A facile method for the preparation of unsymmetrical ureas utilizing zirconium (IV) chloride

Article abstract of DOI:10.1002/bkcs.10646

A facile synthetic method for the preparation of unsymmetrical ureas from amines is described. Carbamoyl imidazole compounds were prepared by the reaction of 1, 1-carbonyldiimidazole with primary or secondary amines, and further activation by treatment with zirconium(IV) chloride to generate the desired urea. This reaction protocol was applied to the synthesis of tri and tetrasubstituted ureas with high yields. This study provides an alternative guideline for the practical preparation of various unsymmetrical ureas.

Full text of DOI:10.1002/bkcs.10646

Article
DOI: 10.1002/bkcs.10646
BULLETIN OF THE
A. Lee et al.
KOREAN CHEMICAL SOCIETY
A Facile Method for the Preparation of Unsymmetrical Ureas Utilizing
Zirconium(IV) Chloride
§
Anna Lee,† Hee-Kwon Kim,‡,§, and David H. Thompson
*
†Department of Chemistry, Myongji University, Yongin 449-728, Republic of Korea
‡Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center,
Biomedical Research Institute, Chonbuk National University Medical School and Hospital, Jeonju 561-712,
Republic of Korea. *E-mail: hkkim717@jbnu.ac.kr,
§Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA
Received July 17, 2015, Accepted October 18, 2015, Published online January 14, 2016
A facile synthetic method for the preparation of unsymmetrical ureas from amines is described.
Carbamoyl imidazole compounds were prepared by the reaction of 1,1-carbonyldiimidazole with
primary or secondary amines, and further activation by treatment with zirconium(IV) chloride to generate
the desired urea. This reaction protocol was applied to the synthesis of tri and tetrasubstituted ureas with
high yields. This study provides an alternative guideline for the practical preparation of various unsymmetrical
ureas.
Keywords: Unsymmetrical urea, Zirconium(IV) chloride, Carbamoyl imidazole
Introduction
though this method improved the reactivity of 1,10-carbamoyl
imidazole, it required two separate steps and a longer reaction
time.28
Ureas and their derivatives are prevalent in nature and have
interesting biological activities such as plant and insect growth
regulators,1,2 enzyme inhibitors,3,4 pseudopeptides,5 natural
receptor antagonists,6,7 anti-mycobacterial agents,8 antitumor
agents,9 and HIV protease inhibitors.10,11 In particular,
unsymmetrical ureas are found in many natural products
and pharmaceuticals.12–14 Unsymmetrical ureas have been
synthesized because of the prevalence of this structural motif
in bioactive compounds and its utility as a synthetic interme-
diate to produce other useful compounds such as molecular
gels,15–18 and self-assembling molecular capsules.19–21
One of the most general methods for the synthesis of ureas
involves the reaction of amines with isocyanates, which can be
prepared by treating an amine with a phosgene or triphos-
gene.22 Carbamoyl chlorides have also been reacted with
the corresponding amine to produce ureas. However, these
methods have drawbacks such as the high toxicity of phosgene
and the instability of the carbamoyl chloride intermediate. In
As part of our ongoing research effort to synthesize a num-
ber of unsymmetrical urea compounds, we have considered
novel methods that proceed with short reaction times and do
not require activation of the carbamoyl imidazole compounds
with excess MeI. In particular, zirconium (Zr) is an attractive
agent to generate high yields of ureas because Zr reagents have
been employed in many organic reactions as mediators or
catalysts.29–31 Here we report an efficient zirconium chloride
(ZrCl4)-mediated synthetic method for the preparation of a
variety of unsymmetrical ureas by the activation of carbamoyl
imidazole compounds.
Experimental
General. All chemicals were purchased from Sigma-Aldrich
1
and were used without further purification. The H and 13C
addition,
p-nitrophenyl
chloroformate
and
1,10-
nuclear magnetic resonance (NMR) spectra were recorded
on a 400 and 100 MHz spectrometer (AV400, Bruker, Bille-
rica, MA, USA), respectively, at room temperature. Chemical
shifts arereported in δunits (ppm) relative totetramethylsilane
and coupling constants (J) are quoted in hertz. Reaction prog-
ress was monitored by thin-layer chromatography (TLC) anal-
ysis. TLC analysis was performed using an aluminum plate
with silica gel 60 F254, and TLC spots were visualized by
UV light (254 nm) exposure. Flash chromatography was per-
formed using 230–400 mesh silica gel and analytical grade
solvents. High-resolution mass spectrometry (HRMS) was
performed on a Q-TOF mass spectrometer (Waters, Milford,
MA, USA).
carbonyldiimidazole (CDI) have been used to produce unsym-
metrical ureas.23–26 However, these methods gave low reac-
tion yields, because the carbamoyl imidazole intermediates
showed insufficient reactivity toward a nucleophilic attack
reaction.
