Synthesis of unsymmetrical 2-pyridyl ureas via selenium-catalyzed oxidative carbonylation of 2-aminopyridine with aromatic amines

Article abstract of DOI:10.1055/s-0033-1338413

A simple, one-pot, phosgene-free approach to a series of unsymmetrical 2-pyridyl ureas starting from 2-aminopyridine and various aromatic amines is reported for the first time. The procedure employs inexpensive selenium as the catalyst, and carbon monoxide (instead of phosgene) as the carbonyl reagent. The products are obtained in moderate to good yields via selenium-catalyzed oxidative cross-carbonylation of the substrate amines in the presence of oxygen. The selenium functions as a phase-transfer catalyst and can be recovered easily and reused without any significant degradation of its catalytic activity.

Full text of DOI:10.1055/s-0033-1338413

PAPER
▌1357
paper
Synthesis of Unsymmetrical 2-Pyridyl Ureas via Selenium-Catalyzed
Oxidative Carbonylation of 2-Aminopyridine with Aromatic Amines
Selenium-Catalyzed Carbonylation toward 2-Pyridyl Ureas
Xiaopeng Zhang,* Desheng Li, Xueji Ma, Yan Wang, Guisheng Zhang*
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Henan Normal University, Xinxiang 453007, P. R. of China
Fax +86(373)3325250; E-mail: zhangxiaopengv@sina.com; E-mail: zgs@htu.cn
Received: 27.01.2013; Accepted after revision: 21.03.2013
ability of transition-metal catalyst systems, together with
the complex and energy-consuming separation processes,
renders these methods uneconomical. The inexpensive
and readily available non-metal, selenium or its oxide,
Abstract: A simple, one-pot, phosgene-free approach to a series of
unsymmetrical 2-pyridyl ureas starting from 2-aminopyridine and
various aromatic amines is reported for the first time. The procedure
employs inexpensive selenium as the catalyst, and carbon monoxide
(instead of phosgene) as the carbonyl reagent. The products are ob- have proved to be efficient and economical catalysts for
the carbonylation approach to urea derivatives,14 includ-
tained in moderate to good yields via selenium-catalyzed oxidative
cross-carbonylation of the substrate amines in the presence of oxy-
gen. The selenium functions as a phase-transfer catalyst and can be
tained by this approach were restricted to the redox
recovered easily and reused without any significant degradation of
its catalytic activity.
ing pyridyl ureas.7 Unfortunately, the pyridyl ureas ob-
carbonylation of nitro compounds with amines catalyzed
by selenium or its oxide, in which only one third of the
Key words: carbonylation, selenium, carbon monoxide, 2-pyridyl
carbon monoxide consumed was transferred to the urea
ureas, 2-aminopyridine
product. To the best of our knowledge, the direct employ-
ment of two different amines as substrates in a one-pot
catalytic carbonylation approach to unsymmetrical pyri-
Pyridyl ureas are an important class of compounds which
dyl ureas has not been disclosed previously. Herein, we
possess a nitrogen-containing heterocycle and a peptide
report a simple, phosgene-free approach toward unsym-
linkage. Many of them possess biological activities,1 and
metrical 2-pyridyl ureas via the selenium-catalyzed oxi-
they are frequently employed as insecticides, agrochemi-
dative carbonylation of 2-aminopyridine with various
cal fungicides, herbicides and plant growth regulators.2 In
aromatic amines in the presence of carbon monoxide and
addition, pyridyl ureas have found important applications
oxygen.
