Synthesis of N-phenyl-N′-pyrimidylurea derivatives by selenium- or selenium dioxide-catalyzed reductive carbonylation of nitroaromatics

Article abstract of DOI:10.1002/ejoc.200300127

Forty unsymmetric N-phenyl-N′-pyrimidylurea derivatives were synthesized in moderate-to-good yields by one-pot reductive carbonylation of nitroaromatics using selenium or selenium dioxide as the catalyst, aminopyrimidine derivatives as co-reagents, and ca

Full text of DOI:10.1002/ejoc.200300127

FULL PAPER
Synthesis of N-Phenyl-NЈ-pyrimidylurea Derivatives by Selenium- or Selenium
Dioxide-Catalyzed Reductive Carbonylation of Nitroaromatics
Jinzhu Chen,[a] Gang Ling,[a] and Shiwei Lu*[a]
Keywords: Carbonylations / Nitrogen heterocycles / Reductions / Selenium
Forty unsymmetric N-phenyl-NЈ-pyrimidylurea derivatives
the reusability of the catalysts. We found that selenium- or
were synthesized in moderate-to-good yields by one-pot re- selenium dioxide-catalyzed reductive carbonylation of the
ductive carbonylation of nitroaromatics using selenium or
selenium dioxide as the catalyst, aminopyrimidine derivat-
ives as co-reagents, and carbon monoxide as the carbonyl
source. The reaction parameters were investigated, as was
nitroaromatics exhibited reaction-controlled phase-transfer
phenomena of the catalysts.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
series of selenium-catalyzed organic synthetic reac-
tions.[16,17] Lu et al. synthesized a series of unsymmetrical
phenyl ureas by one-pot reactions under relatively mild con-
ditions.[18] Additionally, reactions catalyzed by selenium di-
oxide demonstrated that oxidative carbonylation of aro-
matic amines gives diphenylurea derivatives.[19,20] These en-
vironmentally benign reactions present many advantages
over the traditional phosgene routes used for synthesis of
urea derivatives. Actually, the synthesis of unsymmetrical
N-phenyl-NЈ-pyrimidylurea derivatives by catalytic methods
is even more attractive than that of symmetrical ureas, be-
cause conformational behavior of the unsymmetrical urea
derivatives can be studied as model systems for polypep-
tides and proteins.[21]
Pyrimidines are important heterocyclic compounds and
it is well-known that several of their derivatives are biologi-
cally active.[1Ϫ5] In particular, pyrimidylurea derivatives
containing both a peptide bond (ϪCONHϪ) and a pyrimi-
dyl group have been widely used as immunosuppressants
and anti-viral agents.[6,7] N-Phenyl-NЈ-pyrimidylurea de-
rivatives are considered to be promising compounds for the
treatment of autoimmune diseases and viral infection in
mammals.[6,7]
The conventional methods for preparing pyrimidylurea
derivatives, however, utilize highly toxic phosgene as the
carbonyl source.[6] This process has many disadvantages
that are particularly troublesome, such as the toxicity and
corrosive nature of phosgene and the formation of hydrogen
chloride as the by-product.[8,9] Accordingly, catalytic car-
bonylation of organic nitro compounds has been investi-
gated recently by several industrial and academic research
groups.[10,11] The major objective is to find a new catalytic
process for the synthesis of these important chemicals that
avoids the use phosgene. Group VIII transition metals, such
as rhodium, ruthenium, and palladium, have been used
commonly as catalysts for this purpose.[12,13]
Results and Discussion
Selenium- or Selenium Dioxide-Catalyzed Carbonylation of
Nitrobenzene
Treatment of nitrobenzene with 2-aminopyrimidine in a
1:1 molar ratio, using selenium or selenium dioxide as the
catalyst, in the presence of carbon monoxide led to N-phe-
nyl-NЈ-(2-pyrimidyl)urea 1a [Equation (1)]. We investigated
the effects of various parameters on the reaction, such as
the temperature, the amount of catalyst, the choice of or-
ganic base, and the pressure of carbon monoxide [Equa-
tion (1), Table 1].
We found that the reactions catalyzed by either selenium
and selenium dioxide exhibited excellent chemoselectivity.
The chemoselectivity for the formation of unsymmetrical
ureas 1a was higher than 98.1% and there was very little
N,NЈ-diphenylurea in the crude products. We note that sym-
metrical N,NЈ-bis(2-pyrimidyl)urea was not detected in the
crude products by HPLC analysis, which is different from
those reported reactions, yielding a mixture of three sym-
Recently, non-transition metal elements and their oxides,
such as selenium, sulfur, and selenium dioxide, have been
found to also catalyze the carbonylation of nitroaromatics
for the synthesis of urea derivatives. Franz et al. reported
sulfur-catalyzed oxidative carbonylation of amines to give
symmetric urea derivatives.[14,15] Sonoda et al. developed a
[a]
National Engineering Research Center for Catalysis, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences,
161 Zhongshan Road; Dalian, Liaoning, 116011, P. R. China
Fax: (internat.) ϩ 86-411/3698749
E-mail: lusw@dicp.ac.cn (S. Lu),
chenjz@dicp.ac.cn (J. Chen)
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300127
Eur. J. Org. Chem. 2003, 3446Ϫ3452

Synthesis of N-Phenyl-NЈ-pyrimidylurea Derivatives
FULL PAPER
triphenylphosphane (Table 1, run 12), the selenium dioxide-
catalyzed reaction provided 1a in 50.7% yield, but the corre-
sponding selenium-catalyzed reaction did not take place un-
der the same conditions.
