Novel synthesis of N, n′-dialkyl cyclic ureas using sulfur-assisted carbonylation and oxidation

Article abstract of DOI:10.1002/hc.20508

The first example of cyclic urea synthesis from secondary amines by the use of sulfur-assisted carbonylation and oxidation was established. By combined sulfur-assisted carbonylation of secondary a, ay diamines under an ambient pressure of carbon monoxide

Full text of DOI:10.1002/hc.20508

Heteroatom Chemistry
Volume 20, Number 1, 2009
ꢀ
N
ovel Synthesis of N, N -Dialkyl Cyclic Ureas
Using Sulfur-Assisted Carbonylation
and Oxidation
Takumi Mizuno, Takeo Nakai, and Masatoshi Mihara
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku,
Osaka 536-8553, Japan
Received 26 September 2008; revised 6 November 2008, 12 November 2008
are suitable replacements for the carcinogenic sol-
ABSTRACT: The first example of cyclic urea syn-
thesis from secondary amines by the use of sulfur-
assisted carbonylation and oxidation was established.
By combined sulfur-assisted carbonylation of sec-
ondary α,ω-diamines under an ambient pressure of
vent, hexamethylphosphoramide [3,4]. A variety of
ꢀ
synthetic methods for N, N -dialkyl cyclic ureas 1
containing 1a and 1d were developed, based on the
carbonylation of secondary α, ω-diamines 2. Among
them, a general synthetic method for cyclic ureas 1
was based upon the carbonylation of 2 with phos-
gene as a carbonyl source [5,6]. However, use of this
preparative method is considerably limited, because
of high toxicity of phosgene. Urea and carbon diox-
ide in the presence of transition metal catalysts were
recognized as a carbonyl source for the synthesis
of 1 [7–11]. Also, cyclic ureas 1 were given by the
displacement from corresponding cyclic thioureas
◦
carbon monoxide at 20 C with oxidation by molecu-
◦
lar oxygen (0.1 MPa, 20 C), a facile synthetic method
ꢀ
for N,N -dialkyl cyclic ureas including 1,3-dimethyl-2-
imidazolidinone was developed. ꢁC 2009 Wiley Periodi-
cals, Inc. Heteroatom Chem 20:64–68, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20508
[
12,13]. Furthermore, carbon monoxide was a useful
INTRODUCTION
ꢀ
raw material for the preparation of 1. N, N -Dialkyl
cyclic ureas 1 were afforded from secondary α, ω-
diamines 2 and carbon monoxide in the presence of
transition metal catalyst [14].
Recently, we found that sulfur-assisted carbony-
lation with carbon monoxide was strongly acceler-
ated by N, N-dimethylformamide (DMF) or dimethyl
sulfoxide (DMSO) [15] and developed a synthetic
process of acyclic urea derivatives from primary
amines, carbon monoxide, sulfur, and oxygen under
1,3-Dimethyl-2-imidazolidinone (DMI; 1a) (Scheme
1) is a colorless, transparent, high polar solvent with
high thermal and chemical stability and noncorro-
siveness. It can be used in a variety of applications
(detergents, dyestuffs, and electronic materials) and
in the manufacture of polymers. Its versatility can be
attributed to its chemical properties, which are its
excellent solubility for inorganic and organic com-
pounds, high dielectric constant, and solvation ef-
fect [1]. Also, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (1d) (Scheme 1) is used as a polar,
aprotic organic solvent [2]. In particular, 1a and 1d
◦
mild conditions (0.1 MPa, 20 C) [16] or solvent-free
conditions (0.1 MPa) [17]. However, this acyclic urea
synthesis using sulfur-assisted carbonylation and ox-
idation has a serious limitation that is only applica-
ble to the primary amines as reactants.
Therefore, our objective has been to develop
a straightforward synthetic method for 1 by the
Correspondence to: Takumi Mizuno; e-mail: tmizuno@
omtri.city.osaka.jp
ꢀ
c 2009 Wiley Periodicals, Inc.
64