1,10-Carbonylbisbenzotriazole has been used to improve
the synthesis of trisubstituted and tetrasubstituted ureas.27
However, this method required long reaction times. Besides,
1,10-carbamoyl imidazole has been studied to develop an effi-
cient synthetic method to prepare unsymmetrical ureas; how-
ever, excess MeI must be added during this synthetic protocol
to provide an activated carbamoylimidazolium salt. Even
Bull. Korean Chem. Soc. 2016, Vol. 37, 154–160
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General Procedure for the Preparation of Carbamoyl
Imidazole Compounds (2a–2e). To a solution of 1,10-CDI
(1.91 g, 11.8 mmol) in THF (20 mL), aniline (1 g,
10.74 mmol) was added. The reaction mixture was stirred at
was purified by flash column chromatography on silica gel
with hexane–EtOAc as eluent to afford the desired product
4a (0.18 g, 95%).
1-Benzyl-ꢀ3-phenylurea (4a). Yellow solid (95%); mp
173–174 C; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s,
1H), 7.40 (ddd, J = 1.7, 3.2, 4.1 Hz, 2H), 7.28–7.35 (m,
4H), 7.18–7.26 (m, 3H), 6.89 (tt, J = 1.2, 7.5 Hz, 1H), 6.59
(t, J = 5.9 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 154.4, 1398, 139.6, 128.2, 127.6,
126.7, 126.2, 120.4, 117.1, 42.8.; HRMS (ESI) m/z
(M + H)+ calcd for C14H15N2O = 227.1184, found
227.1179.
ꢀ
45 C until completion of the reaction for 15 h. The reaction
mixture was concentrated under reduced pressure, and the
resulting residue was purified by flash column chromatogra-
phy on silica gel to afford the desired product 2a
(1.54 g, 82%).
N-Phenyl-1H-imidazole-1-carboxamide (2a). White solid
1
ꢀ
(82%); mp 114–116 C; H NMR (400 MHz, DMSO-d6) δ
10.25 (br, 1H), 8.38 (dd, J = 1.2, 0.9 Hz, 1H), 7.83 (dd,
J = 1.5, 1.2 Hz, 1H), 7.62 (dd, J = 8.0, 1.1 Hz, 2H), 7.41
(t, J = 8.0 Hz, 2H), 7.18 (td, J = 8.0, 1.1 Hz, 1H), 7.10 (dd,
J = 1.5, 0.9 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ
117.6, 121.6, 125.9, 129.6, 130.1, 136.5, 137.0, 147.3; HRMS
(ESI) m/z (M + H)+ calcd for C10H10N3O = 188.0824, found
188.0829.
1-Cyclohexyl-3-phenylurea (4b). White solid (93%); mp
183–184 C; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s,
ꢀ
1H), 7.36 (d, J = 8.6 Hz, 2H), 7.20 (t, J = 7.9 Hz, 2H),
6.85 (t, J = 7.2 Hz, 1H), 6.02 (d, J = 7.8 Hz, 1H), 3.45 (dd,
J = 7.0, 10.9 Hz, 1H), 1.74–1.84 (m, 2H), 1.61–1.72 (m,
2H), 1.47–1.58 (m, 1H), 1.23–1.38 (m, 2H), 1.05–1.23 (m,
3H); 13C NMR (100 MHz, DMSO-d6) δ 153.8, 140.2,
128.3, 120.4, 117.1, 47.4, 33.1, 25.4, 24.3; HRMS (ESI) m/
z (M + H)+ calcd for C13H19N2O = 219.1497, found
219.1491.
N-(Benzyl)-1H-imidazole-1-carboxamide (2b). White solid
1
ꢀ
(87%); mp 124–126 C; H NMR (400 MHz, DMSO-d6) δ
8.07 (s, 1H), 7.98 (s, 1H), 7.48 (d, J = 1.2 Hz, 1H),
7.21 − 7.40 (m, 5H), 6.95 (d, J = 1.2 Hz, 1H), 4.53 (d,
J = 1.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 149.5,
138.9, 136.4, 130.5, 128.8, 128.4, 127.9, 127.5, 127.3,
117.1, 43.8; HRMS (ESI) m/z (M + H)+ calcd for
C11H12N3O = 202.0980, found 202.0982.
N-Phenylmorpholine-4-carboxamide (4c). White solid
(86%); mp 150–152 C; 1H NMR (400 MHz, CDCl3) δ
ꢀ
7.20 − 7.38 (m, 4H), 6.998 − 7.08 (m, 1H), 6.64 (s, 1H),
3.61 − 3.72 (m, 4H), 3.37 − 3.48 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 155.4, 138.7, 129.01, 123.5, 120.5,
66.4, 44.2; HRMS (ESI) m/z (M + H)+ calcd for
C11H15N2O2 = 207.1134, found 207.1137.
