Efficient synthesis of urea derivatives via a sequential one-pot nucleophilic addition/Ugi five-component reaction under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2011.553697

Urea polyfunctional derivatives were successfully synthesized via a one-pot, five-component nucleophilic addition/Ugi reaction sequence. Simplicity, solvent-free conditions, and good yields of products are advantages of this method.

Full text of DOI:10.1080/00397911.2011.553697

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Efficient Synthesis of Urea Derivatives
via a Sequential One-Pot Nucleophilic
Addition/Ugi Five-Component Reaction
Under Solvent-Free Conditions
Javad Azizian a , Khadijeh Yadollahzadeh b , Hasan Tahermansouri c ,
Davood Chobfrosh Khoei d & Akram Sadat Delbari e
a Department of Chemistry, Science and Research Branch, Islamic
Azad University, Ponak, Tehran, Iran
b Department of Chemistry, Aliabad Katoul Branch, Islamic Azad
University, Aliabad Katoul, Iran
c Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad
University, Amol, Iran
d Department of Chemistry, Shabestar Branch, Islamic Azad
University, Shabestar, Iran
e Department of Chemistry, Islamshahr Branch, Islamic Azad
University, Islamshahr, Iran
Accepted author version posted online: 02 Nov 2011.Published
online: 26 Mar 2012.
To cite this article: Javad Azizian , Khadijeh Yadollahzadeh , Hasan Tahermansouri , Davood
Chobfrosh Khoei & Akram Sadat Delbari (2012) Efficient Synthesis of Urea Derivatives via a Sequential
One-Pot Nucleophilic Addition/Ugi Five-Component Reaction Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:14, 2110-2120, DOI: 10.1080/00397911.2011.553697
To link to this article: http://dx.doi.org/10.1080/00397911.2011.553697
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Synthetic Communications1, 42: 2110–2120, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.553697
EFFICIENT SYNTHESIS OF UREA DERIVATIVES VIA A
SEQUENTIAL ONE-POT NUCLEOPHILIC ADDITION/UGI
FIVE-COMPONENT REACTION UNDER
SOLVENT-FREE CONDITIONS
Javad Azizian,1 Khadijeh Yadollahzadeh,2
Hasan Tahermansouri,3 Davood Chobfrosh Khoei,4 and
Akram Sadat Delbari5
1Department of Chemistry, Science and Research Branch, Islamic Azad
University, Ponak, Tehran, Iran
2Department of Chemistry, Aliabad Katoul Branch, Islamic Azad University,
Aliabad Katoul, Iran
3Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad
University, Amol, Iran
4Department of Chemistry, Shabestar Branch, Islamic Azad University,
Shabestar, Iran
5Department of Chemistry, Islamshahr Branch, Islamic Azad University,
Islamshahr, Iran
GRAPHICAL ABSTRACT
Abstract Urea polyfunctional derivatives were successfully synthesized via a one-pot,
five-component nucleophilic addition/Ugi reaction sequence. Simplicity, solvent-free
conditions, and good yields of products are advantages of this method.
Keywords Five-component reaction; nucleophilic addition; one-pot; solvent-free; Ugi
reaction; urea derivatives
Received August 22, 2010.
Address correspondence to Javad Azizian, Department of Chemistry, Science and Research
Branch, Islamic Azad University, Ponak, Tehran, Iran. E-mail: j-azizian@cc.sbu.ac.ir
2110

SYNTHESIS OF UREA DERIVATIVES
2111
INTRODUCTION
The synthesis of new biologically active molecules is an important challenge in
the development of improved and innovative drugs. Finding a suitable route with
fewer reaction steps for the synthesis of pharmaceutical scaffolds is very interesting.
It has been well established that urea derivatives have a significant place in modern
medicinal chemistry.[1–3] Because of the broad pharmacological interest in urea
derivatives, their synthesis has been of widespread interest. For example, in the past
years, a large variety of urea derivatives were reported to possess potent inhibiting
effects on HIV protease enzyme,[4] receptor tyrosine kinases (RTKs),[5] nicotinamide
adenine dinucleotide hydrate (NADH) oxidase,[6] and acyl-coenzyme A-cholesterol
acyltransferase (ACAT).[7] Various methods have been developed for the syntheses
of these compounds.[8,9] Drawbacks of these methods include harsh thermal con-
ditions, long reaction times, modest yields, use of expensive reagents, multistep reac-
tions, and use of organic solvents. Therefore, the further development of synthetic
methods to produce a variety of these templates remains an important task.
