2W10O32 catalyzed efficient one-pot pseudo-four component synthesis of AT-130 analogues under microwave irradiations

Article abstract of DOI:10.1007/s13738-014-0420-z

Di[1,6-bis(3-methylimidazolium-1-yl)hexane] decatangstate ([C ₆(MIm)₂]₂W₁₀O₃₂) was found to be a novel, powerful and effective catalyst for the preparation of N-benzoylglycine carbamides as derivatives of AT-130 via one-pot multicomponent reaction performed under microwave irradiations. The products were obtained in high to excellent yields, thus providing a unique strategy to the large-scale synthesis of these compounds.

Full text of DOI:10.1007/s13738-014-0420-z

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0420-z
ORIGINAL PAPER
[C6(MIm)2]2W10O32 catalyzed efficient one-pot pseudo-four
component synthesis of AT-130 analogues under microwave
irradiations
•
Mahboubeh Rostami Ahmad R. Khosropour
•
•
Valiollah Mirkhani Iraj Mohammadpoor-Baltork
•
•
Majid Moghadam Shahram Tangestaninejad
Received: 11 September 2013 / Accepted: 15 January 2014
Ó Iranian Chemical Society 2014
Abstract Di[1,6-bis(3-methylimidazolium-1-yl)hexane]
decatangstate ([C6(MIm)2]2W10O32) was found to be a
novel, powerful and effective catalyst for the preparation of
N-benzoylglycine carbamides as derivatives of AT-130 via
one-pot multicomponent reaction performed under micro-
wave irradiations. The products were obtained in high to
excellent yields, thus providing a unique strategy to the
large-scale synthesis of these compounds.
utilized for treating of HBV infections, still the viral
resistance and the side effects of them make the current
treatment not satisfactory [6, 7].. To address the resistance
and toxicity problems of these nucleoside inhibitors, a
major target in the field of pharmacology is to synthesis
and develops non-nucleoside ones [8]. Since the discovery
of the naturally occurring, clinically used of 1 as an anti-
HBV agent AT-130, N-benzoylglycine carbamide phar-
macophore has attracted considerable attention owing to
the biological activity associated with such compounds
(Fig. 1) [8].
Keywords AT-130 Á Aldehydes Á N-benzoylglycine Á
Amines Á Solvent-free Á Microwave irradiation Á Organic–
inorganic hybrid polyoxometalates Á One-pot reactions
For example, compound 2 extracted from Dichondra
repens forens exhibiting high anti-HBV activity [9]. Con-
sequently, the development of novel synthetic strategies
leading to new unsaturated N-benzoylglycine carbamide
derivatives is of paramount importance.
Introduction
Recently, investigation for designing of new and effective
anti hepatitis B virus (HBV) compounds is a challenge for
biologists, pharmaceuticals and organic chemists [1].
Although several nucleosides such as adefovir [2], dipiv-
oxil [3], telbivudine [4] and lamivudine [5] have been
The development of hybrid organic–inorganic frame-
works due to replacing toxic metal catalysts with degrad-
able organic compounds has emerged as one of the most
potentially significant fields of investigation in modern
chemistry [10–12]. Recently, hybrids of ionic liquids with
polyoxometalates (POMs) has grown tremendously; how-
ever, a limited number of these compounds has been
investigated catalytically [13–16]. Considering the number
of structures discovered, it must be realized that hetero-
geneous catalysis using organic cations bonded with POMs
as Keggin anions, especially in microwave-assisted organic
synthesis, is still in an immature state and being one of the
underdeveloped area’s research.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0420-z) contains supplementary
material, which is available to authorized users.
M. Rostami Á A. R. Khosropour (&) Á V. Mirkhani Á
I. Mohammadpoor-Baltork Á M. Moghadam Á
S. Tangestaninejad
Department of Chemistry, University of Isfahan,
Esfaha¯n 81746-73441, Iran
e-mail: khosropour@chem.ui.ac.ir
From the organic synthetic outlook, the design and
development of succession allowing highly selective
access to elaborate molecular scaffolds while combining
structural diversity with eco-compatibility, are great chal-
lenges. In this context, combination of one-pot multicom-
ponent reactions (MCRs) with microwave-assisted provide
M. Rostami
Department of Medicinal Chemistry, School of Pharmacy,
Isfahan University of Medical Sciences, Esfaha¯n 81745-359,
Iran
123

J IRAN CHEM SOC
O
Br
OAc
Table 1 Optimization of the reaction of 4-chlorobenzaldehyde, N-
benzoglycine and ethyl amine
OCH3
O
N
O
O
N
H
O
HN
CHO
NHEt
O
HN
O
HN
EtNH2
l
C
+
Ph
Ac2O
N
CO2H
H
Catalyst
4b
µ
wave
l
C
NO2
AT-130
3b
Entry Catalyst
1
2
mol% Temp.(°C) Time
(min)
Yield
(%)a
Fig. 1 Structures of N-benzoylglycine carbamides having anti-HBV
properties
1
K5CoW12O40
DBMIHClb2
[BMIm]4W10Oc32
10
10
10
90
90
90
90
90
90
90
85
75
100
90
9
5
2
9
42
72
89
75
63
0
a strength tool to generate complex molecular scaffolds
from simple and readily accessible precursors [17]. This
interest fortunately led us to the novel synthesis of AT-130
type derivatives using simple and commercially available
starting materials via a one-pot protocol. So, in continua-
tion of our endeavors in developing novel and practical
reactions to synthesize fine compounds [18–21], herein, we
describe a new approach to synthesizing N-benzoylglycine
carbamides in conjunction with microwave (lwave) irra-
diation to rapidly access differentially substituted motifs in
a one-pot protocol utilizing a catalytic amount of
[C6(MIm)2]2W10O32 [19] (Scheme 1).
