One-pot synthesis of phenylallyl substituted unsymmetrical ureas under microwave irradiation

Article abstract of DOI:10.1080/10426500701407441

A series of phenylallyl-substituted unsymmetrical ureas were synthesized in a one-pot procedure by reactions of cinnamoyl isocyanate, which was prepared from cinnamoyl azide by Curtius rearrangement, with various aromatic amines, 2-amino-5-aryl-1,3,4-thia

Full text of DOI:10.1080/10426500701407441

Phosphorus, Sulfur, and Silicon, 182:2491–2496, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701407441
One-Pot Synthesis of Phenylallyl Substituted
Unsymmetrical Ureas Under Microwave Irradiation
Lan-Qin Chai
Wei-Peng Chen
Xiao-Qiang Wang
Jian-Lin Ge
School of Chemical and Biological Engineering, Lanzhou Jiaotong
University, Lanzhou, Gansu, P. R. China
A series of phenylallyl-substituted unsymmetrical ureas were synthesized in a one-
pot procedure by reactions of cinnamoyl isocyanate, which was prepared from cin-
namoyl azide by Curtius rearrangement, with various aromatic amines, 2-amino-5-
aryl-1,3,4-thiadiazoles 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 prod-
ucts have been characterized by analytical and spectral (IR and 1H NMR) data.
Keywords 1,3,4-thiadiazoles; isocyanate; microwave irradiation (MWI); one-pot synthe-
sis; unsymmetrical urea
INTRODUCTION
In recent years, the use of microwave irradiation to promote reac-
tions has received considerable attention and dramatic rate enhance-
ments have been reported.1 Organic cyclization reactions yielding het-
erocycles under microwave irradiation have attracted the attention of
chemists.2,3 Examples of such applications are the syntheses of unsym-
metrically substituted ureas.
Unsymmetrically substituted ureas are widely used as herbicides,
pesticides, plant growth regulators, and medicinal intermediates.4–6
Ureas bearing heterocyclic substitutents, for example 1,3,4-thiadiazole,
Received January 6, 2007; accepted March 18, 2007.
Financial support of this work by the Foundation (No. 06-40611) of Lanzhou Jiaotong
University is acknowledged.
Address correspondence to Lan-Qin Chai, School of Chemistry and Biological Engi-
neering, Lanzhou Jiaotong University, Lanzhou, 730070, Gansu, P. R. China. E-mail:
chailq@mail.lzjtu.cn
2491

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L.-Q. Chai et al.
have been shown to exert anti-inflammatory,7–9 antibacterial,10 and an-
ticonvulsant activities.11 The synthetic protocols of ureas generally uti-
lize phosgene or phosgene-based isocyanates as starting materials,12,13
both of which are toxic or unstable. These methods also involve longer
reaction times. Therefore, it is necessary to develop phosgene-free and
straight-forward routes for unsymmetrically substituted ureas.
These reasons prompted us to develop an environmentally benign
methodology for the synthesis of some new series of compounds bear-
ing both urea and 1,3,4-thiadiazole moieties, with the objective to in-
vestigate property and structure-activity relationship of these new com-
pounds and to obtain new biologically active compounds.
We herein report a fast and efficient one-pot method for the
preparation of
a series of unsymmetrically substituted ureas.
As described in Scheme 1, N-aryl-Nꢀ-phenylallyl ureas (3a–h),
N-phenylallyl-Nꢀ-(5-aryl-1,3,4-thiadiazol-2-yl) ureas (4a–b) and N-
phenylallyl-Nꢀ-(5-aryloxy- methylene-1,3,4-thiadiazol-2-yl) ureas (5a–
h) were synthesized by reactions of cinnamoyl isocyanate with vari-
ous aromatic amines, 2-amino-5-aryl-1,3,4-thiadiazoles and 2-amino-
5-aryloxymethylene-1,3,4-thiadiazoles, respectively, under microwave
irradiation. Cinnamoyl isocyanate was prepared by treating cinnamic
acid with sodium azide and ethyl chlorocarbamate in the presence of
triethylamine, followed by Curtius rearrangement.14
SCHEME 1
RESULTS AND DISCUSSION
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 32 times faster and proceed with high yields. The results obtained
are reported in Table I.

