An efficient and mild protocol for the synthesis of unsymmetrical ureas in the absence of catalyst and additives

Article abstract of DOI:10.1016/j.cclet.2010.06.014

A new practical method for the synthesis of unsymmetrical ureas was achieved by reaction of phenylurea with primary and secondary amines under neutral and mild condition in very good yields. The reaction took place in refluxing dioxane and does not require any catalyst or additives.

Full text of DOI:10.1016/j.cclet.2010.06.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1171–1174
www.elsevier.com/locate/cclet
An efficient and mild protocol for the synthesis of
unsymmetrical ureas in the absence of catalyst and additives
*
Rahman Hosseinzadeh , Yaghoub Sarrafi, Nora Aghili
Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
Received 24 February 2010
Abstract
A new practical method for the synthesis of unsymmetrical ureas was achieved by reaction of phenylurea with primary and
secondary amines under neutral and mild condition in very good yields. The reaction took place in refluxing dioxane and does not
require any catalyst or additives.
#
2010 Rahman Hosseinzadeh. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Unsymmetrical ureas; Phenylurea; Amines; Uncatalyzed reaction
Substituted ureas, which constitute some of the most important classes of chemical compounds, have found
extensive applications in agriculture as plant growth regulators and pesticides, particularly herbicides [1] and also as
anion binding receptors [2]. Unsymmetrical substituted ureas have been shown to be potent HIV-1 protease inhibitors
[
3]. As a consequence, the development of efficient preparative protocols for such compounds is of fundamental value
for synthetic research. Traditional methods for the synthesis of substituted ureas include the reaction of amines with
phosgene, isocyanates and carbon monoxide [1,4] and also using carbonyldiimidazole [5] or metal-catalyzed oxidative
carbonylation under high-pressure carbon monoxide [6,7]. It is evident that most of these methods utilize hazardous
and toxic reagents. A suitable alternative method to achieve these substances is the coupling reaction of aryl halides
with ureas in the presence of transition metal catalyst. Recently, Beletskaya and co-workers have reported the
palladium catalyzed reaction of aryl halides with ureas [8] and very recently Nandakumar and also we have introduced
an efficient copper catalyzed arylation of ureas [9]. However, these methods suffer from one or more disadvantages,
such as the use of toxic and expensive ligands or catalyst, the formation of only symmetrical diarylureas, and the
formation of some byproducts.
In the present work, we report a new practical protocol for the synthesis of unsymmetrical ureas via the
uncatalyzed/direct condensation of phenylurea with primary or secondary amines under neutral and mild conditions
(
Scheme 1).
Although ureas are very stable compounds and are sometimes prepared as derivatives of amines for characterization
purpose, they can dissociate into the corresponding isocyanates and amine derivatives at high temperature [10]
(
Scheme 2).
*
Corresponding author.
E-mail address: r.hosseinzadeh@umz.ac.ir (R. Hosseinzadeh).
1001-8417/$ – see front matter # 2010 Rahman Hosseinzadeh. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.014

[(Scheme_1)TD$FIG]
1
172
R. Hosseinzadeh et al. / Chinese Chemical Letters 21 (2010) 1171–1174
Scheme 1. Synthesis of unsymmetrical ureas.
[(Scheme_2)TD$FIG]
Scheme 2. Thermal dissociation of arylureas into corresponding isocyanates and amines.
The in situ formed isocyanate intermediate can react with different amines to afford unsymmetrical ureas [11–13].
0
For example N,N -diphenylurea with primary amines in refluxing dioxane for a prolonged period afforded
unsymmetrical ureas in very poor yields (5–40%) [11]. The reaction at very high temperature (refluxing DMF) and in
the presence of triethylamine gave desired products in higher yields [13]. The advantage of our protocol is that,
ammonia is produced in the dissociation of phenylurea which does not compete with amines in the subsequent reaction
with isocyanate intermediate.
To find the optimum conditions, we have chosen the reaction of p-anisidin and phenylurea with different solvents
and different amounts of substrates. Among the solvents examined (xylene, toluene, DMF, dioxane, and THF),
dioxane was the most effective for this reaction; in addition, in nonpolar solvents we observed the formation of aniline
as a side product.
Variation of mole ratio of substrates revealed that a mole ratio of 2:1 p-anisidin to phenylurea in refluxing dioxane
0
provided the highest yield of N-phenyl-N -(4-methylphenyl)urea. When phenylurea was heated in the absence of
0
p-anisidin in refluxing condition, N,N -diphenylurea was formed as sole product, as we previously mentioned [9a].
