Practical synthesis of urea derivatives from primary amines, carbon monoxide, sulfur, and oxygen under mild conditions

Article abstract of DOI:10.1055/s-2006-942491

A new and facile synthetic method for urea derivatives was developed under mild conditions, and contrasts with conventional preparation methods that need highly toxic reagents (phosgene) or severe reaction conditions. In our reaction system, N,N-dimethylformamide or dimethyl sulfoxide as solvent strongly accelerated the carbonylation of primary amines with sulfur under carbon monoxide (1 atm) at 20 °C to give the corresponding thiocarbamate salts. These salts were readily oxidized by molecular oxygen under similarly mild conditions to afford urea derivatives in good to excellent yields. This urea synthesis could also be applied to a new synthesis of aromatic ureas by use of 1,8-diazabicyclo[5.4.0]undec-7-ene in N,N-dimethylformamide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942491

PAPER
2825
Practical Synthesis of Urea Derivatives from Primary Amines, Carbon
Monoxide, Sulfur, and Oxygen under Mild Conditions
Synthesis of
Ur
a
ea
D
erivati
k
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 16 March 2006; revised 1 May 2006
give urea derivatives 1.21–23 However, this reaction re-
quires high temperatures and pressurized carbon monox-
ide. Also, in 1971, Sonoda et al. found that selenium
exhibits excellent catalytic activity toward the carbonyla-
Abstract: A new and facile synthetic method for urea derivatives
was developed under mild conditions, and contrasts with conven-
tional preparation methods that need highly toxic reagents (phos-
gene) or severe reaction conditions. In our reaction system, N,N-
dimethylformamide or dimethyl sulfoxide as solvent strongly accel- tion of amines by carbon monoxide.24,25 The selenium-
erated the carbonylation of primary amines with sulfur under carbon
monoxide (1 atm) at 20 °C to give the corresponding thiocarbamate
catalyzed carbonylation of amines 2 and oxidation of am-
monium salts of selenocarbamates are performed under
salts. These salts were readily oxidized by molecular oxygen under
mild conditions (1 atm, r.t.) to give urea derivatives 1 in
similarly mild conditions to afford urea derivatives in good to excel-
good yields. However, the toxicity of selenium com-
lent yields. This urea synthesis could also be applied to a new syn-
thesis of aromatic ureas by use of 1,8-diazabicyclo[5.4.0]undec-7-
ene in N,N-dimethylformamide.
pounds has considerably limited the use of this prepara-
tive method for large-scale production of ureas 1.
Key words: amines, amides, sulfur, carbonylations, oxidations
In 1993, we published a preliminary report on the carbon-
ylation of amines 2 in tetrahydrofuran by carbon monox-
ide and sulfur, followed by oxidation using molecular
oxygen to provide urea derivatives 1 in good yields and
under mild conditions (1 atm, 20 °C).26 However, this car-
bonylation was sluggish and long reaction times were nec-
essary. Also, the method was difficult to apply to the
synthesis of aromatic urea derivatives. Very recently, we
reported the solvent-assisted thiocarboxylation of amines
2 by carbon monoxide and sulfur, to afford S-alkyl thio-
carbamates in good yields.27 In this reaction system, the
thiocarboxylation of amines 2 by carbon monoxide and
sulfur under mild conditions (1 atm, 20 °C) was consider-
ably assisted by the use of dimethyl sulfoxide or N,N-di-
methylformamide as solvent.