3
9
4
[C6(MIm)2]2W10O32 10
9
5
[C6(MIm)2]2W10O32
[C6(MIm)2]2W10O32
–
7
5
–
9
6
9
7
9
8
[C6(MIm)2]2W10O32 10
[C6(MIm)2]2W10O32 10
[C6(MIm)2]2W10O32 10
[C6(MIm)2]2W10O32 10
9
83
74
90
45
9
9
10
11d
a
9
240
Isolated yield
b
c
d
1,6-bis(3-methylimidazolium-1-yl)hexane dichloride
Tetrakis(1-butyl-3-methylimidazolium) dodecatangestat
Under conventional heating
Results and discussion
processes. During irradiation, the temperature at the bottom
of the vials was monitored by an IR sensor which pre-
vented overheating by controlling MW power levels.
In the preliminary examination, we found that kind of
catalyst and temperature of the reaction can be greatly
affected on this transformation. Among those parameters,
catalyst was found to be critical for this reaction. In the
absence of catalyst, no reaction was observed.
In continuation of our endeavors in developing novel and
practical reactions to synthesis fine compounds [18–21],
herein, we describe a new approach to synthesis of N-
benzoylglycine carbamides in conjunction with microwave
(lwave) irradiation to rapidly access differentially substi-
tuted motifs in a one-pot protocol utilizing a catalytic
amount of [C6(MIm)2]2W10O32[12b] (Scheme 1).
To set the best experimental conditions, we initially
studied the one-pot reaction of 4-chlorobenzaldehyde with
N-benzoylglycine, acetic anhydride and ethylamine under a
variety of reaction conditions under MW energy (Table 1).
All experiments were conducted in 10 ml Teflon-sep-
tum-sealed reaction vessels with a multimode MW reactor
(Micro-Synth) to ensure an optimal reproducibility of the
In comparison with K5CoW12O40, DBMIHCl2 and
[BMIm]4W10O32, [C6(MIm)2]2W10O32 generally gave
better yields (Table 1, entries 1–4). [C6(MIm)2]2W10O32
loadings as low as 10 mol% are well tolerated (Table 1,
entry 4); however, further reductions in catalyst loading
resulted in slow reactions and side product was formed
(Table 1, entries 5 and 6). The temperature was another
Scheme 1 Synthesis of AT-130
analogues
O
N
N
NRR'
O
Ar
N
N
N
N
O
HN
-
4
A
RR'NH
,
W
10O32
ArCHO
+
CO2H
N
Ph
H
90 O
C
µ
wave
,
3
A
N
N
Ac2O
[(C6(Mim)2]2W10O32
4
123

J IRAN CHEM SOC
Table 2 Solvent-free synthesis of AT-130 analogues under microwave irradiation catalyzed by [C6(MIm)2]2W10O32
O
NR1R2
O
O
R1R2NH
+
ArCHO
Ph
N
H
CO2
H
N
3
H
Ar
Ac2O
4
Entry
Ar
Amine
Product
Time (min)
Yield (%)a
1
2
3
4
p-CH3OC6H5
p-ClC6H5
C2H5NH2
C2H5NH2
C2H5NH2
4a
4b
4c
4d
16
17
17
16
83
90
89
92
p-O2NC6H5
p-CH3OC6H5
NH
NH
NH
5
6
p-ClC6H5
4e
4f
18
18
90
94
p-O2NC6H5
7
p-CH3OC6H5
p-ClC6H5
C6H5CH2NH2
C6H5CH2NH2
C6H5CH2NH2
p-CH3C6H4NH2
p-CH3C6H4NH2
p-CH3C6H4NH2
4g
4h
4i
18
19
19
16
17
18
16
87
85
90
84
89
91
81
8
9
p-O2NC6H5
p-CH3OC6H5
p-ClC6H5
10
11
12
13
4j
4k
4l
p-O2NC6H5
p-CH3OC6H5
O
O
O
N
N
N
4m
NH2
NH2
NH2
14
15
p-ClC6H5
4n
4o
16
17
83
87
p-O2NC6H5
Reactions were performed in air atmosphere and the corresponding product was isolated with column chromatography in all cases
a
Isolated yields
key factor that improved the yields. Then optimization of
reaction conditions was also carried out at different tem-
peratures. We investigated the reaction with a temperature-
controlled program. At power 860 watt and 75 °C only
74 % of conversion was registered after 9 min (Table 1,
entry 9). However, by increasing the temperature up to
90 °C, 89 % of carbamide adducts 4 was isolated (Table 1,
entry 4b). Further increasing of the reaction temperature
shows a little impact on the yield (Table 1, entry 10).
