Assembly of N,N-disubstituted-N′-arylureas via a copper-catalyzed one-pot three-component reaction of aryl bromides, potassium cyanate, and secondary amines

Article abstract of DOI:10.1016/j.tet.2013.04.117

A three-component reaction of aryl bromides, potassium cyanate, and secondary amines takes place at 110 C in MeCN under the catalysis of Cu ₂O and 2-(2,6-dimethylphenylamino)-2-oxoacetic acid potassium salt, giving N,N-disubstituted-N′-arylurea

Full text of DOI:10.1016/j.tet.2013.04.117

Tetrahedron 69 (2013) 5326e5330
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Assembly of N,N-disubstituted-N0-arylureas via a copper-catalyzed
one-pot three-component reaction of aryl bromides, potassium
cyanate, and secondary amines
,
b
b
Hongfei Yin a, Bing Chen a, Xiaojing Zhang a , Xinye Yang , Yihua Zhang ,
*
,
Yongwen Jiang c, Dawei Ma c
*
a Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, China
b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
c State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2013
Received in revised form 19 April 2013
Accepted 26 April 2013
Available online 2 May 2013
A three-component reaction of aryl bromides, potassium cyanate, and secondary amines takes place at
110 ꢀC in MeCN under the catalysis of Cu2O and 2-(2,6-dimethylphenylamino)-2-oxoacetic acid potas-
sium salt, giving N,N-disubstituted-N0-arylureas in good to excellent yields. A number of functionalized
aryl bromides and secondary amines were compatible with these conditions, and thereby providing
a facile method for diverse synthesis of trisubstituted ureas.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
In 2011, Kianmehr and Baghersad described that copper-
catalyzed coupling of arylboronic acids with potassium cyanate
N,N-disubstituted-N0-arylurea moiety has been frequently
found as the key skeleton in pharmaceutically important mole-
cules, herbicides, pesticides as well as fungicides. These artificial
products include commercial herbicide neburon,1 antiathero-
sclerotic compounds,2 melanin concentrating hormone receptor 1
(MCH-R1) antagonists,3 neuropeptide Y5 (NPY5) receptor antago-
nists,4 as well as antidepressant agents.5
could provide aryl isocyanates, which were trapped with alcohols in
situ to afford aryl carbamates.13 Soon after that, we discovered that
cheaper aryl halides could be used to replace arylboronic acids for
this transformation if using CuI as
dimethylphenylamino)-2-oxoacetic acid (DMPAO) as
a
catalyst and 2-(2,6-
ligand
a
(Scheme 1),14 while Buchwald reported that palladium-catalyzed
coupling of aryl chlorides and triflates with sodium cyanates could
generate aryl isocyanates and carbamates, which were further
reacted with aniline to deliver N,N0-biarylureas.15 Based on these
studies, we attempted to assemble N,N-disubstituted-N0-arylureas
from aryl bromides via copper-catalyzed coupling reaction. As
For the synthesis of N,N-disubstituted-N0-arylureas, the most
popular method is condensation of aryl isocyanates with secondary
amines.2 In this case preparation of aryl isocyanates is needed,
which normally requires toxic and extremely hazardous reagents,
such as phosgene6 and azides.7 Recently, some other alternative
methods have been developed. For examples, Lu and Yang reported
that selenium-catalyzed reductive carbonylation of nitrobenzene
and amines could afford N,N-disubstituted-N0-arylureas directly;8
Mizuno and co-workers found that unsymmetrical ureas could be
obtained via sulfur-assisted carbonylation with carbon monoxide
and subsequent oxidation;9 while Gabriele group discovered that
direct synthesis of unsymmetrical ureas could be achieved by
palladium-catalyzed oxidative carbonylation of amines.10 Addi-
tionally, in situ formation of isocyanates from acetoacetanilides11
and hydroxamic acids12 were revealed as valuable methods for
preparing unsymmetrically substituted ureas.
* Corresponding authors. E-mail addresses: madw@sioc.ac.cn, madw@mail.sio-
c.ac.cn (D. Ma).