Table 1. Selenium- or selenium dioxide-catalyzed synthesis of N-
phenyl-NЈ-(2-pyrimidyl)urea (1a)
Run Temp. Catalyst[a] Base
PCO
[MPa] [h]
Time Yield (%)
[°C]
mmol
(mmol)
Se SeO2
Reusability of the Catalysts
1
2
3
4
5
6
7
8
9
110
130
150
170
150
150
150
150
150
0.5
0.5
0.5
0.5
0.01
0.05
0.1
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
TEA[b] (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (10)
TEA (30)
TEA (40)
TPP[c] (2.0)
NMP[d] (20)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
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
4.0
4.0
1.0
2.0
8.0
45.6 44.7
70.3 76.1
74.9 79.8
70.8 74.6
30.6 30.1
51.3 52.4
73.5 77.8
75.1 80.8
46.8 50.6
76.1 79.4
78.2 81.8
To test the reusability of the catalysts, the carbonylation
reaction of nitrobenzene with 2-aminopyrimidine [Equa-
tion (1)] was performed using Se or SeO2 in the presence of
CO (3.0 MPa) in toluene at 150 °C for 4.0 h (Table 2). After
the reaction was complete, the mixture was filtered under a
nitrogen atmosphere to remove the insoluble urea derivative
1a. The resultant liquor containing the catalyst was reused
with a fresh charge of nitrobenzene and 2-aminopyrimidine.
Both the selenium and selenium dioxide catalysts exhibited
better activity than they did in the original runs, even after
six reuses. The yields of urea 1a increased upon recycling
the catalysts, suggesting that unchanged substrates might
have participated in the subsequent reaction (Table 2).
10 150
11 150
12 150
13 150
14 150
15 150
16 150
17 150
18 150
19 150
20 150
21 150
22 150
23 150
/
50.7
76.7 80.4
78.3 81.1
81.4 84.2
82.3 85.9
40.1 36.7
66.8 67.0
76.0 80.3
76.8 81.3
40.1 39.8
68.7 69.1
75.8 80.1
DABCO[e] (20) 3.0
DBN[f] (20)
DBU[g] (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
TEA (20)
3.0
3.0
1.0
2.0
4.0
5.0
3.0
3.0
3.0
Table 2. Reusability of the catalysts
[a]
Run
Cycle
Se[a]
Selectivity
SeO2
Yield
(%)
Yield
(%)
Selectivity
(%)
(%)
[a]
Reaction conditions: nitrobenzene (10 mmol), 2-aminopyrimid-
ine (10 mmol), base (10Ϫ40 mmol), CO (1.0Ϫ5.0 MPa). Catalyst:
Se or SeO2 (0.01Ϫ1.0 mmol); toluene (10 mL); 110Ϫ170 °C;
1
2
3
4
5
6
7
0
1
2
3
4
5
6
74.9
79.8
80.1
82.4
83.5
83.8
83.7
98.3
98.1
98.1
98.2
98.2
98.1
98.3
79.8
80.1
80.3
82.3
83.6
83.7
83.8
98.4
98.1
98.2
98.1
98.1
98.1
98.2
[b]
[c]
[d]
1.0Ϫ8.0 h.
pyrrolidine.
Triethylamine. Triphenylphosphane.
N-Methyl-
[e]
[f]
1,4-Diazabicyclo[2,2,2]octane.
1,5-Diazabicy-
[g]
clo[4,3,0]non-5-ene. 1,8-Diazabicyclo[5,4,0]undec-7-ene.
[a]
Reaction conditions: nitrobenzene (10 mmol), 2-aminopyrimid-
ine (10 mmol), Et3N (20 mmol), CO (3.0 MPa), Se or SeO2 catalyst
(0.5 mmol), toluene (10 mL); 140Ϫ150 °C; 4.0 h.
metric and unsymmetrical ureas when primary amines were
used as co-reagents.[16,18,22] Between the temperatures
110Ϫ170 °C, the yields of 1a were increased as the tempera-
ture increased to 150 °C and then decreased with any
further temperature increase (Table 1, runs 1Ϫ4). The de-
crease in yield at temperatures above 150 °C can be rationa-
lized by presuming that 1a decomposed faster than the oc-
currence of carbonylation of the remaining 2-aminopyrimi-
dine during the reaction. The yields of 1a were increased
with increasing amounts of the catalysts (Table 1, runs
5Ϫ8).