In this field, multicomponent condensation reactions based on isocyanides
have been utilized efficiently in conjunction with combinatorial chemistry to prepare
polyfunctional compounds in short reaction sequences.[10,11] One of the best-known
multicomponent reactions is the Ugi four-component coupling (4CC) reaction.[12] In
this reaction, an isocyanide, an amine, a carboxylic acid, and an oxo compound
spontaneously are condensed to yield an acylaminocarboxamide.
Herein we report an efficient and convenient procedure for the synthesis of
urea derivatives under solvent-free conditions at room temperature. Thus, one-pot,
five-component reaction of 2-amino benzoic acid 1, phenyl isocyanate 2, primary
amines 3, oxo compound 4, and isocyanides 5 leading to the urea derivatives is
shown in Scheme 1. The intermediate I contains functional groups that are suitable
for further reactions. The reaction proceeds without any catalyst and separation of
intermediate I (Scheme 1).
RESULTS AND DISCUSSION
Generally, the Ugi 4CR was performed in organic solvents such as methanol or
tetrahydrofuran (THF) at room temperature for 1–2 days.[13] Although this Ugi 4CR
was carried out successfully in methanol at room temperature to afford the desired
compounds, there are some drawbacks in Ugi reaction such as long reaction times
and use of methanol as solvent, leading to side reactions. More recently, Shaabani
Scheme 1. Synthesis of urea derivatives via a five-component reaction.

2112
J. AZIZIAN ET AL.
et al. studied the reaction of carboxylic acids and isocyanides in methanol at ambient
temperature carefully. Aryl amides were obtained in good yield after 24 h. They also
proved that methanol took part in this reaction and converted to methylformate.[14]
Furthermore, it also has been reported that methanol took part in the reaction to
form unintended by-products. For example, Mitchell et al. demonstrated that under
the Ugi reaction conditions, the iminium cation underwent another competing
reaction involving the reaction solvent (methanol) to give an undesired by-
product.[15] These studies have shown that the utility of methanol as solvent led
inevitably to the formation of some undesired side products. Organic syntheses
involving multicomponent reactions (MCRs) under solvent-free conditions have
been receiving much attention.[16] As part of our continuing interest in developing
more efficient and practical methods in organic synthesis, we explored the possibility
of obtaining the products 6a–m by the Ugi 5CR under solvent-free conditions.
We have developed a one-pot, two-step reaction for the synthesis of urea deri-
vatives under solvent-free conditions. Using this novel approach, all five starting
materials were mixed in one pot within short intervals to maximize bond formation
for complexity generation and diversification. The addition of three components
(amine, isonitrile, carbonyl compound) took place a half hour after mixing the two
starting materials (benzoic acid and phenyl isocyanate), which led to the formation
of the product as a precipitate. Compared to the original Ugi reactions, which take
1–2 days, it would appear that this approach has more favorable reaction and puri-
fication conditions such as less than 12 h to complete the two-step reaction and no
need for the double scavenging step. Although the mechanism of the reaction has
not been established experimentally, a possible explanation is proposed in Scheme 2.
1
In Fig. 1, the structures of compounds were characterized by IR, mass, H
NMR, and 13C NMR spectral data. The mass spectra of compounds 6a–6m
1
displayed molecular ion peaks at appropriate m=z values. The IR and H NMR
Scheme 2. Proposed mechanism for the formation of compounds.

SYNTHESIS OF UREA DERIVATIVES
2113
Figure 1. Results of the nucleophilic addition=Ugi MCR reaction.

2114
J. AZIZIAN ET AL.
spectra of 6a–6m exhibited three characteristic peaks for the NH moieties. The
1H-decoupled 13C NMR spectra of 6a–6m showed three distinct resonances for
=
C O. Compounds 6a, 6i, and 6k–m possess stereogenic centers and can exist as
doublets of doublet for CH2 benzyl amine in the NMR spectra. It should be noted
that Passerini-type reactions were not detected in these reactions, even in the reac-
tions that gave the desired products in moderate yields. The results confirm the ver-
satility and efficiency of this method for the preparation of urea derivatives.
CONCLUSION
In conclusion, we have described an efficient method for the synthesis of urea
derivatives in good yields via a one-pot, five-component reaction under mild and
solvent-free conditions. Reaction times were dramatically reduced and yields were
generally improved by this new method. The reaction scope is broad, which permits
the use of four points of diversity in the starting materials. Because of the
well-recognized utility of urea derivatives, many libraries of compounds can be pre-
pared using this method as structural scaffolds for further diversification.