These investigations revealed that 4b could be obtained
in 89 % yield at 90 °C in solventless condition under
microwave irradiation for 9 min. To evaluate the beneficial
of mediation of specific microwave effects, the reaction has
also been examined by utilizing of preheated oil bath for
the same duration and at the same final temperature as
measured at the end of exposure during the microwave-
assisted synthesis. It was found that reaction proceeded
very slowly in 240 min and only 45 % yield of 4b was
obtained under conventional heating at 90 °C (Table 1,
entry 11).
template reaction to 10.0 mmol, keeping the reaction
stoichiometry intact. The reaction was found to proceed
successfully, and the corresponding product was obtained
in 87 %. Next, we focused on recycling A in the above
reaction and found that the catalyst could be recycled intact
after light centrifugation and subsequent decantation of the
organic layer in 85 % average yield up to five times
without any pretreatment.
As exemplified the excellent yields (81–94 %) of the N-
benzoylglycine carbamide 4 were obtained regardless of
having an electron-withdrawing or electron-donating group
in on aldehyde (Table 2, entries 1–15).
The effect of amine was also examined which by primary
amines [ethyl amine (Table 2, entries 1-3, benzylamine
(Table 2, entries 7–9] and [isoxazol-3-yl)methanamine]
(Table 2, entries 13–15), secondary ones [piperidine
(Table 2, entries 4–6)] and anilines [p-toluidine (Table 2,
entries 10–13)] the desired products were obtained more than
80 %. The structures of all products were established com-
pletely based on spectroscopic evidence.
The high catalytic performance of [C6(MIm)2]2W10O32
was also confirmed for the large-scale reaction. Encour-
aged by the above results, we increased the scale of the
A proposed reaction mechanism is depicted in
Scheme 2. The first step involves facile producing of
2-phenyloxazol-5-one (I) that attacks to the activated
123

J IRAN CHEM SOC
O
We must lay emphasis on this fact that the time of
irradiation due to the possibility of intramolecular reaction
for prolonged periods was a key factor. Then strict control
of the reaction time must be maintained during the reaction
in order to avoid the formation of these unwanted side
products. In fact, in some of the experiments aimed at the
synthesis of N-benzoylglycine carbamides, the corre-
sponding of the 1H-imidazol-5(4H)-one (5) were detected.
In order to investigate the general tendency of the N-
benzoylglycine carbamides to produce 1H-imidazol-5(4H)-
ones via the optimized conditions, we continued irradiation
on the several N-benzoylglycine carbamides without iso-
lation from the mixture of reaction. The results are shown
in Table 3.
+
+
ArCHO
Ac2O
OH
NH
Ph
O
OH
O
O
H
N
Ar
Ph
H2O
O
Ar
O
NR1R2
Ph
Ar
HN
O
O
N
O
Ar
I
NR1R2
Ph
Ph
N
As illustrated, these processes required longer reaction
times (55–120 min) to obtain these heterocycles. Encour-
aged by these results, this procedure draws a distinction
between secondary and primary amines, as the ring closure
adducts were obtained only in the case of primary ones
exclusively (Table 3, entry 13).
HO
R1R2NH
Scheme 2 Proposed mechanism
aldehyde via Knoevenagel type condensation and produced
the intermediate (II). Ultimately, amine as nucleophile
attacks to II which activated by the catalyst and subsequent
nucleophilic addition furnished the ring-opened
cycloadduct.
An alternative examination was finally developed in an
attempt to further investigate the generality of this result
with carrying out the reaction on p-phthaldialdehyde (3p)
as a more complicated substrate.