It is known that selenium dioxide reacts with carbon
monoxide in the presence of triethylamine under very mild
conditions (10 °C, 0.1 MPa), forming carbonyl selenide
(COSe) in situ, and shows the same catalytic activity as
selenium.[17,23] In our case, when selenium dioxide ac-
complished its first catalytic cycle, it demonstrated similar
catalytic activity as selenium in subsequent runs, suggesting
that reduction of selenium dioxide by carbon monoxide oc-
curred in the first run to form elemental selenium (Table 2,
runs 2Ϫ7).
Organic bases dramatically affect the formation of the
product (Table 1, runs 9Ϫ16). In addition to triethylamine,
stronger organic bases, such as 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene
Synthesis of N-Phenyl-NЈ-pyrimidylurea Derivatives
Nitroaromatics react with aminopyrimidine derivatives,
(DBN), and the tertiary amines 1,4-diazabicyclo[2.2.2]oc- using selenium or selenium dioxide as the catalyst in the
tane (DABCO) and N-methylpyrrolidine (NMP), were all presence of carbon monoxide, to form urea derivatives 2
effective for the reductive carbonylation of nitrobenzene [Equation (2)]. A series of unsymmetrical N-phenyl-NЈ-pyr-
with 2-aminopyrimidine. Interestingly, in the presence of imidylurea derivatives 2 were synthesized in one-pot reac-
(1)
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J. Chen, G. Ling, S. Lu
FULL PAPER
tions by combining catalytic oxidative carbonylation of am-
inopyrimidine derivatives with reductive carbonylation of
nitroaromatics under relatively mild conditions (Tables 3
and 4). During the reaction the nitroaromatics also act as
oxidants, thereby playing an important role in promoting
the catalytic cycle. Thus, the products 2, as well as the cata-
lysts (Se and SeO2), can be obtained easily by simple
phase separation.
Table 4. Reductive carbonylation of nitroaromatics with 2-amino-
4,6-dimethoxypyrimidine as the co-reagent
Run
R1
Product[a]
m.p. [°C]
Yield (%)
SeO2
Se
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
2-Me
3-Me
4-Me
2-Cl
3-Cl
4-Cl
2-iPr
214Ϫ216
205Ϫ207
223Ϫ224
248Ϫ249
195Ϫ197
227Ϫ230
246Ϫ247
164Ϫ166
166Ϫ167
216Ϫ217
216Ϫ218
245Ϫ247
241
175Ϫ178
199Ϫ202
259Ϫ262
249Ϫ251
180Ϫ183
236
72.3
67.1
67.9
67.8
43.7
83.3
23.9
35.0
80.7
65.1
71.3
61.1
87.7
51.8
67.2
55.4
57.3
64.2
76.7
83.3
77.1
69.9
71.0
70.5
43.9
86.6
23.9
36.6
83.9
66.3
74.9
61.8
89.8
53.9
69.9
56.4
59.1
67.8
79.7
86.0
Table 3. Reductive carbonylation of nitroaromatics with 2-amino-
pyrimidine as the co-reagent
3-iPr
4-iPr
2j
2k
2l
Run R1
Product[a]
m.p. (°C) (ref.)
Yield (%)
Se SeO2
3-COCH3
4-COCH3
3-CF3
2-OMe
4-OEt
4-CN
4-CHO
4-OPh
3-Cl,2-Me
3-Cl,4-Me
2m
2n
2o
2p
2q
2r
2s
2t
1a
H
233Ϫ235 (221Ϫ222),[6]
(225Ϫ227),[24] (233Ϫ235)[7][25]
225 (214Ϫ215)[6]
74.9 79.8
1b
1c
1d
1e
1f
1g
1h
1i
2-Me
3-Me
4-Me
2-Cl
3-Cl
4-Cl
2-iPr
3-iPr
4-iPr
68.6 71.3
74.3 77.2
73.9 74.9
48.5 53.4
85.7 88.7
194Ϫ195
211Ϫ213 (205Ϫ206)[6]
238Ϫ239
226Ϫ227 (224Ϫ227)[7]
244Ϫ246
241Ϫ243 (238),[26] (240Ϫ242)[7] 26.4 27.1
[a]
193Ϫ194
202Ϫ203
268Ϫ269
33.7 35.0
84.8 88.1
65.5 68.6
74.5 77.3
62.3 63.7
87.3 89.8
55.7 60.1
69.4 73.2
55.2 61.3
60.1 63.2
68.7 69.9
80.2 83.3
83.4 87.5
Reaction conditions: nitroaromatics (10 mmol), 2-amino-4,6-di-
methoxypyrimidine (10 mmol), Et3N (20 mmol), CO (3.0 MPa), Se
or SeO2 catalyst (0.5 mmol), toluene (10 mL); 140Ϫ150 °C; 4.0 h.