N-Methyl-N-phenyl-1H-imidazole-1-carboxamide
(2c).
1
ꢀ
Yellow solid (76%); mp 62–64 C; H NMR (400 MHz,
CDCl3) δ 7.55 (s, 1H), 7.29–7.38 (m, 3H), 7.07–7.13 (m,
2H), 6.76–6.84 (m, 2H), 3.47 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 150.2, 142.8, 137.7, 130.3, 128.7, 128.1, 125.8,
118.3, 40.1; HRMS (ESI) m/z (M + H)+ calcd for
C11H12N3O = 202.0980, found 202.0986.
1,1-Diisopropyl-3-phenylurea (4d). White solid (82%); mp
1
ꢀ
123–124 C; H NMR (400 MHz, CDCl3) δ 7.21–7.40 (m,
4H), 6.94–7.04 (m, 1H), 6.18 (s, 1H), 3.99 (m, 2H), 1.33 (d,
J = 6.9, 12H); 13C NMR (100 MHz, CDCl3) δ 154.4,
139.2, 128.6, 122.3, 119.5, 45.3, 21.3; HRMS (ESI) m/z
(M + H)+ calcd for C13H21N2O = 221.1654, found
221.1659.
(3,4-Dihydroquinolin-1(2H)-yl)(1H-imidazol-1-yl metha-
1
ꢀ
none (2d)). Yellow solid (78%); mp 71–73 C; H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 1.0 Hz, 1H), 7.17 (m,
1H), 7.04 (m, 1H), 6.97 (m, 1H), 6.91 (m, 1H), 6.87 (m,
1H), 6.61 (m, 1H), 3.83 (t, J = 6.8 Hz, 2H), 2.82 (t,
J = 6.8 Hz, 2H), 2.07 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 150.1, 137.8, 137.4, 131.8, 129.7, 129.1, 127.3, 125.7,
123.3, 118.2, 45.8, 26.4, 24.0; HRMS (ESI) m/z (M + H)+
calcd for C13H14N3O = 228.1137, found 228.1131.
1-Benzyl-3-(3-methylbenzyl)urea (4e). White solid (95%);
1
ꢀ
mp 133–134 C; H NMR (400 MHz, CDCl3) δ 7.26–7.33
(m, 1H), 7.20–7.27 (m, 3H), 7.14–7.22 (m, 2H), 7.00–7.09
(m, 3H), 4.66 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 2.31 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 158.2, 139.1, 139.0,
138.5, 128.9, 128.77, 128.4, 128.4, 127.6, 127.5, 124.6,
44.9, 44.8, 21.6; HRMS (ESI) m/z (M + H)+ calcd for
C16H19N2O = 255.1497, found 255.1494.
N,N-Dibenzyl-1H-imidazole-1-carboxamide (2e). White
1
ꢀ
solid (73%); mp 62–64 C; H NMR (400 MHz, CDCl3) δ
7.95 (s, 1H), 7.37–7.43 (m, 6H), 7.24–7.36 (m, 5H), 7.05
(s, 1H), 4.63 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 150.1,
137.8, 137.4, 131.8, 129.7, 129.1, 127.3, 125.7, 123.3,
118.2, 45.8, 26.4, 24.0; 152.3, 137.0, 135.2, 129.8, 129.2,
128.4, 127.4, 117.8, 50.6; HRMS (ESI) m/z (M + H)+ calcd
for C18H18N3O = 292.1450, found 292.1454.
1-Benzyl-3-cyclohexylurea (4f). White solid (92%); mp
1
ꢀ
151–154 C; H NMR (400 MHz, CDCl3) δ 7.17 − 7.43
(m, 5H), 5.04 (s, 1H), 4.65 (s, 1H), 4.25 (s, 2H),
3.29 − 3.54 (m, 1H), 1.76 − 1.94 (m, 2H), 1.42 − 1.71 (m,
3H), 0.94 − 1.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
157.4, 139.2, 128.4, 127.6, 127.4, 49.3, 44.6, 33.8, 25.4,
24.7; HRMS (ESI) m/z (M + H)+ calcd for C14H21N2O =
233.1654, found 233.1658.
