Synthesis of benzofuryl substituted unsymmetrical ureas under microwave irradiation

Article abstract of DOI:10.1080/10426500802176689

A series of 2-benzofuryl substituted unsymmetrical ureas were synthesized by reactions of benzofuroyl isocyanate, which was prepared from benzofuroyl azide by Curtius rearrangement, with various aromatic amines, 2-amino-5-(benzo-2-furyl)-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.

Full text of DOI:10.1080/10426500802176689

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Phosphorus, Sulfur, and Silicon
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Synthesis of Benzofuryl
Substituted Unsymmetrical
Ureas Under Microwave
Irradiation
Lan-Qin Chai a , Yony-Xi Chen a , Wei-Peng Chen a
Qi Ding a
&
a School of Chemical and Biological Engineering ,
Lanzhou Jiaotong University , Lanzhou, Gansu, P. R.
China
Published online: 03 Feb 2009.
To cite this article: Lan-Qin Chai , Yony-Xi Chen , Wei-Peng Chen & Qi Ding
(2009) Synthesis of Benzofuryl Substituted Unsymmetrical Ureas Under Microwave
Irradiation, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:2, 453-459,
DOI: 10.1080/10426500802176689
To link to this article: http://dx.doi.org/10.1080/10426500802176689
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Phosphorus, Sulfur, and Silicon, 184:453–459, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802176689
Synthesis of Benzofuryl Substituted Unsymmetrical
Ureas Under Microwave Irradiation
Lan-Qin Chai, Yony-Xi Chen, Wei-Peng Chen, and Qi Ding
School of Chemical and Biological Engineering, Lanzhou Jiaotong
University, Lanzhou, Gansu, P. R. China
A series of 2-benzofuryl substituted unsymmetrical ureas were synthesized by re-
actions of benzofuroyl isocyanate, which was prepared from benzofuroyl azide by
Curtius rearrangement, with various aromatic amines, 2-amino-5-(benzo-2-furyl)-
1,3,4-thiadiazole, and 2-amino-5-aryloxymethylene-1,3, 4-thiadiazoles under mi-
crowave 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 1 H NMR) data.
Keywords 1,3,4-thiadiazoles; curtius rearrangement; isocyanate; microwave irradia-
tion (MWI); 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
unsymmetrically substituted ureas. Unsymmetrical ureas are widely
used as herbicides, pesticides, plant growth regulators, and medicinal
intermediates.4−6 Ureas bearing heterocyclic substitutents, for exam-
ple 1,3,4-thiadiazole, have been shown to exert anti-inflammatory,7−9
anti-bacterial,10 and anti-convulsant activities.11 The synthetic proto-
cols of ureas generally utilize phosgene or phosgene-based isocyanates
Received 18 March 2008; accepted 2 May 2008.
We are thankful for the financial support from the Foundation of Lanzhou Jiaotong
University (No. 06-40611) and the Innovation and Technology Fund of Lanzhou Jiaotong
University (No. DXS-2007-007).
Address correspondence to Lan-Qin Chai, School of Chemistry and Biological En-
gineering, Lanzhou Jiaotong University, Lanzhou, 730070, Gansu, P.R. China. E-mail:
chailq@mail.lzjtu.cn
453

454
L.-Q. Chai et al.
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-torward routes for unsymmetri-
cal ureas.
These reasons prompted us to develop an environmentally benign
methodology to synthesize some new series of compounds bearing both
urea and 1,3,4-thiadiazole moieties, with the objective to investigate
the properties and structure–activity relationships of these new com-
pounds and to obtain new biologically active compounds.
RESULTS AND DISCUSSION
We herein report a fast and efficient method for the prepa-
ration of
a series of unsymmetrical ureas. As described in
Scheme 1, N-aryl-Nꢀ-(benzofuran-2-yl) ureas (3a–k), N-benzofuran-
2-yl-Nꢀ-[5-(benzofuran-2-yl)-1,3,4-thiadiazol-2-yl] urea (4a), and N-
benzofuran-2-yl-Nꢀ-(1,3,4-thiadiazol-2-yl) ureas (5a–i) were synthe-
sized by reactions of benzofuran isocyanate with various aromatic
amines, 2-amino-5-(benzo-2-furyl)-1,3,4-thiadiazole, and 2-amino-5-
aryloxymethylene-1,3,4-thiadiazoles, respectively, under microwave
irradiation. Benzofuran-2-yl isocyanate was prepared by treating
benzofuran-2-carboxylic acid with sodium azide and ethyl chloro-
carbamate in the presence of triethylamine followed by Curtius
rearrangement.14
O
NEt3
NaN3/H2O
ClCOOC2H5
+
N3
C
COOH
O
O
1
O
ArNH2 /MWI
NHC NHAr
N
N
O
3
O
NH2
N
N
N
N
O
/
MWI
S
120 oC
N=C=O
NHC NH
O
N
O
O
S
4
2
O
NH2
ArOCH2
MWI
N
S
Ar
CH2O
NHC NH
O
S
5
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.

