Synthesis of asymmetric semicarbazides using a coumarin ring

Article abstract of DOI:10.3184/174751912X13249848731931

A series of asymmetric semicarbazides were synthesised using 3-coumarin isocyanate, which was prepared from 3-coumarinyl azide by Curtius rearrangement, with acid hydrazides under microwave irradiation using a one-pot procedure. This method has the advantages of mild conditions, easy handling and high yields. The products, which have been characterised by analytical and spectral data, have many medicinal and agrochemical applications.

Full text of DOI:10.3184/174751912X13249848731931

12 RESEARCH PAPER
JANUARY, 12–14
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of asymmetric semicarbazides using a coumarin ring
Lan-Qin Chaia*, Hong-Song Zhangb, Yu-Li Zhanga and Kai Cuia
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 asymmetric semicarbazides were synthesised using 3-coumarin isocyanate, which was prepared from
3-coumarinyl azide by Curtius rearrangement, with acid hydrazides under microwave irradiation using a one-pot
procedure. This method has the advantages of mild conditions, easy handling and high yields. The products, which
have been characterised by analytical and spectral data, have many medicinal and agrochemical applications.
Keywords: Curtius rearrangement, isocyanate, semicarbazides, microwave irradiation
The rapid heating effect of microwave irradiation has been
gained attention because of its remarkable reduction of reac-
tion time and enhancement of reaction yield.1–3 Semicarbazide
derivatives are widely used as medicines and agrochemicals
because of their anti-convulsive,4 herbicidal,5 anti-neoplastic,6
and hypotensive activities.7 Coumarin derivatives have diverse
biological applications, such as anti-bacterial, anti-coagulants,
anti-allergic, hypotensive, anti-HIV and anti-cancer activi-
ties.8–10
The synthetic protocols for the synthesis of semicarbazides
generally utilise phosgene or phosgene-based isocyanates
as starting materials,11,12 both of which are toxic or unstable.
These methods also require long reaction times. Therefore,
phosgene-free and shorter routes to semicarbazides are
needed.
compared to classical heating, the rates of the microwave
irradiated reaction were at least 32 times quicker and also
gave high yields. The results are reported in Table 1.
We selected the synthesis of compound 1b as a model
reaction to study the effects of irradiation power and time on
the yields. The best yields obtained were 88% after 14 minutes
of irradiation with 490 W and using toluene as the solvent.
Greater power or longer irradiation time induces a decrease in
yield (only 74% with 700 W or 76% after 16 minutes) due to
the decomposition of coumarin-3-yl isocyanate.
In summary, the synthesis of asymmetric semicarbazides
has been accomplished employing the Curtius rearrangement
of 3-coumarinyl azide followed by nucleophile addition of
hydrazines to the NCO moiety under microwave irradiation.
Compared to conventional thermal heating, microwave irradia-
tion decreased the reaction time from 8–14 h to 14–25 min.
The main advantages of this method are short reaction times,
high yields, less byproducts and simple handling of starting
materials and products.
We have tried to develop an environmentally benign
method to synthesise a new series of compounds having both
semicarbazide and coumarin moieties, with the objective of
investigating the property and structure–activity relationship
of these new compounds and obtaining new biologically active
compounds.
Experimental
IR spectra were recorded using KBr pellets on a Nicolet VERTEX
70 FT-IR spectrophotometer. H NMR spectra were obtained with a
Results and discussion
1
We report here an expeditious, one-pot and efficient method
for the preparation of a series of asymmetric semicarbazides.
As shown in Scheme 1, 1-benzoyl-4-(3-coumarin) semicarba-
zides (1a–h) and 1-aryloxyacetyl-4-(coumarin-3-yl) semicar-
bazides (2a–h) were synthesised by the reactions of coumarin
isocyanate with various aryl carboxylic acid hydrazides and
aryloxyacetic acid hydrazides, respectively, under microwave
irradiation. Coumarin-3-yl isocyanate was prepared by treat-
ing coumarin-3-carboxylic acid with sodium azide and ethyl
chloroformate in the presence of triethylamine followed by a
Curtius rearrangement.13–14
Mercury plus 400 instrument using DMSO-d6 as solvent and TMS
as the internal standard. Elemental analyses were performed on a
GmbH Vario EL Elemental Analysis instrument. Melting points were
determined with a XT-4 thermal apparatus and were uncorrected.