Urea derivatives 1 (Schemes 1 and 2) are important mate-
rials as fertilizers, agricultural chemicals, medicines, and
polar solvents. Therefore, a variety of synthetic methods
for 1 have been developed, based on the carbonylation of
amines 2. For example, a general synthetic method for the
preparation of urea derivatives 1 includes the carbonyla-
tion of amines 2 with toxic phosgene as the carbonyl
source.1–3 Because of the toxicity of phosgene, the much
safer diphosgene,4 triphosgene,5 and 1,1¢-carbonyl-
diimidazole6,7 have also been used in its place. Urea has
also been recognized as a carbonyl source for the synthe-
sis of 1,8,9 but then the synthesis of urea derivatives 1 from
amines 2 and urea needs to be carried out at high temper-
atures. Carbonates have been similarly effective for the
preparation of urea derivatives 1 from amines 2.10,11 The
industrial method for the production of urea consists of
the reaction of ammonia with carbon dioxide under severe
reaction conditions.12 N,N¢-Dicyclohexylcarbodiimide,13
1,8-diazabicyclo[5.4.0]undec-7-ene,14 and transition-met-
al catalysts15,16 have also been used for the synthesis of
urea derivatives 1 from carbon dioxide. Urea derivatives
1 have also been prepared from the reactions of amines 2
with carbonyl sulfide.17
Therefore, our objective has been to develop a straightfor-
ward synthetic method for urea derivatives 1, including
aromatic urea derivatives, by the carbonylation of amines
2 by carbon monoxide and sulfur, followed by oxidation
with molecular oxygen, under mild conditions (1 atm,
20 °C) in N,N-dimethylformamide or dimethyl sulfoxide.
We here report the full results of the synthesis of urea de-
rivatives 1 from amines 2, carbon monoxide, sulfur, and
oxygen by use of solvent-accelerated carbonylation under
mild conditions (1 atm, 20 °C).
Our investigation into employing N,N-dimethylform-
amide as a solvent led to the successful synthesis of urea
derivative 1a by the carbonylation of cyclohexylamine
(2a) with carbon monoxide and sulfur, followed by oxida-
tion of the intermediate salt 3a by molecular oxygen
(Scheme 1). Cyclohexylamine (2a) readily reacted with
carbon monoxide (1 atm) and sulfur (1.0 equiv) at 20 °C
for four hours in N,N-dimethylformamide as solvent. The
reaction mixture changed from a reddish-black solution to
a pale-green emulsion, and the resulting thiocarbamate
salt 3a in N,N-dimethylformamide solution was oxidized
Carbon monoxide has been a useful raw material for the
preparation of ureas 1 from amines 2. Various urea deriv-
atives 1 have been prepared from amines 2 and carbon
monoxide in the presence of transition-metal catalysts.18–20
In 1961, the Monsanto group introduced sulfur-assisted
carbonylation of primary amines 2 by carbon monoxide to
SYNTHESIS 2006, No. 17, pp 2825–2830
x
x.
x
x
.
2
0
0
6
Advanced online publication: 13.07.2006
DOI: 10.1055/s-2006-942491; Art ID: F04506SS
© Georg Thieme Verlag Stuttgart · New York

2826
T. Mizuno et al.
PAPER
by molecular oxygen under ambient pressure at 20 °C for To demonstrate the efficiency and scope of this method,
one hour. Finally, N,N¢-dicyclohexylurea (1a) was ob- the preparation of a variety of urea derivatives 1a–o from
tained as a pure white solid in 88% yield based on sulfur the corresponding amines 2a–o was investigated at 1 atm,
(Scheme 1; Table 1, entry 1).
20 °C, and for five hours in N,N-dimethylformamide
(Scheme 2, Table 2).
DMF
+
+
S
[c-HexNH3]+[c-HexNHC(O)S]–
2 c-HexNH2
CO
DMF
4 h
+
+
[R1R2NH2]+[R1R2NC(O)S]–
2 R1R2NH
CO
1 atm, 20 °C
S
1 atm, 20 °C
2a
3a
4 h
2
3
O2
(c-HexNH)2CO
O2
1 h
(R1R2N)2CO
1a, 88%
1 h
1
Scheme 1 Synthesis of N,N¢-dicyclohexylurea
Scheme 2 Synthesis of N,N¢-dialkylureas from the corresponding
amines and carbon monoxide in N,N-dimethylformamide
To examine the influence of solvent and reaction time on
this method for the preparation of N,N¢-dicyclohexylurea
(1a), several control reactions were performed (Table 1).
