Solvent-free synthesis of urea derivatives from primary amines and sulfur under carbon monoxide and oxygen at atmospheric pressure

Article abstract of DOI:10.1055/s-2007-990793

A solvent-free carbonylation and oxidation system aimed at green and sustainable chemistry was developed. With these reactions, an environmentally benign synthesis of urea derivatives could be carried out in good to excellent yields from primary amines and sulfur at ambient pressure of carbon monoxide and oxygen. For example, N,N′-dioctylurea was prepared in 99% yield from two equivalents octylamine and one equivalent sulfur in the presence of carbon monoxide (1 atm) at 80°C and oxygen (1 atm) at room temperature, in the complete absence of solvent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990793

PAPER
3135
Solvent-Free Synthesis of Urea Derivatives from Primary Amines and Sulfur
under Carbon Monoxide and Oxygen at Atmospheric Pressure
S
T
olvent-Free Sy
a
nthesis of
k
U
rea
D
erivat
ui ves mi Mizuno,* Masatoshi Mihara, Takeo Nakai, Toshiyuki Iwai, Takatoshi Ito
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638049; E-mail: tmizuno@omtri.city.osaka.jp
Received 28 June 2007; revised 31 July 2007
These reactions, however, need N,N-dimethylformamide
or dimethyl sulfoxide as an organic solvent and accelera-
tor of carbonylation of amines by carbon monoxide and
Abstract: A solvent-free carbonylation and oxidation system
aimed at green and sustainable chemistry was developed. With
these reactions, an environmentally benign synthesis of urea deriv-
atives could be carried out in good to excellent yields from primary sulfur. The increasing need for sustainable strategies in
amines and sulfur at ambient pressure of carbon monoxide and oxy- organic synthesis has led to a growing interest in reactions
gen. For example, N,N¢-dioctylurea was prepared in 99% yield from
two equivalents octylamine and one equivalent sulfur in the pres-
ence of carbon monoxide (1 atm) at 80 °C and oxygen (1 atm) at
room temperature, in the complete absence of solvent.
in the absence of solvent, and the use of water and other
nonclassical solvents (such as supercritical fluids and ion-
ic liquids). In our exploration of cleaner, green chemis-
7–9
try processes, we recently established a successful
synthesis of 1H-quinazoline-2,4-diones in excellent
yields when supercritical carbon dioxide was used as a re-
Key words: urea derivatives, carbon monoxide, oxygen, sulfur,
solvent-free
10
actant and a solvent or when carbon dioxide (1 atm) was
used as a reactant under solvent-free conditions.11 Herein
we report the full results of our research into an environ-
mentally friendly strategy for the synthesis of urea deriv-
atives from primary amines, carbon monoxide, sulfur, and
oxygen in the absence of solvent.
Urea derivative synthesis using carbon monoxide and sul-
1
–3
fur was first reported in 1961. The Monsanto group in-
troduced sulfur-assisted carbonylation of primary amines
by carbon monoxide to form urea derivatives. However,
this reaction requires high temperatures and pressurized
carbon monoxide.
First, the influence of reaction temperature and quantity of
amine on the carbonylation was examined; for this the
control reaction was that of octylamine (2a) leading to
N,N¢-dioctylurea (1a) (Scheme 1, Table 1). Initially, we
examined the synthesis of N,N¢-dioctylurea (1a) under
solvent-free conditions by the carbonylation of octyl-
amine (2a; 25 mmol, 1.25 equiv) with carbon monoxide
In our continuous study on the synthesis of urea deriva-
tives under milder reaction conditions, we first reported
the carbonylation of amines by carbon monoxide and sul-
fur, followed by oxidation by molecular oxygen to pro-
vide urea derivatives in good yields in tetrahydrofuran at
4
2
0 °C and 1 atm. But this carbonylation is sluggish, and
(
1 atm) at 20 °C, followed by oxidation with molecular
the preparative method requires long reaction times. Also,
its application to the synthesis of aromatic urea deriva-
tives has remained difficult.
oxygen (1 atm, r.t.). However, the carbonylation of 2a
proceeded slowly under slurry conditions, and 1a formed
in low yield (30%; Table 1, entry 1).