Thus, the optimized reaction conditions utilized 2 mmol amine, 1 mmol phenylurea in refluxing dioxane under
argon.
To assess the scope of this method, the condensation reaction has been carried out with numerous aryl and alkyl
amines under the optimum reaction conditions and the results are summarized in Table 1 [14].
From Table 1, it can be observed that the corresponding products achieved were in good to excellent yields. Aryl
amine with electron-releasing substituents such as –OMe (entry 2), –OEt (entry 4) and –Me (entries 5 and 6) in the
Table 1
Reaction between phenylurea and amines in dioxan under refluxing condition.
a
Time (h)
b
Yield (%)
Entry
Amine
NH
Product
NHCONHC
1
2
3
4
5
6
7
8
9
C
6
H
5
2
C
6
H
5
6
H
5
6
7
78
88
80
85
85
82
75
80
72
95
95
84
95
95
4-CH
2-CH
4-CH
4-CH
3-CH
2-CH
3
3
3
3
3
3
OC
6
6
2
H
H
4
NH
NH
2
2
4-CH
2-CH
4-CH
4-CH
3-CH
2-CH
3
3
3
3
3
3
OC
OC
CH
6
6
2
H
H
4
NHCONHC
NHCONHC
6
H
H
5
OC
CH
4
4
6
5
8
OC
6
H
4
NH
2
OC
6
H
4
NHCONHC
6
H
5
7
C
6
C
6
C
6
H
H
H
4
NH
4
NH
4
NH
2
2
2
C
C
C
6
H
6
H
6
H
4
4
4
NHCONHC
NHCONHC
NHCONHC
6
6
6
H
H
H
5
5
5
8
8
8
4-ClC
1-NaphthylNH
CH NH
NH
CH NH
NH
CHNH
6
H
4
NH
2
4-ClC
1-NaphthylNHCONHC
CH NHCONHC
NHCONHC
NHCONHCH
6
H
4
NHCONHC
6
H
5
6
2
6
H
5
7
10
11
12
13
14
C
6
H
4
2
2
C
6
H
4
2
6
H
5
8
(C
6
H
5
CH
2
)
2
(C
(C
6
H
H
5
5
CH
2
)
2
6
H
5
8
NH
2
CH
2
2
2
6
2
)
2
12
12
12
CH
3
(CH
CH
2
)
)
4
2
CH
(CH
3
(CH
CH
2
)
)
4
NHCONHC
6 5
H
(CH
3
2
2
2
3
2
2
CHNHCONHC H
6 5
a
Reactions were carried out with 2 mmol of amine, 1 mmol of phenylurea in refluxing dioxin; except entry 14, was carried out with 1 mmol of
amine, 2 mmol of phenylurea.
b
1
Isolated yields, products were characterized by H NMR and mp [15].

R. Hosseinzadeh et al. / Chinese Chemical Letters 21 (2010) 1171–1174
1173
para- and meta-positions and also aryl amine with substituents in ortho-position (entries 3 and 7) gave good to
excellent yields of the corresponding diarylureas. Reaction of 4-choloroaniline (entry 8) and bulky aryl amine,
0
0
1
-naphthylamine, with phenylurea gave N-(4-chlorophenyl)-N -phenylurea and N-(1-naphthyl)-N -phenylurea in good
yields, respectively. Active amines such as benzyl (entry 10) and dibenzyl (entry 11) amines gave excellent yields of
corresponding unsymmetrical urea. Primary aliphatic amines (entries 13 and 14) and diamine (entry 12) reacted with
phenylurea to achieve good to excellent yields of corresponding products. The only exception was the reaction of aryl
amine with electron-withdrawing substituents such as NO , in the para-position, which gave a substantial amount of
2
0
N,N -diphenylurea as a side product. Because of the low nucleophilicity of p-nitroaniline the desired product, N-( p-
0
nitrophenyl), N -phenylurea, was not formed.
In conclusion, we have developed an efficient, safe, and inexpensive method for the synthesis of symmetrical and
unsymmetrical ureas via the direct condensation of phenylurea with primary or secondary amines. This method does
not require any catalyst or additive, and that the byproduct formed is NH makes this procedure clean and convenient.
3
Acknowledgment
Financial support of this work from the Research Council of the University of Mazandaran is gratefully
acknowledged.
References
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[
[
1] T.P. Vyshnyakova, I.A. Golubeva, E.V. Glebova, Russ. Chem. Rev. (Engl. Transl.) 54 (1985) 249.
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(
(
(
b) J. March, Advanced Organic Chemistry, Wiley, New York, 1985, p. 370;
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[
[
[
[
5] R.A. Batey, V. Santhakumar, C. Yoshina-Ishii, et al. Tetrahedron Lett. 39 (1998) 6267.