Unsymmetrical Ureas by Microwave Irradiation
2493
We selected the synthesis of compound 5a as a model reaction to
study the effects of irradiation power and time on the yields. The best
yields obtained are 80% after 16 min of irradiation with 490 W using
toluene as solvent. A higher power or a longer irradiation time induces
a decrease in yield (only 74% with 700 W or 68% after 18 min) due to
the decomposition of cinnamoyl isocyanate.
In summary, the synthesis of unsymmetrically substituted ureas has
been accomplished employing the Curtius rearrangement of cinnamoyl
azide followed by the nucleophilic addition of amines to the NCO moiety
under microwave irradiation. Compared to conventional thermal heat-
ing, microwave irradiation decreased the reaction time from 4–13 h to
8–20 min. The main advantages of this method are short reaction times,
high yields, less by-products, and simple handling of starting materials
and products.
EXPERIMENTAL
IR spectra were recorded using KBr pellets on a Nicolet AVATAR 360
FT-IR spectrophotometer. 1H NMR spectra were obtained with a Bruker
Avance-D2X-200 instrument using DMSO-d6 as solvent and TMS as
internal standard. Elemental analyses were performed on a Vario E-l
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.
2-amino-5-aryl-1,3,4-thiadiazoles15 and 2-amino-5-aryloxymethy-
lene-1,3,4-thiadiazoles16 were prepared according to literature proce-
dures. Aryloxy acetic acids were commercially available and used as
received.
Preparation of Cinnamoyl Azide 1
A mixture of cinnamic acid (10 mmol, 1.48 g), triethylamine (11 mmol,
1.111 g), and ethyl chlorocarbamate (11 mmol, 1.194 g) in dry ace-
tone (30 mL) was stirred at 0◦C for 1 h. Then sodium azide (11 mmol,
0.715 g) dissolved in 15 mL of water 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. The precipitated product was
separated by filtration. Yield: 97.3%. White crystals. M.p. 86–87◦C.
IR (KBr, ν/cm−1): 2162 (N N), 1703 (C O), 1333 (N N); 1H NMR
(DMSO-d6) δ: 6.90–7.36 (m, 5H, ArH). 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.