Scheme 1.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.117

H. Yin et al. / Tetrahedron 69 (2013) 5326e5330
5327
depicted in Scheme 1, we envisioned that aryl isocyanates that
resulted from coupling of aryl bromides and potassium cyanate
might be trapped by amines in an one-pot manner to give rise to
N,N-disubstituted-N0-arylureas directly. Obviously, direct aryl ami-
nation should become a side reaction in this case. To solve this
problem we decided to choose less reactive secondary amines (for
coupling reaction) as the substrates in our study.
influence the reaction dramatically. Changing copper salts to CuI,
CuBr, CuCl or CuBr2 also gave decreased yields (entries 7e10).
Furthermore, attempts to improve the results by increasing re-
action temperatures and changing solvents failed (entries 11e14).
Taken together, we concluded that the optimized conditions are
using Cu2O as the catalyst, L2 as the ligand, CH3CN as solvent, and
carrying out the reaction at 110 ꢀC.
2.2. Reaction scope and limitations
2. Results and discussion
2.1. Condition screening for assembling N,N-disubstituted-N0-
arylureas from aryl bromides
Under the optimized reaction conditions, the reaction scope and
limitations were explored by varying aryl bromides and secondary
amines. As summarized in Table 2, using N-methylcyclohexan-
amine as a condensation partner, a number of aryl bromides that
bear either electron-withdrawing or electron-donating groups
were checked. We were pleased that most of them worked well to
afford the corresponding N-methyl-N-cyclohexanyl-N0-arylureas in
good yields (entries 1e12). In addition, 2-bromopyridine was ap-
plicable for this transformation, providing substituted urea 4n in
74% yield (entry 13).
As indicated in Table 1, we started our exploration by conducting
a three-component reaction of 4-bromoanisole 1a, potassium cy-
anate, and N-methylcyclohexanamine 5a. It was found that under
the catalysis of 20 mol % Cu2O and 40 mol % DMPAO, the reaction of
1a (0.5 mmol), KOCN (1 mmol) and 5a (1 mmol) worked in CH3CN
at 110 ꢀC to afford the desired urea 4a in 20% yield (entry 1), to-
gether with the direct aryl amination product in 20% yield.
Changing the ligand to 2-(2,6-dimethylphenylamino)-2-oxoacetic
acid potassium salt (L2) gave a similar result (entry 2). In order to
inhibit the formation of aryl amination product, we decided to re-
duce the amount of amine. To our delight, when amount of amine
5a was slightly less than 4-bromoanisole 1a, yield of the urea 4a
jumped to 60% (entry 3). The best result was observed by using L2
as the ligand (entry 4). In this case if the ligand was switched to L3
or L4, yields dropped greatly (entries 5 and 6). These results implied
that subtle change in electronic nature of the ligands could
Table 2
Synthesis of N,N-disubstituted-N0-arylureas via copper-catalyzed three-component
reactiona
Entry
1
Product
Yield (%)b
Table 1
Copper-catalyzed three-component reaction of 4-bromoanisole, potassium cyanate,
and N-methylcyclo-hexamine under different conditionsa
84
2
3
4
5
6
75
97
83
73
65
Entry
[Cu]
Ligand
Solvent
Temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuBr
CuI
CuCl
CuBr2
Cu2O
Cu2O
Cu2O
Cu2O
L1
L2
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
L2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
THF
110
110
110
110
110
110
110
110
110
110
120
110
110
110
20
27
60
73
37
40
13
10
21
Trace
35
<5
d
9
10
11
12
13
14
DMF
30
a
Reaction conditions: A (for entries 1 and 2): 4-bromoanisole (0.5 mmol), po-
tassium cyanate (1 mmol), amine (1 mmol), CuX (0.1 mmol), ligand (0.2 mmol),
110 ꢀC, solvent (1.5 mL), 24 h. B (for entries 3e14): 4-bromoanisole (0.5 mmol),
potassium cyanate (1 mmol), amine (0.4 mmol), CuX (0.08 mmol), ligand
(0.16 mmol), 110 ꢀC, solvent (1.5 mL), 24 h.