in supramolecular chemistry for anion recognition, and in
Initially, the reaction conditions were optimized using the
crystal engineering for the organized self-assembly of co-
crystals.3 The conventional procedure for the synthesis of
urea derivatives employs phosgene as a carbonyl reagent,
but this method suffers from drawbacks which include the
toxic and corrosive nature of phosgene, the formation of
corrosive hydrogen chloride as a by-product, and multi-
step syntheses.4 Phosgene-free procedures have been de-
veloped for the synthesis of pyridyl ureas (Scheme 1).1a,5–7
The isocyanate method has been employed frequently for
this purpose.5 However, harmful, expensive and difficult
to obtain isocyanates limit the utility of this approach. In
the presence of a base (e.g. NaOH, K3PO4, t-BuOK) and a
metal catalyst (such as a Cu or Pd complex), pyridyl ha-
lides can be coupled effectively to aromatic ureas to pro-
duce pyridyl ureas.6 Honma and co-workers have reported
a two-step synthetic approach to pyridyl ureas via a 2-pyr-
idinecarbonyl azide intermediate.1a A one-pot catalytic
carbonylation approach to pyridyl ureas is of particular
importance from both synthetic and environmental stand-
points. Various transition metals or their complexes, in-
cluding rhodium,8 ruthenium,9 tungsten,10 palladium,11
thallium12 and cobalt,13 are commonly used as catalysts
for this purpose. However, the high cost and limited avail-
selenium-catalyzed oxidative carbonylation of 2-amino-
pyridine with aniline as a model reaction (Table 1). All re-
agents were used directly without further purification. The
carbonylation reaction did not proceed at all in the ab-
sence of selenium, indicating that the selenium catalyst
was essential for this reaction (Table 1, entry 1). Higher
product yields were afforded on increasing the amount of
the selenium catalyst, with an acceptable yield (82%) be-
ing obtained when the selenium loading was 0.25 mmol
(Table 1, entries 2, 3 and 15). A further increase in the
amount of the selenium catalyst (0.35 mmol) led to no ob-
vious increase in the product yield (Table 1, entry 4). The
carbonylation reaction proceeded poorly in the absence of
a base (Table 1, entry 5), and in the presence of common
bases such as sodium hydroxide, anhydrous sodium ace-
tate and pyridine (Table 1, entries 6–8). When triethyl-
amine was used as the base a satisfactory yield was
obtained (Table 1, entry 15), and thus was the base of
choice for this carbonylation reaction. It is believed that
triethylamine has appropriate alkalinity to be involved in
the generation of an active carbonyl selenide (SeCO)
complex. The choice of solvent for this reaction also
proved to be important. Weakly polar toluene appeared to
be the most suitable (Table 1, entry 15); the product yield
decreased dramatically when polar solvents such as tetra-
hydrofuran, ethyl acetate and acetone were used as the
SYNTHESIS 2013, 45, 1357–1363
Advanced online publication: 25.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338413; Art ID: SS-2013-F0083-OP
© Georg Thieme Verlag Stuttgart · New York

1358
X. Zhang et al.
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O
N
+
NCO
Cl
NaN3
NH2
+
+
N
NH2
ref. 1a
2 steps
ref. 1b, 5
O
N
N
N
ref. 6
H
H
ref. 7
1a
this work
O
NO2
+
CO
+
+
H2N
N
H
N
NH2
N
X
X = Cl, Br, I
NH2
+
CO
+
NH2
O2
+
N
Scheme 1 Phosgene-free methods for preparing 2-pyridyl ureas
solvent (Table 1, entries 9–11), and especially so in the phenyl-N′-(2-pyridyl)urea was obtained in only 51%
case of strongly polar N,N-dimethylformamide (Table 1, yield, along with N,N′-diphenylurea (16%) as a result of
entry 12). The carbonylation reaction was very sensitive the competitive carbonylation reaction of two molecules
to the temperature employed. When the reaction was con- of aniline (Table 1, entry 13). None of the symmetrical
ducted at 120 °C for three hours, the expected product, N- urea, N,N′-di(pyridin-2-yl)urea was detected in any of
Table 1 Optimization of the Reaction Conditionsa
Entry
Temp (°C)
CO (MPa)
O2 (MPa)
Se (mmol)
Base
Solvent
Yield (%)b
1
2
140
140
140
140
140
140
140
140
140
140
140
140
120
130
140
150
140
140
140
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3
2
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0
Et3N
Et3N
Et3N
Et3N
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
0.05
0.15
0.35
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
21
3
57
4
82
5
18
6
NaOH
NaOAc
py
21
7
40
8
20
9
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
57
10
11
12
13
14
15
16
17
18
19
EtOAc
acetone
DMF
69
51
30
toluene
toluene
toluene
toluene
toluene
toluene
toluene
51 (16)c
74 (6)c
82 (trace)c
82 (trace)c
69
83
65
a Reaction conditions: 2-aminopyridine (5 mmol), aniline (5 mmol), base (5 mmol), solvent (5 mL), 3 h.
b Yield of isolated product.
c Yield of N,N′-diphenylurea in parentheses.
