Synthesis of multi-substituted benzamide derivatives under microwave irradiation conditions

Article abstract of DOI:10.1002/cjoc.201180326

A facile microwave-assisted synthesis of N-[(Z)-1-(substituted carbamoyl)-2-arylvinyl] benzamide derivatives is accomplished via reactions of 4-arylmethylene-2-phenyloxazol-5(4H)-ones with different amines (for example methylamine, cyclopropylamine, para-

Full text of DOI:10.1002/cjoc.201180326

FULL PAPER
Synthesis of Multi-substituted Benzamide Derivatives under
Microwave Irradiation Conditions
Jia, Runhonga(贾润红)
Peng, Juhuaa(彭菊花)
Ma, Ningb(马宁)
Yan, Shub(严姝)
Tu, Shujiang*,b(屠树江)
a Lianyungang Teacher's College, Lianyungang, Jiangsu 222006, China
b College of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu 221116, China
A facile microwave-assisted synthesis of N-[(Z)-1-(substituted carbamoyl)-2-arylvinyl] benzamide derivatives is
accomplished via reactions of 4-arylmethylene-2-phenyloxazol-5(4H)-ones with different amines (for example me-
thylamine, cyclopropylamine, para-toluidine, phenylamine) in ethylene glycol. This protocol broadens the scope of
the reaction for the synthesis of N-benzamide derivatives.
Keywords amides, microwave irradiation, open loop, amines
Introduction
Herein, we like to report an unexpected reaction of
4-arylmethylene-2-phenyloxazol-5(4H)-ones (1) with
different amines 2 (for example methylamine, cyclo-
propylamine, para-toluidine, phenylamine) for synthesis
of N-[(Z)-1-(substituted carbamoyl)-2-arylvinyl]benza-
mides under microwave irradiation (MWI) at 120 ℃ in
ethylene glycol (Scheme 1).
A great deal of interest has been generated recently
in the synthesis of dehydro amino acids (DHA), pep-
tides (DHP) and their derivatives. DHA appear in nu-
merous peptides of microbial origin and are thought to
be biological intermediates in the synthesis of important
biologically active compounds such as penicillin.1-6
Several approaches to the synthesis of DHA have been
developed.7 However, the synthesis using hippuric acid
as substrate has seldom reported.
The microwave assisted organic synthesis has been a
topic of continued studies as it could lead to easier op-
eration and shorter reaction time as compared to the
traditional heating methods.8 Use of microwave irradia-
tion (MWI) for the formation of carbon-heteroatom,
especially carbon-nitrogen bonds, has been reported.9-11
In our earlier work, 4-arylmethylene-2-phenyl-1H-
imidazol-5(4H)-one has been synthesised by 4-arylme-
thylene-2-phenyloxazol-5(4H)-ones with urea or am-
monium acetate.12 It was unexpected that when using
other amines instead of urea and ammonium acetate, the
imidazol-5-one was not given. The open loop product,
N-((Z)-1-(substituted carbamoyl)-2-arylvinyl)benzamide,
was obtained (Figure 1).
Scheme 1
O
MWI
Cl
+
CH3NH2
glycol, 120 oC
O
N
Ph
1a
O
H
H3C
N
O
NH
Cl
Ph
3a
Results and discussion
To choose the most appropriate solvents, the
MW-assisted reaction (Scheme 2) of 4-(4-chlorobenzy-
lidene)-2-phenyl oxazol-5(4H)-one (1a, 1 mmol) and
methylamine (1 mmol) was examined using glacial ace-
tic acid (HOAc), ethylene glycol, ethanol (EtOH),
N,N-dimethyl formamide (DMF), water as the solvent
(2.0 mL) at 120 ℃, respectively. All the reactions were
carried out at the maximum power of 300 W. As shown
in Table 1, we could see that the reaction in glycol gave
O
R
H
N
Ar
O
NH
Ph
Figure 1 Structure of compounds 3.
*
E-mail: jiarunhong@126.com.