General Procedure for the Preparation of Urea Com-
pounds (4a–4q). To a solution of 2a (0.2 g, 1.07 mmol) in
THF (10 mL), ZrCl4 (0.25 g, 1.07 mmol) was added. Benzy-
lamine 3a (0.23 g, 2.14 mmol) was added and the reaction
mixture was refluxed for 2 h. The reaction mixture was con-
centrated under reduced pressure, and the resulting residue
N-Benzylpiperidine-1-carboxamide (4g). White solid
(88%); mp 101–104 C; 1H NMR (400 MHz, CDCl3) δ
ꢀ
7.12 − 7.42 (m, 5H), 4.81 (s, 1H), 4.37 − 4.43 (m, 2H),
3.27 − 3.33 (m, 4H), 1.42 − 1.64 (m, 6H); 13C NMR
Bull. Korean Chem. Soc. 2016, Vol. 37, 154–160
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Facile Synthesis of Unsymmetrical Urea
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(100 MHz, CDCl3) δ 157.4, 139.3, 128.6, 127.4, 127.2, 45.0,
44.6, 25.3, 24.2; HRMS (ESI) m/z (M + H)+ calcd for
C13H19N2O = 219.1497, found 219.1493.
14.2; HRMS (ESI) m/z (M + H)+ calcd for C14H19N2O3 =
263.1396, found 263.1391.
(3,4-Dihydroquinolin-1(2H)-yl)(piperidin-1-yl)methanone
(4o). Brown oil (73%); 1H NMR (400 MHz, CDCl3) δ
7.04–7.10 (m, 2H), 7.03 (d, J = 1.2 Hz, 1H), 6.87 (t,
J = 1.2 Hz, 1H), 3.54 (t, J = 6.2 Hz, 2H), 3.24–3.29 (m,
4H), 2.78 (t, J = 6.1 Hz, 2H), 1.93–1.98 (m, 2H), 1.51–1.57
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 160.2, 141.1,
129.2, 127.1, 126.2, 121.8, 119.6, 46.7, 45.4, 27.2, 25.4,
24.5, 23.2; HRMS (ESI) m/z (M + H)+ calcd for
C15H21N2O = 245.1654, found 245.1650.
Methyl 2-(3-benzylureido)-3-methylbutanoate (4h). White
1
ꢀ
solid (91%); mp 83–85 C; H NMR (400 MHz, CDCl3) δ
6.84 − 7.53 (m, 5H), 5.58 − 5.92 (m, 2H), 4.12 − 4.44 (m,
3H), 3.58 (s, 3H), 1.89 − 2.11 (m, 1H), 0.85 (d, J = 6.8 Hz,
3H), 0.75 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.1, 158.3, 1395, 128.2, 127.4, 127.1, 57.7, 51.8, 44.2,
31.3, 18.7, 17.7; HRMS (ESI) m/z (M + H)+ calcd for
C14H21N2O3 = 265.1552, found 265.1557.
1,1-Dibenzyl-3-cyclohexylurea (4p). White solid (84%); mp
3-Benzyl-1,1-diisopropylurea (4i). White solid (86%); mp
1
ꢀ
1
ꢀ
140–142 C; H NMR (400 MHz, CDCl3) δ 7.31–7.35 (m,
4H), 7.22–7.27 (m, 6H), 4.47 (s, 4H), 3.64–3.68 (m, 1H),
1.81–1.83 (m, 2H), 1.52–1.53 (m, 3H), 1.27–1.31 (m, 2H),
1.04–1.07 (m, 1H), 0.91–0.96 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 157.9, 137.9, 128.8, 127.5, 127.3,
50.4, 40.1, 33.7, 25.7, 24.8; HRMS (ESI) m/z (M + H)+ calcd
for C21H27N2O = 323.2123, found 323.2126.
81–83 C; H NMR (400 MHz, CDCl3) δ 7.25 (m, 5H),
4.45 (m, 2H), 3.87 (m, J = 6.3 Hz, 2H), 1.25 (d,
J = 6.9 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 157.0,
139.5, 128.7, 127.4, 127.1, 45.3, 44.8, 21.5; HRMS (ESI)
m/z (M + H)+ calcd for C14H23N2O = 235.1810, found
235.1814.
3-Benzy-1-methyl-1-phenylurea (4j). White solid (83%), mp
N,N-Dibenzylmorpholine-4-carboxamide (4q). White solid
1
ꢀ
92–94 C; H NMR (400 MHz, CDCl3) δ 7.37–7.43 (m,
2 H), 7.19–7.30 (m, 8 H), 4.37 (d, J = 5.7 Hz, 2 H),
3.29 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 157.3,
134.4, 139.6, 130.2, 128.9, 127.5, 127.4, 127.2, 44.8, 37.4;
HRMS (ESI) m/z (M + H)+ calcd for C15H17N2O =
241.1340, found 241.1347.
(75%); mp 106–108 C; 1H NMR (400 MHz, CDCl3) δ
ꢀ
7.25–7.37 (m, 6H), 7.14–7.24 (m, 4H), 4.33 (s, 4H),
3.67–3.72 (m, 4H), 3.30–3.34 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 164.7, 137.2, 128.5, 127.7, 127.3,
66.5, 50.5, 47.6; HRMS (ESI) m/z (M + H)+ calcd for
C19H23N2O2 = 211.1760, found 211.1756.