1j
1k
1l
3-COCH3 229Ϫ231
4-COCH3 252Ϫ255
3-CF3
2-OMe
4-OEt
4-CN
1m
1n
1o
1p
1q
1r
1s
1t
234 (223Ϫ224)[6]
207
209Ϫ211
287 (273Ϫ274)[6]
265Ϫ267
217Ϫ218
benzene, and 2-isopropylnitrobenzene, gave relatively low
yields of the expected products, suggesting that these reac-
tions were sterically sensitive to the ortho substituents
(Tables 3 and 4, runs 1b, 2b; 1e, 2e; 1 h, 2 h; 1n, 2n). meta-
Substituted nitrobenzenes, such as 3-chloronitrobenzene
and 3-trifluoromethylnitrobenzene, gave higher yields of the
corresponding products than nitrobenzene, which reveals
that these reactions are influenced electronically by the sub-
stituents on this aromatic ring (Tables 3 and 4, runs 1f, 2f
and 1m, 2m). 2-Aminopyrimidine gave higher yields of the
corresponding products than did 2-amino-4,6-dimeth-
oxypyrimidine, which indicates that the reactions are also
influenced electronically by substituents on the pyrimidyl
rings (Tables 3 and 4).
4-CHO
4-OPh
3-Cl,2-Me 264Ϫ265 (262Ϫ264)[7]
3-Cl,4-Me 252Ϫ255 (251Ϫ254)[7]
[a]
Reaction conditions: nitroaromatics (10 mmol), 2-aminopyrimi-
dine (10 mmol), Et3N (20 mmol), CO (3.0 MPa), Se or SeO2 cata-
lyst (0.5 mmol), toluene (10 mL); 140Ϫ150 °C; 4.0 h.
Both the selenium- and selenium dioxide-catalyzed reac-
tions show remarkable chemoselectivity. The reaction of
aminopyrimidine derivatives with nitroaromatics resulted in
N-phenyl-NЈ-pyrimidylurea derivatives 2 in moderate-to-
good yields (Tables 3 and 4). Symmetrical N,NЈ-bis(2-pyri-
midyl)urea derivatives, however, were not detected by
HPLC analysis of the crude products, which was the same
observation made for reaction with 2-aminopyrimidine. In
most cases, selenium dioxide showed higher catalytic ac-
tivity than selenium under the same conditions, presumably
because selenium dioxide forms the reactive intermediate
more readily. ortho-Substituted nitrobenzenes such as 2-
methylnitrobenzene, 2-chloronitrobenzene, 2-methoxynitro-
Reaction-Controlled Phase-Transfer Catalysis in Selenium-
or Selenium Dioxide-Catalyzed Systems
During the reductive carbonylation of nitroaromatics
with aminopyrimidine derivatives, the catalyst itself was not
soluble in the organic solvent, but it slowly reacted with
carbon monoxide to form carbonyl selenide species
(SeCO)[23] that are soluble in the reaction medium, leading
subsequently to homogeneous catalytic carbonylation reac
tions. When the starting materials were consumed, the cata-
lyst (elemental selenium) precipitated as a powder. This
(2)
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Synthesis of N-Phenyl-NЈ-pyrimidylurea Derivatives
FULL PAPER
Scheme 1. Formation of urea derivatives by selenium- or selenium dioxide-catalyzed carbonylation
phenomenon manifests a solidϪliquidϪsolid phase transfer is nonmetallic and is much cheaper than noble metal cata-
of the catalyst that is controlled by the degree of completion lysts. They can be considered as ‘‘mobile’’ catalysts that
of the reaction, which is in accordance with the concept transfer between two phases in response to the reaction pro-
of reaction-controlled phase-transfer catalysis.[27] Here, the cess (Scheme 2). We regard the use of the catalytic systems
selenium or selenium dioxide can be referred to as reaction- Se/CO and SeO2/CO as promising methods for the syn-
controlled phase-transfer catalyst. The nitro compounds thesis of unsymmetrical urea derivatives.
can be considered as special oxidants that oxidize the inter-
Proposed Reaction Pathway of Carbonylation
mediate carbonyl selenide species to selenium. This driven
force impels the recycling of the catalyst. After the reaction
Although a detailed study of the reaction mechanism has
reaches end, the catalyst can be separated from the product not been undertaken, the present reactions can be under-
by a simple phase separation and reused as a heterogeneous stood mechanistically by assuming the reaction pathway
catalyst (Scheme 1). That is, the reaction system changes shown in Scheme 3. The initial deoxygenation of substi-
from heterogeneous to homogeneous and then recycles to tuted nitrobenzene derivative 3 with carbonyl selenide
allow heterogeneous separation. Therefore, this catalytic (SeCO), generated in situ by the reaction of elemental sel-
system possesses the advantages of both homogeneous and enium or selenium dioxide with carbon monoxide in the
heterogeneous catalysis.
presence of triethylamine,[23,28] results in the intermediate(s)
In comparison with conventional homogeneous catalysis, nitrene 4 and/or nitrenoid 5 (Scheme 3), which react further
the catalytic system of Se/CO or SeO2/CO is more advan- with carbon monoxide to form aryl isocyanate 6. This com-
tageous because the catalyst can be separated from the solu- pound reacts with aminopyrimidine to afford the desired
tion after the reaction is complete. In addition, the catalyst N-phenyl-NЈ-pyrimidylurea derivatives 2.
