715, 690;1H NMR (300 MHz, DMSO-d6): d 7.04 (t, 1H, CH), 7.14–
7.31 (m, 6H), 7.61–7.72 (m, 5H), 7.81 (d, 2H), 7.92 (s, 1H), 8.00 (d, 2H, NH, D2O
exchangeable); 13C NMR (75 MHz, DMSO-d6): d 59.12, 124.14, 127.5, 128.08, 128.72,
128.81, 129.01, 132.04, 134.32, 137.85, 140.70, 165.61.
Anal. Calcd for C21H17ClN2O2: C, 69.14; H, 4.70; N, 7.68. Found: C, 69.19; H, 4.81;
N, 7.72.
N,N0-(3-Bromophenylmethylene)dibenzamide (3j): IR: 3280, 1675, 1540, 1510,
1480, 1330, 1280, 1080, 715, 690;1H NMR (300 MHz, DMSO-d6): d 6.94 (t, 1H, CH),
7.31–7.42 (m, 6H), 7.51–7.60 (m, 5H), 8.09 (d, 2H), 7.82 (s, 1H), 7.94 (d, 2H, NH, D2O
exchangeable); 13C NMR (75 MHz, DMSO-d6): d 59.31, 114.70, 127.65, 128.08, 128.71,
128.91, 129.91, 132.31, 133.72, 134.91, 159.31, 166.61.
Anal. Calcd for C21H17BrN2O2: C, 61.63; H, 4.18; N, 6.85. Found: C, 61.70; H, 4.23;
N, 6.89.
N,N0-(2-Methylphenylmethylene)dibenzamide (3k): IR: 3290, 1660, 1560, 1510,
1480, 1400, 1150, 720;1H NMR (300 MHz, DMSO-d6): d 2.82 (s, 3H, CH3), 6.92 (t, 1H,
CH), 7.16–7.22 (m, 2H), 7.44–7.56 (m, 8H), 7.91 (d, 4H), 8.80 (d, 2H, NH, D2O
exchangeable); 13C NMR (75 MHz, DMSO-d6): d 58.41, 117.01, 117.61, 128.41, 129.24,
129.61, 129.92, 132.41, 134.68, 137.79, 164.51, 167.70.
Anal. Calcd for C22H20N2O2: C, 76.73; H, 5.85; N, 8.14. Found: C, 76.77; H, 5.87; N,
8.19.
Table 4
Reusability of the H14[NaP5W29MoO110] for the Synthesis of N,N0-(phenylmethylene)-
dibenzamide (3a) after 90 min.
Entry
Number of Recycle
Yield (%)
1
2
3
1
2
3
86
80
72

366
Maleki et al.
N,N0-(3-Phenoxyphenylmethylene)dibenzamide (3m): IR: 3310, 1705, 1580, 1540,
1480, 1340, 1210, 710;1H NMR (300 MHz, DMSO-d6): d 6.91 (t, 1H, CH), 6.97–7.14 (m,
5H), 7.22–7.24 (d, 2H), 7.33–7.57 (m, 9H), 7.86–7.98 (d, 4H), 9.00 (d, 2H, NH, D2O
exchangeable); 13C NMR (75 MHz, DMSO-d6): d d 58.46, 116.49, 117.50, 118.71,
121.58, 123.54, 127.46, 128.28, 129.93, 129.99, 131.56, 133.73, 133.77, 142.53, 156.29,
156.70, 165.59, 165.67.
Anal. Calcd for C27H22N2O3: C, 76.76; H, 5.25; N, 6.63. Found: C, 76.79; H, 5.28; N,
6.67.
Acknowledgments
The author thanks the Research Council of Hakim Sabzevari University for partial sup-
port of this work.
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