Table 3 Time dependence of the reaction to produce the 1H-imidazole-5(4H)-one in the presence of [C6(MIm)2]2W10O32
O
O
O
NHR
O
RNH2
Ar
+
ArCHO
Ph
N
CO2H
+
NR
Ph
N
H
N
3
H
µ
Ar
wave
Ac2O
4
5
Entry
Ar
RNH2
Time (min)
Yield (%)
4
5
1
2
3
4
5
6
7
8
9
10
p-CH3OC6H5
p-ClC6H5
C2H5NH2
80
60
55
85
70
65
110
85
75
100
74
60
45
74
61
55
60
55
50
79
15
30
48
20
34
40
31
40
43
10
C2H5NH2
p-O2NC6H5
p-CH3OC6H5
p-ClC6H5
C2H5NH2
C6H5CH2NH2
C6H5CH2NH2
C6H5CH2NH2
p-CH3C6H4NH2
p-CH3C6H4NH2
p-CH3C6H4NH2
p-O2NC6H5
p-CH3OC6H5
p-ClC6H5
p-O2NC6H5
p-CH3OC6H5
O
O
O
N
N
N
NH2
NH2
NH2
11
12
13
p-ClC6H5
85
80
68
94
10
20
0
p-O2NC6H5
p-O2NC6H5
80
120
NH
Reactions were performed in air atmosphere and the corresponding product was isolated with column chromatography in all cases
a
Isolated yields
123

J IRAN CHEM SOC
Table 4 Solvent-free synthesis of bis-N-benzoylglycine carbamides under microwave irradiation catalyzed by [C6(MIm)2]2W10O32
CHO
O
O
R1R2NH
+
NR1R2
O
Ph
N
CO2H
O
R1R2N
NH
H
[DBMIH]2W10O32
HN
µ
wave
Ac2O
CHO
O
6
3
p
Entry
1
Product
Amine
Product Time (min) Yield (%)a
C2H5NH2
6a
25
92
O
NHEt
O
NH
O
HN
EtHN
O
2
3
4
6b
6c
6d
32
28
25
90
94
95
O
N
O
NH2
N
O
NH
H
O
H
HN
N
N
O
O
N
O
C6H5CH2NH2
O
N
H
O
O
NH
HN
HN
O
O
NH
N
O
O
NH
HN
N
O
5
p-CH3C6H4NH2
6e
30
91
CH3
O
N
H
O
O
NH
HN
HN
O
H3C
a
Isolated yields
One-pot reaction of 3p versus different amines, were
registered acceptable results by collecting bis-N-benzoyl-
glycine carbamides (6 a-e) in high to excellent yields,
although these require higher catalyst loadings (Table 4).
This reaction carried out well with different amines,
including primary (Table 4, entries 1–3) or secondary
amines (Table 4, entry 4) and even anilines with elec-
tron-donating groups (Table 4, entry 5). To the best of
our knowledge, this type of N-benzoylglycine carba-
mides is not unprecedented and has been previously
observed.
carbamides as derivatives of AT-130 via one-pot pseudo-
four component reaction under microwave irradiations in
the presence of [C6(MIm)2]2W10O32. Moreover, other
noteworthy features of this approach as: (1) The product
can be separated by easy work-up and (2)
[C6(MIm)2]2W10O32 could be reused for five times after
simple treatment. The clean reaction profiles, operational
and experimental simplicity, enhanced reaction rates, and
with options of further transformations of the N-benzoyl-
glycine carbamides into synthetically interesting biologi-
cally active compounds, this synthetic methodology is
ideally is suited for automated applications in organic
synthesis.
In conclusion, we have demonstrated a novel and highly
effective procedure for the synthesis of N-benzoylglycine
123

J IRAN CHEM SOC
Experimental section
Ar), 7.46-7.59 (m, 7H, Ar), 7.13 (s, 1H, C=CH); 13CNMR
(125 MHz, DMSO-d6) d (ppm): 165.61, 164.52, 133.74,
133.60, 131.60, 131.33, 131.15, 131.01, 128.22, 127.85,
127.06, 121.45, 33.98, 14.66; Mass (m/z): m/z calcd for
C18H17ClN2O2 (M?) 328.1, found 328.48, 310.41, 266.86,
105.06, 90.99, 76.99.
All products were identified by comparison of their phys-
ical and spectral data with those of authentic samples.
[C6(MIm)2]2W10O32 was synthesized according to the our
previous papers [19, 22]. Melting points were determined
in open capillaries and were uncorrected. IR spectra were
taken on a FT–IR-Tensor 27 spectrometer in KBr pellets
and reported in cm-1. NMR spectra were measured on a
Bruker DPX 400 MHz spectrometer with chemical shift (d)
given in ppm. All experiments were conducted in 10 ml
Teflon-septum-sealed reaction vessels with a multimode
MW reactor (Micro-Synth) to ensure an optimal repro-
ducibility of the processes. During irradiation, the tem-
perature at the bottom of the vials was monitored by an IR
sensor which prevented overheating by controlling MW
power levels. TLC was performed on silica gel on pre-
coated silica gel plates (Merck 60 F254, 0.25 mm).