When dimethyl sulfoxide was employed as the solvent, a
similar solvent effect was found after five hours of reac-
tion to give urea 1a in good yields (82%) (Table 1, entry
4). Shorter reaction times for carbonylation lowered the
yields of N,N¢-dicyclohexylurea (1a) in both N,N-dimeth-
ylformamide and dimethyl sulfoxide (Table 1, entries 2
and 5). Even when N,N¢-dicyclohexylurea (1a) was syn-
thesized on a tenfold scale, it was obtained in considerably
good yield after a longer reaction time (27 h) (Table 1, en-
try 3). In contrast, the yield of urea 1a was lower after four
hours of reaction in tetrahydrofuran (Table 1, entry 6). A
longer reaction time (Table 1, entry 7) gave urea 1a in a
yield similar to that obtained in N,N-dimethylformamide
(Table 1, entry 1). Therefore, we believe that the solvent
is a predominant factor in this urea-derivative synthesis by
the carbonylation of amines 2 with carbon monoxide and
sulfur followed by oxidation in molecular oxygen.
Primary amines 2a–c and 2e–i were suitable for this urea-
derivative synthesis, providing N,N¢-dialkylureas 1a–c
and 1e–i in good to excellent yields under mild conditions
(1 atm, 20 °C) (Table 2, entries 1–3, 5–9). N,N¢-Di-tert-
butylurea (1d) was obtained in moderate yield (59%) de-
spite the bulkiness of the tert-butyl group (Table 2, entry
4). Also, N,N¢-diphenylureas 1j–l were successfully pre-
pared in moderate to good yields from aromatic amines
2j–l in the presence of 1,8-diazabicyclo[5.4.0]undec-7-
ene (Table 2, entries 10–12). The yields of N,N¢-diphenyl-
ureas 1j–m were strongly affected by the basicity of
anilines 2j–m. 4-Methoxyaniline (2k), a basic aniline
with an electron-donating group, gave urea 1k in good
yield (Table 2, entry 11). But 3-nitroaniline (2m), with an
electron-withdrawing group, did not form N,N¢-di(3-nitro-
phenyl)urea (1m) (Table 2, entry 13). We also examined
the synthesis of urea derivatives 1n and 1o from second-
ary amines 2n and 2o (Table 2, entries 14 and 15). Ureas
1n and 1o did not form by this method. Under similar re-
action conditions, S-alkyl N,N-dialkylthiocarbamates
were obtained by esterification of N,N-dialkylthiocarbam-
ate salts with alkyl halides.27 Therefore, the oxidation re-
action did not take place.
Table 1 Influence of Solvent and Reaction Time on the Synthesis
of N,N¢-Dicyclohexylurea
Entry
Solvent
Reaction time (h)
Isolated
Yield (%)a
Carbonyla- Oxidation
tion
In this reaction system, sulfur was recovered from the re-
sulting solution. We also tried using a catalytic amount of
sulfur to prepare N,N¢-dibenzylurea (1i). Benzylamine
(2i) was mixed with 0.1 equivalents sulfur under a carbon
monoxide–oxygen atmosphere (CO–O2, 10:1) at 20 °C
for 24 hours (Scheme 3). However, N,N¢-dibenzylurea
(1i) was not obtained at all, because of insufficient oxida-
tion under a 10:1 CO–O2 atmosphere. Next, the prepara-
tion of N,N¢-dibenzylurea (1i) from benzylamine (2i) in
the presence of 0.5 equivalent sulfur and two carbonyla-
tion–oxidation cycles was examined (Scheme 4). This
gave urea 1i in less than 50% yield. Therefore, the synthe-
sis of urea derivatives 1 by this method can not be carried
out with only catalytic amounts of sulfur.
1
2
3
4
5
6
7
DMF
DMF
DMF
DMSO
DMSO
THF
4
1
1
88
49
79b
82
49
8
0.5
3
24
4
1
1
0.5
1
4
THF
20
4
89c
a Reagents and conditions: cyclohexylamine (2.86 mL, 25 mmol), sul-
fur (321 mg, 10 mmol), solvent (20 mL), CO (1 atm), O2 (1 atm),
20 °C.
S (0.1 equiv), DMF
b Cyclohexylamine (28.6 mL, 250 mmol), sulfur (3.21 g, 100 mmol),
DMF (100 mL), CO (1 atm), O2 (1 atm), 20 °C.
c Ref.26
+
+
O2
2 PhCH2NH2
CO
(PhCH2NH)2CO
24 h, 1 atm, 20 °C
1i, 0%
2i
10 : 1
Scheme
3
Attempted synthesis of N,N¢-dibenzylurea in the
presence of a catalytic amount of sulfur
Synthesis 2006, No. 17, 2825–2830 © Thieme Stuttgart · New York

PAPER
Synthesis of Urea Derivatives
2827
Table 2 Synthesis of Urea Derivatives from the Corresponding
Amines
(Scheme 5, path B), thiocarbamate salts 3 are generated.