Synthesis 2013, 45, 1357–1363
© Georg Thieme Verlag Stuttgart · New York

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Selenium-Catalyzed Carbonylation toward 2-Pyridyl Ureas
1359
these carbonylation reactions at 120 °C, probably due to bonylation of 2-aminopyridine proceeded smoothly with
the weak reactivity of 2-aminopyridine. At lower temper- different substituted anilines and 1-naphthylamine, to af-
atures, the amines themselves were apt to form symmetri- ford the corresponding unsymmetrical pyridyl ureas in
cal ureas, while the reactivity of 2-aminopyridine moderate to good yields. Along with the target unsymmet-
appeared to increase on raising the temperature. Thus, the rical pyridyl ureas, water, as expected, and varying quan-
cross-carbonylation reaction between 2-aminopyridine tities of the corresponding symmetrical N,N′-diarylureas
and the aromatic amine substrates possibly becomes easi- were formed, indicating that competitive carbonylation of
er. Hence, the yield of the unsymmetrical pyridyl urea in- the substituted anilines also occurred. Typically, ortho-
creased on changing the temperature from 120 °C to substituted anilines gave lower yields of the expected
140 °C (Table 1, entries 13–15). When the reaction was products (Table 2, entries 2 and 6) compared to their para-
conducted at 140 °C for three hours, a very good yield of substituted analogues (Table 2, entries 4 and 8), suggest-
the desired product was obtained (Table 1, entry 15); no ing that the reaction was sensitive to steric factors. Thus,
further improvement in the yield was achieved when the it was not surprising that N-(2,6-dimethylphenyl)-N′-(2-
reaction was conducted at a higher temperature (Table 1, pyridyl)urea (1e) was obtained in only 27% yield via the
entry 16). The amounts of carbon monoxide (CO) and ox- selenium-catalyzed oxidative carbonylation of 2-amino-
ygen employed also affected the reaction markedly. When pyridine with 2,6-dimethylaniline, most probably due to
the oxygen pressure was maintained at 0.4 MPa, the yield high steric hindrance (Table 2, entry 5). The reaction also
was improved significantly on increasing the carbon mon- appeared to be extremely sensitive to electronic factors.
oxide pressure (from 1.0 MPa to 2.0 MPa, Table 1, entries Thus, anilines with electron-donating groups (Table 2, en-
15 and 17). A further increase in the carbon monoxide tries 2–4 and 10) were more reactive than those with elec-
pressure to 3.0 MPa did not lead to an appreciable rise in tron-withdrawing groups (Table 2, entries 6–9), leading to
the yield (Table 1, entry 18). Decreasing the oxygen pres- higher product yields. When this reaction was attempted
sure (from 0.4 MPa to 0.2 MPa) resulted in a drop in the with aliphatic amines and benzenesulfonamide, the de-
yield of the pyridyl urea (Table 1, entry 19), which indi- sired products were not obtained. The use of benzylamine
cated that the optimum ratio of carbon monoxide to oxy- resulted in a very high yield of the corresponding symmet-
gen was 2:0.4 (Table 1, entry 15).
ric N,N′-dibenzylurea, most probably due to its high reac-
tivity. In contrast, the low reactivities of n-butylamine,
piperidine (almost certainly due to steric hindrance) and
benzenesulfonamide prevented the desired cross-carbon-
ylation reactions taking place (Table 2, entries 12–15).
With optimized reaction conditions in hand, we next ex-
amined the scope of this selenium-catalyzed oxidative
carbonylation reaction of 2-aminopyridine with a series of
amines (Table 2). The selenium-catalyzed oxidative car-
Table 2 Selenium-Catalyzed Oxidative Carbonylations of 2-Aminopyridine with Aminesa
O
C
N
N
cat. Se
Et3N
+
CO +
1/2 O2
ArNH2
H O
NHAr +
2
NH2
+
NH
1a–k
Entry
Substrate
Product
Yield (%)b
1
2
1a
82 (–)c (trace)d
NH2
NH2
NH2
1b
47 (10)c (15)d
3
4
1c
67 (6)c (9)d
84 (–)c (trace)d
NH2
1d
27 (31)c (trace)d
24 (33)c (trace)d
NH2
NH2
5
6
1e
1f
Cl
© Georg Thieme Verlag Stuttgart · New York
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X. Zhang et al.