N-((Z)-3-(4-methoxyphenyl)-1-oxo-1-(piperidin-1-yl)prop-
2-en-2-yl)benzamide:4d
White crystalline, Mp: 154–156 °C. FTIR (KBr thin film) t
(cm-1): 3,207, 2,939, 2,852, 1,656, 1,614, 1,581, 1,508,
1,478, 1,377, 1,344, 1,281, 1,244, 1,179, 1,133, 692, 530;
1HNMR(500 MHz, DMSO-d6) d (ppm): 10.29 (s, 1H,
benzamide), 7.93 (d, 2H, J = 7.45 Hz, Ar), 7.55 (t, 1H,
J = 7.20 Hz, Ar), 7.47 (t, 2H, J = 7.40 Hz, Ar), 7.17 (d,
2H, J = 8.40 Hz, Ar), 6.87 (d, 2H, J = 8.40 Hz, Ar), 6.59
(s, 1H, C=CH), 3.72 (s, 3H, OCH3), 3.19 (bs, 4H, ali-
phatic), 0.6–1.37 (bm, 6H, aliphatic); 13CNMR (125 MHz,
DMSO-d6) d (ppm): 164.29, 164.16, 158.45, 133.30,
131.70, 130.11, 129.10, 128.29, 127.71, 126.86, 115.68,
113.74, 55.16, 46.92, 23.92–24.38 (t, 3C); Mass (m/z): m/
z calcd for C22H24N2O3 (M?) 364.18, Found 364.05,
345.01, 278.98, 148.01, 104.96,76.97, 51.00.
General method for the synthesis of 4
To a mixture of 1 mmol of aldehyde, 1 mmol (0.179 g)
hippuric acid and 0.1 mmol (0.285 g) of A that well
grinded in a mortar, was added 1 ml of fresh distilled acetic
anhydride and then the mixture was submitted to micro-
wave irradiation at 90 °C (850 W) using a micro-SYNTH
lab station reactor for 9 min, In a high pressure Teflon
reactor equipped with a magnetic stir bar and an IR sensor
(for controlling the reaction temperature) (average tem-
perature of the reaction 90 °C) for preferred time, the
progress of the reaction was monitored by TLC of the
reaction mixture, then after the completion of azlactone
synthesis, 1 mmol of amine was added to the reaction
vessel and irradiation continued until the reaction com-
pletion determined according to the TLC monitoring dur-
ing the irradiation time. For working up the reaction, the
mixture was cooled down to the room temperature, after
the addition of aqueous solution of sodium hydrogen car-
bonate, the mixture of catalyst and related carbamoyl-
benzamides was filtered off and with the re-crystallization
in hot ethanol, the catalyst was recovered and the crystal-
line product isolated. The recovered catalyst can be used in
the further reaction cycle with a simple treating in a vac-
uumed oven with temperature of 80 °C.
N-((Z)-1-(benzylcarbamoyl)-2-(4-
chlorophenyl)vinyl)benzamide:4h
White crystalline, Mp: 194–195. FTIR (KBr thin film) t
(cm-1) 3,261, 3,066, 2,923, 1,641, 1,559, 1,516, 1,480,
1,424, 1,370, 1,269, 1,089, 1,012, 694, 523;
1HNMR(500 MHz, DMSO-d6) d (ppm): 9.96 (s, 1H, NH
benzamide), 8.72 (t, 1H, J = 5.90 Hz, NH carbamoyl),
7.99 (d, 2H, J = 5.00 Hz, Ar), 7.57 (d, 3H, J = 10.00 Hz,
Ar), 7.50 (t, 2H, J = 15.00 Hz, Ar), 7.41 (d, 2H,
J = 5.00 Hz, Ar), 7.30 (d, 4H, J = 5.00 Hz, Ar),
7.18–7.26 (m, 2H, Ar), 4.38 (d, 2H, J = 6.00 Hz, CH2);
13CNMR (125 MHz, DMSO-d6) d (ppm): 165.84, 164.84,
139.61, 133.59, 131.63, 131.37, 131.10, 130.91, 128.22,
128.04, 127.89, 127.81, 127.05, 126.49, 121.63, 42.55;
Mass (m/z): m/z calcd for C23H19ClN2O2 (M?) 390.86,
found 390.44, 372.19, 303.11, 105.06, 76.99, 51.00.
