CeCl3 · 7H2O-KI-catalyzed, environmentally friendly synthesis of N,N′-disubstituted ureas in water under microwave irradiation

Article abstract of DOI:10.1080/00397910500187126

N,N′-Disubstituted ureas were efficiently synthesized by reactions of urea with a variety of amines in water under microwave irradiation using CeCl₃ · 7H₂O-KI as catalyst. This protocol has advantages of not using toxic phosgene and hazardous organic solvents, high reaction rate, high yield, and a simple workup procedure. Copyright Taylor & Francis, Inc.

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CeCl3 · 7H2O‐KI‐Catalyzed,
Environmentally Friendly
Synthesis of N,N′‐Disubstituted
Ureas in Water Under
Microwave Irradiation
Zheng Li a , Zhi‐Yuan Wang a , Wei Zhu a , Yu‐Lin Xing
a & Yan‐Long Zhao a
a Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu, China
Published online: 18 Aug 2006.
To cite this article: Zheng Li , Zhi‐Yuan Wang , Wei Zhu , Yu‐Lin Xing & Yan‐Long
Zhao (2005): CeCl3 · 7H2O‐KI‐Catalyzed, Environmentally Friendly Synthesis
of N,N′‐Disubstituted Ureas in Water Under Microwave Irradiation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:17, 2325-2331
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Synthetic Communicationsw, 35: 2325–2331, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500187126
.
CeCl3 7H2O-KI-Catalyzed,
Environmentally Friendly Synthesis of
N,N0-Disubstituted Ureas in Water Under
Microwave Irradiation
Zheng Li, Zhi-Yuan Wang, Wei Zhu, Yu-Lin Xing, and
Yan-Long Zhao
Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu, China
Abstract: N,N0-Disubstituted ureas were efficiently synthesized by reactions of urea
.
with a variety of amines in water under microwave irradiation using CeCl3 7H2O-KI
as catalyst. This protocol has advantages of not using toxic phosgene and hazardous
organic solvents, high reaction rate, high yield, and a simple workup procedure.
.
Keywords: CeCl3 7H2O-KI, environmentally friendly, microwave irradiation,
PEG-400, N,N0-disubstituted urea, water medium
INTRODUCTION
N,N0-Disubstituted ureas are important subunits present in a number of
naturally occurring compounds and have found numerous applications as
dyes, antioxidants, pesticides, corrosion inhibitors, intermediates for the prep-
aration of pharmaceuticals, and agricultural chemicals.[1] They can generally
be synthesized from amines by phosgenation,[2] reductive carbonylation,[3] or
oxidative carbonylation.[4] However, these reactions are not ecofriendly
Received in Japan February 4, 2005
Address correspondence to Zheng Li, Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, 730070, China. Tel.: 86-931-7971183; Fax: 86-931-7977989; E-mail:
lizheng@nwnu.edu.cn
2325

2326
Z. Li et al.
because of risks associated with using the toxic compounds phosgene and
carbon monoxide. In addition, these reactions usually proceed in volatile
organic solvents, which also cause environmental problems. Recently,
Mojtahedi et al.[5] reported a solventless synthesis of disubstituted ureas by
reactions of urea with arylamines. However, only diaryl-substituted ureas were
given, and the yields of some examples were not satisfactory.
Organic reactions in aqueous media have been the subject of considerable
attention in terms of achieving more environmentally friendly synthetic trans-
formations.[6] In an effort to develop aqueous reactions, in this article, we
.
report the CeCl3 7H2O-KI-catalyzed, environmentally friendly aqueous
method suitable to N,N0-diaryl, dialkyl, and diheterocyclyl substituted ureas,
which utilizes a nontoxic industrial commodity (chemical urea) as starting
material and microwave irradiation as heating source.
RESULTS AND DISCUSSION
In our preliminary experiments we investigated the synthesis of N,N0-dipheny-
lurea, chosen as model process, under various conditions. When aniline
(22 mmol) was treated with aqueous urea (10 mmol) in the absence of
catalyst under reflux for 8 h, only 42% yield of N,N0-diphenylurea was
obtained (entry 1, Table 1). The possible reason is that the poor solubility
of aniline in water makes the process a heterogeneous reaction, which signifi-
cantly decreases the reaction rate. To speed up the reaction and improve the
yield, some phase-transfer catalysts, such as n-Bu4NBr, n-Bu4NI, and poly
(ethylene glycol) (PEG-400) were examined (entries 2, 3, 4). However,
the results were still not good enough. For this reason, some catalytic
.
.
systems, for example, CuCl2 2H2O/PEG-400, FeCl3 6H2O/PEG-400,
.
.
.
CeCl3 7H2O/PEG-400, CeCl3 7H2O-NaI/PEG-400, and CeCl3 7H2O-KI/
PEG-400, were tested for the selected reactions (entries 6–10, Table 1). For-
tunately, all systems improved the reaction yields. Among these, the best
.
result was achieved using the CeCl3 7H2O-KI/PEG-400 system. However,
a prolonged reaction period was still needed for the completion of the
reaction. Therefore, we utilized a microwave-irradiation technique in the
.
reactions (entries 11–15, Table 1). The catalytic system CeCl3 7H2O-KI/
PEG-400 gave the best yield with an approximately 30-fold increase in the
reaction rate (16 min) in comparison with conventional heating (8 h). Conse-
.
quently, we decided to apply CeCl3 7H2O-KI/PEG-400 and microwave
irradiation to the synthesis of all N,N0-disubstituted ureas (Scheme 1). The
results are summarized in Table 2.
The reactions of urea with aromatic amines in water promoted by
microwave irradiation efficiently afforded N,N0-diaryl ureas using
.
CeCl3 7H2O-KI as catalyst and PEG-400 as phase-transfer catalyst (entries
1–10, Table 2). Arylamines bearing electron-donor groups, such as CH3
and CH3O (entries 2–4, Table 2), exhibited higher reaction rates than those