The thus formed thiocarbamate salts 3 are oxidized by
molecular oxygen (Scheme 6), giving urea derivatives 1
via carbamoyl disulfides 5 (path C) or by an alternative
pathway, via isocyanate intermediates 6 (path D). Path D
via isocyanate intermediates 6 is supported by the fact that
oxidation of secondary amines did not proceed at all.29
Entry
1
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
Amine Urea
Yield (%)a
c-Hex
2a
2b
2c
2d
2e
2f
1a
1b
1c
1d
1e
1f
88
92
98
59
88
78
91
89
94
51b
84b
49b
0b
2
Bu
3
s-Bu
A useful synthetic method has been developed to provide
urea derivatives 1 in good to excellent yields, under mild
conditions (1 atm, 20 °C) in N,N-dimethylformamide, and
involves the solvent-assisted carbonylation of amines by
carbon monoxide and sulfur and the oxidation of the re-
sulting thiocarbamate salts by molecular oxygen. In view
of the application in the practical production of urea deriv-
atives 1, this method is very significant because easily
available and cheap carbon monoxide, oxygen, sulfur, and
N,N-dimethylformamide are used, and mild reaction con-
ditions (1 atm, 20 °C) are required.
4
t-Bu
5
(CH2)5Me
(CH2)6Me
(CH2)7Me
(CH2)9Me
Bn
6
7
2g
2h
2i
1g
1h
1i
8
9
10
11
12
13
14
15
Ph
2j
1j
DMF
4-MeOC6H4
4-i-PrC6H4
3-O2NC6H4
2k
2l
1k
1l
RNH2
S8
[RNH3]+ [RNH-Sx-S]–
+
2
4
2m
2n
2o
1m
1n
1o
–
O
+
CO
[RNH3]+ [RNH-Sx-S]–
-(CH2)5-
0
RNH3
RNH-Sx-S-C
4
Pr
Pr
0
a Reagents and conditions: amine 2 (25 mmol), sulfur (321 mg, 10
mmol), DMF (20 mL), CO (1 atm), O2 (1 atm), 20 °C, 5 h.
b DBU (1.50 mL, 10 mmol) was added; no reaction without DBU.
path A
–
–
O
O
+
– Sx
+
C
RNH3
RNH3
Sx
RNHCSx-S
RNH-S
O2
CO, DMF
4 h
+
2 PhCH2NH2
S
1 h
[RNH3]+[RNHC(O)S]–
2i
0.5 equiv
1 atm, 20 °C
3
O2
CO
(PhCH2NH)2CO
19 h
1 h
path B
1i, 35%
–
O
-–
+
+
Scheme 4 Synthesis of N,N¢-dibenzylurea in the presence of 0.5
equivalent sulfur
RNH3
RNH3
S=C=O
RNH-Sx-1-S-S-C
RNH-Sx
+
Schemes 5 and 6 show possible pathways for the synthe-
sis of urea derivatives 1 by the carbonylation of amines 2
followed by oxidation of thiocarbamates 3. We have
found that thiolate salts 4 readily react with carbon mon-
oxide to give thiocarbamate salts 3 (Scheme 5),28 and
therefore propose that a plausible pathway for this sol-
vent-assisted carbonylation of amines 2 with carbon mon-
oxide and sulfur is via thiolate anions 4. At the stage
where amines 2 are carbonylated, elemental sulfur under-
– Sx
[RNH3]+[RNHC(O)S]–
3
Scheme 5 Proposed pathway for the synthesis of thiocarbamate
salts as intermediates in the synthesis of urea derivatives from the cor-
responding amines
Melting points were determined on a Mettler FP 5 instrument and
goes S–S bond fission by the reaction with amines, with are uncorrected. FT-IR spectra were recorded on a JASCO FT/IR-
4100 instrument. 1H and 13C NMR spectra were obtained on a JEOL
JNM-AL300 (300 MHz, 75 MHz) instrument. Chemical shifts d are
reported in ppm relative to tetramethylsilane. Both low- and high-
resolution mass spectra were measured on a JEOL JMS-600 spec-
trometer. Amines 2a–o, DMF, DMSO, THF, DBU, sulfur (99.5%),
CO (99.9%), and O2 (99.9%) were used as purchased.