7
70
b
Isolated yield.
(continued on next page)

5328
H. Yin et al. / Tetrahedron 69 (2013) 5326e5330
Table 2 (continued )
that several functional groups, such as acetyl, nitro, methoxy, car-
boxylate, chloro, trifluoromethyl, olefin, and cyano moieties were
tolerated under our reaction conditions. This advantage would al-
low diverse synthesis. Indeed, through this method we could
conveniently obtain antiatherosclerotic agents 4o and 4p, as well as
herbicide neburon 4s.
Entry
Product
Yield (%)b
8
9
60
3. Conclusions
In summary, we have developed a three-component reaction for
synthesizing N,N-disubstituted-N0-arylureas from aryl bromides,
potassium cyanate, and secondary amines. The key step for this
cascade process is the copper-catalyzed coupling of aryl bromides
and potassium cyanate to form aryl isocyanates. The generality of
this transformation was demonstrated by preparing a wide range of
N,N-disubstituted-N0-arylureas, including some known bioactive
ureas. Thus, our reaction provides a reliable and alternative ap-
proach to assemble N,N-disubstituted-N0-arylureas. It may find
applications in discovery of bioactive compounds.
90
10
11
12
13
63
81
70
74
4. Experimental
4.1. General remarks
All solvents were purified and dried prior to use. 1H NMR and 13
NMR spectra were recorded on a Bruker Avance 400 MHz, and
assigned in parts per million (
). 1H NMR chemical shifts were given
on the scale (ppm) and were referenced to internal TMS. Refer-
C
d
d
ence peaks for chloroform in 13C NMR spectra were set at 77.0 ppm.
For DMSO-d6, the reference peaks in 1H NMR and 13C NMR spectra
were set at 2.50 ppm and 40.0 ppm, respectively. Low-resolution
mass spectra were recorded on a LCMS-2010EV instrument (ESI).
High-resolution mass spectra were recorded on an IonSpec 4.7 T
FTMS instrument. Silica gel plate GF254 were used for thin layer
chromatography (TLC) and silica gel H or 300e400 mesh were used
for flash column chromatography.
14c
74
95
4.2. General procedure for preparation of N,N-disubstituted-
N0-arylureas
15c
An oven-dried Schlenk tube was charged with potassium cy-
anate (1.0 mmol, recrystallization from alcohol and water before
use), Cu2O (0.08 mmol), 2-(2,6-dimethylphenyl-amino)-2-
oxoacetic acid potassium salt (0.16 mmol), and aryl bromide
(0.5 mmol) at room temperature. The tube was evacuated and
backfilled with argon and then secondary amine (0.4 mmol) and
anhydrous CH3CN (1.5 mL) were added via syringe. The reaction
mixture was stirred at 110 ꢀC for 24e48 h. The cooled reaction
mixture was partitioned between ethyl acetate and water. The
organic layer was washed with water and brine, dried over
Na2SO4, and concentrated. The crude product was purified by
flash chromatography to afford the corresponding substituted
urea.
16c
78
60
17c
18c
60
4.2.1. 1-Cyclohexyl-3-(4-methoxyphenyl)-1-methyl-urea (4a). White
powder, 77 mg (74% yield); mp: 203e204 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
7.28 (d, J¼9.0 Hz, 2H), 6.83 (d, J¼9.0 Hz, 2H), 6.13 (s, 1H),
4.16e4.03 (m, 1H), 3.78 (s, 3H), 2.86 (s, 3H), 1.83e1.66 (m, 5H),
a
Reaction conditions: aryl halide (0.5 mmol), potassium cyanate (1 mmol), amine
(0.4 mmol), Cu2O (0.08 mmol), ligand (0.16 mmol), 110 ꢀC, CH3CN (1.5 mL), 24 h.
1.42e1.37 (m, 4H), 1.16e1.01 (m, 1H); 13C NMR (100 MHz, CDCl3)
b
Isolated yield.