EXPERIMENTAL
Materials were purchased from Merck and Fluka companies. Melting points
were obtained using an Electrothermal-9100 apparatus and are uncorrected IR spec-
1
tra were recorded with a Shimadzu IR-460 spectrometer. H and 13C NMR spectra
were recorded with a Bruker DRX-300 Avance instrument using CDCl3 as the deut-
erated solvent containing tetramethylsilane as internal standard, at 300 and 75 MHz,
respectively (d in parts per million, J in hertz). Electron-impact mass spectrometry
(EIMS) (70 eV): Mass spectra were obtained with a Finnigan-MAT-8430 mass spec-
trometer, in m=z. Elemental analyses (C, H, N) were obtained with a Heraeus
CHN-O- Rapid analyzer.
General Procedure for the Synthesis of Urea Derivatives 6a–m
2-Amino benzoic acid 1 (1mmol) was added to phenyl isocyanate 2 (1mmol), and
the mixture was stirred at room temperature for 0.5 h. Then, primary amine 3 (1mmol)
and oxo compound 4 (1.2mmol) were added and stirred for 15min, followed by
addition of isocyanide 5 (1mmol). The reaction was detected by TLC (n-hexane–
EtOAc, 3=1) and completed after 11 h. The evaporable compounds were removed under
reduced pressure, and the residue was dissolved in EtOAc (20 mL). The organic solution
was washed with saturated aqueous NaHCO3 (2ꢀ 20mL) and dried on Na2SO4. The
solvent was removed under reduced pressure and the residue was purified by column
chromatography (SiO2; hexane=EtOAc 3=1) to afford quite pure title compounds.
1-(2-(N-(2-(Cyclohexylcarbamoyl)butan-2-yl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6a)
Yield: 0.54 g (98%), white powder, mp 94–96 ꢁC. IR (KBr) (nmax=cmꢂ1); 3460,
1
3430, 3290, 1664, 1635, 1602 cmꢂ1: H NMR (300 MHz, CDCl3) d: 0.89 (t, J ¼ 7.4,

SYNTHESIS OF UREA DERIVATIVES
2115
3H), 1.12–1.92 (m, 10H), 1.54 (s, 3H), 1.99 (q, J ¼ 7.4, 2H), 3.74 (s, 3H), 3.82 (m,
1H), 4.55 (d, J ¼ 16.8, 1H), 4.70 (d, J ¼ 16.8, 1H), 5.90 (br s, 1H), 6.92 (d, J ¼ 9.0,
2H), 7.20 (m, 3H), 7.30 (m, 5H), 7.45 (d, J ¼ 9.0, 2H), 7.96 (s, 1H), 8.32 (d, J ¼ 8.1,
1H), 8.69 (s, 1H) ppm. 13C NMR (75.46 MHz, CDCl3) d: 9.4 (CH3), 25.1 (CH2),
25.2 (CH3), 25.9 (2CH2), 32.9 (2CH2), 33.2 (CH2), 49.8 (CH2), 50.1 (CꢂN), 55.9
(MeO), 67.1 (C), 114.5 (2CH), 119.7 (CH), 121.0 (2CH), 122.3 (CH), 126.0 (CH),
126.1 (CH), 127.3 (2CH), 127.9 (CH), 129.1 (2CH), 130.4 (C), 133.1 (C), 136.9
=
=
=
(C), 138.3 (C), 153.6 (C), 155.6 (C O), 172.6 (C O), 176.2 (C O) ppm. MS (EI,
70 eV): m=z (%): 556 (Mþ, 4), 307 (12), 281 (100), 162 (94), 134 (15), 120 (87), 106
(21), 91 (40), 78 (12). Anal. calcd. for C33H40N4O4 (556.69): C, 71.20; H, 7.24; N,