substantial assistance from N,N-dimethylformamide, to
form ammonium thiolates 4. The reaction of thiolate an-
ions 4 with carbon monoxide gives the carbonylated spe-
cies. Through an intramolecular rearrangement of the
carbonylated species (Scheme 5, path A) or elimination of
carbonyl sulfide from the carbonylated species
Synthesis 2006, No. 17, 2825–2830 © Thieme Stuttgart · New York

2828
T. Mizuno et al.
PAPER
path C
N,N¢-Di-sec-butylurea (1c)
Recrystallized from hexane.
O2
[RNH3]+[RNHC(O)S]–
Yield: 1.68 g (98%); mp 134.8 °C (Lit.22 135 °C).
IR (KBr): 3331, 2963, 2926, 2875, 1627, 1577, 1451, 1274 cm–1.
(RNHC(O)S)2
– RNH2, – H2O
3
5
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 6 H, 2 × CH3),
1.11 (d, J = 6.6 Hz, 6 H, 2 × CH3), 1.39–1.49 (m, 4 H, 2 × CH2),
3.61–3.70 (m, 2 H, 2 × CH), 4.33 (br s, 2 H, 2 × NH).
RNH2
(RNH)2C=O
– HSSH
1
13C NMR (75 MHz, CDCl3): d = 10.3, 21.0, 30.3, 47.3, 157.5.
MS (EI, 70 eV): m/z (%) = 172 (60) [M+], 143 (100), 72 (35), 58
O2
HSSH
H2O
S
+
(88).
HRMS (EI, 70 eV): m/z calcd for C9H20ON2: 172.1576; found:
172.1576.
path D
– RNH2, – H2S
[RNH3]+[RNHC(O)S]–
R-N=C=O
N,N¢-Di-tert-butylurea (1d)
Washed with toluene.
6
3
Yield: 1.01 g (59%); mp 242.9 °C (sublimed) (Lit.22 245 °C).
IR (KBr): 3356, 2965, 1637, 1560, 1361, 1209 cm–1.
RNH2
(RNH)2C=O
1
1H NMR (300 MHz, DMSO-d6): d = 1.18 (s, 18 H, 6 × CH3), 5.31
O2
(br s, 2 H, 2 × NH).
H2S
H2O
S
+
13C NMR (75 MHz, DMSO-d6): d = 29.3, 48.7, 157.0.
MS (EI, 70 eV): m/z (%) = 172 (7) [M+], 157 (13), 58 (100), 57 (22).
Scheme 6 Proposed pathway for the synthesis of urea derivatives
from the corresponding thiocarbamate salts
HRMS (EI, 70 eV): m/z calcd for C9H20ON2: 172.1576; found:
172.1574.
N,N¢-Dihexylurea (1e)
N,N¢-Dicyclohexylurea (1a); Typical Procedure
Purified by short-column chromatography (silica gel, EtOAc).
A dark-red soln containing cyclohexylamine (2a; 2.86 mL, 25
mmol) and powdered sulfur (321 mg, 10 mmol) in DMF (20 mL)
was vigorously stirred under CO (1 atm) at 20 °C for 4 h. Into the
resulting pale-green emulsion of thiocarbamate salt 3a, O2 (1 atm)
was charged at 20 °C (exothermic reaction). The mixture was
stirred for an additional 1 h at 20 °C. The resulting pale-yellow
emulsion was then poured into 1 M HCl (100 mL), and the deposit-
ed white solid was washed with toluene (200 mL) to give pure 1a.
Yield: 2.00 g (88%); mp 76.1 °C (Lit.22 73–74 °C).
IR (KBr): 3332, 2957, 2931, 2856, 1617, 1577, 1478, 1462, 1251,
1222 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.0 Hz, 6 H, 2 × CH3),
1.28–1.35 (m, 12 H, 6 × CH2), 1.43–1.50 (m, 4 H, 2 × CH2), 3.11–
3.17 (m, 4 H, 2 × CH2), 4.63 (br s, 2 H, 2 × NH).
