Synthesis of styryl substituted semicarbazides under microwave irradiation

Article abstract of DOI:10.3184/174751913X13686117077447

A series of styryl substituted semicarbazides were synthesised by reaction of trans-styryl isocyanate, prepared by Curtius rearrangement of cinnamoyl azide, with acid hydrazides under microwave irradiation using a one-pot procedure. The effects of microwa

Full text of DOI:10.3184/174751913X13686117077447

356 RESEARCH PAPER
JUNE, 356–358
JOURNAL OF CHEMICAL RESEARCH 2013
Synthesis of styryl substituted semicarbazides under microwave
irradiation
Lan-Qin Chaia*, Hong-Song Zhangb, Gang Liu, Jiao-Jiao Huanga and Qiao-Qiao Chenga
aSchool of Chemistry and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, P. R. China
bSecond Hospital of Lanzhou University, Lanzhou, Gansu 730030, P. R. China
A series of styryl substituted semicarbazides were synthesised by reaction of trans-styryl isocyanate, prepared by
Curtius rearrangement of cinnamoyl azide, with acid hydrazides under microwave irradiation using a one-pot proce-
dure. The effects of microwave irradiation in promoting the condensation of trans-styryl isocyanate with hydrazides
were investigated alongside a conventional heating method (oil bath at 120 °C). When compared with classical
methods, microwave irradiation has the advantages of mild conditions, easy handling, and high yields. The products
have been characterised by analytical and spectral (IR and 1H NMR) data.
Keywords: Curtius rearrangement, isocyanate, semicarbazides, microwave irradiation
The rapid heating effect of microwave irradiation has caught
the attention of synthetic chemists in recent years due to the
remarkable reduction of reaction time and enhancement of
reaction yield.1–3 Semicarbazide derivatives are widely used
as medicines and agrochemicals because of their anticonvul-
sive,4 herbicidal,5 antineoplastic,6 and hypotensive activities.7
The synthetic protocols for the synthesis of semicarbazides
generally utilise phosgene or phosgene-based isocyanates as
the starting materials,8,9 both of which are toxic or unstable.
These methods also need long reaction times. Therefore, it is
necessary to develop phosgene-free and shorter routes to
semicarbazides.
We have tried to develop an environmentally benign meth-
odology to synthesise a new series of compounds bearing
both semicarbazide and coumarin or benzofuran moieties,10,11
with the objective of investigating the property and structure–
activity relationships of these new compounds and obtaining
new biologically active molecules.
conventional heating method (oil bath at 120 °C). When com-
pared to classical heating, the rates of the microwave irradiated
reactions were increased by at least 32 times and also gave
high yields. The results obtained are reported in Table 1.
We selected the synthesis of compound 3b as a model reac-
tion to study the effects of irradiation power and time on the
yields. The best yields obtained were 84% after 13 minutes of
irradiation with 490W and using toluene as the solvent. Greater
power or longer irradiation times induced a decrease in yield
(only 73% with 700 W or 72% after 15 minutes) due to the
decomposition of trans-styryl isocyanate.
In summary, the synthesis of unsymmetrically substituted
semicarbazides has been accomplished employing the Curtius
rearrangement of cinnamoyl azide followed by nucleophile
addition of hydrazines to the NCO moiety under microwave
irradiation. Compared to conventional thermal heating, micro-
wave irradiation decreased the reaction time from 8–12 h to
13–18 min. The main advantages of this method are short reac-
tion times, high yields, less byproducts and simple handling of
starting materials and products.