ꢀ
Novel Synthesis of N, N -Dialkyl Cyclic Ureas 65
ꢀ
vent led to the successful synthesis of N, N -
ꢀ
dialkyl cyclic ureas 1 (Schemes 2 and 3). N, N -
Dimethylethylenediamine (2a) readily reacted with
carbon monoxide (0.1 MPa) and sulfur (1.5 equiv.)
in the presence of 1,4-diazabicyclo[2.2.2]octane
®
◦
(
Dabco ) (0.5 equiv.) at 20 C for 4 h in N, N-
dimethylformamide solvent. Then, the generated
thiocarbamate salt 3a in the DMF solution was
oxidized by molecular oxygen under an ambient
SCHEME 1 1,3-Dimethyl-2-imidazolidinone (1a) and 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1d).
◦
pressure at 20 C for 1 h. Finally, 1,3-dimethyl-2-
imidazolidinone (1a) was obtained in 94% yield (GC
yield) based on 2a.
carbonylation of 2 with carbon monoxide and sul-
fur followed by oxidation with molecular oxygen
under mild conditions (0.1 MPa, 20 C). To the best
of our knowledge, this is the first example of cyclic
urea synthesis from secondary amines by the sulfur-
assisted carbonylation with carbon monoxide and
oxidation using molecular oxygen.
First, the influence of base and solvent was
examined on the synthesis of 1a by the sulfur-
assisted carbonylation and oxidation of 2a (Table
1). In the absence of additional base, 1a was ob-
tained in good yield in N, N-dimethylformamide
solvent (Entry 1). By addition of 0.5 equiv. of
◦
®
Dabco , 1-methylpyrrolidine, or triethylamine in
DMF, yields of 1a were improved (Entries 2–
RESULTS AND DISCUSSION
4). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) did
Our investigation into the sulfur-assisted carbony-
not have an additional effect for the prepara-
lation and oxidation of secondary α,ω-diamines
tion of 1a (Entry 5), and potassium carbonate
2
employing N, N-dimethylformamide as a sol-
(K
2
CO
3
) lowered the yield of 1a, because of low
SCHEME 2 Synthesis of 1,3-dimethyl-2-imidazolidinone (1a).
DMF / DABCO
NH2+ N-Sx-S
NH
NH
+
S8
CH3
CH3
CH3
CH3
2
a
5a
O
O
CO
O2
NH2+ N-S-Sx-C
CH3
NH2+ N-C-S
CH3
CH3
CH3 3a
O
NH
N-C-S
CH3
N
N
CH3
CH3
CH3
2
O
4a
1a
SCHEME 3 Proposed pathway for the synthesis of 1,3-dimethyl-2-imidazolidinone (1a).
Heteroatom Chemistry DOI 10.1002/hc