Recently, we reported on the solvent-assisted thiocarbox-
ylation of amines by carbon monoxide and sulfur to afford
S-alkyl thiocarbamates in good yields. In this reaction
system, the thiocarboxylation of amines by carbon mon-
oxide and sulfur was powerfully assisted by dimethyl sul-
foxide or N,N-dimethylformamide as a solvent under mild
conditions (1 atm, 20 °C). We explored a straightforward
synthetic method toward urea derivatives, including aro-
4
h
+
3
–
2
OctylNH2
+
1 S + CO
[OctylNH ] [OctylNHC(O)S]
5
1 atm, 80 °C
2
a
3a
O2, 1 h
(
OctylNH)2CO
1 atm, 20 °C
1
a, 99%
matic urea derivatives, by the carbonylation of amines Scheme 1 Solvent-free synthesis of N,N¢-dioctylurea (1a)
with carbon monoxide and sulfur followed by oxidation
with molecular oxygen in N,N-dimethylformamide or
Increasing the temperature of the carbonylation from 60 to
50 °C did have an effect on the yield of 1a (Table 1). At
temperatures between 80 and 120 °C (Table 1, entries 3,
, and 11), N,N¢-dioctylurea (1a) was obtained in good
yield (60–68%) from 1.25 equivalents of 2a. Use of an ex-
cess of octylamine (2a) resulted in remarkable improve-
ments in the yield of 1a, with 2.0 equivalents of
dimethyl sulfoxide under mild conditions (1 atm, 20 °C).
The corresponding urea derivatives were obtained by
these reactions from primary amines in good to excellent
1
8
6
yields under mild conditions.
SYNTHESIS 2007, No. 20, pp 3135–3140
x
x.
x
x
.
2
0
0
7
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990793; Art ID: F12307SS
Georg Thieme Verlag Stuttgart · New York
©

3
136
T. Mizuno et al.
PAPER
Table 1 Influence of Temperature (of Carbonylation Reaction) and
Quantity of Amine 2a on the Synthesis of Urea 1a
4 h
1
2
1
2
+
1
2
–
2
R R NH + 1 S + CO
[R R NH2] [R R NC(O)S]
a
1
atm, 80 °C
2
3
b
c
Entry
Temp (°C)
Quantity of 2a (equiv) Yield (%)
O2, 1 h
1
2
3
4
5
6
7
8
9
20
60
1.25
1.25
1.25
1.5
30
39
60
87
99
66c
56d
67
79
93
68
96
96
54
1 2
(
R R N)2CO
1
atm, 20 °C
1
80
Scheme 2 Synthesis of N,N¢-dialkylureas 1a–p from the correspon-
ding amines 2a–p
80
Table 2 Synthesis of Urea Derivatives 1a–p from Amines 2a–pa
80
2.0
Entry R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Pr
Amine 2 Urea 1 Yield (%)
80
1.0
80
1.0
1
2
pentyl
2b
2c
2d
2e
2f
1b
1c
1d
1e
1f
76
97
89
90
81
99
17
94
82
70
100
100
100
120
120
120
150
1.25
1.5
(CH ) OMe
2
3
3
hexyl
1
1
1
1
0
1
2
3
4
2.0
4
Cy
1.25
1.5
5
heptyl
6
octyl
2a
2g
2h
2i
1a
1g
1h
1i
2.0
7
1,1,3,3-tetramethylbutyl
1
1.25
8
decyl
Bn
a
Reagents and conditions: (i) S (321 mg, 10 mmol), CO (1 atm), 4 h
carbonylation); (ii) O (1 atm), 20 °C, 1 h (oxidation).
Temperature during the carbonylation reaction.
Isolated yield (of 1a).
Et N (1.0 equiv, 20 mmol) was added.
DBU (1.0 equiv, 20 mmol) was added.
9
(
2
b
10
11
PMB
Ph
2j
1j
c
c
d
0, 10b
2k
2l
1k
1l
3
1
1
1
1
2
3
4
5
6
PMP
4-i-PrC H
30b
22b
2m
2n
2o
2p
1m
1n
1o
1p
6
4
octylamine (2a) giving 1a in almost quantitative yield
Table 1, entries 5, 10, and 13).
3-O NC H
4
0b,c
2
6
(
Pr
(CH2)5
0
0
In this solvent-free reaction system, octylamine (2a, 40
mmol, 2.0 equiv) readily reacted with carbon monoxide (1
atm) and sulfur (10 mmol, 1.0 equiv) at 80 °C within four
hours in the absence of solvent (Scheme 1; Table 1, entry
1
a
Reagents and conditions: (i) amine 2 (40 mmol), S (321 mg, 10
mmol), CO (1 atm), 80 °C, 4 h (carbonylation); (ii) O (1 atm), 20 °C,
2
5
). This resulted in the color of the solution, now includ-
ing the N-octylammonium salt of N-octylthiocarbamate
3a), changing from reddish black to pale yellow. The re-
1
h (oxidation).
b
Modified conditions: amine 2 (30 mmol), DBU (1.50 mL, 10 mmol).