13C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 26.6, 30.3, 31.5, 40.5,
Yield: 1.96 g (88%); mp 231.7 °C (Lit.22 229–230 °C).
IR (KBr): 3327, 2928, 2850, 1627, 1576, 1311, 1244, 1089 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.99–1.32 (m, 10 H, 5 × CH2),
1.47–1.75 (m, 10 H, 5 × CH2), 3.28–3.40 (m, 2 H, 2 × CH), 5.49 (d,
J = 8.1 Hz, 2 H, 2 × NH).
13C NMR (75 MHz, DMSO-d6): d = 24.2, 25.1, 33.1, 47.3, 156.5.
158.5.
MS (EI, 70 eV): m/z (%) = 228 (100) [M+], 199 (45), 185 (51), 158
(33).
HRMS (EI, 70 eV): m/z calcd for C13H28ON2: 228.2202; found:
228.2198.
MS (EI, 70 eV): m/z (%) = 224 (80) [M+], 143 (46), 99 (65), 56
(100).
N,N¢-Diheptylurea (1f)
Recrystallized from MeOH.
HRMS (EI, 70 eV): m/z calcd for C13H24ON2: 224.1889; found:
224.1886.
Yield: 2.00 g (78%); mp 91.2 °C.
IR (KBr): 3335, 2955, 2928, 2854, 1617, 1578, 1478, 1465 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.86 (t, J = 6.8 Hz, 6 H, 2 ×
CH3), 1.24–1.39 (m, 20 H, 10 × CH2), 2.95 (t, J = 6.6 Hz, 4 H, 2 ×
CH2), 5.42 (br s, 2 H, 2 × NH).
13C NMR (75 MHz, DMSO-d6): d = 13.6, 21.8, 26.1, 28.2, 29.8,
31.0, 39.1, 157.9.
MS (EI, 70 eV): m/z (%) = 256 (100) [M+], 213 (45), 199 (39), 172
(29).
N,N¢-Dibutylurea (1b)
Recrystallized from hexane.
Yield: 1.58 g (92%); mp 67.8 °C (Lit.22 67–69 °C).
IR (KBr): 3330, 2958, 2933, 2871, 1620, 1577, 1460, 1233 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.2 Hz, 6 H, 2 × CH3),
1.30–1.50 (m, 8 H, 4 × CH2), 3.14 (q, J = 6.4 Hz, 4 H, 2 × CH2), 5.56
(br s, 2 H, 2 × NH).
13C NMR (75 MHz, CDCl3): d = 13.7, 20.0, 32.5, 39.9, 159.3.
HRMS (EI, 70 eV): m/z calcd for C15H32ON2: 256.2515; found:
256.2518.
MS (EI, 70 eV): m/z (%) = 172 (100) [M+], 130 (17), 101 (16), 57
(13).
Anal. Calcd for C15H32ON2: C, 70.26; H, 12.58; N, 10.92. Found: C,
70.34; H, 12.65; N, 11.08.
HRMS (EI, 70 eV): m/z calcd for C9H20ON2: 172.1576; found:
172.1572.
N,N¢-Dioctylurea (1g)
Recrystallized from MeOH.
Synthesis 2006, No. 17, 2825–2830 © Thieme Stuttgart · New York

PAPER
Synthesis of Urea Derivatives
2829
Yield: 2.57 g (91%); mp 91.0 °C (Lit.22 89–90 °C).
MS (EI, 70 eV): m/z (%) = 272 (29) [M+], 123 (58), 122 (100), 108
(62), 80 (32), 69 (39).
IR (KBr): 3334, 2956, 2925, 2850, 1615, 1579, 1478, 1463 cm–1.
HRMS (EI, 70 eV): m/z calcd for C15H16O3N2: 272.1161; found:
272.1154.
1H NMR (300 MHz, DMSO-d6): d = 0.85 (t, J = 6.6 Hz, 6 H, 2 ×
CH3), 1.23–1.34 (m, 24 H, 12 × CH2), 2.93 (t, J = 6.8 Hz, 4 H, 2 ×
CH2), 5.60 (br s, 2 H, 2 × NH).