3-Cyclohexyl-1-methꢀyl-1-phenylurea (4k). White solid
(90%); mp112–113 C; 1H NMR (400 MHz, CDCl3) δ
7.35 (t, J = 8.0 Hz, 2H), 7.12–7.25 (m, 3H), 4.15 (d,
J = 7.2 Hz, 1H), 3.55–3.61 (m, 1H), 3.18 (s, 3H),
0.88–1.81 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 156.4,
143.5, 129.7, 126.99, 126.8, 49.1, 36.8, 33.4, 25.4, 24.6;
HRMS (ESI) m/z (M + H)+ calcd for C14H21N2O =
233.1654, found 233.1657.
Procedures for the Preparation of 1,10-(Octane-1,8-diyl)bis
(3-methyl-3-phenylurea) (4r). To a solution of 2c (1.12 g,
5.55 mmol) in THF (30 mL), ZrCl4 (1.29 g, 5.55 mmol)
was added. 1,8-Diaminooctane 3k (0.2 g, 1.39 mmol) was
added, and the reaction mixture was refluxed for 3 h. The reac-
tion mixture was concentrated under reduced pressure, and the
resulting residue was then purified by flash column chroma-
tography on silica gel with hexane–EtOAc as eluent to afford
the desired product 4r (0.41 g, 72%). White solid (72%); mp
130–132 C; H NMR (400 MHz, CDCl3) δ 7.39–7.43 (m,
4H), 7.28–7.39 (m, 2H), 7.22–7.26 (m, 4H), 4.28(s, 2H),
3.26 (s, 6H), 3.11–3.14 (m, 4H), 1.33–1.38 (m, 4H), 1.18
(m, 8H); 13C NMR (100 MHz, CDCl3) δ 157.4, 143.7,
130.1, 127.4, 127.3, 40.9, 39.2, 30.2, 29.2, 26.8; HRMS
(ESI) m/z (M + H)+ calcd for C24H35N4O2 = 411.2760,
found 411.2761.
N-Methyl-N-phenylpyrrolidine-1-carboxamide (4l). Peach-
1
ꢀ
1
ꢀ
colored solid (75%); mp 64–66 C; H NMR (400 MHz,
CDCl3) δ 7.27–7.33 (m, 2H), 7.08–7.12 (m, 3H), 3.21 (s,
3H), 3.03 (t, J = 6.5 Hz, 4H), 1.65–1.68 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 159.8, 146.4, 129.3, 125.4, 124.6,
48.3, 39.8, 25.5; HRMS (ESI) m/z (M + H)+ calcd for
C12H17N2O2 = 205.1341, found 205.1347.
1,1-Diisopropyl-3-methyl-3-phenylurea (4m). Colorless oil
1
(78%); H NMR (400 MHz, CDCl3) δ 7.27–7.36 (m, 2H),
7.04–7.12 (m, 3H), 3.62 (m, 2H), 3.04 (s, 3H), 1.08 (d,
J = 6.9 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 161.4,
148.3, 129.2, 124.3, 47.6, 40.2, 20.4; HRMS (ESI) m/z
(M + H)+ calcd for C14H23N2O = 235.1810, found
235.1815.
Results and Discussion
Unsymmetrical ureas were synthesized via a simple two-step
procedure thatincludedthepreparationofthecarbamoyl imid-
azole and activation with ZrCl4. In the first step, carbamoyl
imidazole compounds were synthesized by the reaction of
CDI, an inexꢀpensive solid, with the primary or secondary
amines at 45 C for 15 h. The desired compounds were iso-
lated as stable solids at room temperature (Scheme 1).