The carbonylation was carried out at 120 °C.
(
c
sulting solution was oxidized by molecular oxygen under
ambient pressure at 20 °C within one hour. Finally, N,N¢-
dioctylurea (1a) was obtained as a pure white solid in 99%
yield, based on sulfur (Scheme 1; Table 1, entry 5).
at 80 °C for four hours, followed by oxidation with oxy-
gen (1 atm) at 20 °C for one hour (Scheme 2; Table 2).
Primary amines 2a–f and 2h–j were suitable reagents for
this synthetic method, and provided the corresponding
N,N¢-dialkylureas 1a–f and 1h–j in good to excellent
yields under solvent-free conditions (Table 2, entries 1–6
and 8–10). However, N,N¢-bis(1,1,3,3-tetramethylbu-
tyl)urea (1g) was obtained in a low yield (17%), because
of the bulkiness of (1,1,3,3-tetramethylbutyl)amine (2g)
Next, the effect of the addition of tertiary amines (20
mmol, 1.0 equiv) to the reaction with 1.0 equivalent (20
mmol) of octylamine (2a) was tested. The addition of tri-
ethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene had no
effect, with the yield of N,N¢-dioctylurea (1a) remaining
at 66% and 56% respectively (Table 1, entries 6 and 7).
Therefore, an excess of primary amine 2a is necessary for
the synthesis of urea 1a in quantitative yield.
(
Table 2, entry 7). N,N¢-Diphenylureas 1k–m were ob-
tained in low yields from aromatic amines 2k–m in the
To demonstrate the efficiency and scope of the solvent- presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (Table 2,
free synthetic method, we investigated the preparation of entries 11–13), but in the absence of 1,8-diazabicy-
a variety of urea derivatives 1a–p from the corresponding clo[5.4.0]undec-7-ene, there was no formation of 1k
amines 2a–p (2.0 equiv) under carbon monoxide (1 atm) (Table 2, entry 11). The low yields of N,N¢-diphenylureas
Synthesis 2007, No. 20, 3135–3140 © Thieme Stuttgart · New York

PAPER
k–n (Table 2, entries 11–14) are the consequence of the
basicity of anilines 2k–n. 3-Nitroaniline (2n), with an
electron-withdrawing group on the ring, formed no N,N¢-
bis(3-nitrophenyl)urea (1n) under these conditions
Solvent-Free Synthesis of Urea Derivatives
3137
– [RNH3] [HS]–
+
6
1
+
[
RNH3] [RNHC(O)S]–
R-N=C=O
3
7
RNH2
(
Table 2, entry 14).
(RNH)2C=O
We also examined the reactions of secondary amines 2o
and 2p under these conditions, but urea derivatives 1o and
1
1
p did not form (Table 2, entries 15 and 16). Under simi-
O2
+
[
RNH3] [HS]–
RNH2
+
H2O
+
S
lar solvent-free conditions, S-methyl N,N-dialkylthiocar-
bamates 4o and 4p were obtained in moderate yields (43
and 53%, respectively) by esterification of N,N-dialkyl-
thiocarbamate salts 3o and 3p with methyl iodide
6
Scheme 5 Proposed pathway for the synthesis of urea derivatives 1
by oxidation of thiocarbamates 3
(
Scheme 3). Therefore, 3o and 3p could not be oxidized
with oxygen.
At the reaction stage where amines 2 are carbonylated,
elemental sulfur undergoes S–S bond fission by the reac-
tion with amines 2, and ammonium salts of thiolate anions
5 form (Scheme 4). The reaction of thiolate anions 5 with
carbon monoxide gives the carbonylated species. Through
an intramolecular rearrangement of the carbonylated spe-
cies (Scheme 4, path A) or elimination of carbonyl sulfide
from the carbonylated species (path B), ammonium salts
of thiocarbamates 3 are generated. This reaction proceeds
at high temperature under liquid conditions.
4
h
1
2
1
2
+
1
2
–
2
R R NH
+
CO + S
[R R NH2] [R R NC(O)S]
1
atm, 80 °C
2
3
MeI, 1 h
atm, 20 °C
1
2
R R NC(O)SMe
1
1
2
R , R = Pr, Pr : 4o, 43%
R , R = -(CH2)5- : 4p, 53%
1
2
The ammonium salts of thiocarbamates 3 thus formed are
then converted into urea derivatives 1, via isocyanate in-
termediates 7, and ammonium hydrogensulfide salts 6
Scheme 3 Synthesis of thiocarbamates 4o and 4p
Possible pathways for this synthesis of urea derivatives 1
from amines 2 by carbonylation followed by oxidation are
shown in Schemes 4 and 5. For the carbonylation step
(
Scheme 5). Therefore, excess amounts of amines 2 (>1.5
equiv) are needed for the quantitative synthesis of ureas 1.