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Table 2 Selenium-Catalyzed Oxidative Carbonylations of 2-Aminopyridine with Aminesa (continued)
O
C
N
N
cat. Se
Et3N
+
CO +
1/2 O2
ArNH2
H O
NHAr +
2
NH2
+
NH
1a–k
Entry
Substrate
Product
Yield (%)b
Cl
7
1g
55 (12)c (10)d
NH2
40 (20)c (7)d
55 (11)c (9)d
90 (–)c (trace)d
Cl
Br
NH2
8
9
1h
1i
NH2
NH2
EtO
NH2
10
1j
11
1k
81 (–)c (trace)d
CH2NH2
12
13
14
–
–
–
– (7)c (84)d
– (56)c (16)d
– (57)c (trace)d
NH2
NH
– (12)c (trace)d
SO2NH2
15
–
a Reaction conditions: 2-aminopyridine (5 mmol), amine (5 mmol), Se (0.25 mmol), Et3N (5 mmol), CO (2.0 MPa), O2 (0.4 MPa), toluene (5
mL), 140 °C, 3 h.
b Isolated yield of the unsymmetrical 2-pyridyl urea.
c Isolated yield of N,N′-di(pyridin-2-yl)urea.
d Isolated yield of the symmetrical urea formed from the substrate amine.
Generally, it is difficult to separate catalysts from a homo- A plausible route to the unsymmetrical 2-pyridyl ureas is
geneous system for further use. However, the present cat- presented in Scheme 2. The reaction is initiated by forma-
alytic system does not suffer this disadvantage due to its tion of carbonyl selenide 2,14b,15 which is generated in situ
role as a phase-transfer catalyst in the reaction. Selenium from the reaction of carbon monoxide with selenium in
powder is insoluble in the organic solvent prior to the ox- the presence of triethylamine. Next, nucleophilic attack of
idative carbonylation reaction; it then reacts with carbon 2-aminopyridine and the amine on complex 2 leads to for-
monoxide to form carbonyl selenide (SeCO) in situ,
Table 3 Recycling of the Selenium Catalysta
which is soluble in the reaction mixture, and is able to pro-
mote the homogeneous catalytic carbonylation reaction
Entry
Cycle
Yield (%)b
efficiently. After completion of the reaction, selenium
powder can be precipitated conveniently from the reaction
medium after oxidation. Thus, the selenium powder can
be recovered easily by filtration and drying, and can be
used directly in subsequent reactions. This recycling pro-
tocol was repeated four times and the percentage of the
catalyst recovery was always greater than 95%. An exam-
ination of the reusability of the selenium catalyst using an-
iline as a model substrate was undertaken (Table 3).
Successive recycling of the recovered catalyst gave the
desired product in yields almost as high as those obtained
using fresh selenium.
1
2
3
4
5
0
1
2
3
4
82
81
81
80
80
a Reaction conditions: 2-aminopyridine (5 mmol), aniline (5 mmol),
Se (0.25 mmol), Et3N (5 mmol), CO (2.0 MPa), O2 (0.4 MPa), toluene
(5 mL), 140 °C, 3 h.
b Yield of isolated product.
Synthesis 2013, 45, 1357–1363
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Selenium-Catalyzed Carbonylation toward 2-Pyridyl Ureas
1361
H2O
Se
CO
1/2 O2
SeCO
Et3N
H2Se⋅Et3N
2
4
ArNH2
O
C
N
N
NH2
NH
NHAr
OH
C
1
N
NH
SeH⋅Et3N
NHAr
3
Scheme 2 Proposed reaction pathway
mation of the intermediate 3.14a,b Subsequently, species 3
undergoes elimination to afford the target unsymmetrical
2-pyridyl urea product 1, accompanied by the formation
of hydrogen selenide 4, which is then oxidized in the pres-
ence of oxygen to give selenium for the ensuing catalytic
cycle.
gel, EtOAc–PE, 1:5–1:10), or by crystallization from EtOH, to give
the desired unsymmetrical 2-pyridyl urea.
N-Phenyl-N′-(2-pyridyl)urea (1a)
Yield: 874 mg (82%); colorless needles; mp 191–192 °C (Lit.16
190–193 °C).
