Synthesis of unsymmetrical ureas with coumarin and thiadiazole ring under microwave irradiation

Article abstract of DOI:10.1080/10426500903036022

A series of coumarin-3-yl substituted unsymmetrical ureas were synthesized by the reaction of 3-coumarin isocyanate, which was prepared from 3-coumarinyl azide by Curtius rearrangement, with various aromatic amines, 2-amino-5-phenyl-1,3,4-thiadiazole, and 2-amino-5-aryloxymethylene-1,3,4- thiadiazoles under microwave irradiation. Compared to conventional methods, this synthesis has the advantages of mild reaction conditions, easy handling, and high yields. The products have been characterized by analytical and spectral (IR and 1H NMR) data. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903036022

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis of Unsymmetrical Ureas with
Coumarin and Thiadiazole Ring Under
Microwave Irradiation
Lan-Qin Chai a , Hong-Song Zhang b , Wen-Kui Dong a & Yan-Ling
Zhao a
a School of Chemical and Biological Engineering , Lanzhou Jiaotong
University , Lanzhou, Gansu, P. R. China
b Second Hospital of Lanzhou University , Lanzhou, Gansu, P. R.
China
Published online: 03 Jul 2010.
To cite this article: Lan-Qin Chai , Hong-Song Zhang , Wen-Kui Dong & Yan-Ling Zhao (2010)
Synthesis of Unsymmetrical Ureas with Coumarin and Thiadiazole Ring Under Microwave
Irradiation, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:7, 1332-1337, DOI:
10.1080/10426500903036022
To link to this article: http://dx.doi.org/10.1080/10426500903036022
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Phosphorus, Sulfur, and Silicon, 185:1332–1337, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903036022
SYNTHESIS OF UNSYMMETRICAL UREAS WITH
COUMARIN AND THIADIAZOLE RING UNDER
MICROWAVE IRRADIATION
Lan-Qin Chai,1 Hong-Song Zhang,2 Wen-Kui Dong,1
and Yan-Ling Zhao1
1School of Chemical and Biological Engineering, Lanzhou Jiaotong University,
Lanzhou, Gansu, P. R. China
2Second Hospital of Lanzhou University, Lanzhou, Gansu, P. R. China
A series of coumarin-3-yl substituted unsymmetrical ureas were synthesized by the re-
action of 3-coumarin isocyanate, which was prepared from 3-coumarinyl azide by Cur-
tius rearrangement, with various aromatic amines, 2-amino-5-phenyl-1,3,4-thiadiazole, and
2-amino-5-aryloxymethylene-1,3,4-thiadiazoles under microwave irradiation. Compared to
conventional methods, this synthesis has the advantages of mild reaction conditions, easy
handling, and high yields. The products have been characterized by analytical and spectral
(IR and 1H NMR) data.
Keywords Coumarin; Curtius rearrangement; isocyanate; microwave irradiation (MWI); 1,3,4-
thiadiazoles; unsymmetrical urea
INTRODUCTION
In recent years, the use of microwave irradiation to promote reactions has received
considerable attention, and dramatic rate enhancements have been reported.1 Organic cy-
clization reactions yielding heterocycles under microwave irradiation have attracted the
attention of chemists.2,3 Examples of such applications are the syntheses of unsymmet-
rically substituted ureas. Unsymmetrical ureas are widely used as herbicides, pesticides,
plant growth regulators, and medicinal intermediates.4–6 Ureas bearing heterocyclic sub-
stitutents, for example 1,3,4-thiadiazole, have been shown to exert anti-inflammatory,7–9
antibacterial,10 and anticonvulsant activities.11 Meanwhile, coumarin derivatives have also
attracted much attention due to their diverse biological activities, such as antibacterial, anti-
coagulant, antiallergic, hypotensive, anti-HIV, and anticancer activities.12–14 The synthetic
protocols of ureas generally utilize phosgene or phosgene-based isocyanates as starting ma-
terials,15,16 both of which are toxic or unstable. These methods also involve longer reaction
times. Therefore, it is necessary to develop phosgene-free and straightforward routes for
unsymmetrical ureas.
Received 8 February 2009; accepted 8 May 2009.
We are thankful for the financial support from the Foundation of Lanzhou Jiaotong University (No.
06-40611) and the Foundation of Lanzhou Chengguan Science and Technology Bureau (No. 09-5-9).
Address correspondence to Lan-Qin Chai, School of Chemical and Biological Engineering, Lanzhou
Jiaotong University, Lanzhou, Gansu 730070, P. R. China. E-mail: chailq@mail.lzjtu.cn
1332