Scheme 2. Reaction-controlled phase-transfer catalysis in the selenium or selenium dioxide-catalyzed carbonylation of nitroaromatics
Scheme 3. Proposed reaction pathway of carbonylation
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J. Chen, G. Ling, S. Lu
FULL PAPER
N-(2-Methylphenyl)-NЈ-(2-pyrimidyl)urea (1b): M.p. 225 °C. 1H
NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.36 (s, 3 H, CH3), 7.00
(t, J ϭ 4.8 Hz, 1 H, 9-H), 7.15 (t, J ϭ 4.8 Hz, 1 H, 4-H), 7.20 (d,
J ϭ 8.0 Hz, 1 H, 3-H), 7.25 (t, J ϭ 8.0 Hz, 1 H, 5-H), 8.09 (d, J ϭ
8.0 Hz, 1 H, 6-H), 8.70 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.26 (s,
1 H, PyNH), 11.41 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz,
[D6]DMSO, 23 °C): δ ϭ 18.13 (CH3), 114.98 (C-9), 120.34 (C-6),
123.12 (C-4), 126.38 (C-5), 127.16 (C-2), 130.25 (C-3), 137.12 (C-
1), 151.48 (CϭO), 157.82 (C-7), 158.18 (C-8, C-10) ppm.
Conclusion
In view of the simple precursors, the mild reaction con-
ditions, the good yields, the high chemoselectivities, the
one-step synthesis, and the replacement of noxious phos-
gene with carbon monoxide, the present procedures seem
to be very useful ones for the preparation of N-phenyl-NЈ-
pyrimidylurea derivatives. In summary, we have developed
a catalytic synthetic method for preparing unsymmetrical
N-phenyl-NЈ-pyrimidylurea derivatives by combining re-
ductive carbonylation of nitroaromatics with oxidative car-
bonylation of aminopyrimidine derivatives in a oneϪpot re-
action.
N-(2-Chlorophenyl)-NЈ-(2-pyrimidyl)urea (1e): M.p. 238Ϫ239 °C.
1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 7.08 (t, J ϭ 4.6 Hz,
1 H, 9-H), 7.17 (t, J ϭ 4.8 Hz, 1 H, 4-H), 7.35 (t, J ϭ 7.8 Hz, 1 H,
5-H), 7.54 (d, J ϭ 8.0 Hz, 1 H, 3-H), 8.39 (d, J ϭ 8.0 Hz, 1 H, 6-
H), 8.72 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.43 (s, 1 H, PyNH),
12.12 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23
°C): δ ϭ 115.33 (C-9), 120.97 (C-6), 122.16 (C-2), 123.91 (C-4),
127.77 (C-5), 129.27 (C-3), 135.84 (C-1), 151.38 (CϭO), 157.53 (C-
7), 158.24 (C-8, C-10) ppm.
Experimental Section
General Remarks: The organic solvents were all reagent grade and
used without further purification. Aminopyrimidines, elemental
selenium (99.999%), selenium dioxide (98.0%), carbon monoxide
(99.9%), nitroaromatics, triethylamine, and other organic bases
were all used as received. The purity and selectivity of products
were determined by using a Waters HPLC with MeOH/H2O as
eluent. Melting points were determined on a Taike X-4 apparatus
(Beijing, China) and are uncorrected. 1H and 13C NMR spectra
were obtained on a Bruker DRX 400 MHz spectrometer. Chemical
shifts are reported in ppm relative to tetramethylsilane (δ scale).
[D6]Dimethylsulfoxide was the solvent.
N-(3-Chlorophenyl)-NЈ-(2-pyrimidyl)urea (1f): M.p. 226Ϫ227 °C. 1H
NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 7.13 (t, J ϭ 4.6 Hz, 1
H, 9-H), 7.16 (d, J ϭ 7.6 Hz, 1 H, 4-H), 7.36 (t, J ϭ 7.6 Hz, 1 H,
5-H), 7.51 (d, J ϭ 7.6 Hz, 1 H, 6-H), 7.84 (s, 1 H, 2-H), 8.70 (d,
J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.03 (s, 1 H, PyNH), 11.67 (s, 1 H,
PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 115.26
(C-9), 117.91 (C-6), 118.84 (C-2), 122.75 (C-4), 130.55 (C-5), 133.30
(C-3), 140.15 (C-1), 151.50 (CϭO), 157.75 (C-7), 158.28 (C-8, C-
10) ppm.