10.06. Found: C, 71.33; H, 7.30; N, 10.24.
1-(2-(N-(1-(Cyclohexylcarbamoyl)cyclopentyl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6b)
Yield: 0.55 g (96%), white powder, mp 90–92 ꢁC. IR (KBr) (nmax=cmꢂ1); 3360,
1
3330, 3290, 1654, 1635, 1590 cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.12–1.39 (m,
8H), 1.53–1.78 (m, 10H), 3.74 (s, 3H), 3.82 (m, 1H), 4.70 (s, 2H), 5.90 (br, 1H), 6.88
(d, J ¼ 9, 2H), 7.19 (m, 3H), 7.30(m, 5H), 7.45 (d, J ¼ 9, 2H), 8.02 (s, 1H), 8.36 (d,
J ¼ 9, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46 MHz, CDCl3) d: 23.8 (2CH2), 25.0
(2CH2), 25.8 (CH2), 32.8 (2CH2), 36.5 (2CH2), 50.1 (CꢂN), 52.5 (CH2), 55.9 (MeO),
69.1 (C), 114.5 (2CH), 119.7 (CH), 120.8 (2CH), 122.1 (CH), 125.7 (CH), 125.8
(CH), 126.4 (2CH), 127.7 (CH), 129.2 (2CH), 130.3 (C), 133.1 (C), 136.8 (C), 138.8
=
=
=
(C), 153.6 (C), 155.6 (C O), 172.6 (C O), 176.2 (C O) ppm; MS (EI, 70 eV): m=z
(%): 568 (Mþ, 5), 320 (20), 291 (100), 172 (90), 103 (70), 91 (50). Anal. calcd. for
C34H40N4O4 (568.70): C, 71.33; H, 7.30; N, 10.94. Found: C, 71.81; H, 7.09; N, 9.85.
1-(2-(N-(1-(Cyclohexylcarbamoyl)cyclohexyl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6c)
Yield: 0.57g (98%), white powder, mp 89–91 ꢁC. IR (KBr) (nmax=cmꢂ1); 3390,
1
3365, 3290, 1674, 1645, 1588cmꢂ1; H NMR (300MHz, CDCl3) d: 1.16–1.48 (m,
10H), 1.87–2.30 (m, 10H), 3.70 (s, 3H), 3.80 (m, 1H), 4.80 (s, 2H), 6.50 (br, 1H), 6.78
(d, J ¼ 9, 2H), 7.19 (m, 3H), 7.30 (m, 5H), 7.45 (d, J ¼ 9, 2H), 8.02 (br, 1H), 8.36 (d,
J ¼ 9, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46MHz, CDCl3) d: 23.6 (2CH2), 24.2
(2CH2), 25.5 (CH2), 33.8 (CH2), 34.5 (2CH2), 36.2 (2CH2), 50.3 (CꢂN), 52.9 (CH2),
55.8 (OMe), 67.1 (C), 114.6 (2CH), 120.1 (CH), 120.9 (2CH), 122.8 (CH), 125.2
(CH), 126.1 (CH), 126.6 (2CH), 127.7 (CH), 129.7 (2CH), 130.3 (C), 133.1 (C), 136.8
=
=
=
(C), 138.8 (C), 152.6 (C), 156.6 (C O), 172.6 (C O), 174.2 (C O) ppm; MS (EI,
70eV): m=z (%): 582 (Mþ, 4), 334 (17), 306 (100), 188 (87), 105 (67), 91 (50). Anal. calcd.
for C35H42N4O4 (582.73): C, 72.14; H, 7.26; N, 9.61. Found: C, 72.33; H, 7.30; N, 10.04.
1-(2-(N-(1-(Cyclohexylcarbamoyl)cyclohexyl)-N-
ethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6d)
Yield: 0.49 g (94%), white powder, mp 98–100 ꢁC. IR (KBr) (nmax=cmꢂ1); 3490,
1
3435, 3265, 1674, 1623, 1611 cmꢂ1: H NMR (300 MHz, CDCl3) d: 1.09 (t, J ¼ 9,

2116
J. AZIZIAN ET AL.
3H), 1.16–1.48 (m, 10H), 1.87–2.30 (m, 10H), 3.40 (q, J ¼ 9, 2H), 3.80 (s, 3H), 3.86
(m, 1H), 6.13 (br, 1H), 6.85 (d, J ¼ 9.14, 2H), 6.99 (t, J ¼ 6, 1H), 7.14 (d, J ¼ 9.14,
1H) 7.34 (t, J ¼ 6, 1H), 7.42 (d, J ¼ 9, 2H), 8.02 (s, 2H), 8.30 (d, J ¼ 9.14, 1H)
ppm; 13C NMR (75.46 MHz, CDCl3) d: 17.4 (CH3), 23.4 (CH2), 25.1 (2CH2), 25.9
(2CH2), 26.0 (2CH2), 32.9 (2CH2), 33.0 (CH2), 40.7 (CH2), 50.3 (CꢂN), 55.9
(MeO), 66.4 (C), 114.5 (2CH), 120.0 (CH), 121.0 (2CH), 122.2 (CH), 125.3 (CH),
=
126.8 (CH), 130.1 (C), 134.2 (C), 136.6 (C), 153.6 (C),155.6 (C O), 171.9 (C O),
=
þ
=
175.5 (C O) ppm; MS (EI, 70 eV) m=z (%): 520 (M , 6), 272 (16), 244 (100), 126
(77), 43 (67), 29 (40). Anal. calcd. for C30H40N4O4 (520.66): C, 69.20; H, 7.74; N,