455

456
L.-Q. Chai et al.
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 84% after 10 min of irradiation with 490 W using
toluene as solvent. A greater power or longer irradiation time induces
a decrease in yield (only 78% with 700 W or 68% after 12 min) due to
the decomposition of benzofuran-2-yl isocyanate.
In summary, the synthesis of unsymmetrical ureas has been accom-
plished employing the Curtius rearrangement of 2-benzofuroyl azide
followed by nucleophile addition of amines to the NCO moiety under
microwave irradiation. Compared to conventional thermal heating, mi-
crowave irradiation decreased the reaction time from 4–16 h to 8–28
min. The main advantages of this method are short reaction times, high
yields, less byproducts, and simple handling of slashing 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
Avanci-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.
Benzofuran-2-carboxylic acid,16 2-amino-5-(benzo-2-furyl)-1,3,4-
thiadiazole,17 and 2-amino-5-aryloxymethylene-1,3,4-thiadiazoles18
were prepared according to literature procedures. Aryloxy acetic acids
were commercially available and used as received.
Preparation of Benzofuroyl Azide 1
A mixture of benzofuran-2-carboxylic acid (10 mmol, 1.87 g), triethy-
lamine (11 mmol, 1.111 g), and ethyl chlorocarbamate (11 mmol,
1.194 g) in dry acetone (30 mL) was stirred at 0◦C for 1 h. Then sodium
azide (11 mmol, 0.715 g) dissolved in 15 mL 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: 96.3 %. White crystal. M.p.
110–111◦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, benzofuran H). MS: m/z =
187. Anal. Calcd. for C9H5O2N3: C, 57.76; H, 2.69; N, 22.45. Found: C,
57.83; H, 2.71; N, 22.52.

Benzofuryl Substituted Unsymmetrical Ureas
457
TABLE II IR and 1H NMR Spectroscopic Data for Compounds 3a–k,
4a, and 5a–i
Product
IR (KBr) cm−1
1H NMR /δ/(ppm)
3a
3314, 3276 (N H); 1649 (C O)
9.82 (s, 1H, NH); 9.01 (s, 1H, NH);
7.95–6.49 (m, 10H, ArH & benzofuran
H).
3b
3c
3d
3e
3f
3284, 3264 (N H); 1653 (C O)
3282, 3274 (N H); 1659 (C O)
3288, 3269 (N H); 1646 (C O)
3280, 3261 (N H); 1655 (C O)
3302, 3273 (N H); 1654 (C O)
3290, 3271 (N H); 1660 (C O)
3281, 3264 (N H); 1648 (C O)
3288, 3269 (N H); 1657 (C O)
3278, 3261 (N H); 1665 (C O)
3275, 3265 (N H); 1661 (C O)
9.79 (s, 1H, NH); 8.99 (s, 1H, NH);
7.93–6.47 (m, 9H, ArH & benzofuran
H); 2.44 (s, 3H, CH3).
9.78 (s, 1H, NH); 9.00 (s, 1H, NH);
7.94–6.48 (m, 9H, ArH & benzofuran
H); 2.43 (s, 3H, CH3).
9.90 (s, 1H, NH); 9.04 (s, 1H, NH);
8.11–6.54 (m, 9H, ArH & benzofuran
H).
9.87 (s, 1H, NH); 9.03 (s, 1H, NH);
8.13–6.51 (m, 9H, ArH & benzofuran
H).
9.88 (s, 1H, NH); 9.04 (s, 1H, NH);
8.21–6.60 (m, 9H, ArH & benzofuran
H).
9.80 (s, 1H, NH); 9.01 (s, 1H, NH);
7.96–6.52 (m, 9H, ArH & benzofuran
H).
9.79 (s, 1H, NH); 9.03 (s, 1H, NH);
8.09–6.51 (m, 9H, ArH & benzofuran
H).
9.82 (s, 1H, NH); 9.02 (s, 1H, NH);
7.95–6.49 (m, 9H, ArH & benzofuran
H).
3g
3h
3i
3j
9.81 (s, 1H, NH); 9.01 (s, 1H, NH);
8.01–6.51 (m, 12H, ArH & benzofuran
H).
9.80 (s, 1H, NH); 9.00 (s, 1H, NH);
8.03–6.47 (m, 12H, ArH & benzofuran
H).
3k
4a
5a
5b
3283, 3175 (N H); 1658 (C O); 9.80 (s, 1H, NH); 9.22 (s, 1H, NH);
and 1574, 1495, 1324, 1044
(C S)
7.95–6.86 (m, 10H, benzofuran H); 5.41
(s, 2H, CH2O).
N
N C
3277, 3179 (N H); 1667 (C O); 9.82 (s, 1H, NH); 9.20 (s, 1H, NH);
and 1577, 1496, 1321, 1045
(C S)
7.96–6.89 (m, 10H, ArH & benzofuran
H); 5.42 (s, 2H, CH2O).
N
N C
3283, 3176 (N H); 1661 (C O); 9.80 (s, 1H, NH); 9.18 (s, 1H, NH);
and 1584, 1494, 1322, 1048
(C S)
7.95–6.87 (m, 9H, ArH & benzofuran
H); 5.38 (s, 2H, CH2O); 2.28 (s, 3H,
CH3O).
N
N C
(Continued on next page)