N-(2-Isopropylphenyl)-NЈ-(2-pyrimidyl)urea (1h): M.p. 193Ϫ194 °C.
1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 1.21 [d, J ϭ 6.8 Hz,
6 H, -CH(CH3)2], 2.51Ϫ2.54 [m, 1 H, -CH(CH3)2], 7.09 (t, J ϭ
4.8 Hz, 1 H, 4-H), 7.12 (t, J ϭ 4.6 Hz, 1 H, 9-H), 7.29 (t, J ϭ
8.0 Hz, 1 H, 5-H), 7.61 (d, J ϭ 8.0 Hz, 1 H, 3-H), 7.96 (d, J ϭ
8.0 Hz, 1 H, 6-H), 8.67 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.24 (s,
1 H, PyNH), 11.41 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz,
[D6]DMSO, 23 °C): δ ϭ 22.65 [-CH(CH3)2], 33.74 [-CH(CH3)2],
115.01 (C-9), 122.14 (C-6), 123.97 (C-4), 125.17 (C-5), 126.03 (C-
3), 135.76 (C-1), 139.73 (C-2), 151.78 (CϭO), 157.90 (C-7), 158.17
(C-8, C-10) ppm.
The carbonylation reaction was carried out in a 100-mL stainless-
steel autoclave that was placed in a thermostatic oil bath. The stir-
ring rate was kept constant for all the experiments. Reaction mate-
rials, including aminopyrimidine, nitro compound, organic solvent,
selenium or selenium dioxide as catalyst, triethylamine or other or-
ganic base as co-catalyst, were introduced successively into the
autoclave. The reactor was sealed, flushed three times with carbon
monoxide (1.0 MPa), pressurized with carbon monoxide, and then
placed in an oil bath preheated at the stated temperature. After
the reaction was finished, the apparatus was cooled to ambient
temperature, and the remaining carbon monoxide was evacuated.
The reaction mixture was filtered, and N-phenyl-NЈ-pyrimidylurea
derivatives were collected and further purified by flash chromatog-
raphy (silica gel: hexane/ EtOAc, 10:3).
N-(3-Isopropylphenyl)-NЈ-(2-pyrimidyl)urea (1i): M.p. 202Ϫ203 °C.
1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 1.22 [d, J ϭ 6.8 Hz,
6 H, -CH(CH3)2], 2.86Ϫ2.89 [m, 1 H, -CH(CH3)2], 6.96 (d, J ϭ
7.6 Hz, 1 H, 4-H), 7.15 (t, J ϭ 4.6 Hz, 1 H, 9-H), 7.25 (t, J ϭ
7.6 Hz, 1 H, 5-H), 7.44 (d, J ϭ 7.6 Hz, 1 H, 6-H), 7.47 (s, 1 H, 2-
H), 8.70 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.16 (s, 1 H, PyNH),
11.42 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23
°C): δ ϭ 23.90 [-CH(CH3)2], 33.55 [-CH(CH3)2], 115.00 (C-9),
117.12 (C-6), 117.53 (C-2), 121.04 (C-4), 128.82 (C-5), 138.50 (C-1),
149.27 (C-3), 151.50 (CϭO), 157.88 (C-7), 158.24 (C-8, C-10) ppm.
Data of Some Representative N-Phenyl-NЈ-pyrimidylurea Derivatives
N-(4-Acetylphenyl)-NЈ-(2-pyrimidyl)urea (1l): M.p. 252Ϫ255 °C. 1H
NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.53 (s, 3 H, -COCH3),
7.18 (t, J ϭ 5.0 Hz, 1 H, 9-H); 7.76 (d, J ϭ 8.4 Hz, 2 H, 2-H/6-H),
7.96 (d, J ϭ 8.4 Hz, 2 H, 3-H/5-H), 8.71 (d, J ϭ 4.8 Hz, 2 H, 8-H/
10-H), 10.37 (s, 1 H, PyNH), 11.82 (s, 1 H, PhNH) ppm. 13C NMR
(400 MHz, [D6]DMSO, 23 °C): δ ϭ 26.47 (CH3), 115.32 (C-9),
118.53 (C-2, C-6), 129.65 (C-3, C-5), 131.54 (C-4), 143.08 (C-1),
151.33 (NHCONH), 157.61 (C-7), 158.30 (C-8, C-10), 196.53 (Ph-
COCH3) ppm.