48 h.
d
155.8, 155.6, 132.5, 122.2 (2C), 114.0 (2C), 55.5, 54.0, 30.6 (2C), 28.4,
c
25.8 (2C), 25.6; ESI-MS m/z 263.7 (MþH)þ; HRMS (ESI) calcd for
C15H23N2O2 (MþH)þ 263.1754, found 263.1754.
The reactions with other secondary amines like dibutylamine,
diallylamine, and N-methylbutylamine were found to be more
sluggish, but satisfactory conversion could be reached by pro-
longing the reaction time to 48 h (entries 14e18). Noteworthy is
4.2.2. 1-Cyclohexyl-3-(4-acetylphenyl)-1-methyl-urea (4b). White
powder, 92 mg (84% yield); mp: 186e187 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
7.90 (d, J¼8.8 Hz, 2H), 7.50 (d, J¼8.8 Hz, 2H), 6.49 (s, 1H),

H. Yin et al. / Tetrahedron 69 (2013) 5326e5330
5329
4.15e4.05 (m, 1H), 2.90 (s, 3H), 2.56 (s, 3H), 1.85e1.67 (m, 5H),
1.45e1.40 (m, 4H), 1.17e1.04 (m, 1H); 13C NMR (100 MHz, CDCl3)
25.5; ESI-MS m/z 267.3 (MþH)þ; HRMS (ESI) calcd for
C14H19ClN2NaO (MþNa)þ 289.1078, found 289.1069.
d
197.2,154.7,144.1,131.5,129.7 (2C),118.4 (2C), 54.3, 30.5 (2C), 28.6,
26.4, 25.7 (2C), 25.5; ESI-MS m/z 275.3 (MþH)þ; HRMS (ESI) calcd
4.2.10. 1-Cyclohexyl-3-(4-methylthiophenyl)-1-methyl-urea (4j). White
powder, 100 mg (80% yield); mp: 187e188 ꢀC; 1H NMR
for C16H23N2O2 (MþH)þ 275.1754, found 275.1751.
(400 MHz, CDCl3)
d
7.33 (d, J¼8.4 Hz, 2H), 7.21 (d, J¼8.4 Hz, 2H),
4.2.3. 1-Cyclohexyl-3-(3-acetylphenyl)-1-methyl-urea (4c). White
powder, 82 mg (75% yield); mp: 172e173 ꢀC; 1H NMR (400 MHz,
6.26 (s, 1H), 4.16e4.04 (m, 1H), 2.86 (s, 3H), 2.45 (s, 3H),
1.83e1.66 (m, 5H), 1.42e1.37 (m, 4H), 1.13e1.04 (m, 1H); 13C NMR
CDCl3)
d
7.91 (s, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.59 (d, J¼8.0 Hz, 1H),
(100 MHz, DMSO-d6) d 155.1, 138.6, 129.5, 127.2 (2C), 120.6 (2C),
7.38 (t, J¼8.0 Hz, 1H), 6.47 (s, 1H), 4.17e4.04 (m, 1H), 2.90 (s, 3H),
53.1, 29.8 (2C), 28.1, 25.4 (2C), 25.0, 16.0; ESI-MS m/z 279.3
(MþH)þ; HRMS (ESI) calcd for C15H23N2OS (MþH)þ 279.1526,
found 279.1515.
2.59 (s, 3H),1.84e1.66 (m, 5H),1.43e1.41 (m, 4H),1.14e1.06 (m,1H);
13C NMR (100 MHz, CDCl3)
d 198.4, 155.3, 140.1, 137.6, 129.0, 124.7,
122.6, 119.4, 54.1, 30.5 (2C), 28.5, 26.7, 25.7 (2C), 25.5; ESI-MS m/z
275.7 (MþH)þ; HRMS (ESI) calcd for C16H23N2O2 (MþH)þ 275.1754,
found 275.1755.