UNSYMMETRICAL UREAS WITH COUMARIN AND THIADIAZOLE RING
1333
These reasons prompted us to develop an environmentally benign methodology to
synthesize some new series of urea compounds bearing both coumarin ring and 1,3,4-
thiadiazole moieties, with the objective to investigate the properties and structure–activity
relationships of these new compounds and to obtain new biologically active compounds.
RESULTS AND DISCUSSION
In this article, we report a fast and efficient method for the preparation of a series
of unsymmetrical ureas. As described in Scheme 1, N-aryl-Nꢁ-(coumarin-3-yl) ureas
(3a–h), N-(coumarin-3-yl)-Nꢁ-(2-amino-5-phenyl-1,3,4-thiadiazol-2-yl) urea (4a), and
N-(coumarin-3-yl)-Nꢁ-(2-amino-5-aryloxymethylene-1,3,4-thiadiazol-2-yl) ureas 5a–i
were synthesized by reactions of coumarin isocyanate with various aromatic amines,
2-amino-5-phenyl-1,3,4-thiadiazole, and 2-amino-5-aryloxymethylene-1,3,4-thiadiazoles,
respectively, under microwave irradiation. Coumarin-3-yl isocyanate was prepared by
treating coumarin-3-carboxylic acid with sodium azide and ethyl chlorocarbamate in the
presence of triethylamine followed by Curtius rearrangement.17,18
Scheme 1
To investigate the effects of microwave irradiation, all the reactions were performed
in an oil bath at 120◦C. When compared to classical heating, the reactions performed under
microwave irradiation are at least 30 times faster and proceed with high yields. The results
obtained are reported in Table I.
We selected the synthesis of compound 3a as a model reaction to study the effects
of irradiation power and time on the yields. The best yields obtained are 78% after 20 min
of irradiation with 490 W using toluene as a solvent. A greater power or longer irradiation
time induces a decrease in yield (only 68% with 700 W or 63% after 22 min) due to the
decomposition of coumarin-3-yl isocyanate.
In summary, the synthesis of unsymmetrical ureas has been accomplished employing
the Curtius rearrangement of 3-coumarinyl azide followed by nucleophile addition of
amines to the NCO moiety under microwave irradiation. Compared to conventional thermal
heating, microwave irradiation decreased the reaction time from 15–21 h to 18–28 min.
The main advantages of this method are short reaction times, high yields, fewer byproducts,
and simple handling of starting materials and products.