Received March 12, 2011; revised April 20, 2011; accepted May 10, 2011.
Project supported by the National Natural Science Foundation of China (No. 20672090), Natural Science Foundation of Jiangsu Province (No.
BK2006033), and the Qing Lan Project of Jiangsu Province (No. 08QLT001).
Chin. J. Chem. 2011, 29, 1869— 1872
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Jia et al.
FULL PAPER
the best results (Table 1, Entry 2).
Table 2 Temperature optimization for the synthesis of 3a under
MWI
Scheme 2
Entry
Temp./℃
90
Time/min
Yield/%
21
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
O
Ar
Ar
OH
NHR
O
100
46
Ar
N
O
R-NH3
110
59
N
Ph
120
91
Ph
1
130
85
4
O
O
140
72
R
H
N
150
50
Ar
NH2
====
RN
O
NH
160
45
Ph
O
Ph
5
3
Under the optimal conditions [glycol, 120 ℃, 300
W (maximum power)], reactions of different 4-arylme-
thylene-2-phenyloxazol-5(4H)-ones were performed,
which led to the corresponding N-[(Z)-1-(substituted
carbamoyl)-2-arylvinyl]benzamides with good yields.
The electronic effect of the aryl group in 4-arylmethy-
lene-2-phenyloxazol-5(4H)-ones was investigated. As
shown in Table 3, both electron-withdrawing (such as
nitro) and electron-donating (such as alkoxy) groups
readily provided compounds 3 in good yields.
Table 1 Solvent optimization for the synthesis of 3a under
MWI
Entry
Solvent
HOAc
Glycol
EtOH
DMF
Temp./℃
120
Time/min
Yield/%
trac
91
1
2
3
4
5
5
5
5
5
5
120
120
59
120
70
Water
120
22
We envisaged that amino group attacks on carbonyl
group in 4-arylmethylene-2-phenyloxazol-5(4H)-ones
(1) as a nucleophile. Bond formation should lead di-
rectly to product 3 via ring opening, which then poised
to attack adjacent reactive carbonyl group (Scheme 3).
The reaction temperatures affected the reaction.
When the reaction temperature was 120 ℃, the open
loop product, N-[(Z)-1-(substitutedcarbamoyl)-2-aryl-
vinyl]benzamide, was given. When the reaction tem-
perature was 150 ℃, the closed loop product, 4-aryl-
methylene-2-phenyl-1H-imidazol-5(4H)-one, was given.
The synthesis of these compounds has reported in our
previous study.13 This further proved the closed loop
product needs higher temperature.
To further optimize reaction conditions, the same
reaction was performed in ethylene glycol and 300 W at
the temperatures ranging from 90 ℃ to 160 ℃ in in-
crements of 10 ℃ each time. The yield of product 3a
was improved from 21% to 91%, when the temperature
was raised from 90 to 120 ℃ (Table 2, Entries 1—4).
However, no significant increase in the yield of product
3a was observed as the reaction temperature was raised
from 130 to 160 ℃ (Table 2, Entries 5—8). Therefore,
120 ℃ phenyloxazol-5(4H)-ones were performed,
which led to the corresponding multi-substituted ben-
zamide derivatives with good yields.
Table 3 Physical and analytical data of compounds 3
Entry
1
Compd.