4.2.11. 1-Cyclohexyl-3-(4-methylphenyl)-1-methyl-urea (4k). White
powder, 62 mg (63% yield); mp: 188e190 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
7.27 (d, J¼8.0 Hz, 2H), 7.07 (d, J¼8.0 Hz, 2H), 6.20 (s, 1H),
4.2.4. 1-Cyclohexyl-3-(4-nitrophenyl)-1-methyl-urea (4d). Yellow
4.16e4.04 (m, 1H), 2.86 (s, 3H), 2.29 (s, 3H), 1.82e1.65 (m, 5H),
powder, 108 mg (97% yield); mp: 197 ꢀC; 1H NMR (400 MHz, CDCl3)
1.42e1.37 (m, 4H), 1.16e1.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
8.16 (d, J¼9.2 Hz, 2H), 7.57 (d, J¼9.2 Hz, 2H), 6.67 (s,1H), 4.14e4.03
(m, 1H), 2.91 (s, 3H), 1.85e1.67 (m, 5H), 1.45e1.38 (m, 4H), 1.16e1.06
(m, 1H); 13C NMR (100 MHz, CDCl3)
154.2, 145.8, 142.3, 125.0 (2C),
d 155.5, 136.8, 132.3, 129.3 (2C), 120.1 (2C), 53.9, 30.6 (2C), 28.5,
25.8 (2C), 25.6, 20.7; ESI-MS m/z 247.2 (MþH)þ; HRMS (ESI)
d
calcd for C15H22N2NaO (MþNa)þ 269.1624, found 269.1619.
118.5 (2C), 54.5, 30.5 (2C), 28.7, 25.7 (2C), 25.4; ESI-MS m/z 278.3
(MþH)þ; HRMS (ESI) calcd for C14H20N3O3 (MþH)þ 278.1499, found
278.1502.
4.2.12. 1-Cyclohexyl-3-(4-biphenyl)-1-methyl-urea (4l). White pow-
der, 100 mg (81% yield); mp: 218 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J¼7.2 Hz, 2H), 7.54e7.46 (m, 4H), 7.40 (t, J¼7.2 Hz, 2H), 7.30
4.2.5. 1-Cyclohexyl-3-(3-nitrophenyl)-1-methyl-urea (4e). Yellow
(t, J¼7.2 Hz, 1H), 6.33 (s, 1H), 4.18e4.08 (m, 1H), 2.90 (s, 3H),
powder, 92 mg (83% yield); mp: 203 ꢀC; 1H NMR (400 MHz, CDCl3)
1.83e1.67 (m, 5H), 1.47e1.39 (m, 4H), 1.18e1.03 (m, 1H); 13C NMR
d
8.23 (s, 1H), 7.85e7.82 (m, 2H), 7.41 (t, J¼8.0 Hz, 1H), 6.62 (s, 1H),
(100 MHz, CDCl3) d 155.2, 140.8, 138.8, 135.6, 128.7 (2C), 127.5 (2C),
4.18e4.01 (m, 1H), 2.90 (s, 3H), 2.29 (s, 3H), 1.85e1.67 (m, 5H),
126.8,126.7 (2C),120.1 (2C), 54.1, 30.6 (2C), 28.5, 25.8 (2C), 25.6; ESI-
MS m/z 309.7 (MþH)þ; HRMS (ESI) calcd for C20H25N2O (MþH)þ
309.1961, found 309.1959.
1.45e1.38 (m, 4H), 1.17e1.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
154.7, 148.7, 140.7, 129.5, 125.6, 117.3, 114.3, 54.4, 30.5 (2C), 28.6,
25.7 (2C), 25.5; ESI-MS m/z 278.3 (MþH)þ; HRMS (ESI) calcd for
C14H20N3O3 (MþH)þ 278.1499, found 278.1497.