66 Mizuno et al.
ꢀ
TABLE 1 Effect of Base and Solvent on Synthesis of DMI
1a)
TABLE 2 Synthesis of N, N -Dialkyl Cyclic Ureas (1a–e) and
(
Acyclic Ureas (1f–g)
Entry
Base
Solvent
Yield (%)a
Yield
(%)
Yield
(%)
a
a
Product
Product
1
2
3
4
5
6
7
8
9
None
Dabco
1-Methylpyrrolidine
Triethylamine
DBU
DMF
DMF
DMF
DMF
DMF
81
94
92
87
81
27
87
73
17
0
N
N
94
N
N
17
Me
Me
Me
Et
Me
1d
K CO
DMF
O
1a
O
2
3
Dabco
Dabco
Dabco
Dabco
Dabco
DMAc
DMSO
THF
MTBE
Toluene
72b
70
1
1
0
1
N
N
N
N
Trace
0
Et
Et
1b
Et
1e
ꢀ
Reaction conditions: N, N -dimethylethylenediamine (2a) (1.07 mL,
O
O
1
0 mmol), sulfur (481 mg, 15 mmol), base (5 mmol), solvent (20 mL),
◦
◦
CO (1 atm), 20 C, 4 h for carbonylation, and O
2
(1 atm), 20 C, 1 h for
oxidation.
GC yields.
a
N
N
b−d
4
1
(Pr N) C O 1f
0
2
2
i-Pr
i-Pr
1c
O
solubility of K
2
CO in DMF (Entry 6). Using N, N-
3
dimethylacetoamide (DMAc) or dimethyl sulfoxide
as a solvent in the presence of Dabco , 1a was given
®
0c
N
C=O 1g
in good yields (Entries 7,8). However, tetrahydrofu-
ran (THF), t-butyl methyl ether (MTBE), and toluene
were unsuitable for the preparation of 1,3-dimethyl-
2
Reaction conditions: Amine (10 mmol), sulfur (481 mg, 15 mmol),
Dabco (561 mg, 5 mmol), DMF (20 mL), CO (1 atm), 20 C, 4 h for
◦
2
-imidazolidinone (1a) (Entries 9–11).
◦
carbonylation, and O
2
(1 atm), 20 C, 1 h for oxidation.
ꢀ
a
Next, several N, N -dialkyl cyclic ureas (1a–
GC yields.
Isolated yields.
Amine (20 mmol) was used.
b
d) including 1a were synthesized by the sulfur-
assisted carbonylation with carbon monoxide
and oxidation with molecular oxygen under
c
d
Bis(N, N-dipropylcarbamoyl) disulfide (4f) was formed in 36% (1.81
mmol).
◦
mild condition (0.1 MPa. 20 C) (Table 2). 1,3-
Dimethyl-2-imidazolidinone (1a) and 1,3-diethyl-2-
imidazolidinone (1b) were obtained in good to ex-
cellent yields. However, the yield of 1c was lowered
by bulkiness of N-isopropyl groups. Furthermore,
the present method was ineffective in the formation
of six-membered rings (1d and 1e).
Under similar mild conditions, S-methyl N, N-
dipropylthiocarbamate was obtained in excellent
yield by esterification of N, N-dipropylthio-
carbamates salt (3f) with methyl iodide [15].
However, secondary amines, dipropylamine (2f),
and piperidine (2g) did not give acyclic ureas (1f, g)
at all. In the case of 2f, bis(N, N-dipropylcarbamoyl)
disulfide (4f) was formed in place of tetrapropylurea
emental sulfur undergoes S–S bond fission by the
reaction with 2a, to form ammonium thiolate (5a).
The reaction of 5a with carbon monoxide gives the
carbonylated species. Through an intramolecular re-
arrangement or elimination of carbonyl sulfide from
the carbonylated species, thiocarbamate salt (3a) is
generated. The thus formed thiocarbamate salt (3a)
is oxidized by molecular oxygen, giving 1a via di-
carbamoyl disulfide (4a). Indeed, in the case of the
reaction with 2f, bis(N, N-dipropylcarbamoyl) disul-
fide (4f) was obtained in place of 1f.
(
1f). Therefore, 4f could not receive the nucleophilic
substitution of 2f by the bulkiness of 2f and 4f.
Scheme 3 shows possible pathways for the syn-
thesis of 1a by the carbonylation of 2a followed by
oxidation of the thiocarbamate 3a. We have found
that thiolate salts 5 readily react with carbon monox-
ide to give thiocarbamate salts 3 (Scheme 4) [18],
and therefore we propose that a plausible pathway
for this sulfur-assisted carbonylation of 2a with car-
bon monoxide is via thiolate anion 5a. At first, el-
SCHEME 4 The reaction of thiolate aniones 5 with carbon
monoxide.
Heteroatom Chemistry DOI 10.1002/hc