458
L.-Q. Chai et al.
TABLE II IR and 1H NMR Spectroscopic Data for Compounds 3a–k,
4a, and 5a–i (Continued)
Product
IR (KBr) cm−1
1H NMR /δ/(ppm)
5c
3280, 3174 (N H); 1653 (C O); 9.79 (s, 1H, NH); 9.17 (s, 1H, NH);
and 1575, 1493, 1323, 1047
(C S)
7.92–6.84 (m, 9H, ArH & benzofuran
H); 5.37 (s, 2H, CH2O); 2.26 (s, 3H,
CH3).
N
N C
5d
5e
3285, 3172 (N H); 1658 (C O); 9.81 (s, 1H, NH); 9.16 (s, 1H, NH);
and 1583, 1495, 1325, 1049
(C S)
7.96–6.85 (m, 9H, ArH & benzofuran
H); 5.40 (s, 2H, CH2O); 2.27 (s, 3H,
CH3).
N
N C
3278, 3170 (N H); 1653 (C O); 9.78 (s, 1H, NH); 9.14 (s, 1H, NH);
and 1576, 1490, 1326, 1046
(C S)
7.93–6.86 (m, 9H, ArH & benzofuran
H); 5.38 (s, 2H, CH2O); 2.24 (s, 3H,
CH3).
N
N C
5f
3281, 3168 (N H); 1662 (C O); 9.81 (s, 1H, NH); 9.21 (s, 1H, NH);
and 1574, 1492, 1319, 1045
(C S)
7.95–6.88 (m, 9H, ArH & benzofuran
H); 5.45 (s, 2H, CH2O).
N
N C
5g
5h
5i
3288, 3174 (N H); 1652 (C O); 9.84 (s, 1H, NH); 9.18 (s, 1H, NH);
and 1573, 1493, 1320, 1044
(C S)
7.98–6.92 (m, 8H, ArH & benzofuran
H); 5.47 (s, 2H, CH2O).
N
N C
3293, 3167 (N H); 1654 (C O); 9.83 (s, 1H, NH); 9.23 (s, 1H, NH);
and 1570, 1491, 1317, 1042
(C S)
7.96–6.90 (m, 9H, ArH & benzofuran
H); 5.48 (s, 2H, CH2O).
N
N C
3287, 3173 (N H); 1657 (C O); 9.82 (s, 1H, NH); 9.21 (s, 1H, NH);
and 1573, 1488, 1327, 1044
(C S)
7.98–6.89 (m, 12H, ArH & benzofuran
H); 5.44 (s, 2H, CH2O)
N
N C
General Procedure for the Synthesis of Compounds 3a–k, 4a,
and 5a–i
A solution of 2-benzofuroyl azide (1) (0.5 mmol) in toluene (20 mL)
was heated at 120◦C for 4 h to give benzofuran-2-yl isocyanate 2,
which is not isolated and treated in situ with the respective aro-
matic amine, 2-amino-5-(benzo-2-furyl)-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 reac-
tion (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 products3a–k, 4a, and 5a–i were isolated by recrystal-
lization from DMF-EtOH. The spectral data of compounds are listed in
Table II.

Benzofuryl Substituted Unsymmetrical Ureas
459
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