4.2.13. 1-Cyclohexyl-3-phenyl-1-methyl-urea (4m).16 White pow-
der, 65 mg (70% yield); mp: 170 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.39
4.2.6. 1-Cyclohexyl-3-(4-methoxycarbonylphenyl)-1-methyl-urea
(d, J¼7.6 Hz, 2H), 7.29 (d, J¼7.6 Hz, 2H), 6.99 (t, J¼7.4 Hz,1H), 6.27 (s,
(4f). White powder, 85 mg (73% yield); mp: 180 ꢀC; 1H NMR
1H), 4.17e4.04 (m, 1H), 2.87 (s, 3H), 1.83e1.66 (m, 5H), 1.43e1.38
(400 MHz, CDCl3)
d
7.96 (d, J¼8.8 Hz, 2H), 7.48 (d, J¼8.8 Hz, 2H),
(m, 4H), 1.18e1.02 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 155.3,
6.47 (s, 1H), 4.15e4.05 (m, 1H), 3.88 (s, 3H), 2.90 (s, 3H), 1.84e1.67
139.4, 129.0 (2C), 122.8, 119.9 (2C), 54.0, 30.5 (2C), 28.5, 25.7 (2C),
25.4; ESI-MS m/z 233.2 (MþH)þ; HRMS (ESI) calcd for C14H20N2NaO
(MþNa)þ 255.1468, found 255.1475.
(m, 5H), 1.44e1.38 (m, 4H), 1.15e1.05 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 166.9, 154.7, 144.0, 130.7 (2C), 123.9, 118.5 (2C), 54.2, 51.9;
30.5 (2C), 28.6, 25.7 (2C), 25.5; ESI-MS m/z 291.7 (MþH)þ; HRMS
(ESI) calcd for C16H23N2O3 (MþH)þ 291.1703, found 291.1700.
4.2.14. 1-Cyclohexyl-3-(pyridin-2-yl)-1-methyl-urea (4n). White
powder, 69 mg (74% yield); mp: 84 ꢀC; 1H NMR (400 MHz,
4.2.7. 1-Cyclohexyl-3-(4-cyanophenyl)-1-methyl-urea (4g). White
CDCl3)
d
8.19 (d, J¼4.0 Hz, 1H), 8.07 (d, J¼8.4 Hz, 1H), 7.66e7.62
powder, 67 mg (65% yield); mp: 162 ꢀC; 1H NMR (400 MHz, CDCl3)
(m, 1H), 7.10 (s, 1H), 6.94e6.91 (m, 1H), 4.15e4.03 (m, 1H), 2.89
(s, 3H), 1.83e1.66 (m, 5H), 1.48e1.35 (m, 4H), 1.18e1.03 (m, 1H);
d
7.56e7.51 (m, 4H), 6.55 (s, 1H), 4.13e4.05 (m, 1H), 2.90 (s, 3H),
1.84e1.67 (m, 5H), 1.43e1.37 (m, 4H), 1.15e1.03 (m, 1H); 13C NMR
13C NMR (100 MHz, CDCl3)
d 154.4, 153.0, 147.4, 138.0, 118.2,
(100 MHz, CDCl3)
d
154.5, 144.0, 133.0 (2C), 119.4, 119.3 (2C), 104.9,
113.3, 54.2, 30.5 (2C), 28.5, 25.7 (2C), 25.5; ESI-MS m/z 234.2
(MþH)þ; HRMS (ESI) calcd for C13H19N3NaO (MþNa)þ 256.1420,
found 256.1417.
54.3, 30.5 (2C), 28.7, 25.7 (2C), 25.4; ESI-MS m/z 258.3 (MþH)þ;
HRMS (ESI) calcd for C15H20N3O (MþH)þ 258.1601, found 258.1600.
4.2.8. 1-Cyclohexyl-3-(4-trifluoromethylphenyl)-1-methyl-urea
(4h). White powder, 84 mg (70% yield); mp: 184 ꢀC; 1H NMR
4.2.15. 1,1-Dibutyl-3-(4-methoxylphenyl)urea (4o). White powder,
79 mg (71% yield); mp: 78e79 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.27
(400 MHz, CDCl3)
(s, 3H), 1.84e1.67 (m, 5H), 1.47e1.35 (m, 4H), 1.19e1.03 (m, 1H); 13C
NMR (125 MHz, DMSO-d6)
(q, J¼269 Hz), 121.8 (q, J¼31.6 Hz), 119.5 (2C), 53.8, 30.2 (2C), 29.0,
25.8 (2C), 25.5; ESI-MS m/z 301.3 (MþH)þ; HRMS (ESI) calcd for
C15H20F3N2O (MþH)þ 301.1522, found 301.1523.