The ammonium hydrogensulfide salts 6 forming from 3
are oxidized by molecular oxygen, and thus sulfur and
amines 2 are recovered with water (Scheme 5). The reac-
tion path via isocyanates 7 is supported by the attempted
reactions of secondary amines 2o and 2p, which did not
form the corresponding ureas 1o and 1p, because oxida-
tion of the corresponding thiocarbamate salts 3o and 3p
did not proceed.13
(
Scheme 4), on the basis of our finding that salts of thi-
olates 5 readily react with carbon monoxide to form salts
1
2
of thiocarbamates 3, we suggest a plausible pathway via
thiolate anions 5 for this solvent-free carbonylation of
amines 2 in the presence of carbon monoxide and sulfur.
path A
–
–
O
C
O
+
+
– Sx
An environmentally benign method for the synthesis of
urea derivatives 1 in good to excellent yields under ambi-
ent pressure has been developed. It includes the solvent-
free carbonylation of amines 2 with carbon monoxide and
sulfur, and the oxidation of the resulting ammonium salts
of hydrogensulfide 6 with molecular oxygen. This syn-
thetic method of 1 is very significant in terms of green and
sustainable chemistry, proceeding without organic sol-
vent, under atmospheric pressure, and requiring easily
available and inexpensive carbon monoxide, oxygen, and
sulfur.
RNH3
RNH3
RNHCSx-S
Sx
RNH-S
+
[
RNH3] [RNHC(O)S]–
3
path B
–
O
-–
+
+
RNH3
RNH-Sx-1-S-S-C
RNH3
RNH-Sx + S=C=O
Melting points were determined on a Mettler FP 5 instrument and
are uncorrected. FT-IR spectra were recorded on a JASCO FT/IR-
–
Sx
+
–
[
RNH3] [RNHC(O)S]
1
13
4
100 instrument. H (300 MHz) and C NMR (75 MHz) spectra
3
were obtained on a JEOL JNM-AL300 instrument. Chemical shifts
d are reported in ppm relative to TMS. Both low- and high-resolu-
tion mass spectra were measured on a JEOL JMS-600 spectrometer.
Amines 2a–p, Et N, DBU, sulfur (99.5%), CO (99.9%), and O
Scheme 4 Proposed pathway for the synthesis of thiocarbamates 3
by carbonylation of amines 2
3
2
(99.9%) were used as purchased.
Synthesis 2007, No. 20, 3135–3140 © Thieme Stuttgart · New York

3
138
T. Mizuno et al.
PAPER
1
N,N¢-Dioctylurea (1a); Typical Procedure
H NMR (300 MHz, CDCl ): d = 0.88 (t, J = 6.6 Hz, 6 H, 2 × CH ),
3
3
Octylamine (2a; 6.63 mL, 40 mmol) and powdered sulfur (321 mg,
1.26–1.34 (m, 12 H, 6 × CH ), 1.44–1.50 (m, 4 H, 2 × CH ), 3.14 (q,
2
2
1
0 mmol) were placed in a 100-mL flask under an argon atmo-
J = 6.6 Hz, 4 H, 2 × CH ), 4.43 (br s, 2 H, 2 × NH).
2
sphere. The flask was charged with an ambient pressure of CO, and
vigorously stirred under CO from a balloon (1 atm) at 80 °C for 4 h.
The color of the soln then changed from reddish black to pale yel-
13
C NMR (75 MHz, CDCl ): d = 14.0, 22.6, 26.6, 30.2, 31.5, 40.6,
3
1
58.4.
+
MS (EI, 70 eV): m/z (%) = 228 (100) [M ], 199 (45), 185 (51), 158
(
low. The flask was purged of CO, and charged with O (1 atm) at
2
33).
2
0 °C (slightly exothermic reaction). The reaction mixture was
stirred under O from a balloon (1 atm) for another 1 h at 20 °C. The
2
HRMS (EI, 70 eV): m/z calcd for C H ON : 228.2202; found:
1
3
28
2
resulting pale yellow solid was then poured into 1 M HCl (200 mL),
and the deposited white solid was washed with toluene (100 mL)
and MTBE (100 mL); this gave pure 1a.