ZrCl4 was used in the second step to activate the carbamoyl
imidazole compounds for generation of urea structures. Our
initial attempt in the second step to synthesize an unsymmet-
rical substituted urea used aniline, which served as a model
Ethyl 2-(1,2,3,4-tetrahydroquinoline-1-carboxamido) ace-
tate (4n). White solid (91%); mp 48–50 C; 1H NMR
ꢀ
(400 MHz, CDCl3) δ 7.44 (m, 1H), 7.13–7.27 (m, 2H),
7.05 (m, 1H), 5.65 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.03
(d, J = 5.2 Hz, 2H), 3.75 (t, J = 6.0 Hz, 2H), 2.78 (t,
J = 6.7 Hz, 2H), 1.95 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.2, 156.5, 139.0, 132.5,
129.8, 126.5, 124.6, 123.5, 61.4, 43.8, 42.7, 27.2, 24.3,
Bull. Korean Chem. Soc. 2016, Vol. 37, 154–160
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Facile Synthesis of Unsymmetrical Urea
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reaction to determine the optimum condition. First, the carba-
moyl imidazole compounds were reacted with a series of
equivalents of ZrCl4 (0.2, 0.5, 1.0, and 1.5 equiv) in THF to
generate the desired ureas. Reaction yields were checked after
2 h. It turned out that the amount of ZrCl4 was crucial for the
formation of ureas. The reaction yields were poor in the pres-
enceof0.2equivofZrCl4 (Table1, entries1and2)butincreas-
ing the amount of ZrCl4 improved the reaction yields (Table 1,
entries 4–8). However, adding more than one equiv of ZrCl4
did not provide further enhancement in the yield. Thus, reac-
tion with one equiv of ZrCl4 was chosen for further study. The
effect of temperature on the reaction yield was also investi-
gated. By increasing the reaction temperature, yields
improved (Table 1, entries 6–8). Next, various solvents such
as 1,4-dioxane, CH3CN, and toluene were screened to identify
the optimal reaction conditions (entries 10–12). The reaction
worked well in toluene, CH3CN, and THF solvents (Table 1,
entries 8, 11, and 12). However, the use of 1,4-dioxane
reduced the reaction yield (Table 1, entry 10). THF and
CH3CN provided the best results in terms of reactivity. How-
ever, THF was selected as the optimal solvent because the
reaction could be carried out at a milder reaction temperature
(Table 1, entry 8 vs. 11).
spectroscopy. To our knowledge, this is the first report
describing a protocol using ZrCl4 to prepare unsymmetrical
ureas.
With the optimized reaction conditions in hand, screening
experiments were carried out using different substrates
(Table 2). First, reactions of aromatic compounds to form
unsymmetrical ureaswereexplored. Afterthetreatmentofani-
line with CDI produced N-phenyl carbamoyl imidazole com-
pounds, reactions with different amines generated good yield
of the desired unsymmetrical ureas (4a–4d) starting from car-
bamoyl imidazole compounds.
Next, N-benzyl carbamoyl imidazole was employed using
the reaction condition to extend the reaction scope. The results
demonstrated that our reaction protocol was efficient for
synthesizing various unsymmetrical ureas and that ZrCl4
was as a good activating agent for the reactions, affording high
yields of N-benzylurea (4e–4i).
It is known that carbamoyl imidazoles prepared from sec-
ondary amines with CDI are stable and have low reactivity
to nucleophiles. Thus, preparations of trisubstituted and tetra-
substituted ureas are often limited.32 In the present study, the
utilization range of ZrCl4 was extended to carbamoyl imidaz-
ole starting from a secondary amine to prepare trisubstituted
and tetrasubstituted ureas. First, the activation of N-
methylaniline carbamoyl imidazole with ZrCl4 and treatment
with benzylamine was examined, which resulted in rapid for-
mation of the target unsymmetrical urea in high yield (93%).
Similarly, reactions of carbamoyl imidazole from secondary
amines led to efficient conversions to the corresponding sub-
stituted ureas (4j–4m). In order to verify the reactivity of car-
bamoyl imidazole compounds from secondary amines (2c–
2e), carbamoyl imidazole 2d, synthesized starting from
The structures and purities of the desired prepared com-
1
pounds were confirmed by HRMS and H and 13C NMR
Scheme 1. Synthesis of carbamoylimidazoles.
Table 1. Screening of reaction conditions for the preparation of urea.a
NH2
O
O
ZrCl4
+
N
N
N
N
H
H
N
solvent, 2h
H
2a
3a
4a
Entry
ZrCl4 (equiv)
Solvent
Temp.
Yieldb (%)
1
2
3
4
5
6
7
8
0.2
0.2
0.5
0.5
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
THF
THF
THF
THF
THF
THF
THF
THF
THF
r.t.
Reflux
r.t.
12
18
23
41
47
61
74
95
95
23
95
72
Reflux
r.t.
ꢀ
40 C
ꢀ
55 C
Reflux
Reflux
9
ꢀ
10
11
12
a
1,4-Dioxane
CH3CN
Toluene
75 C
ꢀ
75 C
ꢀ
75 C
Reaction conditions: 2a carbamoyl imidazole (1.0 mmol), amine (2.0 mmol), solvent (10 mL, 0.1 M).