10.76. Found: C, 70.33; H, 7.90; N, 10.04.
1-(2-(N-(2-(Cyclohexylcarbamoyl)propan-2-yl)-N-
ethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6e)
Yield: 0.46 g (96%), white powder, mp 87–89 ꢁC. IR (KBr) (nmax=cmꢂ1): 3467,
3425, 3265, 1674, 1623, 1611 cmꢂ1: 1H NMR (300 MHz, CDCl3) d: 1.02 (t, J ¼ 10.8,
3H), 1.46–2.08 (m, 10H), 1.87 (s, 6H), 3.40 (q, J ¼ 10.8, 2H), 3.80 (s, 3H), 3.86 (m,
1H), 6.41 (br, 1H), 6.85 (d, J ¼ 9, 2H), 6.99 (t, J ¼ 6, 1H), 7.14 (t, J ¼ 9, 1H), 7.34 (t,
J ¼ 6, 1H), 7.42 (d, J ¼ 9, 2H), 8.02 (s, 2H), 8.30 (d, J ¼ 9, 1H), ppm; 13C NMR
(75.46 MHz, CDCl3) d: 15.4 (CH3), 23.4 (2CH3), 25.1 (2CH2), 29.9 (2CH2), 33.0
(CH2), 40.76 (CH2), 50.3 (CꢂN), 55.6 (MeO), 66.1 (C), 114.5 (2CH), 120.0 (CH),
121.0 (2CH), 122.2 (CH), 125.3 (CH), 126.8 (CH), 131.1 (C), 133.2 (C), 136.6 (C),
=
=
=
153.6 (C), 155.6 (C O), 170.9 (C O), 174.5 (C O) ppm; MS (EI, 70 eV) m=z (%):
480 (Mþ, 6), 232 (20), 204 (100), 86 (84), 43 (67), 29 (40). Anal. calcd. for
C27H36N4O4 (480.59): C, 67.48; H, 7.55; N, 11.66. Found: C, 66.93; H, 7.90; N, 11.04.
1-(2-(N-(2-(Cyclohexylcarbamoyl)propan-2-yl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6f)
Yield: 0.49g (92%), white powder, mp 89–91ꢁC. IR (KBr) (nmax=cmꢂ1); 3460,
1
3430, 3290, 1664, 1635, 1602cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.15 (s, 6H),
1.27–2.17 (m, 10H), 3.70 (s, 3H), 3.80 (m, 1H), 4.80 (s, 2H), 6.50 (br, 1H), 6.78 (d,
J ¼ 9, 2H), 7.19 (m, 3H), 7.30 (m, 5H), 7.45 (d, J ¼ 9, 2H), 8.02 (s, 1H), 8.36 (d, J ¼ 9,
1H), 8.58 (s, 1H) ppm; 13C NMR (75.46MHz, CDCl3) d: 20.9 (2CH3), 23.6 (2CH2),
25.5 (CH2), 34.5 (2CH2), 50.3 (CꢂN), 52.9 (CH2), 55.8 (MeO), 67.1 (C), 114.6 (2CH),
120.1 (CH), 120.9 (2CH), 122.8 (CH), 125.2 (CH), 126.1 (CH), 126.6 (2CH), 127.7
=
(CH), 129.7 (2CH), 130.3 (C), 133.1 (C), 136.8 (C), 138.8 (C), 152.6 (C), 156.6 (C O),
þ
=
=
172.6 (C O), 174.2 (C O) ppm; MS (EI, 70eV): m=z (%): 542 (M , 5), 294 (17), 266
(100), 148 (87), 133 (67),119 (43), 105 (56), 91 (50), 78 (32). Anal. calcd. for
C32H38N4O4 (542.66): C, 70.82; H, 7.06; N, 10.32. Found: C, 71.33; H, 7.30; N, 10.04.