Results and discussion
We now report an expeditious, one-pot and efficient method
for the preparation of a series of unsymmetrically substituted
semicarbazides. As shown in Scheme 1, 1-benzoyl-4-styryl
semicarbazides (3a–h) and 1-aryloxyacetyl-4-styrylsemicar-
bazides (4a–h) were synthesised by reaction of trans-styryl
isocyanate with various aryl carboxylic acid hydrazides and
aryloxyacetic acid hydrazides, respectively, under microwave
irradiation. trans-Styryl isocyanate was prepared by sequential
treatment of cinnamic acid with ethyl chloroformate and
sodium azide in the presence of triethylamine followed by
Curtius rearrangement.12–14
Experimental
IR spectra were recorded using KBr pellets on a Nicolet VERTEX 70
FT-IR spectrophotometer. H NMR spectra were obtained with a
1
Varian Mercury plus (400 MHz or 300 MHz) instrument using DMSO-
d6 as solvent and TMS as internal standard. Elemental analyses were
performed on a ElementarAnalysensysteme GmbH Vario EL Elemen-
tal Analysis instrument. Melting points were determined with a XT-4
thermal apparatus supplied by the Beijing Electronic Design and
Optical Instruments Factory, China and are uncorrected. Microwave
irradiations were carried out in a Galanz domestic microwave oven in
which a hole was made in the roof of the oven to permit a condenser
to be fitted to the flask undergoing irradiation. Irradiation was carried
The effects of microwave irradiation in promoting the con-
densation of 2 with hydrazides were investigated alongside a
Scheme 1
* Correspondent. E-mail: chailq@mail.lzjtu.cn

JOURNAL OF CHEMICAL RESEARCH 2013 357
Table 1 Yields, reaction times, melting points, and elemental
analyses of compounds 3a–h and 4a–h
completion of the reaction, monitored by TLC, ethyl acetate and
petroleum ether (b.p. 60–90 °C) (2:3) as eluent, the solvent was
removed under reduced pressure. From the residue the products 3a–h
and 4a–h were isolated by recrystallisation from DMF–EtOH.
1-Benzoyl-4-styrylsemicarbazide (3a): IR (KBr, ν/cm−1): 3296,
Compd
Ar
Yield/%
Reaction time
M.p./°C
MWIa Refluxb MWI/mina Reflux/hb
1
3278 (N–H), 1685, 1652 (C=O); 1610 (C=C); H NMR (400 MHz,
3a
3b
80
84
71
73
14
13
8
8
153–154
228–230
DMSO-d6) δ = 10.08 (s, 1H, NH), 8.82 (d, 1H, J = 9.9 Hz, NH), 8.76
(s, 1H, NH), 8.23–7.16 (m, 11H, ArH and CH), 6.06 (d, 1H, J = 14.4
Hz, CH). MS: m/z = 281. Anal. Calcd for C16H15N3O2: C, 68.31; H,
5.37; N, 14.94. Found: C, 68.52; H, 5.51; N, 15.12%.
1-(4-Methylbenzoyl)-4-styrylsemicarbazide (3b): IR (KBr, ν/cm−1):
3304, 3286 (N–H), 1694, 1658 (C=O); 1618 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.14 (s, 1H, NH), 8.88 (d, 1H, J = 10.2 Hz,
NH), 8.80 (s, 1H, NH), 8.32–7.24 (m, 10H, ArH and CH), 6.10 (d, 1H,
J = 14.8 Hz, CH), 2.31 (s, 3H,CH3). MS: m/z = 295. Anal. Calcd for
C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 69.32; H, 5.95; N,
14.41%.
3c
81
75
72
66
14
16
8
216–218
205–206
3d
10
3e
3f
72
74
76
63
64
65
16
15
15
10
9
>300
1-(4-Chlorobenzoyl)-4-styrylsemicarbazide (3c): IR (KBr, ν/cm−1):
3298, 3281 (N–H), 1682, 1650 (C=O); 1615 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.18 (s, 1H, NH), 9.01 (d, 1H, J = 10.5 Hz,
NH), 8.96 (s, 1H, NH), 8.36–7.27 (m, 10H, ArH and CH), 6.08 (d, 1H,
J = 14.7 Hz, CH). MS: m/z = 315. Anal. Calcd for C16H14N3O2Cl: C,
60.86; H, 4.47; N, 13.31. Found: C, 60.98; H, 4.62; N, 13.45%.
1-(3-Nitrobenzoyl)-4-styrylsemicarbazide (3d): IR (KBr, ν/cm−1):
3302, 3284 (N–H), 1690, 1656 (C=O); 1616 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.24 (s, 1H, NH), 9.08 (d, 1H, J = 10.8 Hz,
NH), 9.03 (s, 1H, NH), 8.78–7.32 (m, 10H, ArH and CH), 6.12 (d, 1H,
J = 15.2 Hz, CH). MS: m/z = 326. Anal. Calcd for C16H14N4O4: C,
58.89; H, 4.32; N, 17.17. Found: C, 59.01; H, 4.48; N, 17.32%.
1-(4-Nitrobenzoyl)-4-styrylsemicarbazide (3e): IR (KBr, ν/cm−1):
3296, 3279 (N–H), 1688, 1654 (C=O); 1613 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.21 (s, 1H, NH), 9.05 (d, 1H, J = 10.5 Hz,
NH), 9.01 (s, 1H, NH), 8.76–7.28 (m, 10H, ArH and CH), 6.10 (d, 1H,
J = 14.8 Hz, CH). MS: m/z = 326. Anal. Calcd for C16H14N4O4: C,
58.89; H, 4.32; N, 17.17. Found: C, 59.98; H, 4.51; N, 17.34%.