Isolated yield after column purification.
b
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Facile Synthesis of Unsymmetrical Urea
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Table 2. Scope of urea formation from amines.a
O
O
N
R3
ZrCl4
R1
N
R3
NH
N
R2
N
R4
+
R1
N
THF, reflux, 2-4h
R4
3
R2
2
4
Entry
1
Carbamoylimidazole
Amine
Product
Yieldc (%)
95
O
NH2
O
O
3a
2a
4a
4b
N
H
N
N
H
N
H
N
2
3
93
NH2
O
O
3b
3c
2a
2a
N
H
N
N
N
H
N
H
N
N
86b
NH
O
O
4c
4d
O
N
H
N
N
H
O
4
82b
O
3d
NH
2a
N
H
N
N
H
N
N
5
6
95
92
O
H3C
O
NH2
3e
CH3
4e
N
N
N
N
N
N
N
H
H
H
2b
2b
O
NH2
O
O
3b
3f
N
H
4f
N
H
N
H
7
8
88b
91
O
O
NH
4g
N
H
N
N
N
H
N
N
N
2b
2b
O
NH2
O
N
H
4h
N
N
CH3
3g
O
H
H
O
H3C
O
9
86b
93
O
O
3d
NH
N
H
N
N
N
4i
N
H
2b
2c
10
11
12
13
O
NH2
O
3a
4j
N
N
N
N
N
N
N
N
H
CH3
CH3
90
NH2
O
O
3b
3h
4k
4l
N
N
N
N
N
N
2c
2c
2c
H
CH3
CH3
75b
78b
O
O
NH
N
N
N
CH3
CH3
O
O
4m
3d
NH
N
N
N
CH3
CH3
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KOREAN CHEMICAL SOCIETY
Table 2 (continued)
Entry
14
Carbamoylimidazole
Amine
Product
Yieldc (%)
91
O
O
O
3i
NH2
O
O
4n
O
N
N
N
N
N
N
2d
2d
N
N
H
15
16
73b
84
O
NH
O
3f
4o
N
N
NH2
O
O
3b
3c
4p
4q
N
N
N
N
N
N
N
2e
2e
N
N
H
17
75b
O
NH
O
O
N
O
a
Reaction conditions: carbamoyl imidazole (1.0 mmol), amine (2.0 mmol), ZrCl4 (1.0 mmol), THF, reflux for 2 h.
Reflux for 4 h.
Isolated yield after column purification.
b
c
O
N
N
N
CH3
2c
ZrCl4 (4 equiv)
THF
O
CH3
H
N
N
N
N
+
H
reflux, 3h
CH3
O
4r
NH2
H2N
3k
Scheme 2. Synthesis of bis-ureas.
1,2,3,4-hydroquinoline, was treated with ZrCl4 for the prepa-
ration ofsubstitutedureas. Through our new reaction protocol,
treatment of 2d with different amines gave the desired ureas in
good yields (73–91%) without any side reactions. In addition,
dibenzyl carbamoyl imidazole (2e) successfully reacted with
various amines to produce the corresponding trisubstituted
and tetrasubstituted ureas.
Furthermore, the reaction protocol was applied to prepare
bis-ureas to determine the synthetic utility of the method.
As shown in Scheme 2, four equiv of carbamoyl imidazole
2c was treated with four equiv of ZrCl4, followed by addition
of one equiv of 1,8-diaminooctane to readily produce the bis-
urea compound (4r) in good yield (72%).
Acknowledgments. The work was supported by Basic Sci-
ence Research Program through the National Research Foun-
dation of Korea (NRF) funded by the Ministry of Education
(2014R1A1A2057943).
References
1. A. Abad, C. Agulló, A. C. Cuñat, R. Jiménez, C. Vilanova,
J. Agric. Food Chem. 2004, 52, 4675.
2. W. Lu, Q. Zhou, G. Liu, J. Agric. Food Chem. 2004, 52, 7759.
3. D. J. Kempf, K. C. Marsh, D. A. Paul, M. F. Knigge, D. W.
Norbeck, W. E. Kohlbrenner, L. Codacovi, S. Vaeavanonda,
P. Bryant, X. C. Wang, Antimicrob. Agents Chemother. 1991,
35, 2209.
4. D. P. Getman, G. A. DeCrescenzo, R. M. Heintz, K. L. Reed,
J. J. Talley, M. L. Bryant, M. Clare, K. A. Houseman,
J. J. Marr, J. Med. Chem. 1993, 36, 288.
Conclusions
In conclusion, an efficient method to synthesize unsymmetri-
cal ureas has been developed. Di, tri, and tetrasubstituted ureas
were obtained in high yields using our protocol, which
included the activation of carbamoyl imidazole compounds
with ZrCl4. Furthermore, ZrCl4 was successfully applied to
the synthesis of bis-ureas. Therefore, this new method to syn-
thesize various unsymmetrical ureas using ZrCl4 is efficient,
practical, and generally applicable.
5. J. Gante, Synthesis 1989, 405.
6. P. G. Baraldi, A. Bovero, F. Fruttarolo, R. Romagnoli,
M. A. Tabrizi, D. Preti, K. Varani, P. A. Borea,
A. R. Moorman, Bioorg. Med. Chem. 2003, 11, 4161.
7. J. N. Burrows, J. G. Cumming, S. M. Fillery, G. A. Hamlin,
J. A. Hudson, R. J. Jackson, S. McLaughlin, J. S. Shaw, Bioorg.
Med. Chem. Lett. 2005, 15, 25.