1H NMR (400 MHz, DMSO-d6): δ = 10.49 (s, 1 H), 9.42 (s, 1 H),
8.26 (d, J = 4.8 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.50 (d, J = 7.6
Hz, 2 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 2 H), 7.02–
6.98 (m, 2 H).
In summary, a simple, one-pot, phosgene-free approach to
unsymmetrical 2-pyridyl ureas has been developed. The
procedure employs the inexpensive, readily available and
recyclable non-metal, selenium as the catalyst, triethyl-
amine as the cocatalyst, and carbon monoxide (instead of
phosgene) as the carbonylation reagent. The carbonyl-
ation reaction of 2-aminopyridine proceeds smoothly with
a range of common aromatic amines to afford the corre-
sponding unsymmetrical 2-pyridyl ureas in moderate to
good yields. The low-cost, high atom economy and one-
pot, phosgene-free conditions should make this approach
very promising toward this class of compounds.
N-(2-Methylphenyl)-N′-(2-pyridyl)urea (1b)
Yield: 534 mg (47%); colorless needles; mp 209–219 °C (Lit.7b
208–220 °C).
1H NMR (400 MHz, CDCl3): δ = 10.91 (s, 1 H), 9.76 (s, 1 H), 8.26
(d, J = 4.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.74 (t, J = 8.0 Hz, 1
H), 7.26 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.15 (t,
J = 7.6 Hz, 1 H), 6.99 (t, J = 5.2 Hz, 1 H), 6.95 (t, J = 7.2 Hz, 1 H),
2.30 (s, 3 H).
N-(3-Methylphenyl)-N′-(2-pyridyl)urea (1c)
Yield: 761 mg (67%); colorless needles; mp 161–163 °C (Lit.7b
160–162 °C).
1H NMR (400 MHz, CDCl3): δ = 11.70 (s, 1 H), 8.90 (s, 1 H), 8.28
(d, J = 4.4 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1
H), 7.45 (s, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 6.97–6.92 (m, 3 H), 2.31
(s, 3 H).
Carbon monoxide (99.95%) and selenium (99.95%) were used as
purchased. All other chemicals were AR grade and were used with-
out further purification. Petroleum ether (PE) refers to the fraction
boiling in the 60–90 °C range. Column chromatography was ac-
complished on silica gel (200–300 mesh). Melting points were de-
termined using a Keyi XT4 apparatus (Beijing, China) and are
uncorrected. IR spectra were obtained using a Perkin-Elmer Avatar
360 E. S. P. FTIR spectrophotometer. 1H and 13C NMR spectra were
recorded on a Bruker DPX-400 spectrometer using CDCl3 or
DMSO-d6 as the solvent and TMS as the internal standard. High-
resolution mass spectrometry (HRMS) was performed using a
Bruker micrOTOF instrument.
N-(4-Methylphenyl)-N′-(2-pyridyl)urea (1d)
Yield: 954 mg (84%); colorless needles; mp 178–179 °C (Lit.7b
179–180 °C).
1H NMR (400 MHz, CDCl3): δ = 11.68 (s, 1 H), 8.27 (d, J = 4.8 Hz,
1 H), 7.65 (t, J = 6.8 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.17 (d,
J = 8.0 Hz, 2 H), 6.95 (t, J = 6.0 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H),
2.35 (s, 3 H).
Unsymmetrical 2-Pyridyl Ureas; General Procedure
N-(2,6-Dimethylphenyl)-N′-(2-pyridyl)urea (1e)
The Se-catalyzed oxidative carbonylation reactions were carried out
in a 100 mL stainless steel autoclave equipped with a magnetic stir-
rer, using a thermostatic oil bath. 2-Aminopyridine (5 mmol), the
appropriate amine (5 mmol), Se (0.25 mmol), Et3N (5 mmol) and
toluene (5 mL) were added to the autoclave. The autoclave was
sealed and flushed three times with a mixed gas combination of CO
and O2 (5:1). Next, the autoclave was pressurized with the mixed
gas to the desired pressure, placed into an oil bath preheated to the
required temperature and the contents stirred. Upon completion of
the reaction, the reactor was cooled to r.t. and the residual gas re-
leased. The mixture was stirred for 30 min to precipitate Se, which
was collected by suction filtration. The filtrate was concentrated
and the residue purified either by column chromatography (silica
Yield: 326 mg (27%); colorless solid; mp >300 °C.