(E)-1-Cinnamoyl-4-styrylsemicarbazide (3f): IR (KBr, ν/cm−1):
3302, 3283 (N–H), 1684, 1657 (C=O); 1614 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.06 (s, 1H, NH), 8.98 (d, 1H, J = 10.2 Hz,
NH), 8.92 (s, 1H, NH), 8.22–7.21 (m, 12H, ArH and CH), 6.88 (d, 1H,
J = 15.3 Hz, CH), 6.06 (d, 1H, J = 14.4 Hz, CH). MS: m/z = 307. Anal.
Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C, 70.52;
H, 5.73; N, 13.81%.
1-(Benzofuran-2-carbonyl)-4-styrylsemicarbazide (3g): IR (KBr,
ν/cm−1): 3294, 3283 (N–H), 1687, 1655 (C=O); 1611 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.14 (s, 1H, NH), 9.06 (d, 1H, J = 10.0 Hz,
NH), 9.02 (s, 1H, NH), 8.67–7.25 (m, 11H, ArH, CH and benzofuran-
H), 6.06 (d, 1H, J = 14.4 Hz, CH). MS: m/z = 321. Anal. Calcd for
C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.42; H, 4.88; N,
13.21%.
1-(Coumarin-3-carbonyl)-4-styrylsemicarbazide (3h): IR (KBr,
ν/cm−1): 3314, 3284 (N–H), 1698, 1660 (C=O); 1614 (C=C); 1H NMR
(400 MHz, DMSO-d6) δ = 10.28 (s, 1H, NH), 9.12 (d, 1H, J = 10.8 Hz,
NH), 9.08 (s, 1H, NH), 8.92–7.18 (m, 11H, ArH, CH and coumarin-
H), 6.08 (d, 1H, J = 14.7 Hz, CH)). MS: m/z = 349. Anal. Calcd for
C19H15N3O4: C, 65.32; H, 4.33; N, 12.03. Found: C, 65.46; H, 4.47; N,
12.21%.
170–171
194–195
3g
9
3h
71
62
18
12
>300
4a
4b
81
82
70
71
16
15
10
9
228–229
208–209
4c
4d
4e
80
84
85
70
73
74
16
15
14
10
9
220–222
232–233
222–223
8
4f
83
72
18
12
207–208
4g
4h
75
84
66
72
16
16
10
10
200–201
213–214
a Irradiated by microwave at 490 W; b heated at 120 °C.
out at 490W typically for about 13–18 minutes. In periods of irradia-
tion, precautions were taken to avoid exposure to experimentalists.
Benzofuran-2-carboxylic acid,15 coumarin-3-carboxylic acid, aryl
carboxylic acid hydrazides,16 and aryloxyacetic acid hydrazides17
were prepared according to literature procedures. Aryloxyacetic acids
were commercially available and used as-received.
Synthesis of cinnamoyl azide 1
A mixture of cinnamic acid (10 mmol, 1.482 g), triethylamine
(11 mmol, 1.111 g), and ethyl chloroformate (11 mmol, 1.194 g) in
dry acetone (40 mL) was stirred at 0 °C for 1 h. Then sodium azide
(11 mmol, 0.715 g) in water (15 mL) was added, and the mixture was
kept at 0 °C for 7 h. After the reaction was completed (monitored
by TLC), the mixture was poured onto ice. Then the suspension was
filtered, and the product was obtained. Yield: 97.3%, white crystals;
m.p. 86–87 °C (86 °C18–20). IR (KBr, ν/cm−1): 2162 (N≡N), 1703
1-(2-Phenoxyacetyl)-4-styrylsemicarbazide (4a): IR (KBr, ν/cm−1):
3300, 3264 (N–H), 1678, 1663 (C=O); 1613 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ = 10.08 (s, 1H, NH), 8.98 (d, 1H, J = 10.8 Hz,
NH), 8.45 (s, 1H, NH), 7.98–6.82 (m, 11H, ArH and CH), 6.08 (d, 1H,
J = 14.7 Hz, CH), 4.78 (s, 2H, CH2O). MS: m/z = 311. Anal. Calcd for
C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.71; H, 5.68; N,
13.72%.