N-((Z)-1-(p-tolylcarbamoyl)-2-(4-
chlorophenyl)vinyl)benzamide:4k
N-((Z)-1-(ethylcarbamoyl)-2-(4-
chlorophenyl)vinyl)benzamide:4b
White crystalline solid, Mp: 241–243 °C. FTIR (KBr thin
film) t (cm-1): 3,205, 3,046, 1,639, 1,607, 1,560, 1,513,
1,485, 1,371, 1,294, 1,261, 1,013, 906, 815, 696, 531, 513;
1HNMR(500 MHz, DMSO-d6) d (ppm): 10.11 (s, 1H, NH
benzamide), 10.08 (s, 1H, NH carbamoyl), 7.99 (d, 2H,
J = 7.50 Hz, Ar), 7.58–7.63 (m, 5H, Ar), 7.52 (t, 2H,
J = 7.70 Hz, Ar), 7.44 (d, 2H, J = 8.55 Hz, Ar), 7.12 (d,
White crystalline solid, Mp: 216–218 °C. FTIR (KBr thin
film) t (cm-1); 3,243 (br), 2,926, 2,854, 1,644, 1,482,
1,446, 1,311, 1,093, 713, 526; HNMR(500 MHz, DMSO-
1
d6) d (ppm): 9.86 (s, 1H, NH benzamide), 8.17 (t, 1H,
J = 5.50 Hz, NH carbamoyl), 7.97 (d, 2H, J = 7.50 Hz,
123

J IRAN CHEM SOC
2H, J = 8.35 Hz, Ar), 7.09 (s, 1H, C=CH), 2.28 (s, 3H,
CH3); 13CNMR (125 MHz, DMSO-d6) d (ppm): 165.85,
163.92, 136.66, 133.30, 132.83, 132.27, 131.73, 130.97,
128.82, 128.47, 128.30, 127.85, 126.47, 120.03, 20.41;
Mass (m/z): m/z calcd for C23H19ClN2O2 (M?) 390.86,
found 372.09 (M?-18), 194.18, 105.10, 77.13; Anal Calcd
for C23H19ClN2O2: C, 70.68; H, 4.90; N, 7.17. Found: C,
71.00; H, 5.48; N, 6.98.
7.44–7.58 (m, 10H, Ar), 7.15 (s, 2H, C=CH), 3.14 (q, 4H,
J = 6.50 Hz, CH2 Ethyl), 1.03 (t, 6H, J = 7.20 Hz, CH3
Ethyl). 13CNMR (125 MHz, DMSO-d6) d (ppm): 165.72,
164.69, 131.49, 129.22, 129.09, 128.29, 128.17, 128.09,
127.83, 127.72, 34.00, 14.71. FTIR (KBr thin film) t
(cm-1): 3,000–3,700 (b), 2,873, 1,720, 1,611, 1,541, 1,449,
1,104, 671. Mass (m/z): m/z calcd for C30H30N4O4 (M?),
510.23, Found 420.23 (M?-90), 366.89, 353.83, 142.00,
104.95, 76.93, 63.01.
N-((Z)-1-(5-methylisoxazol-3-ylcarbamoyl)-2-(4-
6b: Pale yellow powder, Mp: 275–278 °C.
1HNMR(500 MHz, DMSO-d6) d (ppm); 11.35 (s, 2H,
benzamide), 10.32 (s, 2H, carbamoyl), 7.94 (d, 4H,
J = 7.30, Ar), 7.44–7.58 (m, 10H, Ar), 7.15 (s, 2H,
C=CH), 6.68 (s, 2H, CH isoxsazole), 2.35 (s, 6H, CH3).
13CNMR (125 MHz, DMSO-d6) d (ppm): 168.12, 165.00,
162.89, 158.24, 132.15, 131.96, 130.94, 129.18, 127.33,
127.01, 125.12, 122.27, 95.99, 12.07. FTIR (KBr thin film)
t (cm-1): 3,410, 3,197, 2,923, 1,697, 1,666, 1,616, 1,434,
1,325, 1,171, 1,108, 816, 704, 595, 452. Mass (m/z): m/
z calcd for C34H28N6O6 (M?) 616.21, Found 420.20,
281.03, 207.02, 194.15, 105.05, 76.91, 67.04, 54.08. Anal
Calcd for C34H38N6O6: C, 65.23; H, 4.58; N, 13.63 found:
C, 64.95; H, 4.65; N, 13.25.