Bull. Korean Chem. Soc. 2016, Vol. 37, 154–160
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
159

BULLETIN OF THE
Article
Facile Synthesis of Unsymmetrical Urea
KOREAN CHEMICAL SOCIETY
8. A. Scozzafava, A. Mastrolorenzo, C. T. Supuran, J. Enzyme
Inhib. 2001, 16, 425.
9. H. Gurulingappa, M. L. Amador, M. Zhao, M. A. Rudek,
M. Hidalgo, S. R. Khan, Bioorg. Med. Chem. Lett. 2004,
14, 2213.
21. I. Gallou, Org. Prep. Proced. Int. 2007, 39, 355.
22. M. D. McReynolds, K. T. Sprott, P. R. Hanson, Org. Lett. 2002,
4, 4673.
23. D. Ke, C. Zhan, X. Li, A. D. Q. Li, J. Yao, Tetrahedron 2009,
65, 8269.
10. A. C. Myers, J. A. Kowalski, M. A. Lipton, Bioorg. Med. Chem.
Lett. 2004, 14, 5219.
11. A. R. Katritzky, A. Oliferenko, A. Lomaka, M. Karelson,
Bioorg. Med. Chem. Lett. 2002, 12, 3453.
24. H. S. Radeke, A. Purohit, T. D. Harris, K. Hanson, R. Jones,
C. Hu, P. Yalamanchili, M. Hayes, M. Yu, M. Guaraldi,
M. Kagan, M. Azure, M. Cdebaca, S. Robinson, D. Casebier,
ACS Med. Chem. Lett. 2011, 2, 650.
12. B. D. Schwartz, T. S. Skinner-Adams, K. T. Andrews,
M. J. Coster, M. D. Edstein, D. MacKenzie, S. A. Charman,
M. Koltun, S. Blundell, A. Campbell, R. H. Pouwer,
R. J. Quinn, K. D. Beattie, P. C. Healy, R. A. Davis, Org. Biomol.
Chem. 2015, 13, 1558.
13. J. D. Sidda, L. Song, V. Poon, M. Al-Bassam, O. Lazos,
M. J. Buttner, G. L. Challis, C. Corre, Chem. Sci. 2014, 5, 86.
14. T. J. Barker, K. K. Duncan, K. Otrubova, D. L. Boger, ACS Med.
Chem. Lett. 2013, 4, 985.
25. S. Shibata, J. R. Gillespie, R. M. Ranade, C. Y. Koh, J. E. Kim,
J. U. Laydbak, F. H. Zucker, W. G. J. Hol, C. L. M. J. Verlinde,
F. S. Buckner, E. Fan, J. Med. Chem. 2012, 55, 6342.
26. H. Deng, T. D. Bannister, L. Jin, R. E. Babine, J. Quinn, P.
Nagafuji, C. A. Celatka, J. Lin, T. I. Lazarova, M. J. Rynkiewicz,
F. Bibbins, P. Pandey, J. Gorga, H. V. Meyers, S. S. Abdel-
Meguid, J. E. Strickler, Bioorg. Med. Chem. Lett. 2006, 16, 3049.
27. A. R. Katritzky, D. P. M. Pleynet, B. Yang, J. Org. Chem. 1997,
62, 4155.
15. J. W. Steed, Chem. Commun. 2011, 47, 1379.
16. L. Fischer, G. Guichard, Org. Biomol. Chem. 2010, 8, 3101.
17. C. Dou, C. Wang, H. Zhang, H. Gao, Wang, Y. Chem. -Eur. J.
2010, 16, 10744.
18. P. Byrne, G. O. Lloyd, L. Applegarth, K. M. Anderson,
N. Clarke, J. W. Steed, New J. Chem. 2010, 34, 2261.
19. V. Bohmer, M. O. Vysotsky, Aust. J. Chem. 2001, 54, 671.
20. M. V. Gool, J. M. Bartolome, G. Macdonald, Tetrahedron Lett.
2008, 49, 7171.
28. J. A. Grzyb, M. Shen, C. Yoshina-Ishii, W. Chi, S. Brown,
R. A. Batey, Tetrahedron 2005, 61, 7153.
29. Y. Yang, S. B. Bae, Y. Hwang, TetrahedronLett. 2013, 54, 1239.
30. R. Doran, L. Duggan, S. Singh, C. D. Duffy, P. Guiry, Eur.
J. Org. Chem. 2011, 35, 7097.
31. C. Han, J. A. Porco Jr., Org. Lett. 2007, 9, 1517.
32. A. Velavan, S. Sumathi, K. K. Balasubramanian, Org. Biomol.
Chem. 2012, 10, 6420.
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