1-(2-Methylphenyloxyacetyl)-4-styrylsemicarbazide (4b): IR (KBr,
ν/cm−1): 3295, 3258 (N–H), 1670, 1658 (C=O); 1611 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ = 10.11 (s, 1H, NH), 8.97 (d, 1H, J = 10.5 Hz,
NH), 8.48 (s, 1H, NH), 7.92–6.84 (m, 10H, ArH and CH), 6.11 (d, 1H,
J = 15.0 Hz, CH), 4.72 (s, 2H, CH2O), 2.26 (s, 3H, CH3). MS: m/z =
325. Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found:
C, 66.62; H, 5.98; N, 13.13%.
1
(C=O), 1546 (C=C), 1333 (N=N); H NMR (400 MHz, DMSO-d6)
δ = 6.90–7.36 (m, 6H, ArH and CH), 6.06 (d, 1H, J = 14.4 Hz, CH).
MS: m/z = 173. Anal. Calcd for C9H7ON3: C, 62.42; H, 4.07; N, 24.26.
Found: C, 62.58; H, 4.19; N, 24.45%.
Synthesis of compounds 3a–h and 4a–h; general procedure
A solution of cinnamoyl azide 1 (0.5 mmol) in toluene (20 mL) was
heated at 120 °C for 4 h to give trans-styryl isocyanate 2, which
was not isolated but treated in situ with various aryl carboxylic acid
hydrazides and aryloxyacetic acid hydrazides, respectively, under
microwave irradiation at 490 W for the time given in Table 1. After the
1-(3-Methylphenyloxyacetyl)-4-styrylsemicarbazide (4c): IR (KBr,
ν/cm−1): 3298, 3260 (N–H), 1673, 1653 (C=O); 1613 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ = 10.06 (s, 1H, NH), 8.96 (d, 1H, J = 10.2 Hz,

358 JOURNAL OF CHEMICAL RESEARCH 2013
NH), 8.44 (s, 1H, NH), 7.94–6.86 (m, 10H, ArH and CH), 6.10 (d, 1H,
J = 14.8 Hz, CH), 4.57 (s, 2H, CH2O), 2.28 (s, 3H, CH3). MS: m/z =
325. Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found:
C, 66.64; H, 6.01; N, 13.14%.
1-(4-Methylphenyloxyacetyl)-4-styrylsemicarbazide (4d): IR (KBr,
ν/cm−1): 3300, 3262 (N–H), 1680, 1652 (C=O); 1612 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ = 10.03 (s, 1H, NH), 8.92 (d, 1H, J = 9.9 Hz,
NH), 8.41 (s, 1H, NH), 7.96–6.88 (m, 10H, ArH and CH), 6.08 (d, 1H,
J = 14.7 Hz, CH), 4.70 (s, 2H, CH2O), 2.24 (s, 3H, CH3). MS: m/z =
325. Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found:
C, 66.61; H, 6.03; N, 13.12%.
We are thankful for the financial support by the Natural
Science Foundation of Gansu Province (No. 1107RJZA165),
and the Innovation and Technology Fund of Lanzhou Jiaotong
University (No. DXS-2013-035).
Received 8 February 2013; accepted 28 March 2013
Paper 1301785 doi: 10.3184/174751913X13686117077447
Published online: 12 June 2013
References
1-(4-Methoxyphenyloxyacetyl)-4-styrylsemicarbazide (4e): IR
(KBr, ν/cm−1): 3293, 3265 (N–H), 1685, 1665 (C=O); 1614 (C=C); 1H
NMR (300 MHz, DMSO-d6) δ = 9.96 (s, 1H, NH), 8.97 (d, 1H, J =
10.5 Hz, NH), 8.38 (s, 1H, NH), 7.35–7.25 (m, 5H, ArH), 7.12–7.07
(m, 1H, CH), 6.96–6.83 (m, 4H, ArH), 6.06 (d, 1H, J = 14.4 Hz, CH),
4.53 (s, 2H, CH2O), 3.70 (s, 3H, CH3O). MS: m/z = 341. Anal. Calcd
for C18H19N3O4: C, 63.33; H, 5.61; N, 12.31. Found: C, 63.54; H, 5.52;
N, 12.48%.