3a
R
Ar
4-ClC6H4
Time/min
Yield/%
91
m.p./℃
Methyl
Methyl
Methyl
Methyl
4
5
6
6
4
5
5
6
5
5
6
6
4
207—208
218—219
216—217
234—235
211—212
204—205
195—196
193—194
239—240
260—261
241—242
219—221
254—256
2
3b
3c
2,4-Cl2C6H3
81
3
3,4-OCH2OC6H3
4-(CH3)2NC6H4
87
4
3d
3e
82
5
Cyclopropyl 4-ClC6H4
Cyclopropyl 4-BrC6H4
Cyclopropyl C6H5
81
6
3f
83
7
3g
80
8
3h
3i
Cyclopropyl 4-(CH3)2NC6H4
4-CH3C6H4 4-BrC6H4
4-CH3C6H4 C6H5
85
9
88
10
11
12
13
3j
81
3k
3l
4-CH3C6H4 4-CH3C6H4
84
C6H5
C6H5
4-ClC6H4
4-BrC6H4
89
3m
88
1870
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Chin. J. Chem. 2011, 29, 1869— 1872

Synthesis of Multi-substituted Benzamide Derivatives
Scheme 3
MHz) δ: 2.70 (d, J＝4.4 Hz, 3H), 7.16 (s, 1H), 7.37 (d,
J＝8.4 Hz, 1H), 7.47—7.57 (m, 4H), 7.70 (s, 1H), 7.91
(d, J＝7.6 Hz, 2H), 8.24 (d, J＝4.4 Hz, 1H), 9.91 (s,
1H); IR (KBr) v: 3313, 3238, 3067, 1637, 1551, 1483,
O
O
Ar
H
N
O
R
MWI
Ar
+
RNH2
O
N
glycol, 120 oC
NH
－
1
2
1279, 868, 788, 693 cm ; HRMS calcd for C17H14Cl2-
Ph
Ph
N2O2 371.0325, found 371.0326.
1
3
N-[(Z)-1-(Methylcarbamoyl)-2-(benzo[d][1,3]di-
oxol-5-yl)vinyl]benzamide (3c) 1H NMR (DMSO,
400 MHz) δ: 2.66 (d, J＝4.8 Hz, 3H), 5.99 (s, 2H), 6.91
(d, J＝8.0 Hz, 1H), 7.07 (dd, J＝7.6, 1.2 Hz, 1H), 7.14
(s, 1H), 7.22 (s, 1H), 7.52 (t, J＝7.2 Hz, 2H), 7.59 (d,
J＝7.2 Hz, 1H), 8.02 (d, J＝7.2 Hz, 3H), 9.84 (s, 1H);
R = Me, cyclopropyl, phenyl, p-methylphenyl
Conclusions
In summary, we demonstrated a simple method, us-
ing readily available starting materials and simple ex-
perimental procedures, for the efficient synthesis of
N-[(Z)-1-(substituted carbamoyl)-2-arylvinyl]benzamides.
Particularly valuable features of this cascade reaction
included operational simplicity, high yields, increased
safety for small-scale high-speed synthesis, and broader
substrate scope.
IR (KBr) v: 3418, 3218, 3066, 2896, 1644, 1626, 1482,
－
1255, 1037, 928, 698 cm 1; HRMS calcd for
C18H16N2O4 347.1003, found 347.1002.
N-{(Z)-1-(Methylcarbamoyl)-2-[4-(dimethyla-
mino)phenyl] vinyl}benzamide (3d)
1H NMR
(DMSO, 400 MHz) δ: 2.66 (d, J＝4.8 Hz, 3H), 2.90 (s,
6H), 6.63 (d, J＝8.8 Hz, 2H), 7.22 (s, 1H), 7.41 (d, J＝
8.8 Hz, 2H), 7.53 (t, J＝7.6 Hz, 2H), 7.58 (d, J＝7.2 Hz,
1H), 7.84 (d, J＝4.4 Hz, 1H), 8.04 (d, J＝7.6 Hz, 2H),
9.75 (s, 1H); IR (KBr) v: 3310, 3217, 2932, 2806, 1657,
1643, 1525, 1279, 693 cm － 1; HRMS calcd for
C19H21N3O2 346.1526, found 346.1538.