1-(2-(N-(3-(Cyclohexylcarbamoyl)-2,2,4,4-tetramethylpentan-3-yl)-N-
benzylcarb amoyl)phenyl)-3-(4-methoxyphenyl)urea (6g)
Yield: 0.57 g (91%), white powder, mp 99–101 ꢁC. IR (KBr) (nmax=cmꢂ1): 3487,
1
3328, 3290, 1654, 1635, 1590 cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.01 (s, 18H),
1.27–2.17 (m, 10H), 3.70 (s, 3H), 3.80 (m, 1H), 4.80 (s, 2H), 6.50 (br, 1H), 6.78 (d,

SYNTHESIS OF UREA DERIVATIVES
2117
J ¼ 8.7, 2H), 7.19 (m, 3H), 7.30 (m, 5H), 7.45 (d, J ¼ 8.7, 2H), 8.02 (s, 1H), 8.36 (d,
J ¼ 8.7, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46 MHz, CDCl3) d: 21.99 (6CH3), 24.6
(2CH2), 25.7 (2C), 25.9 (CH2), 34.5 (2CH2), 51.3 (CꢂN), 52.9 (CH2), 55.8 (OMe),
78.1 (C), 114.7 (2CH), 120.8 (CH), 121.9 (2CH), 123.8 (CH), 126.2 (CH), 127.1
(CH), 127.6 (2CH), 128.5 (CH), 129.7 (2CH), 131.8 (C), 133.1 (C), 136.8 (C),
=
=
=
138.8 (C), 152.6 (C), 156.6 (C O) 172.6 (C O), 174.2 (C O) ppm; MS (EI,
70 eV) m=z (%): 626 (Mþ, 6), 378 (17), 350 (100), 232 (77), 175 (68), 119 (43), 105
(56), 91 (50), 78 (42). Anal. calcd. for C38H50N4O4 (626.82): C, 72.81; H, 8.04; N,
8.94. Found: C, 71.83; H, 7.69; N, 8.04.
1-(2-(N-(3-(Cyclohexylcarbamoyl)-2,2,4,4-tetramethylpentan-3-yl)-N-
ethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6h)
Yield: 0.57 g (91%), white powder, mp 100–102 ꢁC. IR (KBr) (nmax=cmꢂ1): 3413,
3363, 3310, 1664, 1635, 1600cmꢂ1; 1H NMR (300MHz, CDCl3) d: 0.97 (t, J ¼ 9, 3H),
1.02 (s, 18H), 1.27–2.07 (m, 10H), 3.52 (q, J ¼ 9, 2H), 3.70 (s, 3H), 3.80 (m, 1H), 6.50
(br, 1H), 6.85 (d, J ¼ 9.3, 2H), 6.99 (t, J ¼ 6, 1H), 7.14 (t, J ¼ 9, 1H), 7.34 (t, J ¼ 6,
1H), 7.42 (d, J ¼ 9.3, 2H), 8.02 (s, 2H), 8.30 (d, J ¼ 9.3, 1H) ppm; 13C NMR
(75.46MHz, CDCl3) d: 15.7 (CH3), 21.5 (6CH3), 24.2 (2CH2), 24.9 (2C), 25.1 (CH2),
33.5 (2CH2), 44.8 (CH2), 51.3 (CꢂN), 55.8 (OMe), 78.1 (C), 114.5 (2CH), 120.0
(CH), 121.0 (2CH), 122.2 (CH), 125.3 (CH), 126.8 (CH), 131.1 (C), 133.2 (C), 136.6
=
=
=
(C), 153.6 (C), 155.6 (C O), 170.9 (C O), 174.5 (C O) ppm; MS (EI, 70eV): m=z
(%): 564 (Mþ, 6), 317 (20), 288 (100), 170 (81), 113 (58),57 (43), 29 (16). Anal. calcd.
for C33H48N4O4 (564.75): C, 70.18; H, 8.57; N, 9.92. Found: C, 70.83; H, 8.69; N, 9.04.
1-(2-(N-(2-(2,4,4-Trimethylpentan-2-ylcarbamoyl)butan-2-yl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6i)
Yield: 0.56g (91%), white powder, mp 94–96 ꢁC. IR (KBr) (nmax=cmꢂ1); 3345,
1
3397, 3278, 1667, 1624, 1590cmꢂ1; H NMR (300 MHz, CDCl3) d: 0.96 (t, J ¼ 7.3,
3H), 1.05 (s, 9H), 1.37 (s, 3H), 1.41 (s, 3H), 1.52 (s, 2H), 1.61 (s, 3H), 1.99 (q,
J ¼ 7.3, 2H), 3.74 (s, 3H), 4.55 (d, J ¼ 16.8, 1H), 4.70 (d, J ¼ 16.8, 1H), 5.90 (br, 1H),
6.92 (d, J ¼ 9, 2H), 7.20 (m, 3H), 7.30 (m, 5H), 7.45 (d, J ¼ 9, 2H),7.96 (s, 1H), 8.32
(d, J ¼ 8.1, 1H), 8.69 (s,1H) ppm; 13C NMR (75.46MHz, CDCl3) d: 9.4 (CH3), 25.8
(C), 28.9 (3CH3), 30.9 (CH3), 31.9 (CH3), 33.2 (CH3), 35.8 (CH2), 51.1 (CH2), 51.8
(C-N), 55.9 (MeO), 63.1 (C), 114.5 (2CH), 119.7 (CH), 121.0 (2CH), 122.3 (CH),
126.0 (CH), 126.1 (CH), 127.3 (2CH), 127.9 (CH), 129.1 (2CH), 130.4 (C), 133.1 (C),
=
=
=
136.9 (C), 138.3 (C), 153.6 (C), 155.6 (C O), 172.6 (C O), 176.2 (C O), ppm; MS
(EI, 70eV) m=z (%): 586 (Mþ, 4), 309 (12), 280 (100), 162 (94), 133 (15), 119 (87),
105 (21), 91 (40), 78 (12). Anal. calcd. for C35H46N4O4 (586.76): C, 71.64; H, 7.90, N,