N-Phenyl-NЈ-(2-pyrimidyl)urea (1a): M.p. 233Ϫ235 °C. 1H NMR
(400 MHz, [D6]DMSO, 23 °C): δ ϭ 7.06 (t, J ϭ 7.2 Hz, 1 H, 4-H),
7.12 (t, J ϭ 4.8 Hz, 1 H, 9-H), 7.33 (t, J ϭ 7.6 Hz, 2 H, 3-H/5-H),
7.59 (d, J ϭ 8.0 Hz, 2 H, 2-H/6-H), 8.67 (d, J ϭ 4.8 Hz, 2 H, 8-H/
10-H), 9.94 (s, 1 H, PyNH), 11.36 (s, 1 H, PhNH) ppm. 13C NMR
(400 MHz, [D6]DMSO, 23 °C): δ ϭ 114.60 (C-9), 119.18 (C-2, C- N-(2-Methyl-3-chlorophenyl)-NЈ-(2-pyrimidyl)urea
6), 122.66 (C-4), 128.42 (C-3, C-5), 138.20 (C-1), 151.00 (CϭO),
157.50 (C-7), 157.70 (C-8, C-10) ppm.
(1s):
M.p.
264Ϫ265 °C. 1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.10
(s, 3 H, Ph-CH3), 6.86 (d, J ϭ 7.6 Hz, 1 H, 4-H), 7.16 (t, J ϭ
3450
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3446Ϫ3452

Synthesis of N-Phenyl-NЈ-pyrimidylurea Derivatives
FULL PAPER
4.8 Hz, 1 H, 9-H), 7.25 (t, J ϭ 7.8 Hz, 1 H, 5-H), 7.71 (d, J ϭ N-(4-Isopropylphenyl)-NЈ-(2-pyrimidyl)urea (2j): 216Ϫ217 °C. 1H
8.0 Hz, 1 H, 6-H), 8.70 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.33 (s, NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 1.19 [d, J ϭ 6.8 Hz, 6
1 H, PyNH), 11.54 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, H, -CH(CH3)2], 2.83Ϫ2.89 [m, 1 H, -CH(CH3)2], 3.94 (s, 6 H, Py-
[D6]DMSO, 23 °C): δ ϭ 14.78 (Ph-CH3), 112.70 (C-6), 115.12 (C- OCH3), 5.58 (s, 1 H, 9-H), 7.20 (d, J ϭ 6.0 Hz, 2 H, 3-H/5-H), 7.43
9), 118.25 (C-4), 127.20 (C-5), 133.57 (C-2), 138.63 (C-3), 148.34 (t, J ϭ 6.0 Hz, 2 H, 2-H/6-H), 9.88 (s, 1 H, PyNH), 11.21 (s, 1 H,
(C-1), 151.46 (CϭO), 158.01 (C-7), 158.21 (C-8, C-10) ppm
PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 23.97
[-CH(CH3)2], 32.83 [-CH(CH3)2], 54.35 (Py-OCH3), 82.65 (C-9),
119.34 (C-2, C-6), 126.71 (C-3, C-5), 135.92 (C-1), 143.22 (C-4),
151.14 (CϭO), 156.90 (C-7), 171.22 (C-8, C-10) ppm.
N-(3-Chloro-4-methylphenyl)-NЈ-(2-pyrimidyl)urea (1t):
M.p.
252Ϫ255 °C. 1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.29
(s, 3 H, Ph-CH3), 7.14 (t, J ϭ 4.8 Hz, 1 H, 9-H), 7.30 (d, J ϭ
6.0 Hz, 1 H, 5-H), 7.69 (d, J ϭ 6.0 Hz, 1 H, 6-H), 8.21 (s, 1 H, 2-
H), 8.78 (d, J ϭ 4.8 Hz, 2 H, 8-H/10-H), 10.22 (s, 1 H, PyNH),
11.55 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23
°C): δ ϭ 18.91 (Ph-CH3), 115.17 (C-9), 117.13 (C-6), 118.04 (C-2),
129.61 (C-4), 131.29 (C-5), 133.22 (C-3), 139.05 (C-1), 151.34 (Cϭ
O), 157.73 (C-7), 158.25 (C-8, C-10) ppm.
N-(3-Acetylphenyl)-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea (2k): M.p.
216Ϫ218 °C. 1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.54
(s, 3 H, -COCH3), 3.96 (s, 6 H, Py-OCH3), 5.85 (s, 1 H, 9-H), 7.46
(t, J ϭ 7.8 Hz, 1 H, 5-H), 7.64 (d, J ϭ 7.6 Hz, 1 H, 4-H), 7.75 (d,
J ϭ 8.0 Hz, 1 H, 6-H), 8.09 (s, 1 H, 2-H), 9.49 (s, 1 H, PyNH),
11.00 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23
°C): δ ϭ 25.97 (-COCH3), 53.80 (Py-OCH3), 82.40 (C-9), 118.21
(C-2), 122.44 (C-4), 123.29 (C-6), 128.76 (C-5), 137.46 (C-3), 138.42
(C-1), 150.63 (CϭO), 156.44 (C-7), 171.06 (C-8, C-10), 196.87 (Ph-
COCH3) ppm.