Experimental
All reactions were performed in a monomodal Em-
rysTM Creator from Personal Chemistry, Uppsala, Swe-
den. Melting points were determined in open capillaries
and are uncorrected. IR spectra were recorded on a
N-[(Z)-1-(Cyclopropylcarbamoyl)-2-(4-chlorophe-
nyl) vinyl]benzamide (3e) 1H NMR (DMSO, 400
MHz) δ: 0.51—0.53 (m, 2H), 0.63—0.65 (m, 2H),
2.73—2.76 (m, 1H), 7.03 (s, 1H), 7.40 (d, J＝8.8 Hz,
2H), 7.49—7.57 (m, 5H), 7.97 (d, J＝7.6 Hz, 2H), 8.23
(d, J＝4.0 Hz, 1H), 9.87 (s, 1H); IR (KBr) v: 3231, 2998,
1
FT-IR-tensor 27 spectrometer in KBr. H NMR spectra
were measured on a DPX 400 MHz spectrometer using
TMS as an internal standard and DMSO-d6 as solvent.
HRMS was determined by using microTOF-Q||
HRMS/MS instrument (BRUKER).
－
1
1669, 1644, 1524, 1486, 1311, 887, 810, 714 cm ;
HRMS calcd for C19H17ClN2O2 363.0871, found
363.0880.
Synthesis of N-[(Z)-1-(substituted carbamoyl)-2-
arylvinyl]benzamide (3)
In a 10 mL EmrysTM reaction via l, 4-arylmethylene-
2-phenyloxazol-5(4H)-ones (1) (1 mmol) with different
amine 2 (methylamine, cyclopropylamine, para-tolui-
dine, phenylamine) (1.5 mmol), in ethylene glycol (2.0
mL) were mixed and then capped. The mixture was ir-
radiated by microwave at 300 W and 120 ℃ for a
given time. The automatic mode stirring helped the
mixing and uniform heating of the reactants. Upon
completion, monitored by TLC, the reaction mixture
was cooled to room temperature and then poured into
cold water, filtered to give the crude products, which
were further purified by recrystallization from 95%
EtOH. The reaction time and the yields are listed in Ta-
ble 3. The analytical data of new products are as fol-
lows.
N-[(Z)-1-(Cyclopropylcarbamoyl)-2-(4-bromophe-
nyl) vinyl]benzamide (3f) 1H NMR (DMSO, 400
MHz) δ: 0.51—0.53 (m, 2H, CH2), 0.63—0.65 (m, 2H,
CH2), 2.73—2.74 (m, 1H, CH), 7.00 (s, 1H, CH),
7.46—7.59 (m, 7H, ArH), 7.97 (d, J＝7.2 Hz, 2H, ArH),
8.26 (d, J＝4.0 Hz, 1H, NH), 9.89 (s, 1H, NH); IR (KBr)
v: 3361, 3230, 3048, 2995, 1666, 1643, 1524, 1485, 886,
－
1
712 cm ; HRMS calcd for C19H17BrN2O2 407.0366,
found 407.0360.
N-[(Z)-1-(Cyclopropylcarbamoyl)-2-phenylvinyl]-
benzamide (3g) 1H NMR (DMSO, 400 MHz) δ:
0.52—0.54 (m, 2H), 0.63—0.65 (m, 2H), 2.73—2.75
(m, 1H), 7.08 (s, 1H), 7.27—7.35 (m, 3H), 7.49—7.58
(m, 5H), 7.99 (d, J＝7.6 Hz, 2H), 8.18 (d, J＝4.0 Hz,
1H), 9.86 (s, 1H); IR (KBr) v: 3244, 3054, 1641, 1518,
1482, 842, 690 cm－ 1; HRMS calcd for C19H18N2O2
329.1261, found 329.1264.