1-(2,4-Dichlorophenyloxyacetyl)-4-styrylsemicarbazide (4f): IR
(KBr, ν/cm−1): 3286, 3275 (N–H), 1688, 1656 (C=O); 1616 (C=C);
1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H, NH), 8.92 (d, 1H, J =
9.9 Hz, NH), 8.33 (s, 1H, NH), 7.84–6.68 (m, 9H, ArH and CH), 6.12
(d, 1H, J = 15.2 Hz, CH), 4.78 (s, 2H, CH2O). MS: m/z = 379. Anal.
Calcd for C17H15Cl2N3O3: C, 53.70; H, 3.98; N, 11.05. Found: C,
53.62; H, 3.81; N, 11.26%.
1
2
3
4
A.K. Bose, M.S. Manhas, S.N. Ganguly, A.H. Sharma and B.K. Banik,
Synthesis, 2002, 32, 1579.
X.C. Wang, M.G. Wang, Z.J. Quan and Z. Li, Synth. Commun., 2005, 35,
2881.
Z. Li, J.L. Yu, R.B. Ding, Z.Y. Wang and X.C. Wang, Synth. Commun.,
2005, 35, 2981.
M. Takumi, K. Takanobu, I. Takatoshi and M. Toshiyuki, Synth. Commun.,
2000, 30, 1675.
J.L. Vidalu, F. Calmel and D. Bigg, J. Med. Chem., 1994, 37, 689.
M.J. Gil, M.A. Mañú and C. Arteaga, Bioorg. Med. Chem. Lett., 1999, 16,
2321.
E.G. Chalina, L. Chakarova and D.T. Staneva, Eur. J. Med. Chem., 1998,
33, 985.
A. Arrieta and C. Palomo, Tetrahedron Lett., 1981, 22, 1729.
R.A. Batey, V. Santhakumar, C. Yoshina-Ishii and S.D. Taylor, Tetrahedron
Lett., 1998, 39, 6267.
5
6
7
8
9
10 L.Q. Chai, H.S. Zhang, Y.L. Zhang and K. Cui, J. Chem. Res., 2012, 36,
12.
1-(1-Naphthyloxyacetyl)-4-styrylsemicarbazide (4g): IR (KBr,
ν/cm−1): 3312, 3270 (N–H), 1696, 1663 (C=O); 1615 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ 10.05 (s, 1H, NH), 9.02 (d, 1H, J = 10.2 Hz,
NH), 8.45 (s, 1H, NH), 7.55–6.87 (m, 13H, ArH and CH), 6.08 (d, 1H,
J = 14.7 Hz, CH), 4.82 (s, 2H, CH2O). MS: m/z = 361. Anal. Calcd for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.94; H, 5.49; N,
11.88%.
11 X.C. Wang, L.Q. Chai, M.G. Wang, Z.J. Quan and Z. Li, Synth. Commun.,
2006, 36, 645.
12 L.Q. Chai, H.S. Zhang, W.K. Dong and Y.L. Zhao, Phosphorus, Sulfur,
Silicon, 2010, 185, 1332.
13 L.Q. Chai,Y.X. Chen, W.P. Chen and Q. Ding, Phosphorus, Sulfur, Silicon,
2009, 184, 453.
14 L.Q. Chai, W.P. Chen, X.Q. Wang and J.L. Ge, Phosphorus, Sulfur, Silicon,
2007, 182, 2491.
1-(2-Naphthyloxyacetyl)-4-styrylsemicarbazide (4h): IR (KBr,
ν/cm−1): 3308, 3271 (N–H), 1694, 1657 (C=O); 1613 (C=C); 1H NMR
(300 MHz, DMSO-d6) δ 10.07 (s, 1H, NH), 9.02 (d, 1H, J = 10.2 Hz,
NH), 8.44 (s, 1H, NH), 7.57–6.97 (m, 13H, ArH and CH), 6.10 (d, 1H,
J = 14.8 Hz, CH), 4.82 (s, 2H, CH2O). MS: m/z = 361. Anal. Calcd for
C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.92; H, 5.52; N,
11.85%.
15 S. Tanaka, J. Am. Chem. Soc., 1951, 73, 872.
16 N.T. Fan, Dictionary of organic synthesis, Beijing University of Technology
Publishing House, Beijing, 1992, pp. 214.
17 M.I. Husain and M. Amir, J. Ind. Chem. Soc., 1986, 63, 317.
18 M.O. Forster, J. Chem. Soc., 1909, 95, 437.
19 L.W. Jones and J.P. Mason, J. Am. Chem. Soc., 1927, 49, 2531.
20 Z.G. Li, Preparation of organic intermediates, Chemical Industry
Publishing House, Beijing, 2001, pp. 76–77.

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