2
28.2198.
N,N¢-Dicyclohexylurea (1e)
Compound 1e was purified by washing with toluene.
2
Yield: 2.816 g (99%); mp 91.0 °C (Lit. 89–90 °C).
2
–
1
Yield: 2.006 g (90%); mp 231.7 °C (Lit. 229–230 °C).
IR (KBr): 3334, 2956, 2925, 2850, 1615, 1579, 1478, 1463 cm .
–
1
1
IR (KBr): 3327, 2928, 2850, 1627, 1576, 1311, 1244, 1089 cm .
H NMR (300 MHz, DMSO-d , 50 °C): d = 0.86 (t, J = 6.6 Hz, 6 H,
6
2
2
× CH ), 1.25–1.36 (m, 24 H, 12 × CH ), 2.95 (t, J = 6.4 Hz, 4 H,
1
3
2
H NMR (300 MHz, DMSO-d ): d = 0.97–1.31 (m, 10 H, 5 × CH ),
1.48–1.72 (m, 10 H, 5 × CH ), 3.27–3.36 (m, 2 H, 2 × CH), 5.55 (br
6
2
× CH ), 5.61 (t, J = 5.4 Hz, 2 H, 2 × NH).
2
2
1
3
s, 2 H, 2 × NH).
C NMR (75 MHz, DMSO-d , 50 °C): d = 13.6, 21.8, 26.1, 28.4,
6
2
8.5, 29.8, 31.0, 39.0, 157.9.
13
C NMR (75 MHz, DMSO-d ): d = 24.4, 25.3, 33.3, 47.5, 156.6.
6
+
MS (EI, 70 eV): m/z (%) = 284 (100) [M ], 241 (25), 227 (35), 213
(
+
MS (EI, 70 eV): m/z (%) = 224 (80) [M ], 143 (46), 99 (65), 56
33), 186 (23), 57 (25).
(
100).
HRMS (EI, 70 eV): m/z calcd for C H ON : 284.2828; found:
1
7
36
2
HRMS (EI, 70 eV): m/z calcd for C H ON : 224.1889; found:
1
3
24
2
2
84.2816.
2
24.1886.
N,N¢-Dipentylurea (1b)
N,N¢-Diheptylurea (1f)
Compound 1b was purified by short-column chromatography (sili-
Compound 1f was purified by recrystallization from MeOH.
ca gel, EtOAc).
Yield: 1.517 g (76%); mp 85.6 °C (Lit.14 88 °C).
6
Yield: 2.075 g (81%); mp 88.7 °C (Lit. 91.2 °C).
–
1
IR (KBr): 3335, 2955, 2928, 2854, 1617, 1578, 1478, 1465 cm .
–
1
IR (KBr): 3336, 2955, 2932, 2861, 1623, 1579 cm .
1
H NMR (300 MHz, DMSO-d , 50 °C): d = 0.86 (t, J = 6.8 Hz, 6 H,
6
1
H NMR (300 MHz, DMSO-d ): d = 0.85 (t, J = 6.9 Hz, 6 H, 2 ×
3
6
2 × CH ), 1.25–1.39 (m, 20 H, 10 × CH ), 2.95 (t, J = 6.6 Hz, 4 H,
3
2
CH ), 1.17–1.38 (m, 12 H, 6 × CH ), 2.93 (q, J = 6.5 Hz, 4 H, 2 ×
2
2 × CH ), 5.58 (br s, 2 H, 2 × NH).
2
CH ), 5.68 (t, J = 5.6 Hz, 2 H, 2 × NH).
2
13
C NMR (75 MHz, DMSO-d , 50 °C): d = 13.6, 21.7, 26.1, 28.2,
6
1
3
C NMR (75 MHz, DMSO-d ): d = 13.9, 21.8, 28.6, 29.7, 39.1,
6
29.8, 31.0, 39.0, 157.9.
1
58.0.
+
MS (EI, 70 eV): m/z (%) = 256 (100) [M ], 213 (45), 199 (39), 172
+
MS (EI, 70 eV): m/z (%) = 200 (100) [M ], 171 (46), 144 (24), 101
(
29).
(
16).
HRMS (EI, 70 eV): m/z calcd for C H ON : 256.2515; found:
256.2518.
1
5
32
2
HRMS (EI, 70 eV): m/z calcd for C H ON : 200.1889; found:
1
1
24
2
2
00.1879.
Anal. Calcd for C H ON : C, 70.26; H, 12.58; N, 10.92. Found: C,
1
5
32
2
7
0.34; H, 12.65, N, 11.08.