13C NMR (75 MHz, DMSO-d6): d = 13.6, 21.8, 26.1, 28.4, 28.5,
29.8, 31.0, 39.1, 157.9.
MS (EI, 70 eV): m/z (%) = 284 (100) [M+], 241 (25), 227 (35), 213
(33), 186 (23), 57 (25).
N,N¢-Bis(4-isopropylphenyl)urea (1l)
Recrystallized from MeOH.
Yield: 1.46 g (49%); mp 238.4 °C.
IR (KBr): 3314, 2959, 1648, 1598, 1553, 1514, 1309, 1235 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.17 (d, J = 7.2 Hz, 12 H, 4 ×
CH3), 2.77–2.86 (m, 2 H, 2 × CH), 7.12 (d, J = 8.2 Hz, 4 H, 4 × CH),
7.34 (d, J = 8.2 Hz, 4 H, 4 × CH), 8.53 (s, 2 H, 2 × NH).
HRMS (EI, 70 eV): m/z calcd for C17H36ON2: 284.2828; found:
284.2816.
N,N¢-Didecylurea (1h)30
Recrystallized from MeOH.
13C NMR (75 MHz, DMSO-d6): d = 24.0, 32.7, 118.2, 126.4, 137.5,
141.7, 152.6.
Yield: 3.03 g (89%); mp 101.1 °C (Lit.22 99–100 °C).
MS (EI, 70 eV): m/z (%) = 296 (30) [M+], 135 (26), 120 (100), 91
(30).
IR (KBr): 3336, 2956, 2924, 2849, 1612, 1578, 1476, 1466 cm–1.
HRMS (EI, 70 eV): m/z calcd for C19H24ON2: 296.1889; found:
296.1886.
MS (EI, 70 eV): m/z (%) = 340 (100) [M+], 297 (24), 283 (18), 255
(30), 241 (28), 214 (19).
Anal. Calcd for C19H24ON2: C, 76.99; H, 8.16; N, 9.45. Found: C,
76.70; H, 8.09; N, 9.55.
HRMS (EI, 70 eV): m/z calcd for C21H44ON2: 340.3454; found:
340.3431.
N,N¢-Dibenzylurea (1i)
Washed with toluene.
References
(1) Papesch, V.; Schroeder, E. F. J. Org. Chem. 1951, 16, 1879.
(2) Clark, R. L.; Pessolano, A. A. J. Am. Chem. Soc. 1958, 80,
1657.
(3) The reaction of isocyanates with amines 2 is a typical
synthetic method for the preparation of urea derivatives.
However, isocyanates are also prepared from phosgene and
primary amines 2.
(4) Pfaendler, H. R.; Weisner, F. Heterocycles 1995, 40, 717.
(5) Cortez, R.; Rivero, I. A.; Somanathan, R.; Aguirre, G.;
Ramirez, F.; Hong, E. Synth. Commun. 1991, 21, 285.
(6) Staab, H. A. Angew. Chem. 1956, 68, 754.
(7) Staab, H. A. Justus Liebigs Ann. Chem. 1957, 609, 75.
(8) Beaver, D. J.; Roman, D. P.; Stoffel, P. J. J. Am. Chem. Soc.
1957, 79, 1236.
(9) Ayyangar, R.; Chowdhary, A. R.; Kalkote, U. R.; Nath, A.
A. Chem. Ind. 1988, 599.
(10) Fox, J. J.; Van Praag, D. J. Am. Chem. Soc. 1960, 82, 486.
(11) Davoll, J.; Laney, D. H. J. Chem. Soc. 1960, 314.
(12) Mavrovic, I. In Kirk–Othmer Encyclopedia of Chemical
Technology, Vol. 21; Mark, H. F., Ed.; Wiley Interscience:
New York, 1970, 37.
(13) Ogura, H.; Takeda, K.; Tokue, R.; Kobayashi, T. Synthesis
1978, 394.
(14) Cooper, C. F.; Falcone, S. J. Synth. Commun. 1995, 25,
2467.
Yield: 2.26 g (94%); mp 169.4 °C (Lit.22 169–171 °C).