2494

Unsymmetrical Ureas by Microwave Irradiation
2495
TABLE II IR and 1H NMR Spectroscopic Data for Compounds 3a–h,
4a–b, and 5a–h
IR (KBr) cm−1
1H NMR δ (ppm)
3a
3b
3c
3d
3e
3f
3314, 3276 (N-H); 1649 (C=O);
1614 (C=C)
9.72 (s, 1H, NH); 9.03 (s, 1H, NH); 7.86–6.55
(m, 10H, ArH)
3282, 3272 (N-H); 1651 (C=O);
1614 (C=C)
9.66 (s, 1H, NH); 9.01 (s, 1H, NH); 7.82–6.50
(m, 9H, ArH); 2.42 (s, 3H, CH3)
9.68 (s, 1H, NH); 9.00 (s, 1H, NH); 7.84–6.52
(m, 9H, ArH); 2.44 (s, 3H, CH3)
9.74 (s, 1H, NH); 9.04 (s, 1H, NH); 7.90–6.58
(m, 9H, ArH)
9.78 (s, 1H, NH); 9.06 (s, 1H, NH); 7.93–6.62
(m, 9H, ArH)
9.80 (s, 1H, NH); 9.08 (s, 1H, NH); 7.96–6.63
(m, 9H, ArH)
9.75 (s, 1H, NH); 9.04 (s, 1H, NH); 7.88–6.58
(m, 12H, ArH)
9.73 (s, 1H, NH); 9.02 (s, 1H, NH); 7.85–6.56
(m, 12H, ArH)
10.83 (s, 1H, NH); 10.16 (s, 1H, NH);
7.95–6.86 (m, 10H, ArH)
10.81 (s, 1H, NH); 10.14 (s, 1H, NH);
7.93–6.85 (m, 9H, ArH); 2.26 (s, 3H, CH3)
11.82 (s, 1H, NH); 10.20 (s, 1H, NH);
7.96–6.89 (m, 10H, ArH); 5.42 (s, 2H,
CH2O)
11.80 (s, 1H, NH); 10.18 (s, 1H, NH);
7.95–6.87 (m, 9H, ArH); 5.39 (s, 2H,
CH2O); 2.28 (s, 3H, CH3O)
11.79 (s, 1H, NH); 10.17 (s, 1H, NH);
7.92–6.84 (m, 9H, ArH); 5.37 (s, 2H,
CH2O); 2.26 (s, 3H, CH3)
11.81 (s, 1H, NH); 10.15 (s, 1H, NH);
7.96–6.85 (m, 9H, ArH); 5.40 (s, 2H,
CH2O); 2.27 (s, 3H, CH3)
3284, 3274 (N-H); 1653 (C=O);
1616 (C=C)
3278, 3270 (N-H); 1650 (C=O);
1612 (C=C)
3282, 3271 (N-H); 1655 (C=O);
1610 (C=C)
3281, 3272 (N-H); 1659 (C=O);
1612 (C=C)
3g
3279, 3270 (N-H); 1658 (C=O);
1613 (C=C)
3h 3280, 3273 (N-H); 1656 (C=O);
1615 (C=C)
4a
4b
5a
3278, 3176 (N-H); 1659 (C=O);
1613 (C=C)
3280, 3178 (N-H); 1660 (C=O);
1616 (C=C)
3278, 3178 (N-H); 1666 (C=O);
1614 (C=C); 1577, 1496, 1321,
1045 (C=N-N=C-S)
5b
5c
5d
5e
5f
3283, 3170 (N-H); 1661 (C=O);
1610 (C=C); 1585, 1496, 1320,
1049 (C=N-N=C-S)
3279, 3175 (N-H); 1655 (C=O);
1611 (C=C); 1575, 1494, 1323,
1047 (C=N-N=C-S)
3280, 3172 (N-H); 1658 (C=O);
1613 (C=C); 1583, 1494, 1325,
1048 (C=N-N=C-S)
3278, 3170 (N-H); 1653 (C=O);
1612 (C=C); 1576, 1493, 1326,
1046 (C=N-N=C-S)
11.78 (s, 1H, NH); 10.16 (s, 1H, NH);
7.93–6.86 (m, 9H, ArH); 5.38 (s, 2H,
CH2O); 2.24 (s, 3H, CH3)
11.84 (s, 1H, NH); 10.18 (s, 1H, NH);
7.98–6.92 (m, 8H, ArH); 5.47 (s, 2H, CH2O)
3286, 3172 (N-H); 1650 (C=O);
1614 (C=C); 1571, 1490, 1317,
1042 (C=N-N=C-S)
5g
3289, 3165 (N-H); 1652 (C=O);
1616 (C=C); 1568, 1489, 1315,
1040 (C=N-N=C-S)
11.88 (s, 1H, NH); 10.23 (s, 1H, NH);
8.01–6.95 (m, 9H, ArH); 5.48 (s, 2H, CH2O)
5h 3285, 3171 (N-H); 1656 (C=O);
1615 (C=C); 1572, 1487, 1325,
1043 (C=N-N=C-S)
11.82 (s, 1H, NH); 10.21 (s, 1H, NH);
7.98–6.89 (m, 12H, ArH); 5.44 (s, 2H,
CH2O)

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L.-Q. Chai et al.
General Procedure for the Synthesis of Compounds 3a–h,
4a–b, and 5a–h
A solution of cinnamoyl azide (1) (0.5 mmol) in toluene (20 mL) was
heated at 120◦C for 4 h to give cinnamoyl isocyanate 2, which is not
isolated and treated in situ with the respective aromatic amine, 2-
amino-5-aryl-1,3,4-thiadiazole, or 2-amino-5-aryloxymethylene-1,3,4-
thiadiazole 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 prod-
ucts 3a–h, 4a–b, and5a–h were isolated by recrystallization from
DMF-EtOH.
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