Synthesis of N,N0-Disubstituted Ureas
2327
Table 1. Effect of catalytic systems and reaction conditions on the yield of
N,N0-diphenylurea in watera
Reaction
time
Yieldb
(%)
Entry
Catalytic system
Reaction condition
1
2
None
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
Reflux, 1008C
MW
8 h
8 h
42
50
54
64
76
87
89
91
96
97
51
71
83
95
97
Bu4NBr
Bu4NI
PEG-400
3
8 h
8 h
4
.
5
CeCl3 7H2O
8 h
8 h
.
6
CuCl2 2H2O, PEG-400
.
7
FeCl3 6H2O, PEG-400
8 h
8 h
.
8
CeCl3 7H2O, PEG-400
.
9
CeCl3 7H2O-NaI, PEG-400
.
CeCl3 7H2O-KI, PEG-400
8 h
8 h
10
11
12
13
14
15
None
PEG-400
16 min
16 min
16 min
16 min
16 min
MW
MW
.
CeCl3 7H2O
.
CeCl3 7H2O, PEG-400
.
CeCl3 7H2O-KI, PEG-400
MW
MW
aReaction conditions: urea (10 mmol), aniline (22 mmol), catalyst (0.2 mmol), H2O
(0.4 mL).
bOf isolated product.
containing electron-withdrawing groups, such as NO2 (entry 8, Table 2).
Arylamines bearing ortho substituents (entries 3, 5, Table 2) showed certain
steric hindrance compared with their para isomers (entries 4, 6, Table 2),
which led to lower yields of the product. The reactions of urea with
aliphatic amines in water (entries 11–13, Table 2) were faster than with
aromatic amines. All reactions were complete within 8 min, giving high
yields. The reactions of urea with heterocyclic amines (pyridine-4-amine,
thiazole-2-amine) (entries 14, 15, Table 2), also efficiently produced corre-
sponding disubstituted ureas. Furthermore, PEG-400 was not necessary for
these two reactions owing to the good solubility of heterocyclic amines in
water.
Most N,N0-disubstituted ureas can be readily separated from the final
reaction mixture by hot filtration of aqueous solutions, except entries 11,
12, and 14, which required the cooling of the aqueous solutions to room temp-
erature before filtration.
Scheme 1.

2328
Z. Li et al.
Table 2. CeCl3.7H2O-KI-catalyzed synthesis of N,N0-disubstituted ureas in water
under microwave irradiationa,b
Irradiation
time (min) Mp (8C)
Yieldc
(%)
Entry
1
Amine
Product
16
242
96
95
2
12
269
3
4
12
12
185
240
82
96
5
16
225–226
86
6
7
8
9
16
16
20
20
302
295
94
95
83
93
305–306
277–278
10
20
4
293–294
121–122
94
87
11d,e
12
13
8
8
71–72
95
95
165–166
14d
15d
8
197–198
222–223
88
85
12
aReaction conditions: urea (10 mmol), aniline (22 mmol), CeCl3 7H2O (0.2 mmol),
PEG-400 (0.2 mol), H2O (0.4 mL).
.
bAll products were identified by 1H NMR, IR, and elemental analyses and compared
with authentic samples.
cYields refer to the isolated products.
dNo PEG-400 was added.
eThe aqueous solution of ethylamine (70%) was used as starting material.