9.55. Found: C, 71.33; H, 7.30; N, 10.04.
1-(2-(N-(2-(2,4,4-Trimethylpentan-2-ylcarbamoyl)propan-2-yl)-N-
ethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6j)
Yield: 0.48 g (96%), white powder, mp 101–103 ꢁC. IR (KBr) (nmax=cmꢂ1);
1
3460, 3330, 3270, 1654, 1645, 1598 cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.05 (t,

2118
J. AZIZIAN ET AL.
J ¼ 7.35, 3H), 1.23 (s, 9H), 1.37 (s, 6H), 1.44 (s, 6H), 1.54 (s, 2H), 3.49 (q, J ¼ 7.35, 2H),
3.80 (s, 3H), 5.90 (br, 1H), 6.78 (d, J ¼ 9, 2H), 7.19 (m, 3H), 7.45 (d, J ¼ 9, 2H), 8.02 (s,
1H), 8.36 (d, J ¼ 9, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46 MHz, CDCl3) d: 18.7
(CH3), 24.5 (3CH3), 25.8 (C), 26.4 (2CH3), 28.9 (2CH3), 33.2 (CH2), 37.9 (C), 49.8
(CH2), 55.9 (MeO), 63.1 (C), 114.5 (2CH), 119.7 (CH), 120.8 (2CH), 122.1 (CH),
=
125.7 (CH), 127.7 (CH), 130.3 (C), 133.1 (C), 136.8 (C), 153.6 (C)þ, 155.6 (C O),
=
=
172.6 (C O), 176.2 (C O) ppm; MS (EI, 70 eV) m=z (%): 510 (M , 7), 233 (15),
204 (100), 119 (94), 85 (15), 71 (87), 57 (21), 43 (40), 29 (12). Anal. calcd. for
C29H42N4O4 (510.66): C, 68.21; H, 8.29; N, 10.97. Found: C, 69.33; H, 7.98; N, 10.04.
1-(2-(N-((Cyclohexylcarbamoyl)(phenyl)methyl)-N-
benzylcarbamoyl)phenyl)-3-phenylurea (6k)
Yield: 0.54 g (81%), white powder, mp 130–132 ꢁC. IR (KBr) (nmax=cmꢂ1):
3494, 3437, 3310, 1654, 1635, 1590 cmꢂ1
;
1H NMR (300 MHz, CDCl3) d:
1.15–1.99 (m, 10H), 3.82 (m, 1H), 4.55 (d, J ¼ 16.8, 1H), 4.70 (d, J ¼ 16.8, 1H),
5.90 (br, 1H), 6.34 (s, 1H), 7.14 (m, 5H), 7.33 (m, 5H), 7.63 (m, 4H), 7.94 (m,
4H), 8.02 (s, 1H), 8.36 (d, J ¼ 9, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46 MHz,
CDCl3) d: 24.5 (2CH2), 25.8 (CH), 33.2 (2CH2), 49.8 (CH2), 51.1 (C-N), 68.1
(CH), 121.5 (2CH2), 121.8 (CH), 122.3 (CH), 123.9 (C), 124.1 (CH), 125 (CH),
127.7 (2CH2), 128.1 (2CH2), 128.9 (2CH2), 129.4 (2CH2), 130.3 (CH), 130.2 (CH),
=
131.0 (2CH2), 131.8 (CH), 133.1 (C), 135.5 (C), 136.1 (C), 136.9 (C)þ, 155.6 (C O),
=
=
172.6 (C O), 176.2 (C O) ppm; MS (EI, 70 eV): m=z (%): 560 (M , 4), 342 (15),
314 (100), 196 (94), 119 (64), 105 (15), 91 (51). Anal. calcd. for C35H36N4O3
(560.27): C, 74.98; H, 6.47, N, 9.99. Found: C, 74.33; H, 7.01; N, 10.04.