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(
b) A.G. Sergeev, G.A. Artamkina, I.P. Beletskaya, Tetrahedron Lett. 44 (2003) 4719.
9] (a) R. Hosseinzadeh, Y. Sarrafi, M. Mohadjerani, et al. Tetrahedron Lett. 49 (2008) 840;
b) M.V. Nandakumar, Tetrahedron Lett. 45 (2004) 1989.
[
(
[
[
[
[
[
10] J.C. Stowell, S.J. Padegimas, J. Org. Chem. 39 (1974) 2448.
11] Y. Furuya, K. Itoho, Chem. Ind. (1967) 359.
12] R. Nec, Chem. Prum. 29 (1979) 589.
13] K. Ramadas, N. Srinivasan, Org. Prep. Proced. Int. 25 (1993) 600.
14] General procedure for the synthesis of unsymmetrical ureas (Table 1): To a mixture of amine (2 mmol) and phenylurea (1 mmol) added dioxane
(
5 mL) and stirred at 100–110 8C for specified times under argon atmosphere (Table 1). The progress of the reaction was monitored by TLC. On
completion, the reaction was cooled to room temperature, ethyl acetate (20 mL) was added to this solution then washed with HCl (1 mol/L) (3ꢀ
0 mL) and water. The organic layer was dried over Na2SO4 and concentrated to small volume. The crude product was purified by
recrystallization from methanol.
15] The spectroscopic data for the known products was identical with the reported data and melting points. N,N -diphenylurea (Table 1, entry 1).
1
0
[
1
White solid; mp 236–238 8C (lit. [9b] 238 8C); H NMR (500 MHz, DMSO-d
6
): d 8.67 (s, 2H), 7.47 (d, 4H, J = 8.4 Hz), 7.29 (t, 4H,
0
J = 7.7 Hz), 6.97 (t, 2H, J = 7.2 Hz). N-(4-methoxyphenyl)-N -phenylurea (Table 1, entry 2). White solid; mp 186–187 8C (lit. [16a] 186–
1
1
90 8C); H NMR (500 MHz, acetone-d
6
): d 8.00 (s, 1H), 7.90 (s, 1H), 7.52 (d, 2H, J = 8.1 Hz), 7.43 (d, 2H, J = 9.8 Hz), 7.25 (t, 2H,
0
J = 7.5 Hz), 6.95 (t, 1H, J = 7.38 Hz), 6.86 (d, 2H, J = 9.8 Hz), 3.76 (s, 3H). N-(2-methoxyphenyl)-N -phenylurea (Table 1, entry 3). White
1
solid; mp 150–153 8C (lit. [16b] 146.2–146.8 8C); H NMR (500 MHz, acetone-d
6
): d 8.60 (s, 1H), 8.30 (d, 1H, J = 7.7 Hz), 7.86 (s, 1H), 7.55
0
(
d, 2H, J = 8.1 Hz), 7.27 (t, 2H, J = 7.5 Hz), 6.98–6.90 (m, 4H), 3.87 (s, 3H). N-(4-ethoxyphenyl)-N -phenylurea (Table 1, entry 4). White solid;
1
mp 189–190 8C (lit. [16b] 188.2–188.8 8C); H NMR (500 MHZ, CDCl
7
3
): d 8.06 (s, 1H), 8.08 (s, 1H), 7.37–7.35 (m, 3H), 7.27–7.18 (m, 2H),
0
.10 (s, 1H), 7.04 (t, 1H, J = 7.3 Hz), 6.83 (d, 2H, J = 8.5 Hz), 3.99 (q, 2H, J = 6.9 Hz), 1.4 (t, 3H, J = 6.9 Hz). N-(4-methylphenyl)-N -
1
phenylurea (Table 1, entry 5). White solid; mp 222–223 8C (lit. [16b] 222–223 8C); H NMR (500 MHz, DMSO-d
6
): d 8.57 (s, 1H), 8.50 (s,
1
H), 7.42 (d, 2H, J = 7.9 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.25 (t, 2H, J = 7.9 Hz), 7.07 (d, 2H, J = 7.9 Hz), 6.94 (t, 1H, J = 7.3 Hz), 2.23 (s, 3H).