Synthesis of N,N0-Disubstituted Ureas
2329
Scheme 2.
A plausible reaction mechanism for the title reactions is illustrated in
Scheme 2. Urea reacts with one molecule of amine, librating one molecule
of ammonia, and is transformed to monosubstituted urea 1. Subsequently,
the monosubstituted urea is converted to an isocyanate 2 with loss of
another molecule of ammonia. Then, the isocyanate reacts with another
amine molecule to produce N,N0-disubstituted urea. The CeCl3 7H2O-KI is
.
possibly first converted to CeClnI3-n (n ¼ 0, 1, 2), which functions as a
Lewis acid[7] to efficiently promote the elimination of ammonia.
In conclusion, we have developed a rapid, high-yield synthesis of N,N0-
diaryl, dialkyl, and diheterocyclyl substituted ureas by reactions of urea
with a variety of amines in water under microwave irradiation, which effi-
ciently circumvents the use of toxic phosgene and volatile organic solvents.
The synthesis is an environmentally friendly alternative to previous methods.
EXPERIMENTAL
IRwererecordedusingKBrpelletsonanAlphaCentauriFTIRspectrophotometer
1
and H NMR spectra on an Avanci-D2X-200 instrument using (CD3)2SO as
solvent and Me4Si as internal standard. Elemental analyses were performed on
a Vario E1 elemental-analysis instrument. Mass spectra were recorded on a QP-
1000A GC-MS using the impact mode (70 eV). Melting points were observed
in an electrothermal melting-point apparatus and are uncorrected.
Preparation of N,N0-Diphenylurea under Microwave Irradiation
.
A mixture of urea (0.60 g, 10 mmol), aniline (2.05 g, 22 mmol), CeCl3 7H2O
(0.07 g, 0.2 mmol), KI (0.03 g, 0.2 mmol), PEG-400 (0.08 g, 0.2 mmol) in

2330
Z. Li et al.
0.4 mL of water was charged in a round-bottom glass flask fitted with a reflux
condenser attached to a water aspirator to remove ammonia. Then, the flask
was placed in a modified microwave oven and subjected to microwave
irradiation at 700 W for an appropriate time (Table 2). After the reaction was
complete, the flask was removed from the microwave oven, the resulting
mixture was quickly filtered, and the solid was washed with water to give
white solid as product. An analytical sample was obtained by recrystallization
from ethanol.
The other N,N0-disubstituted ureas were prepared in a similar way except
the following:
Entries 11, 14, 15: no PEG-400 added.
Entry 8 product was recrystallized from DMF.
Entry 15 product was recrystallized from ethyl acetate.
Entries 11, 12, 14 products were recrystallized from water.
All products were identified by 1H NMR, IR, and elemental analyses and
compared with authentic samples. The physical and spectral data of some
representative compounds are given here:
N,N0-Di(2-methoxyphenyl)urea: 1H NMR: (DMSO-d6, 200 MHz): d 8.36
3
(2H, s, NH, exchangeable with D2O), 6.84 (4H, d, J ¼ 8.8 Hz, Ar-H), 7.32
3
(4H, d, J ¼ 8.8 Hz, Ar-H), 3.69 (3H, s, CH3); IR (KBr, n, cm21): 3312
(N-H), 1606 (C55O). MS: m/z, 272 (Mþ). Anal. calcd. for C15H16N2O3: C,
66.16; H, 5.92; N, 10.29. Found: C, 66.09; H, 5.98; N, 10.33.
1
N,N0-Di(4-bromophenyl)urea: H NMR: (DMSO-d6, 200 MHz): d 8.48
3
(2H, s, NH, exchangeable with D2O), 6.93 (4H, d, J ¼ 8.9 Hz, Ar-H), 7.44
3
(4H, d, J ¼ 8.9 Hz, Ar-H); IR (KBr, n, cm21): 3288 (N-H), 1640 (C55O).
MS: m/z, 340 (Mþ). Anal. calcd. for C13H10Br2O: C, 45.65; H, 2.95; N,
4.68. Found: C, 45.72; H, 2.89; N, 4.63.
N,N0-Di(pyrid-4-yl)urea: 1H NMR: (DMSO-d6, 200 MHz): d 9.32 (2H, s,
3
NH, exchangeable with D2O), 8.37 (4H, d, J ¼ 6.0 Hz, Py-H), 7.44 (4H, d,
3J ¼ 6.0 Hz, Py-H); IR (KBr, n, cm21): 3340 (N-H), 1740 (C55O). MS:
m/z, 214 (Mþ). Anal. calcd. for C11H10N4O: C, 61.67; H, 4.71; N, 26.15.
Found: C, 61.73; H, 4.78; N, 26.09.
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