1334

UNSYMMETRICAL UREAS WITH COUMARIN AND THIADIAZOLE RING
1335
Table II IR and 1H NMR spectroscopic data for compounds 3a–h, 4a, and 5a–i
Product
3a
IR (KBr) cm−1
1H NMR / δ /(ppm)
3321, 3192 (N H); 1682, 1554 (C O)
3312, 3188 (N H); 1676, 1546 (C O)
3315, 3198 (N H); 1669, 1542 (C O)
3324, 3193 (N H); 1690, 1548 (C O)
3326, 3189 (N H); 1698, 1547 (C O)
3320, 3183 (N H); 1708, 1541 (C O)
3312, 3188 (N H); 1712, 1537 (C O)
3324, 3185 (N H); 1681, 1545 (C O)
10.81 (s, 1H, NH); 10.05 (s, 1H, NH); 9.18–7.26
(m, 10H, ArH & coumarin H).
3b
10.78 (s, 1H, NH); 10.03 (s, 1H, NH); 9.15–7.23
(m, 9H, ArH & coumarin H); 3.52 (s, 3H, CH3).
10.76 (s, 1H, NH); 10.01 (s, 1H, NH); 9.13–7.25
(m, 9H, ArH & coumarin H); 3.48 (s, 3H, CH3).
10.80 (s, 1H, NH); 10.04 (s, 1H, NH); 9.15–7.27
(m, 9H, ArH & coumarin H).
10.84 (s, 1H, NH); 10.06 (s, 1H, NH); 9.18–7.31
(m, 9H, ArH & coumarin H).
10.86 (s, 1H, NH); 10.08 (s, 1H, NH); 9.21–7.35
(m, 9H, ArH & coumarin H).
3c
3d
3e
3f
3g
10.81 (s, 1H, NH);10.06 (s, 1H, NH); 9.16–7.31
(m, 12H, ArH & coumarin H).
10.83 (s, 1H, NH); 10.08 (s, 1H, NH); 9.23–7.38
(m, 12H, ArH & coumarin H).
3h
4a
3435, 3318 (N H); 1705, 1603 (C O); 1544, 11.65 (s, 1H, NH); 11.02 (s, 1H, NH); 9.27–7.35
1421, 1365, 1203 (C S) (m, 10H, ArH & coumarin H).
3327, 3261 (N H); 1728, 1607 (C O); 1538, 12.15 (s, 1H, NH); 11.14 (s, 1H, NH); 9.54–7.88
N
N C
5a
1421, 1366, 1226 (C
N
N
C
S)
(m, 10H, ArH & coumarin H); 5.58 (s, 2H,
CH2O).
5b
5c
5d
3333, 3264 (N H); 1713, 1611 (C O); 1541, 12.11 (s, 1H, NH); 11.12 (s, 1H, NH); 9.51–7.84
1457, 1363, 1197 (C
N
N
C
S)
(m, 9H, ArH & coumarin H); 5.56 (s, 2H, CH2O);
3.22 (s, 3H, CH3).
3324, 3279 (N H); 1715, 1614 (C O); 1538, 12.13 (s, 1H, NH); 11.11 (s, 1H, NH); 9.53–7.87
1464, 1369, 1206 (C
N
N
C
S)
(m, 9H, ArH & coumarin H); 5.58 (s, 2H, CH2O);
3.24 (s, 3H, CH3).
3331, 3274 (N H); 1701, 1610 (C O); 1541, 12.15 (s, 1H, NH); 11.13 (s, 1H, NH); 9.50–7.83
1457, 1362, 1243 (C
N
N
C
S)
(m, 9H, ArH & coumarin H); 5.54 (s, 2H, CH2O);
3.36 (s, 3H, CH3O).
5e
5f
3326, 3270 (N H); 1676, 1601 (C O); 1537, 12.18 (s, 1H, NH); 11.17 (s, 1H, NH); 9.56–7.89
1461, 1371, 1252 (C S) (m, 9H, ArH & coumarin H); 5.61 (s, 2H, CH2O).
3338, 3326 (N H); 1718, 1671(C O); 1535, 12.16 (s, 1H, NH); 11.14 (s, 1H, NH); 9.55–7.86
1462, 1368, 1229 (C S) (m, 8H, ArH & coumarin H); 5.58 (s, 2H, CH2O).
3327, 3276 (N H); 1683, 1607 (C O); 1538, 12.21 (s, 1H, NH); 11.20 (s, 1H, NH); 9.58–7.92
1459, 1372, 1228 (C S) (m, 9H, ArH & coumarin H); 5.64 (s, 2H, CH2O).
3323, 3270 (N H); 1693, 1677 (C O); 1536, 12.15 (s, 1H, NH); 11.13 (s, 1H, NH); 9.52–7.84
N
N C
N
N C
5g
5h
N
N C
1458, 1364, 1228 (C
N
N
C
S)
(m, 12H, ArH & coumarin H); 5.53 (s, 2H,
CH2O).
5i
3325, 3273 (N H); 1705, 1654 (C O); 1541, 12.18 (s, 1H, NH); 11.15 (s, 1H, NH); 9.54–7.87
1462, 1364, 1228 (C
N
N
C
S)
(m, 12H, ArH & coumarin H); 5.56 (s, 2H,
CH2O).
EXPERIMENTAL
IR spectra were recorded using KBr pellets on a Nicolet VERTEX 70 FT-IR spec-
trophotometer. 1H NMR spectra were obtained with a Mercury plus 400 instrument using
DMSO-d6 as solvent and TMS as 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 are uncorrected. Microwave irradiation was carried out in a
Galanz domestic microwave oven.

1336
L.-Q. CHAI ET AL.
Coumarin-3-carboxylic acid,19 2-amino-5-aryl-1,3,4-thiadiazole,20 and 2-amino-5-
aryloxymethylene-1,3,4-thiadiazoles21 were prepared according to the procedures in the
literature. Aryloxy acetic acids were commercially available and used as received.
Preparation of 3-Coumarinyl Azide 1
The mixture of coumarin-3-carboxylic acid (10 mmol, 1.90 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) dissolved in water (15
mL) was added, and the mixture was kept at 0◦C for 7 h. After the reaction was complete
(monitored by TLC), the mixture was poured onto ice. Then the suspension was filtered,
and the product was obtained. Yield: 91.3%, yellowish crystals. Mp 85–86◦C. IR (KBr,
ν/cm−1): 2167 (N≡N), 1753, 1680 (C O), 1378 (N N). 1H NMR (400 MHz, DMSO-d6)
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.
General Procedure for the Synthesis of Compounds 3a–h, 4a, and 5a–i
The solution of 3-coumarinyl azide (1) (0.5 mmol) in toluene (20 mL) was heated at
120◦C for 16 h to give coumarin isocyanate 2, which was not isolated originally and treated
in situ with various aromatic amines, 2-amino-5-phenyl-1,3,4-thiadiazole, and 2-amino-5-
aryloxymethylene-1,3,4-thiadiazoles, respectively, under microwave irradiation at 490 W
for the time given in Table I. After the completion of the reaction, monitored by TLC
using ethyl acetate and petroleum ether (2:3) as eluent, the solvent was removed under
reduced pressure, and from the residue, the products 3a–h, 4a, and 5a–i were isolated by
recrystallization from DMF-EtOH. The spectral data of compounds are listed in Table II.
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