1
0
N-(3-methylphenyl)-N -phenylurea (entry 6). White solid; mp 165–167 8C (lit. [16c] 173–174 8C); H NMR (300 MHz, DMSO-d
6
): d 8.62 (s,
H), 8.56 (s, 1H), 7.43 (d, 2H, J = 8.0 Hz), 7.28–7.19 (m, 4H), 7.13 (t, 1H, J = 7.6 Hz), 6.94 (t, 1H, J = 7.3 Hz), 6.77 (d, 1H, J = 7.2 Hz), 2.26 (s,
1
0
1
3
6
H). N-(2-methylphenyl)-N -phenylurea (Table 1, entry 7). White solid; mp 210–213 8C (lit. [16d] 212 8C); H NMR (500 MHz, DMSO-d ): d

1174
R. Hosseinzadeh et al. / Chinese Chemical Letters 21 (2010) 1171–1174
8
.98 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H, J = 8.02 Hz), 7.45 (d, 2H, J = 7.9 Hz), 7.27 (t, 2H, J = 7.8 Hz), 7.16–7.11 (m, 2H), 6.96–6.91 (m, 2H),
1
0
2
.23 (s, 3H). N-(4-chlorophenyl)-N -phenylurea (Table 1, entry 8). White solid; mp 237–239 8C (lit. [16e] 239–240 8C); H NMR (300 MHz,
0
DMSO-d
6
): d 8.79 (s, 1H), 8.68 (s, 1H), 7.48–7.41 (m, 4H), 7.32–7.24 (m, 4H), 6.96 (t, 1H, J = 7.3 Hz). N-(1-naphtyl)-N -phenylurea (Table 1,
1
entry 9). White solid; mp 184–186 8C (lit. [16f] 223 8C); H NMR (500 MHz, DMSO-d
6
): d 9.04 (s, 1H), 8.75 (s, 1H), 8.12 (d, 1H, J = 8.4 Hz),
.00 (d, 1H, J = 7.5 Hz), 7.93 (d, 1H, J = 7.9 Hz), 7.63 (d, 1H, J = 8.2 Hz), 7.59 (t, 1H, J = 7.3 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.50–7.45 (m, 3H),
8
0
.30 (t, 2H, J = 7.9 Hz), 6.98 (t, 1H, J = 7.3 Hz). N-benzyl-N -phenylurea (Table 1, entry 10). White solid; mp 167–168 8C (lit. [16g] 168 8C);
H NMR (300 MHz, DMSO-d ): d 8.54 (s, 1H), 7.40–7.17 (m, 9H), 6.87 (t, 1H, J = 7.8), 6.60 (t, 1H, J = 5.9 Hz), 4.28 (d, 2H, J = 5.9 Hz). N,N-
6
7
1
0
1
dibenzyl-N -phenylurea (Table 1, entry 11). White solid; mp 120–123 8C (lit. [16h] 126–128 8C); H NMR (300 MHz, CDCl
3
): d 7.41–7.31 (m,
0H), 7.26–7.20 (m, 5H), 6.33 (s, 1H), 4.62 (s, 4H). N,N -bis(phenylcarbamoyl)ethylenediamine (Table 1, entry 12). White solid; mp 249–
0
1
1
2
50 8C (lit. [16i] 247–248 8C) H NMR (300 MHz, DMSO-d
6
): d 8.53 (s, 2H), 7.37 (d, 4H, J = 8.1 Hz), 7.19 (t, 4H, J = 7.8 Hz), 6.86 (t, 2H,
0
J = 7.3 Hz), 6.19 (br s, 2H), 3.17 (t, 4H, J = 2.5 Hz). N-pentyl-N -phenylurea (Table 1, entry 13). White solid; mp 91–92 8C (lit. [16j] 90.5–
1
9
1.5 8C); H NMR (300 MHz, CDCl
3
): d 8.33 (s, 1H), 7.36 (dd, 2H, J = 9.5, 1.0 Hz), 7.19 (t, 2H, J = 7.0 Hz), 6.85 (t, 1H, J = 7.3 Hz), 6.07 (t,
0
1
H, J = 5.5 Hz), 3.08–3.02 (m, 2H), 1.43–1.36 (m, 2H), 1.32–1.22 (m, 4H), 0.86 (t, 3H, J = 6.8 Hz). N-(1-ethylpropyl)-N -phenylurea (Table 1,
1
entry 14). White solid; mp 138–140 8C (lit. [16k] 145 8C) H NMR (300 MHz, DMSO-d
H, J = 7.0 Hz), 6.85 (t, 1H, J = 7.3 Hz), 5.87 (d, 1H, J = 8.6 Hz), 3.46–3.43 (m, 1H), 1.48–1.27 (m, 4H), 0.84 (t, 6H, J = 7.4 Hz).
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): d 8.24 (s, 1H), 7.35 (dd, 2H, J = 9.6, 1.0 Hz), 7.19 (t,
2
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(
(
(
(
(
(
(
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(
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