IR (KBr): 3323, 3031, 1628, 1573, 1453, 1248, 696 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.23 (s, 4 H, 2 × CH2), 6.42 (br
s, 2 H, 2 × NH), 7.18–7.33 (m, 10 H, 10 × CH).
13C NMR (75 MHz, DMSO-d6): d = 42.9, 126.5, 126.9, 128.1,
140.8, 158.0.
MS (EI, 70 eV): m/z (%) = 240 (82) [M+], 149 (31), 106 (100), 91
(63).
HRMS (EI, 70 eV): m/z calcd for C15H16ON2: 240.1263; found:
240.1259.
N,N¢-Diphenylurea (1j)
Washed with toluene.
Yield: 1.08 g (51%); mp 241.0 °C (Lit.31 241–242 °C).
IR (KBr): 3327, 1649, 1595, 1556, 1233, 754, 698 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.95 (t, J = 7.6 Hz, 2 H, 2 ×
CH), 7.27 (t, J = 7.6 Hz, 4 H, 4 × CH), 7.44 (d, J = 7.6 Hz, 4 H, 4 ×
CH), 8.67 (s, 2 H, 2 × NH).
13C NMR (75 MHz, DMSO-d6): d = 118.1, 121.7, 128.7, 139.7,
152.5.
MS (EI, 70 eV): m/z (%) = 212 (36) [M+], 119 (12), 93 (100).
(15) Sasaki, Y. Nippon Kagaku Kaishi 1996, 109.
(16) Fournier, J.; Bruneau, C.; Dixneuf, P. H.; Lecolier, S. J. Org.
Chem. 1991, 56, 4456.
HRMS (EI, 70 eV): m/z calcd for C13H12ON2: 212.0950; found:
212.0903.
(17) Baiocchi, F.; Franz, R. A.; Horwitz, L. J. Org. Chem. 1956,
21, 1546.
(18) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J. Mol.
Catal. 1990, 60, 41.
(19) Giannoccaro, P. J. Organomet. Chem. 1987, 336, 271.
(20) Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.; Lapidus, A.
L. Synth. Commun. 1991, 21, 1923.
(21) Franz, R. A.; Applegath, F. J. Org. Chem. 1961, 26, 3304.
(22) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. J.
Org. Chem. 1961, 26, 3306.
N,N¢-Bis(4-methoxyphenyl)urea (1k)
Washed with toluene and t-BuOMe.
Yield: 2.30 g (84%); mp 232.4 °C (Lit.23 232–234 °C).
IR (KBr): 3303, 1633, 1608, 1560, 1511, 1246, 827 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.70 (s, 6 H, 2 × CH3), 6.84 (d,
J = 9.0 Hz, 4 H, 4 × CH), 7.33 (d, J = 9.0 Hz, 4 H, 4 × CH), 8.41 (br
s, 2 H, 2 × NH).
13C NMR (75 MHz, DMSO-d6): d = 55.1, 113.9, 119.8, 132.9,
152.9, 154.3.
(23) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.;
Bolze, C. J. Org. Chem. 1961, 26, 3309.
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PAPER
(29) In the previous report25 of urea synthesis from primary
amines and carbon monoxide with the use of a selenium
catalyst, the same reaction pathway was suggested.
(30) NMR data are not reported, as measurement of NMR spectra
was difficult because of the very low solubility of 1h in
organic solvents.
(24) Sonoda, N.; Yasuhara, T.; Kondo, K.; Ikeda, T.; Tsutsumi, S.
J. Am. Chem. Soc. 1971, 93, 6344.
(25) Sonoda, N. Pure Appl. Chem. 1993, 65, 699.
(26) Mizuno, T.; Matsumoto, M.; Nishiguchi, I.; Hirashima, T.
Heteroat. Chem. 1993, 4, 455.
(27) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron 2005, 61, 9157.
(28) Mizuno, T.; Daigaku, T.; Nishiguchi, I. Tetrahedron Lett.
1995, 36, 1533.
(31) Boivin, P. A.; Bridgeo, W.; Boivin, J. L. Can. J. Chem. 1954,
32, 242.
Synthesis 2006, No. 17, 2825–2830 © Thieme Stuttgart · New York