6c: White powder, Mp: 228–230 °C. 1HNMR
(500 MHz, DMSO-d6) d (ppm): 9.98 (s, 2H, benzamide),
8.70–8.72 (t, 2H, J = 5.65 Hz, carbamoyl), 7.96 (d, 4H,
J = 7.45 Hz, Ar), 7.44–7.58 (m, 10H, Ar), 7.20–7.31 (m,
9H, Ar), 7.17–7.20 (m, 3H, Ar), 4.36 (d, 4H, J = 5.75 Hz,
CH2 benzylic). 13CNMR (125 MHz, DMSO-d6) d (ppm):
165.99, 164.89, 139.71, 134.47, 133.79, 131.58, 130.58,
129.35, 128.19, 128.06, 127.86, 127.73, 127.06, 126.49,
and 42.57. FTIR (KBr thin film) t (cm-1) 3,315, 3,062,
2,924, 1,651.7, 1,521.6, 1,474, 1,276, 697. Mass (m/z): m/
z calcd for C40H34N4O4 (M?), 634.26, Found, 419.97,
326.98, 281.14, 207.12, 105.01, 77.04, 60.10.
6d: Pale yellow powder, Mp: 267–269 °C. 1HNMR
(300 MHz, DMSO-d6) d (ppm): 10.38 (s, 2H, benzamide),
7.93 (d, 4H, J = 7.14 Hz, Ar), 7.49–7.60 (m, 6H, Ar), 7.23
(s, 4H, Ar), 6.57 (s, 2H, C=CH), 3.50 (bs, 2H, CH ali-
phatic), 3.22 (bs, 6H, CH aliphatic), 1.40 (bm, 12H, CH
aliphatic). 13CNMR (75 MHz, DMSO-d6) d (ppm): 164.90,
164.41, 136.60, 135.72, 133.73, 132.40, 128.93, 128.19,
118.62, 115.32, 47.49, 41.86, 24.67–25.02. FTIR (KBr thin
film) t (cm-1) 3,197, 2,938, 2,854, 1,668, 1,602, 1,530,
1,475, 1,445, 1,343, 1,279, 696, 562. Mass (m/z): m/z calcd
for C36H38N4O4 (M?) 590.29, Found 420.14 (M?-170.2),
105, 77, 56. Anal Calcd for C36H38N4O4: C, 73.20; H, 6.48;
N, 9.48. Found: C, 72.98; H, 6.68; N, 8.95.
nitrophenyl)vinyl)benzamide:4o
White crystalline, Mp: 238–240. FTIR (KBr thin film) t
(cm-1) 3,257, 3,073, 2,931, 1,655, 1,627, 1,526, 1,471,
1
1,426, 1,341, 1,280, 699, 525; HNMR(500 MHz, DMSO-
d6) d (ppm): 11.35 (s, 1H, NH benzamide), 10.31 (s, 1H,
carbamoyl), 8.23 (d, 2H, J = 8.70 Hz, Ar), 7.98 (d, 2H,
J = 7.55 Hz, Ar), 7.84 (d, 2H, J = 8.75 Hz, Ar), 7.61 (t,
1H, J = 7.20 Hz, Ar), 7.52 (t, 2H, J = 7.60 Hz, Ar), 7.22
(s, 1H, C=CH), 6.68 (s, 1H, CH isoxazole), 2.39 (s, 3H,
CH3); 13CNMR (125 MHz, DMSO-d6) d (ppm): 169.32,
165.99, 163.89, 158.44, 146.64, 141.09, 133.15, 132.96,
131.94, 130.38, 128.33, 128.01, 126.32, 123.57, 96.66,
12.07; Mass (m/z): m/z calcd for C20H16N4O5 (M?) 392.11,
found 294.06 (M?-98), 130.93, 104.97, 76.96, 50.99.
General method for the synthesis of 6a-e
To a mixture of 1 mmol (0.134 g) of p-phthaldialdehyde,
2.1 mmol (0.376 g) hippuric acid and 0.2 mmol (0.570 g)
of A that well grinded in a mortar, was added 1 ml of fresh
distilled acetic anhydride and then the mixture was sub-
mitted to microwave irradiation at 90 °C (850 W) using a
micro-SYNTH lab station reactor for 9 min, In a high
pressure Teflon reactor equipped with a magnetic stir bar
and an IR sensor (for controlling the reaction temperature)
(average temperature of the reaction 90 °C) for preferred
time. The progress of the reaction was monitored by TLC
of the reaction mixture, then after the completion of az-
lactone synthesis, 2.1 mmol of amine was added to the
reaction vessel and irradiation continued until the reaction
completion determined according to the TLC monitoring
during the irradiation time. For working up the reaction, the
mixture was cooled down to the room temperature, after
the addition of aqueous solution of sodium hydrogen car-
bonate, the mixture was filtered and re-crystallization in
hot ethanol. The catalyst was recovered and the crystalline
product isolated. The recovered catalyst can be used in the
further reaction cycle with a simple treating in a vacuumed
oven with temperature of 80 °C.