N,N¢-Bis(3-methoxypropyl)urea (1c)
Compound 1c was purified by recrystallization from hexane.
N,N¢-Bis(1,1,3,3-tetramethylbutyl)urea (1g)
Compound 1g was purified by short-column chromatography (sili-
ca gel, EtOAc).
2
Yield: 1.983 g (97%); mp 52.5 °C (Lit. 47–49 °C).
–
1
IR (KBr): 3366, 2930, 2874, 1639, 1571, 1120 cm .
2
1
Yield: 487 mg (17%); mp 149.0 °C (Lit. 145–147 °C).
IR (KBr): 3368, 2957, 1637, 1555, 1363, 1282 cm–1.
H NMR (300 MHz, DMSO-d ): d = 1.57 (quin, J = 6.5 Hz, 4 H, 2
6
×
3
CH ), 2.99 (q, J = 6.5 Hz, 4 H, 2 × CH ), 3.20 (s, 6 H, 2 × CH ),
2
2
3
.30 (t, J = 6.5 Hz, 4 H, 2 × CH ), 5.77 (t, J = 5.6 Hz, 2 H, 2 × NH).
2
1
H NMR (300 MHz, DMSO-d ): d = 0.94 (s, 18 H, 6 × CH ), 1.21
6
3
1
3
C NMR (75 MHz, DMSO-d ): d = 30.0, 36.5, 57.8, 69.7, 158.0.
6
(s, 12 H, 4 × CH ), 1.62 (s, 4 H, 2 × CH ), 5.32 (br s, 2 H, 2 × NH).
13
3
2
+
MS (EI, 70 eV): m/z (%) = 204 (36) [M ], 189 (100), 90 (38), 88
C NMR (75 MHz, DMSO-d ): d = 30.0, 31.1, 31.3, 51.0, 52.4,
6
(
39).
1
56.5.
MS (EI, 70 eV): m/z (%) = 284 (1) [M ], 213 (49), 114 (42), 58
100), 57 (83).
HRMS (EI, 70 eV): m/z calcd for C H ON : 284.2828; found:
HRMS (EI, 70 eV): m/z calcd for C H O N : 204.1474; found:
+
9
20
3
2
2
04.1471.
(
1
7
36
2
N,N¢-Dihexylurea (1d)
Compound 1d was purified by short-column chromatography (sili-
2
84.2831.
ca gel, EtOAc).
N,N¢-Didecylurea (1h)
Compound 1h was purified by washing with toluene and MTBE.
2
Yield: 2.031 g (89%); mp 76.1 °C (Lit. 73–74 °C).
IR (KBr): 3332, 2957, 2931, 2856, 1617, 1577, 1478, 1462, 1251,
2
Yield: 3.185 g (94%); mp 96.8 °C (Lit. 99–100 °C).
–
1
1
222 cm .
–
1
IR (KBr): 3336, 2956, 2924, 2849, 1612, 1578, 1476, 1466 cm .
Synthesis 2007, No. 20, 3135–3140 © Thieme Stuttgart · New York

PAPER
Solvent-Free Synthesis of Urea Derivatives
3139
1
13
H NMR (300 MHz, DMSO-d , 100 °C): d = 0.87 (t, J = 6.8 Hz, 6
C NMR (75 MHz, DMSO-d ): d = 55.1, 113.9, 119.7, 133.0,
6
6
H, 2 × CH ), 1.27–1.42 (m, 32 H, 16 × CH ), 2.98 (t, J = 6.8 Hz, 4
152.9, 154.2.
3
2
H, 2 × CH ), 4.78 (br s, 2 H, 2 × NH).
+
2
MS (EI, 70 eV): m/z (%) = 272 (29) [M ], 123 (58), 122 (100), 108
(62), 80 (32), 69 (39).
1
3
C NMR (75 MHz, DMSO-d , 100 °C): d = 13.1, 21.4, 25.8, 28.0,
6
2
8.2, 28.3, 28.4, 29.5, 30.6, 38.9, 157.7.
HRMS (EI, 70 eV): m/z calcd for C H O N : 272.1161; found:
272.1154.
1
5
16
3
2
+
MS (EI, 70 eV): m/z (%) = 340 (100) [M ], 297 (24), 283 (18), 255
30), 241 (28), 214 (19).
(
N,N¢-Bis(4-isopropylphenyl)urea (1m)
HRMS (EI, 70 eV): m/z calcd for C H ON : 340.3454; found:
2
1
44
2
Compound 1m was purified by recrystallization from MeOH.