IR (KBr): 3373, 3204, 3112, 3057, 2984, 1700, 1591, 1554, 1509,
1481, 1445, 1420, 1313, 1297, 1239, 1150, 1061, 1037, 780, 748,
730, 670, 554 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1 H), 9.54 (s, 1 H),
8.23 (d, J = 4.4 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.4
Hz, 1 H), 7.08 (s, 3 H), 6.97 (t, J = 6.0 Hz, 1 H), 2.20 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 153.8, 153.1, 147.1, 138.9,
135.5, 135.4, 128.2, 126.5, 117.5, 112.2, 18.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H16N3O: 242.1293; found:
242.1300.
© Georg Thieme Verlag Stuttgart · New York
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X. Zhang et al.
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N-(2-Chlorophenyl)-N′-(2-pyridyl)urea (1f)
Yield: 297 mg (24%); colorless needles; mp 204–205 °C (Lit.17
200–201 °C).
1H NMR (400 MHz, DMSO-d6): δ = 11.82 (s, 1 H), 10.01 (s, 1 H),
8.34 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 4.4 Hz, 1 H), 7.78 (t, J = 7.6
Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.32 (t, J = 6.0 Hz, 1 H), 7.23 (d,
J = 8.0 Hz, 1 H), 7.07 (t, J = 4.0 Hz, 1 H), 7.04 (t, J = 6.0 Hz, 1 H).
References
(1) (a) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.;
Machida, T.; Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.;
Suzuki-Takahashi, I.; Iwasawa, Y.; Hayama, T.; Nishimura,
S.; Morishima, H. J. Med. Chem. 2001, 44, 4615.
(b) Perveen, S.; Khan, K. M.; Lodhi, M. A.; Choudhary, M.
I.; Attaur, R.; Voelter, W. Lett. Drug Des. Discovery 2008,
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Watanabe, H.; Suzuki, S.; Umeki, Y.; Hanabe, H. EP Patent
293839, 1988; Chem. Abstr. 1989, 110, 212610. (b) Henrie,
R.; Green, C. M.; Sticker, R. E. US Patent 4787931, 1988;
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K.; Takatoshi, I.; Toshiyuki, M. Synth. Commun. 2000, 30,
1675.
N-(3-Chlorophenyl)-N′-(2-pyridyl)urea (1g)
Yield: 681 mg (55%); colorless needles; mp 169–172 °C (Lit.18
170–171 °C).
1H NMR (400 MHz, DMSO-d6): δ = 10.73 (s, 1 H), 9.52 (s, 1 H),
8.28 (d, J = 5.2 Hz, 1 H), 7.77 (s, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.45
(d, J = 8.4 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.30 (d, J = 6.0 Hz, 1
H), 7.06 (d, J = 7.2 Hz, 1 H), 7.01 (t, J = 6.0 Hz, 1 H).
N-(4-Chlorophenyl)-N′-(2-pyridyl)urea (1h)
Yield: 495 mg (40%); colorless needles; mp 202–204 °C (Lit.19
203–204 °C).
1H NMR (400 MHz, CDCl3): δ = 11.94 (s, 1 H), 8.75 (s, 1 H), 8.26
(s, 1 H), 7.66 (d, J = 6.0 Hz, 1 H), 7.58 (d, J = 5.6 Hz, 2 H), 7.32 (d,
J = 5.6 Hz, 2 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.89 (d, J = 7.8 Hz, 1 H).
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X.; Li, X.; Weng, L.; Zhou, X. Dalton Trans. 2010, 39, 221.
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A. Org. Lett. 2009, 11, 947. (b) Abad, A.; Agullo, C.; Cunat,
A. C.; Vilanova, C. Synthesis 2005, 915. (c) Gavade, S. N.;
Balaskar, R. S.; Mane, M. S.; Pabrekar, P. N.; Shingare, M.
S.; Mane, D. V. Chin. Chem. Lett. 2011, 22, 675.
(d) Gavade, S. N.; Balaskar, R. S.; Mane, M. S.; Pabrekar, P.
N.; Shingare, M. S.; Mane, D. V. Chin. Chem. Lett. 2011, 22,
292.