6e: Pale yellow powder, Mp: 287–290 °C. 1HNMR
(500 MHz, DMSO-d6) d (ppm): 10.17 (s, 2H, carbamoyl),
9.98 (s, 1H, benzamide), 7.87 (d, 4H, J = 7.45 Hz, Ar),
7.50–7.55 (m, 6H, Ar), 7.47 (t, 4H, J = 7.40 Hz, Ar),
7.21–7.31 (m, 8H, Ar), 7.18–7.20 (bs, 2H, C=CH), 2.19 (s,
6a: Pale yellow powder, Mp: 232–234 °C. 1HNMR
(500 MHz, DMSO-d6) d (ppm): 10.00 (s, 2H, benzamide),
8.20 (bs, 2H, carbamoyl), 7.94 (d, 4H, J = 7.30 Hz, Ar),
123

J IRAN CHEM SOC
6H, CH3). 13CNMR (125 MHz, DMSO-d6) d (ppm):
167.96, 167.01, 136.83, 135.23, 132.01, 131.76, 128.97,
127.93, 125.49, 124.87, 122.20, 122.18, 120.00, 118.98,
23.89. FTIR (KBr thin film) t (cm-1): 3,100–3,500 (b),
2,927, 1,610, 1,547, 1,449, 1,054, 1,028, 948, 671, 618,
469. Mass (m/z): m/z calcd for C40H34N4O4 (M?) 634.26,
Found 420.04, 166.94, 148.92, 104.94, 76.96, 56.91.
(4Z)-4-(4-methoxybenzylidene)-2-phenyl-1-p-tolyl-1H-
imidazol-5(4H)-one:5j
Yellow crystalline solid, Mp: 198–200 °C. FTIR (KBr thin
film) t (cm-1): 2,920, 2,844, 1,710, 1,638, 1,593, 1,509,
1,445, 1,377, 1,290, 1,260, 1,162, 1,021, 946, 905, 831,
1
785, 691, 508; HNMR(500 MHz, CDCl3) d (ppm): 8.28
(d, 2H, J = 8.70 Hz, Ar), 7.59 (d, 2H, J = 7.75 Hz, Ar),
7.42 (t, 1H, J = 7.70 Hz, C=CH), 7.33 (t, 3H,
J = 7.75 Hz, Ar), 7.22 (d, 2H, J = 8.10 Hz, Ar), 7.06 (d,
2H, J = 8.10 Hz, Ar), 6.98 (d, 2H, J = 8.70 Hz, Ar), 3.89
(s, 3H, OCH3), 2.39 (s, 3H, CH3); 13CNMR (125 MHz,
DMSO-d6) d (ppm): 169.15, 164.98, 147.85, 135.27,
133.30, 132.83, 132.27, 131.73, 130.97, 128.83, 128.48,
128.30, 127.85, 126.47, 122.00, 114.13, 58.31, 20.41; Mass
(m/z): m/z calcd for C24H20N2O2 (M?), 368.15, Found,
368.17, 194.1, 146.06, 104.98, 90.99, 88.98, 76.98, 66.00.
General method for the synthesis of Carbamoyl
benzamide and imidazol-5(4H)-one 5:
To a mixture of 1 mmol of aldehyde, 1 mmol hippuric acid
(0.179 g) and 0.1 mmol (0.285 g) of hydride catalyst that
well ground in a mortar, was added 1 ml of fresh distilled
acetic anhydride and then the mixture was submitted to
microwave irradiation at 90 °C (850 W) using a micro-
SYNTH lab station reactor for 9 min, In a high pressure
Teflon reactor equipped with a magnetic stir bar and an IR
sensor (for controlling the reaction temperature) (average
temperature of the reaction 90 °C) for preferred time, the
progress of the reaction was monitored by TLC of the
reaction mixture, then after the completion of azlactone
synthesis, 1 mmol of amine was added to the reaction
vessel and irradiation continued until the amount of the
imidazole-5(4H)-one reached to be highest level deter-
mined according to the TLC monitoring. For working up
the reaction, the mixture was cooled down to the room
temperature, after the addition of aqueous solution of
sodium hydrogen carbonate, the mixture of catalyst and
products were filtered off and with the dissolution in hot
ethylacetate/ethanol, the catalyst is recovered and the
mixture of products [carbamoyl-benzamide and imidazole-
5(4H)-one] 5 obtained in this manner were isolated by
column chromatography. The recovered catalyst can be
used in the further reaction cycle with a simple treating in a
vacuumed oven with temperature of 80 °C.
Acknowledgments The authors are grateful to the ‘Center of
Excellence of Chemistry of University of Isfahan (CECUI) and also
the Research Council of the University of Isfahan for financial sup-
port of this work.
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Yellow crystalline solid, Mp: 177–179 °C. FTIR (KBr thin
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131.2, 131.1, 131.0, 129.9, 128.2, 127.8, 123.8, 121.4,
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123