3
40.3431.
6
Yield: 642 mg (22%); mp 239.8 °C (Lit. 238.4 °C).
N,N¢-Dibenzylurea (1i)
IR (KBr): 3314, 2959, 1648, 1598, 1553, 1514, 1309, 1235 cm–1.
Compound 1i was purified by washing with toluene.
1
H NMR (300 MHz, DMSO-d ): d = 1.17 (d, J = 6.9 Hz, 12 H, 4 ×
3
2
6
Yield: 1.978 g (82%); mp 169.4 °C (Lit. 169–171 °C).
CH ), 2.77–2.83 (m, 2 H, 2 × CH), 7.12 (d, J = 8.7 Hz, 4 H, 4 × CH),
–
1
IR (KBr): 3323, 3031, 1628, 1573, 1453, 1248, 696 cm .
7.34 (d, J = 8.7 Hz, 4 H, 4 × CH), 8.57 (s, 2 H, 2 × NH).
1
13
H NMR (300 MHz, DMSO-d ): d = 4.23 (s, 4 H, 2 × CH ), 6.43 (br
C NMR (75 MHz, DMSO-d ): d = 24.0, 32.7, 118.2, 126.4, 137.5,
6
2
6
s, 2 H, 2 × NH), 7.18–7.33 (m, 10 H, 10 × CH).
1
141.6, 152.6.
3
+
C NMR (75 MHz, DMSO-d ): d = 42.9, 126.5, 126.9, 128.1,
MS (EI, 70 eV): m/z (%) = 296 (30) [M ], 135 (26), 120 (100), 91
6
1
40.8, 158.0.
(30).
+
MS (EI, 70 eV): m/z (%) = 240 (82) [M ], 149 (31), 106 (100), 91
63).
HRMS (EI, 70 eV): m/z calcd for C H ON : 296.1889; found:
296.1886.
1
9
24
2
(
HRMS (EI, 70 eV): m/z calcd for C H ON : 240.1263; found:
Anal. Calcd for C H ON : C, 76.99; H, 8.16; N, 9.45. Found: C,
19 24 2
1
5
16
2
2
40.1259.
76.70; H, 8.09, N, 9.55.
N,N¢-Bis(4-methoxybenzyl)urea (1j)
S-Methyl N,N-Dipropylthiocarbamate (4o)
Compound 4o was purified by short-column chromatography (sili-
ca gel, EtOAc).
Yield: 761 mg (43%); oil.5,16
Compound 1j was purified by washing with toluene and MTBE.
2
Yield: 2.087 g (70%); mp 173.8 °C (Lit. 176–177 °C).
IR (KBr): 3353, 3320, 2955, 2925, 2837, 1626, 1580, 1513, 1248
–
1
IR (neat): 2964, 2931, 2875, 1650, 1406, 1222, 1123 cm–1.
cm .
1
1
H NMR (300 MHz, DMSO-d ): d = 3.71 (s, 6 H, 2 × CH ), 4.14 (d,
H NMR (300 MHz, CDCl ): d = 0.90 (t, J = 7.4 Hz, 6 H, 2 × CH ),
6
3
3
3
J = 5.7 Hz, 4 H, 2 × CH ), 6.28 (t, J = 5.7 Hz, 2 H, 2 × NH), 6.86 (d,
1.57–1.65 (m, 4 H, 2 × CH ), 2.32 (s, 3 H, CH ), 3.28 (br s, 4 H, 2
× CH ).
13
2
2
3
J = 8.7 Hz, 4 H, 4 × CH), 7.16 (d, J = 8.7 Hz, 4 H, 4 × CH).
2
1
3
C NMR (75 MHz, DMSO-d ): d = 42.4, 55.0, 113.6, 128.3, 132.7,
C NMR (75 MHz, CDCl ): d = 11.2, 12.9, 21.4, 49.5, 168.2.
6
3
1
57.9, 158.0.
+
MS (EI, 70 eV): m/z (%) = 175 (100) [M ], 128 (89), 86 (79), 75
(65).
+
MS (EI, 70 eV): m/z (%) = 300 (13) [M ], 179 (16), 136 (46), 121
(100), 78 (27), 77 (27).
HRMS (EI, 70 eV): m/z calcd for C H ONS: 175.1031; found:
8
17
HRMS (EI, 70 eV): m/z calcd for C H O N : 300.1474; found:
175.1012.
1
7
20
3
2
3
00.1485.
S-Methyl Piperidinecarbothioate (4p)
Compound 4p was purified by short-column chromatography (sili-
ca gel, EtOAc).