d
7.52 (s, 4H), 6.45 (s, 1H), 4.15e4.04 (m, 1H), 2.89
(d, J¼8.4 Hz, 2H), 6.82 (d, J¼8.4 Hz, 2H), 6.12 (s, 1H), 3.77 (s, 3H),
3.27 (t, J¼7.6 Hz, 4H), 1.62e1.58 (m, 4H), 1.39e1.33 (m, 4H), 0.95 (t,
d
155.3, 145.1, 125.9 (q, J¼3.8 Hz, 2C), 125.1
J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 155.7, 155.4, 132.4, 122.1
(2C), 114.1 (2C), 55.6, 47.5 (2C), 30.8 (2C), 20.3 (2C), 13.9 (2C); ESI-
MS m/z 279.6 (MþH)þ; HRMS (ESI) calcd for C16H27N2O2 (MþH)þ
279.2067, found 279.2058.
4.2.9. 1-Cyclohexyl-3-(3-chlorophenyl)-1-methyl-urea (4i). White
powder, 64 mg (60% yield); mp: 196e197 ꢀC; 1H NMR (400 MHz,
4.2.16. 1,1-Dibutyl-3-(4-acetylphenyl)urea (4p).17 White powder,
110 mg (95% yield); mp: 90e91 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.88
CDCl3)
1H), 4.17e4.02 (m, 1H), 2.87 (s, 3H), 1.83e1.66 (m, 5H), 1.46e1.40
(m, 4H), 1.18e1.01 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
155.4,
142.9, 133.1, 130.3, 121.5, 119.5, 118.4, 53.8, 30.3 (2C), 28.9, 25.9 (2C),
d
7.52 (s, 1H), 7.24e7.16 (m, 2H), 6.99e6.97 (m, 1H), 6.30 (s,
(d, J¼8.8 Hz, 2H), 7.48 (d, J¼8.8 Hz, 2H), 6.60 (s, 1H), 3.29 (t,
J¼7.6 Hz, 4H), 2.54 (s, 3H), 1.64e1.56 (m, 4H), 1.41e1.32 (m, 4H),
d
0.95 (t, J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 197.1, 154.2,
144.1, 131.5, 129.7 (2C), 118.3 (2C), 47.6 (2C), 30.8 (2C), 26.4, 20.2

5330
H. Yin et al. / Tetrahedron 69 (2013) 5326e5330
(2C), 13.9 (2C); ESI-MS m/z 291.3 (MþH)þ; HRMS (ESI) calcd for
C17H26N2NaO2 (MþNa)þ 313.1887, found 313.1895.
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences and
the National Natural Science Foundation of China (grant 20921091
and 20872156) for their financial support.
4.2.17. 1,1-Diallyl -3-(4-methoxylphenyl)urea (4q). Colorless oil,
77 mg (78% yield); 1H NMR (400 MHz, CDCl3)
d
7.22 (d, J¼8.8 Hz,
2H), 6.82 (d, J¼8.8 Hz, 2H), 6.34 (s, 1H), 5.93e5.83 (m, 2H),
5.31e5.24 (m, 4H), 3.96e3.95 (m, 4H), 3.77 (s, 3H); 13C NMR
References and notes
(100 MHz, CDCl3)
d 156.0, 155.7, 134.2 (2C), 132.2, 121.9 (2C), 117.2
(2C), 114.1 (2C), 55.5, 49.8 (2C); ESI-MS m/z 247.6 (MþH)þ; HRMS
1. (a) Voroshazy, L.; Torok, S.; Daroczi, I.; Galambos, P.; Ormenyi, Z. WO8102156A1,
1981. (b) Asrar, J.; Ding, Y.; Bourque, J. E.; Sanders, E. F. WO2004095926A2,
2004.
(ESI) calcd for C14H19N2O2 (MþH)þ 247.1441, found 247.1444.