Microwave irradiations were carried out in a Galanz domestic micro-
wave 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 out at 490 W typically for about 14–25 minutes. During
periods of irradiation, precautions were taken by the experimentalists
to avoid exposure.
Coumarin-3-carboxylic acid, aryl carboxylic acid hydrazides,15 and
aryloxyacetic acid hydrazides16 were prepared according to literature
procedures. Aryloxyacetic acids were commercially available and
used as received.
To investigate the effects of microwave irradiation, all the
reactions were performed in an oil bath at 120 °C. When
Scheme 1
* Correspondent. E-mail: chailq@mail.lzjtu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 13
Table 1 Yields, reaction times, melting points and elemental analyses of compounds 1a–h and 2a–h
Compd
Ar
Yield/%
Reaction time
M.p./°C
MWIa
81
Refluxb
75
MWI/mina
Reflux/hb
1a
C6H5
15
8
211–212
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
2d
2e
2f
4-CH3OC6H4
3-CH3C6H4
4-CH3C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
88
85
72
70
76
74
84
83
82
81
84
86
73
70
76
81
80
66
64
70
69
78
80
79
78
81
82
69
65
72
14
14
18
18
16
16
16
20
20
20
18
18
25
24
22
8
8
>300
219–220
238–239
220–221
222–224
184–186
>300
9
9
9
9
4-ClC6H4
10
10
11
12
8
C6H5
215–216
230–231
221–223
217–218
216–217
232–233
227–228
229–230
2-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
2, 4-Cl2C6H4
1-Naphthyl
2-Naphthyl
12
14
10
12
2g
2h
aIrradiated by microwave at 490 W; bheated at 120 °C.
Preparation of 3-coumarinyl azide
DMSO-d6) δ = 10.84 (s, 1H, NH), 9.06 (s, 1H, NH), 9.02 (s, 1H, NH),
8.81–7.31 (m, 9H, ArH and coumarin H). MS: m/z = 368. Anal. Calcd
for C17H12N4O6: C, 55.44; H, 3.28; N, 15.21. Found: C, 55.41; H, 3.32;
N, 15.26%.
1-(4-Nitrobenzoyl)-4-(coumarin-3-yl) semicarbazide (1f): IR (KBr,
ν/cm−1): 3321, 3083 (N–H), 1690, 1540 (C=O); 1H NMR (400 MHz,
DMSO-d6) δ = 10.85 (s, 1H, NH), 9.08 (s, 1H, NH), 9.03 (s, 1H, NH),
8.83–7.35 (m, 9H, ArH and coumarin H). MS: m/z = 368. Anal. Calcd
for C17H12N4O6: C, 55.44; H, 3.28; N, 15.21. Found: C, 55.40; H, 3.31;
N, 15.25%.
The mixture of coumarin-3-carboxylic acid (10 mmol, 1.90 g), trieth-
ylamine (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) dissolved 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: 91.3 %,
yellowish crystals; m.p. 85–86 °C. IR (KBr, ν/cm-1): 2167 (N≡N),
1
1753, 1680 (C=O), 1378 (N=N). H NMR (400 MHz, DMSO-d6)
1-(2-Chlorobenzoyl)-4-(coumarin-3-yl) semicarbazide (1g): IR
(KBr, ν/cm−1): 3318, 3088 (N–H), 1697, 1538 (C=O); 1H NMR
(400 MHz, DMSO-d6) δ = 10.81 (s, 1H, NH), 9.06 (s, 1H, NH), 9.02
(s, 1H, NH), 8.79–7.25 (m, 9H, ArH and coumarin H). MS: m/z = 358.
Anal. Calcd for C17H12ClN3O4: C, 57.07; H, 3.38; N, 11.75. Found: C,
57.12; H, 3.41; N, 11.79%.
1-(4-Chlorobenzoyl)-4-(coumarin-3-yl) semicarbazide (1h): IR
(KBr, ν/cm−1): 3314, 3084 (N–H), 1694, 1533 (C=O); 1H NMR
(400 MHz, DMSO-d6) δ = 10.82 (s, 1H, NH), 9.05 (s, 1H, NH), 9.01
(s, 1H, NH), 8.78–7.24 (m, 9H, ArH and coumarin H). MS: m/z = 358.