N-[(Z)-1-(Methylcarbamoyl)-2-(4-chlorophenyl)-
vinyl] benzamide (3a) 1H NMR (DMSO, 400 MHz) δ:
2.68 (d, J＝3.6 Hz, 3H), 7.19 (s, 1H), 7.41 (d, J＝7.6
Hz, 2H), 7.50—7.61 (m, 5H), 7.99 (d, J＝7.6 Hz, 2H),
8.15 (d, J＝4.0 Hz, 1H), 9.95 (s, 1H); IR (KBr) v: 3442,
N-[(Z)-1-(Cyclopropylcarbamoyl)-2-(4-(dimethyl-
amino) phenyl)vinyl]benzamide (3h)
1H NMR
(DMSO, 400 MHz) δ: 0.50—0.51 (m, 2H), 0.61—0.63
(m, 2H), 2.71—2.74 (m, 1H), 2.90 (s, 6H), 6.63 (d, J＝
8.8 Hz, 2H), 7.10 (s, 1H), 7.41 (d, J＝8.8 Hz, 2H),
7.50—7.53 (m, 2H), 7.57 (d, J＝7.2 Hz, 1H), 7.94 (d,
J＝4.0 Hz, 1H), 8.02 (d, J＝7.2 Hz, 2H), 9.67 (s, 1H);
IR (KBr) v: 3245, 3056, 3007, 2892, 2803, 1645, 1602,
－
1
3243, 3072, 2940, 1644, 1518, 1484, 816, 607 cm ;
HRMS calcd for C17H15ClN2O2 337.0715, found
337.0736.
N-[(Z)-1-(Methylcarbamoyl)-2-(2,4-dichlorophen-
yl)vinyl] benzamide (3b) 1H NMR (DMSO, 400
Chin. J. Chem. 2011, 29, 1869— 1872
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1871

Jia et al.
FULL PAPER
－
1525, 1480, 813, 697 cm 1; HRMS calcd for
C21H23N3O2 372.1678, found 372.1678.
2H), 7.51—7.73 (m, 9H), 8.01 (d, J＝7.2 Hz, 2H),
10.13 (s, 1H), 10.23 (s, 1H); IR (KBr) v: 3266, 3134,
3063, 1650, 1547, 1505, 1443, 1323, 1257, 1075, 691
cm ; HRMS calcd for C22H17BrN2O2 443.0371, found
443.0376.
N-((Z)-1-(p-Tolylcarbamoyl)-2-(4-bromophenyl)-
vinyl)benzamide (3i) 1H NMR (DMSO, 400 MHz) δ:
2.27 (s, 3H), 7.06 (s, 1H), 7.13 (d, J＝8.0 Hz, 2H),
7.53—7.61 (m, 9H), 7.99 (d, J＝7.6 Hz, 2H), 10.13 (s,
1H), 10.17 (s, 1H); IR (KBr) v: 3213, 3118, 3060, 1645,
－
1
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1601, 1513, 1288, 1185, 1074, 818 cm ; HRMS calcd
1
2
3
4
5
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found 379.1449.
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3H), 2.28 (s, 3H), 7.11 (s, 1H), 7.13—7.20 (m, 4H),
7.51—7.61 (m, 7H), 8.02 (d, J＝7.6 Hz, 2H), 10.04 (s,
1H), 10.05 (s, 1H); IR (KBr) v: 3218, 3118, 3029, 1648,
1602, 1514, 1481, 1406, 1323, 1258, 1184, 818, 694
6
7
－
1
8
9
cm ; HRMS calcd for C24H22N2O2 393.1579, found
393.1616.
N-[(Z)-1-(Phenylcarbamoyl)-2-(4-chlorophenyl)-
vinyl]benzamide (3l) 1H NMR (DMSO, 400 MHz) δ:
7.07—7.09 (m, 1H), 7.10 (s, 1H), 7.33 (t, J＝8.0 Hz,
2H), 7.46—7.73 (m, 9H), 8.01 (d, J＝7.2 Hz, 2H),
10.14 (s, 1H), 10.23 (s, 1H); IR (KBr) v: 3272, 3134,
3064, 1650, 1550, 1509, 1475, 1324, 1259, 1098, 707
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－
1
cm ; HRMS calcd for C22H17ClN2O2 399.0876, found
399.0891.
N-((Z)-1-(Phenylcarbamoyl)-2-(4-bromophenyl)-
vinyl)benzamide (3m) 1H NMR (DMSO, 400 MHz)
δ: 7.05—7.08 (m, 1H), 7.09 (s, 1H), 7.32 (t, J＝8.0 Hz,
(E1103012 Sun, H.; Fan, Y.)
1872
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1869— 1872