2. DeVries, V. G.; Bloom, J. D.; Dutia, M. D.; Katocs, A. S., Jr.; Largis, E. E. J. Med.
Chem. 1989, 32, 2318.
4.2.18. 1-Butyl-3-(4-methoxylphenyl-2-yl)-1-methyl-urea (4r). Colorless
oil, 57 mg (60% yield); 1H NMR (400 MHz, CDCl3)
d
7.27 (d, J¼8.8 Hz,
3. Palani, A.; Shapiro, S.; McBriar, M. D.; Clader, J. W.; Greenlee, W. J.; Spar, B.;
Kowalski, T. J.; Farley, C.; Cook, J.; van Heek, M. J. Med. Chem. 2005, 48, 4746.
4. Fotsch, C.; Sonnenberg, J. D.; Chen, N.; Hale, C.; Karbon, W.; Norman, M. H. J.
Med. Chem. 2001, 44, 2344.
5. Perveen, S.; Fatima, N.; Khan, M. A.; Dar, A.; Khan, K. M.; Afza, N.; Voelter, W.
Med. Chem. Res. 2012, 21, 2709.
6. Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894.
7. Yang, Y.; Lu, S. Tetrahedron Lett. 1999, 40, 4845.
8. Barrett, A. G. M.; Kwon, H.; Wallace, E. M. J. Chem. Soc., Chem. Commun. 1993,
1760.
9. Mizuno, T.; Kino, T.; Ito, T.; Miyata, T. Synth. Commun. 2000, 30, 1675.
10. Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69, 4741.
11. Wei, Y.; Liu, J.; Lin, S.; Ding, H.; Liang, F.; Zhao, B. Org. Lett. 2010, 12, 4220.
12. Yadav, D. K.; Yadav, A. K.; Srivastava, V. P.; Watal, G.; Yadav, L. D. S. Tetrahedron
Lett. 2012, 53, 2890.
13. Kianmehr, E.; Baghersad, M. H. Adv. Synth. Catal. 2011, 353, 2599.
14. Yang, X.; Zhang, Y.; Ma, D. Adv. Synth. Catal. 2012, 354, 2443.
15. Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 11132.
16. Hwu, J. R.; King, K. Y. Chem.dEur. J. 2005, 11, 3805.
17. Thavonekham, B. Synthesis 1997, 10, 1189.
2H), 6.82 (d, J¼8.8 Hz, 2H), 6.18 (s,1H), 3.77 (s, 3H), 3.30 (t, J¼7.2 Hz, 2H),
2.98 (s, 3H), 1.60e1.53 (m, 2H), 1,40e1.31 (m, 2H), 0.95 (t, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3)
d 155.9, 155.7, 132.4, 122.3 (2C), 114.0 (2C),
55.5, 48.8, 34.5, 30.2, 20.1, 13.9; ESI-MS m/z 237.2 (MþH)þ; HRMS (ESI)
calcd for C13H21N2O2 (MþH)þ 237.1597, found 237.1593.
4.2.19. 1-Butyl-3-(3,4-dichlorophenyl)-1-methyl-urea (4s).18 White
powder, 66 mg (60% yield); mp: 99e100 ꢀC; 1H NMR (400 MHz,
CDCl3)
d
7.63 (d, J¼2.4 Hz, 1H), 7.32 (d, J¼8.4 Hz, 2H), 7.22 (dd,
J1¼2.4 Hz, J2¼8.8 Hz, 1H), 6.27 (s, 1H), 3.34 (t, J¼7.6 Hz, 2H), 3.01
(s, 3H), 1.61e1.54 (m, 2H), 1.39e1.32 (m, 2H), 0.96 (t, J¼7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d 154.8, 138.9, 132.4, 130.1, 125.6,
121.4, 119.1, 48.9, 34.6, 30.2, 20.1, 13.9; ESI-MS m/z 275.2 (MþH)þ;
HRMS (ESI) calcd for C12H17Cl2N2O1 (MþH)þ 275.0713, found
275.0719.
18. Mizuno, T.; Nakai, T.; Mihara, M. Synthesis 2009, 15, 2492.