ꢀ
Novel Synthesis of N, N -Dialkyl Cyclic Ureas 67
In our previous reports [16,17] of urea synthe-
sis from primary amines by sulfur-assisted carbony-
lation using carbon monoxide and oxidation with
oxygen, isocyanate intermediates were suggested in
this oxidation stage. Therefore, because of difficulty
of aminolysis of bulky dicarbamoyl disulfides 4, the
formation of ureas 1 from the thiocarbamate salts
1,3-Dimethyl-2-imidazolidinone
(1a). Yield:
◦
1.64 g (72%) yield; bp 107–109 C, 30 hPa (Lit. [1]
◦
1
106–108 C, 23 hPa); H NMR (CDCl ): δ (ppm) 2.78
3
13
(s, 6H, CH ), 3.27 (s, 4H, CH ); C NMR (CDCl ): δ
3
2
3
+
(ppm) 31.3, 44.9, 161.9; MS m/z (%): 114 (M , 100),
113 (54), 85 (11), 72 (10), 58 (14), 56 (21).
For the identification of 1a, retention time of GC
and NMR and MS spectra of 1a was compared with
those of commercially available DMI.
3
generated from primary amines is generally much
easier, compared with from secondary amines.
CONCLUSION
Procedure for the Formation of
Bis(N,N-dipropylcarbamoyl) Disulfide 4f
ꢀ
In summary, a novel synthetic method for N, N -
dialkyl cyclic ureas 1, especially 1,3-dimethyl-2-
imidazolidinone (1a), has been developed under
Dipropylamine (2f; 2.73 mL, 20 mmol), Dabco®
(561 mg, 5 mmol), powdered sulfur (481 mg, 15
mmol), and DMF (10 mL) were placed in a 100-
mL flask under an argon atmosphere. The flask was
charged with an ambient pressure of CO, and vigor-
ously stirred under CO from a balloon (0.1 MPa)
◦
mild conditions (0.1 MPa, 20 C) in DMF, in which
includes the sulfur-assisted carbonylation of sec-
ondary diamines 2 with carbon monoxide, and the
oxidation of resulting thiocarbamate salts 3 with
molecular oxygen. From the viewpoint of application
to practical production of 1a, the present method is
very significant in terms of the use of easily avail-
able and cheap carbon monoxide, oxygen, sulfur,
◦
at 20 C for 4 h. The color of the solution then
changed from red to reddish black. The flask was
purged of CO and charged with O
(slightly exothermic reaction). The reaction mixture
◦
2
(0.1 MPa) at 20 C
and DMF, and mild reaction conditions (0.1 MPa,
was stirred under O
2
from a balloon (0.1 MPa) for
◦
◦
20 C).
another 1 h at 20 C. The resulting orange solution
was then poured into 1 M HCl (100 mL) and ex-
tracted by t-butyl methyl ether (200 mL). Bis(N, N-
dipropylcarbamoyl) disulfide (4f) was purified as
an oil, by short-column chromatography (silica gel,
EtOAc).
EXPERIMENTAL
FT-IR spectra were recorded on a JASCO FT/IR-
1
13
4
100 instrument. H and C NMR spectra were
obtained on a JEOL JNM-AL300 (300, 75 MHz) in-
strument. Chemical shifts were reported in ppm rel-
ative to tetramethylsilane (δ-units). Mass and exact
mass spectra were measured on a JEOL JMS-600
spectrometer. Amines 2a–g, DMF, DMAc, DMSO,
Bis(N,N-dipropylcarbamoyl)
Disulfide
(4f).
Yield: 581 mg (36%, 1.81 mmol) yield; IR (neat,
−
1
cm ): ν 2964, 2874, 1681(C O), 1467, 1404, 1218,
1
1
118; H NMR (CDCl
3
): δ (ppm) 0.82–1.03 (m, 12H,
®
CH
3
), 1.53–1.80 (m, 8H, CH ), 3.36 (br s, 8H, CH );
2
2
THF, MTBE, toluene, Dabco , 1-methylpyrrolidine,
13
triethylamine, DBU, K
2
CO
3
, sulfur (99.5%), carbon
C NMR (CDCl
MS m/z (%): (ppm) 320 (M , 15), 129 (13), 128
3
): δ = 11.1, 20.9, 22.0, 50.3, 163.3;
+
monoxide (99.9%), and oxygen (99.9%) were used as
purchased.
(
3
100), 86 (41); Exact MS: calcd for C14
20.1592; found: 320.1611.
H
28
O
2
N
2
2
S :
Typical Procedure for the Synthesis of DMI 1a
ꢀ
A
dark
red
solution
containing
N, N -
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(0.1 MPa) was charged at 20 C
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stirred for an additional 1 h at 20 C. DMF was
evaporated from the resulting brown emulsion, and
,3-dimethyl-2-imidazolidinone (1a) was given by
®
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Heteroatom Chemistry DOI 10.1002/hc