N-phenyl-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea (2a): M.p. 214Ϫ216
1
°C. H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 3.95 (s, 6 H, -
OCH3), 5.91 (s, 1 H, 9-H), 7.06 (t, J ϭ 7.2 Hz, 1 H, 4-H), 7.324 (t,
J ϭ 8.0 Hz, 2 H, 3-H/5-H), 7.54 (d, J ϭ 8.0 Hz, 2 H, 2-H/6-H), 9.99
(s, 1 H, PyNH), 11.11 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz,
[D6]DMSO, 23 °C): δ ϭ 54.39 (Py-OCH3), 82.70 (C-9), 119.25 (C-
2, C-6), 123.10 (C-4), 129.00 (C-3, C-5), 138.34 (C-1), 151.14 (Cϭ
O), 156.81 (C-7), 171.23 (C-8, C-10) ppm.
N-(3-Trifluoromethylphenyl)-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea
1
(2m): M.p. 241 °C. H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ
3.94 (s, 6 H, Py-OCH3), 5.30 (s, 1 H, 9-H), 7.40 (d, J ϭ 7.2 Hz, 1
H, 4-H), 7.57 (t, J ϭ 7.8 Hz, 1 H, 5-H), 7.61 (d, J ϭ 8.0 Hz, 1 H,
6-H), 8.13 (s, 1 H, 2-H), 10.16 (s, 1 H, PyNH), 11.31 (s, 1 H, PhNH)
ppm. 13C NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 54.41 (Py-
OCH3), 82.92 (C-9), 115.26 (C-6), 118.61 (Ph-CF3), 119.43 (C-2),
122.95 (C-4), 129.20 (C-3), 130.18 (C-5), 139.19 (C-1), 151.29 (Cϭ
O), 156.66 (C-7), 171.25 (C-8, C-10) ppm.
N-(3-Methylphenyl)-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea (2c): M.p.
223Ϫ224 °C. 1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.29
(s, 3 H, Ph-CH3), 3.94 (s, 6 H, Py-OCH3), 5.91 (s, 1 H, 9-H), 6.89
(d, J ϭ 6.8 Hz, 1 H, 4-H), 7.21 (t, J ϭ 7.6 Hz, 1 H, 5-H), 7.30 (d,
J ϭ 7.2 Hz, 1 H, 6-H), 7.39 (s, 1 H, 2-H), 9.96 (s, 1 H, PyNH),
11.04 (s, 1 H, PhNH) ppm. 13C NMR (400 MHz, [D6]DMSO, 23
°C): δ ϭ 21.23 (Ph-CH3), 54.40 (Py-OCH3), 82.64 (C-9), 116.45 (C-
2), 119.75 (C-4), 123.84 (C-6), 128.84 (C-5), 137.22 (C-3), 138.25
(C-1), 151.10 (CϭO), 156.82 (C-7), 171.24 (C-8, C-10) ppm.
N-(3-Chloro-4-methylphenyl)-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea
1
(2t): M.p. 244Ϫ246 °C. H NMR (400 MHz, [D6]DMSO, 23 °C):
δ ϭ 2.26 (s, 3 H, Ph-CH3), 3.94 (s, 6 H, Py-OCH3), 5.91 (s, 1 H,
9-H), 7.30 (d, J ϭ 6.0 Hz, 1 H, 5-H), 7.68 (d, J ϭ 6.0 Hz, 1 H, 6-
H), 8.80 (s, 1 H, 2-H), 10.06 (s, 1 H, PyNH), 11.11 (s, 1 H, PhNH)
ppm. 13C NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 18.82 (Ph-
CH3), 54.38 (Py-OCH3), 82.76 (C-9), 117.08 (C-6), 118.15 (C-2),
128.40 (C-4), 131.17 (C-5), 133.11 (C-3), 138.59 (C-1), 152.26 (Cϭ
O), 156.66 (C-7), 171.23 (C-8, C-10) ppm.
N-(4-Methylphenyl)-NЈ-(4,6-dimethoxy-2-pyrimidyl)urea (2d): M.p.
248Ϫ249 °C. 1H NMR (400 MHz, [D6]DMSO, 23 °C): δ ϭ 2.25
(s, 3 H, Ph-CH3), 3.94 (s, 6 H, Py-OCH3), 5.90 (s, 1 H, 9-H), 7.14
(d, J ϭ 8.0 Hz, 2 H, 3-H/5-H), 7.42 (d, J ϭ 8.0 Hz, 2 H, 2-H/6-H),
9.94 (s, 1 H, PyNH), 11.03 (s, 1 H, PhNH) ppm. 13C NMR
(400 MHz, [D6]DMSO, 23 °C): δ ϭ 20.40 (Ph-CH3), 54.38 (Py-
OCH3), 82.61 (C-9), 119.26 (C-2, C-6), 129.38 (C-3, C-5), 132.04
(C-4), 135.79 (C-1), 151.21 (CϭO), 156.91 (C-7), 171.22 (C-8, C-
10) ppm.
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Eur. J. Org. Chem. 2003, 3446Ϫ3452