Anal. Calcd for C17H12ClN3O4: C, 57.07; H, 3.38; N, 11.75. Found: C,
57.16; H, 3.45; N, 11.78%.
1-Phenyloxyacetyl-4-(coumarin-3-yl) semicarbazide (2a): IR (KBr,
ν/cm−1): 3331, 3264 (N–H), 1698, 1553 (C=O); 1H NMR (400 MHz,
DMSO-d6) δ = 10.13 (s, 1H, NH), 8.84 (s, 1H, NH), 8.78 (s, 1H, NH),
8.47–6.82 (m, 10H, ArH and coumarin H), 4.58 (s, 2H, CH2O). MS:
m/z = 353. Anal. Calcd for C18H15N3O5: C, 61.19; H, 4.28; N, 11.89.
Found: C, 61.25; H, 4.24; N, 11.82%.
δ = 7.80–8.12 (m, 5H). MS: m/z = 215. Anal. Calcd for C10H5N3O3:
C, 55.82; H, 2.34; N, 19.53. Found: C, 55.94; H, 2.48; N, 19.63%.
Synthesis of compounds 1a–h and 2a–h; general procedure
The solution of 3-coumarinyl azide (0.5 mmol) in toluene (20 mL)
was heated at 120 °C for 16 h to give coumarin-3-yl isocyanate, which
was not isolated originally and treated in situ with various aryl carbox-
ylic acid hydrazides and aryloxyacetic acid hydrazides, respectively,
under microwave irradiation at 490 W for the time given in Table 1.
After the completion of the reaction, monitored by TLC using ethyl
acetate and petroleum ether (2:3) as the eluent, the solvent was
removed under reduced pressure and from the residue the products
1a–h and 2a–h were isolated by recrystallisation from DMF-EtOH.
1-Benzoyl-4-(coumarin-3-yl) semicarbazide (1a): IR (KBr, ν/cm−1):
3323, 3084 (N–H), 1695, 1536 (C=O); 1H NMR (400MHz, DMSO-d6)
δ = 10.80 (s, 1H, NH), 9.04 (s, 1H, NH), 9.01 (s, 1H, NH), 8.81–7.26
(m, 10H, ArH and coumarin H). MS: m/z = 323. Anal. Calcd for
C17H13N3O4: C, 63.16; H, 4.05; N, 13.00. Found: C, 63.22; H, 4.11; N,
13.15%.
1-(2-Methylphenyloxyacetyl)-4-(coumarin-3-yl) semicarbazide (2b):
1
IR (KBr, ν/cm−1): 3329, 3268 (N–H), 1710, 1548 (C=O); H NMR
1-(4-Methoxybenzoyl)-4-(coumarin-3-yl) semicarbazide (1b): IR
(KBr, ν/cm−1): 3312, 3078 (N–H), 1690, 1530 (C=O); 1H NMR
(400 MHz, DMSO-d6) δ = 10.78 (s, 1H, NH), 9.03 (s, 1H, NH), 8.98
(s, 1H, NH), 8.78–7.23 (m, 9H, ArH and coumarin H), 3.78 (s,
3H,CH3O). MS: m/z = 353. Anal. Calcd for C18H15N3O5: C, 61.19; H,
4.28; N, 11.89. Found: C, 61.24; H, 4.23; N, 11.85%.
(400 MHz, DMSO-d6) δ = 10.11 (s, 1H, NH), 8.82 (s, 1H, NH), 8.76
(s, 1H, NH), 8.49–6.84 (m, 9H, ArH and coumarin H), 4.56
(s, 2H, CH2O), 2.22 (s, 3H, CH3). MS: m/z = 367. Anal. Calcd for
C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 62.18; H, 4.71; N,
11.49%.
1-(3-Methylbenzoyl)-4-(coumarin-3-yl) semicarbazide (1c): IR
(KBr, ν/cm−1): 3318, 3086 (N–H), 1694, 1532 (C=O); 1H NMR
(400 MHz, DMSO-d6) δ = 10.76 (s, 1H, NH), 9.01 (s, 1H, NH), 8.96
(s, 1H, NH), 8.76–7.25 (m, 9H, ArH and coumarin H), 2.23 (s, 3H,
CH3). MS: m/z = 337. Anal. Calcd for C18H15N3O4: C, 64.09; H, 4.48;
N, 12.46. Found: C, 64.12; H, 4.51; N, 12.52%.