1-(2-(N-((Cyclohexylcarbamoyl)(4-nitrophenyl)methyl)-N-
benzylcarbamoyl)phenyl)-3-phenylurea (6l)
Yield: 0.53 g (73%), white powder, mp 128–130 ꢁC. IR (KBr) (nmax=cmꢂ1): 3434,
1
3937, 3387, 1654, 1615, 1590 cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.15–1.99 (m,
10H), 3.82 (m, 1H), 4.55 (d, J ¼ 16.8, 1H), 4.70 (d, J ¼ 16.8, 1H), 5.90 (br, 1H), 6.34
(s, 1H), 7.14 (m, 5H), 7.22 (d, J ¼ 9, 2H), 7.33 (m, 5H), 7.43 (m, 3H), 7.98 (d, J ¼ 9,
2H), 8.02 (s, 1H), 8.36 (d, J ¼ 9, 1H), 8.58 (s, 1H) ppm; 13C NMR (75.46 MHz, CDCl3)
d: 24.5 (2CH2), 25.8 (CH), 33.2 (2CH2), 49.8 (CH2), 51.1 (C-N), 68.1 (CH), 121.5
(2CH2), 122.3 (CH), 123.9 (C), 124.1 (CH), 127.7 (2CH2), 128.1 (2CH2), 128.5
(CH), 128.9 (2CH2), 129.4 (2CH2), 130.3 (CH), 130.6 (CH), 131.0 (2CH2), 131.8
=
(CH), 133.1 (C), 135.5 (C), 136.6 (C), 138.1 (C), 149.9 (C), 155.6 (C O), 172.6
þ
=
=
(C O), 176.2 (C O) ppm; MS (EI, 70 eV) m=z (%): 605 (M , 5), 387 (15), 359
(100), 241 (94), 119 (64), 105 (15), 91 (51). Anal. calcd. for C35H35N5O5 (605.68): C,
69.41; H, 5.82; N, 11.56. Found: C, 69.33; H, 5.01; N, 11.04.
1-(2-(N-((Cyclohexylcarbamoyl)(4-nitrophenyl)methyl)-N-
benzylcarbamoyl)phenyl)-3-(4-methoxyphenyl)urea (6m)
Yield: 0.54 g (75%), white powder, mp 131–133 ꢁC. IR (KBr) (nmax=cmꢂ1): 3494,
1
3437, 3310, 1634, 1625, 1590 cmꢂ1; H NMR (300 MHz, CDCl3) d: 1.15–2.09 (m,

SYNTHESIS OF UREA DERIVATIVES
2119
10H), 3.82 (m, 1H), 4.55 (d, J ¼ 16.8, 1H), 3.87 (s, 3H), 4.70 (d, J ¼ 16.8, 1H), 5.90 (br,
1H), 6.34 (s, 1H), 6.92 (d, J ¼ 9, 2H), 7.20 (m, 3H), 7.30 (m, 5H), 7.32 (d, J ¼ 9, 2H),
7.55 (d, J ¼ 9, 2H), 7.95 (d, J ¼ 9, 2H), 8.01 (s, 1H), 8.32 (d, J ¼ 8.1, 1H), 8.69 (s, 1H)
ppm; 13C NMR (75.46 MHz, CDCl3) d: 24.5 (2CH2), 25.8 (CH), 33.2 (2CH2), 49.8
(CH2), 51.1 (C-N), 55.9 (OMe), 68.1 (CH), 114.5 (2CH), 119.7 (CH), 121.0 (2CH),
122.3 (CH), 123 (2CH), 125 (CH), 126.0 (CH), 126.1 (CH), 127.3 (2CH), 127.9
(CH), 129.1 (2CH), 130.4 (C), 131 (CH), 133.1 (C), 136.9 (C), 138.3 (C), 142 (C),
=
=
=
147 (C), 153.6 (C), 155.6 (C O), 172.6 (C O), 176.2 (C O) ppm; MS (EI, 70 eV)
m=z (%): 635 (Mþ, 5), 485 (15), 387 (100), 359 (94), 241 (64), 119 (23), 105 (15), 91
(51). Anal. calcd. for C36H37N5O6 (635.70): C, 68.02; H, 5.87; N, 11.02. Found: C,
68.33; H, 5.01; N, 11.04.
ACKNOWLEDGMENT
Financial support of this work by the Research Council of Science and
Research Branch of Islamic Azad University is gratefully acknowledged.
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