N-(4-Bromophenyl)-N′-(2-pyridyl)urea (1i)
Yield: 803 mg (55%); colorless needles; mp 209–210 °C.
IR (KBr): 3215, 3115, 3087, 3061, 2978, 1695, 1600, 1582, 1555,
1509, 1488, 1479, 1420, 1400, 1319, 1239, 1154, 1074, 1005, 820,
776, 503 cm–1.
1H NMR (400 MHz, CDCl3): δ = 11.96 (s, 1 H), 8.92 (s, 1 H), 8.27
(d, J = 4.8 Hz, 1 H), 7.68 (t, J = 6.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2
H), 7.47 (d, J = 8.4 Hz, 2 H), 6.97 (t, J = 6.4 Hz, 1 H), 6.92 (d,
J = 8.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 153.1, 152.5, 147.3, 139.0,
138.9, 132.0, 121.2, 118.0, 114.4, 112.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H11BrN3O: 292.0085;
found: 292.0078.
N-(4-Ethoxyphenyl)-N′-(2-pyridyl)urea (1j)
Yield: 1158 mg (90%); colorless needles; mp 190–191 °C (Lit.7b
180–181 °C).
1H NMR (400 MHz, CDCl3): δ = 11.53 (s, 1 H), 8.26 (d, J = 4.8 Hz,
1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H), 7.25 (d,
J = 8.8 Hz, 1 H), 6.95 (t, J = 6.0 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 2 H),
4.07–4.01 (m, 2 H), 1.43 (t, J = 6.4 Hz, 3 H).
(7) (a) Xue, Y.; Lu, S. W. Chin. J. Catal. 2001, 22, 387.
(b) Chen, J. Z.; Lu, S. W. Appl. Catal. A. 2004, 261, 199.
(8) Takanori, M.; Tomoya, T.; Masahiro, M. J. Am. Chem. Soc.
2007, 209, 12596.
(9) Mitsudo, T.; Suzuki, N.; Kondo, T. J. Org. Chem. 1994, 59,
7759.
(10) Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.;
Chlebowski, M.; Kokka, M.; McElwee-White, L. J. Org.
Chem. 2002, 67, 4086.
(11) Orito, K.; Miyazawa, M.; Nakamura, T. J. Org. Chem. 2006,
71, 5951.
(12) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.; Tsutsumi, S.
Bull. Chem. Soc. Jpn. 1981, 54, 1460.
N-Naphthalen-1-yl-N′-(2-pyridyl)urea (1k)
Yield: 1066 mg (81%); colorless needles; mp 197–199 °C (Lit.20
197–199 °C).
1H NMR (400 MHz, DMSO-d6): δ = 11.41 (s, 1 H), 9.87 (s, 1 H),
8.40 (d, J = 4.8 Hz, 1 H), 8.18–8.15 (m, 2 H), 7.95 (d, J = 8.0 Hz, 1
H), 7.81–7.77 (m, 1 H), 7.67–7.62 (m, 2 H), 7.56 (t, J = 7.2 Hz, 1
H), 7.48 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.05 (t,
J = 6.0 Hz, 1 H).
(13) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J. Mol.
Catal. 1990, 60, 41.
Acknowledgment
(14) (a) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.;
Tsutsumi, S. J. Am. Chem. Soc. 1971, 93, 6344. (b) Sonoda,
N. Pure Appl. Chem. 1993, 65, 699. (c) Yang, Y.; Lu, S. W.
Tetrahedron Lett. 1999, 40, 4845. (d) Mei, J. T.; Yang, Y.;
Xue, Y.; Lu, S. W. J. Mol. Catal. A.: Chem. 2003, 191, 135.
(e) Chen, J. Z.; Ling, G.; Lu, S. W. Tetrahedron 2003, 59,
8251. (f) Ling, G.; Chen, J. Z.; Lu, S. W. J. Mol. Catal. A:
Chem. 2003, 202, 23. (g) Wu, X. W.; Yu, Z. K. Tetrahedron
Lett. 2010, 51, 1500.
We gratefully acknowledge financial support from the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1061), Henan Normal University (2009PL06, Young Back-
bone Teachers Training Fund), and The Education Department of
Henan Province, China (2009B150013).
Synthesis 2013, 45, 1357–1363
© Georg Thieme Verlag Stuttgart · New York

PAPER
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1357–1363