N,N¢-Diphenylurea (1k)
Compound 1k was purified by washing with toluene.
Yield: 203 mg (10%); mp 241.0 °C (Lit.15 241–242 °C).
Yield: 838 mg (53%); oil.5,16
–
1
IR (neat): 2935, 2855, 1650, 1412, 1250, 1209 cm–1.
IR (KBr): 3327, 1649, 1595, 1556, 1233, 754, 698 cm .
1
1
H NMR (300 MHz, DMSO-d ): d = 6.95 (t, J = 7.6 Hz, 2 H, 2 ×
H NMR (300 MHz, CDCl ): d = 1.56–1.64 (m, 6 H, 3 × CH ), 2.32
6
3
2
CH), 7.26 (t, J = 7.6 Hz, 4 H, 4 × CH), 7.44 (d, J = 7.6 Hz, 4 H, 4 ×
(s, 3 H, CH ), 3.48 (br s, 4 H, 2 × CH ).
13
3
2
CH), 8.70 (s, 2 H, 2 × NH).
C NMR (75 MHz, CDCl ): d = 12.8, 24.5, 25.6, 45.8, 167.2.
3
1
3
C NMR (75 MHz, DMSO-d ): d = 118.1, 121.7, 128.7, 139.7,
+
6
MS (EI, 70 eV): m/z (%) = 159 (56) [M ], 112 (100), 75 (18), 69
(
1
52.5.
72), 56 (13).
+
MS (EI, 70 eV): m/z (%) = 212 (36) [M ], 119 (12), 93 (100).
HRMS (EI, 70 eV): m/z calcd for C H ONS: 159.0718; found:
7
13
HRMS (EI, 70 eV): m/z calcd for C H ON : 212.0950; found:
159.0704.
1
3
12
2
2
12.0903.
References
N,N¢-Bis(4-methoxyphenyl)urea (1l)
Compound 1l was purified by washing with toluene and MTBE.
(
1) Franz, R. A.; Applegath, F. J. Org. Chem. 1961, 26, 3304.
3
Yield: 0.819 g (30%); mp 232.4 °C (Lit. 232–234 °C).
(2) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. J.
Org. Chem. 1961, 26, 3306.
–
1
IR (KBr): 3303, 1633, 1608, 1560, 1511, 1246, 827 cm .
(
3) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.;
Bolze, C. J. Org. Chem. 1961, 26, 3309.
1
H NMR (300 MHz, DMSO-d ): d = 3.70 (s, 6 H, 2 × CH ), 6.84 (d,
6
3
J = 9.0 Hz, 4 H, 4 × CH), 7.33 (d, J = 9.0 Hz, 4 H, 4 × CH), 8.53 (br
s, 2 H, 2 × NH).
(
4) Mizuno, T.; Matsumoto, M.; Nishiguchi, I.; Hirashima, T.
Heteroat. Chem. 1993, 4, 455.
Synthesis 2007, No. 20, 3135–3140 © Thieme Stuttgart · New York

3
140
T. Mizuno et al.
PAPER
(
(
5) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron 2005, 61, 9157.
6) Mizuno, T.; Mihara, M.; Iwai, T.; Ito, T.; Ishino, Y.
Synthesis 2006, 2825.
7) Hailes, H. C. Org. Process Res. Dev. 2007, 11, 114.
8) Rayner, C. M. Org. Process Res. Dev. 2007, 11, 121.
9) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios,
J. C. Angew. Chem. Int. Ed. 2006, 45, 3904.
(12) Mizuno, T.; Daigaku, T.; Nishiguchi, I. Tetrahedron Lett.
1995, 36, 1533.
(13) In the previous report on urea synthesis from primary amines
and carbon monoxide in the presence of a selenium catalyst,
the same reaction pathway was suggested: Sonoda, N. Pure
Appl. Chem. 1993, 65, 699.
(14) Farlow, M. W.; Adkins, H. J. Am. Chem. Soc. 1935, 57,
2222.
(15) Boivin, P. A.; Bridgeo, W.; Boivin, J. L. Can. J. Chem. 1954,
32, 242.
(
(
(
(
(
10) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron Lett. 2004, 45,
073.
11) Mizuno, T.; Mihara, M.; Nakai, T.; Iwai, T.; Ito, T. Synthesis
007, 2524.
7
2
(16) Mizuno, T.; Takahashi, J.; Ogawa, A. Tetrahedron 2003, 59,
1327.
Synthesis 2007, No. 20, 3135–3140 © Thieme Stuttgart · New York