1-(4-Methylbenzoyl)-4-(coumarin-3-yl) semicarbazide (1d): IR
(KBr, ν/cm−1): 3324, 3081 (N–H), 1690, 1538 (C=O); 1H NMR
(400MHz, DMSO-d6) δ = 10.77 (s, 1H, NH), 9.02 (s, 1H, NH), 8.98
(s, 1H, NH), 8.78–7.27 (m, 9H, ArH and coumarin H), 2.22 (s, 3H,
CH3). MS: m/z = 337. Anal. Calcd for C18H15N3O4: C, 64.09; H, 4.48;
N, 12.46. Found: C, 64.13; H, 4.52; N, 12.51%.
1-(4-Methylphenyloxyacetyl)-4-(coumarin-3-yl) semicarbazide (2c):
1
IR (KBr, ν/cm−1): 3324, 3279 (N–H), 1715, 1545 (C=O); H NMR
(400 MHz, DMSO-d6) δ = 10.13 (s, 1H, NH), 8.84 (s, 1H, NH), 8.79
(s, 1H, NH), 8.51–6.88 (m, 9H, ArH and coumarin H), 4.58
(s, 2H, CH2O), 2.24 (s, 3H, CH3). MS: m/z = 367. Anal. Calcd for
C19H17N3O5: C, 62.12; H, 4.66; N, 11.44. Found: C, 62.17; H, 4.70; N,
11.50%.
1-(4-Methoxyphenyloxyacetyl)-4-(coumarin-3-yl) semicarbazide (2d):
1
IR (KBr, ν/cm−1): 3321, 3274 (N–H), 1710, 1550 (C=O); H NMR
(400 MHz, DMSO-d6) δ = 10.15 (s, 1H, NH), 8.86 (s, 1H, NH), 8.77
(s, 1H, NH), 8.53–6.86 (m, 9H, ArH and coumarin H), 4.54 (s, 2H,
CH2O), 3.75 (s, 3H, CH3O). MS: m/z = 383. Anal. Calcd for
C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.57; H, 4.50;
N, 10.99%.
1-(3-Nitrobenzoyl)-4-(coumarin-3-yl) semicarbazide (1e): IR (KBr,
ν/cm−1): 3326, 3089 (N–H), 1698, 1535 (C=O); 1H NMR (400 MHz,

14 JOURNAL OF CHEMICAL RESEARCH 2012
1-(4-Nitrophenyloxyacetyl)-4-(coumarin-3-yl) semicarbazide (2e):
Received 14 October 2011; accepted 16 December 2011
Paper 1100932 doi: 10.3184/174751912X13249848731931
Published 0nline: 31 January 2012
1
IR (KBr, ν/cm−1): 3329, 3270 (N–H), 1705, 1552 (C=O); H NMR
(400 MHz, DMSO-d6) δ = 10.21 (s, 1H, NH), 8.92 (s, 1H, NH), 8.82
(s, 1H, NH), 8.61–6.98 (m, 9H, ArH and coumarin H), 4.65 (s, 2H,
CH2O). MS: m/z = 398. Anal. Calcd for C18H14N4O7: C, 54.28; H,
3.54; N, 14.07. Found: C, 54.33; H, 3.58; N, 14.13%.
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1-(2, 4-Dichlorophenyloxyacetyl)-4-(coumarin-3-yl) semicarbazide
1
2
3
4
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(KBr, ν/cm−1): 3320, 3270 (N–H), 1716, 1550 (C=O); 1H NMR
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1H, NH), 8.54–6.84 (m, 12H, ArH and coumarin H), 4.59 (s, 2H,
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We are thankful for the financial support from the Foundation
of Lanzhou Chengguan Science and Technology Bureau (No.
09-5-9), the Natural Science Foundation of Gansu Province
(No. 1107RJZA165) and the Innovation and Technology Fund
of Lanzhou Jiaotong University (No. DXS-2011-001).

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