Preparation of mono-, di-, and trisubstituted ureas by carbonylation of aliphatic amines with S,S-dimethyl dithiocarbonate

Article abstract of DOI:10.1055/s-2007-990813

General procedures are reported to prepare N-alkylureas, N,N′-dialkylureas (both symmetrical and unsymmetrical), and N,N,N′-trialkylureas by carbonylation of aliphatic amines, employing S,S-dimethyl dithiocarbonate (DMDTC) as a phosgene substitute. All reactions were carried out in water. Symmetrical disubstituted ureas were prepared directly working at 60°C with a molar ratio of DMDTC:amine = 1:2, preferably under nitrogen. Unsymmetrical ureas were prepared in two steps via S-methyl N-alkyl-thiocarbamate intermediates, which are formed selectively in the first step at room temperature. These intermediates react in the second step with ammonia or various aliphatic amines, both primary and secondary, at temperatures varying between 50 and 70°C. All the target ureas were obtained in high yields (28 examples, average yield 94%) and with very high purity (generally >99.2%). Also to be noted is the recovery of a co-product of industrial interest, methanethiol, in an amount of two moles for each mole of DMDTC, with complete exploitation of the reagent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990813

PAPER
3497
Preparation of Mono-, Di-, and Trisubstituted Ureas by Carbonylation of
Aliphatic Amines with S,S-Dimethyl Dithiocarbonate
Preparation of
M
m
ono-, Di-, and Tris
m
ubstituted Ureas a Artuso, Iacopo Degani,1 Rita Fochi,* Claudio Magistris
Dipartimento di Chimica Generale ed Organica Applicata dell’Università, Università degli Studi di Torino,
C. so M. D’Azeglio 48, 10125 Torino, Italy
E-mail: rita.fochi@unito.it
Received 19 July 2007; revised 22 August 2007
bon dioxide, or carbon monoxide and oxygen, or carbon
dioxide in addition to carbon monoxide and air, in the
presence of various catalysts and under rather harsh con-
ditions (at high pressure and high temperatures). Due to
Abstract: General procedures are reported to prepare N-alkylureas,
N,N¢-dialkylureas (both symmetrical and unsymmetrical), and
N,N,N¢-trialkylureas by carbonylation of aliphatic amines, employ-
ing S,S-dimethyl dithiocarbonate (DMDTC) as a phosgene substi-
tute. All reactions were carried out in water. Symmetrical the growing importance of the variously substituted ureas,
disubstituted ureas were prepared directly working at 60 °C with a
during the last years a great deal of research has been
molar ratio of DMDTC:amine = 1:2, preferably under nitrogen. Un-
dedicated to the development of alternative, safer, and
symmetrical ureas were prepared in two steps via S-methyl N-alkyl-
simpler procedures for their preparation.2–6
thiocarbamate intermediates, which are formed selectively in the
The present work is part of a wide ranging project that ad-
dresses the development of new, safe, and soft synthetic
methodologies for the production of intermediates and
products, particularly of industrial interest, based on the
use of S,S-dimethyl dithiocarbonate (1, DMDTC).
DMDTC is a reagent that can be easily prepared and in
high yield on both the laboratory7 and industrial8 scale by
rearrangement of the corresponding inexpensive O,S-
dimethyl dithiocarbonate. DMDTC has already been used
as a methanethiol precursor for the synthesis of organic
sulfides,9 including triazine derivatives,10 as well as mesyl
chloride and its derivatives.11 In more recent applications,
DMDTC has been used as a phosgene substitute in the
carbonylation of amines for the synthesis of N,N¢-dialkyl-
ureas,12 N,N-dimethyl-N¢-arylureas,13 and S-methyl N-
alkylthiocarbamates.14 In this last role, unlike phosgene
which is a highly toxic gaseous reagent, hazardous to han-
dle and store, and difficult to measure,15 DMDTC is a liq-
uid nontoxic reagent that can be measured, handled, and
stored in complete safety. The present research reports the
preparation of monosubstituted 9, disubstituted symmetri-
cal 3 and unsymmetrical 10, as well as trisubstituted ureas
11 by reaction of DMDTC (1) with aliphatic amines
(Schemes 1 and 2).
first step at room temperature. These intermediates react in the sec-
ond step with ammonia or various aliphatic amines, both primary
and secondary, at temperatures varying between 50 and 70 °C. All
the target ureas were obtained in high yields (28 examples, average
yield 94%) and with very high purity (generally >99.2%). Also to
be noted is the recovery of a co-product of industrial interest, meth-
anethiol, in an amount of two moles for each mole of DMDTC, with
complete exploitation of the reagent.
Key words: ureas, carbonylation, amines, dithiocarbonates, thio-
carbamates
Substituted ureas have always attracted great attention by
virtue of their numerous important applications.2–5 In-
deed, they are widely used in the agricultural field as plant
growth regulators and pesticides, particularly herbicides,
in the medical field as tranquillizing, anticonvulsant, and
antidiabetic agents as well as inhibitors of HIV-1 pro-
tease, etc., and in organic synthesis as starting materials
(especially for the production of carbamates, isocyanates,
polymers, and surfactants) and intermediates (especially
for the production of pharmaceuticals, cosmetics, and
agrochemicals). Moreover, ureas have found extensive
applications in many other fields ranging from their use as
dyes for cellulose fibers, antioxidants in gasoline, deter-
gent additives, corrosion inhibitors, to polar solvents, etc.
A great variety of procedures have been proposed for the
preparation of substituted ureas.2,3,6 The procedures of
widest use, which are also of practical interest for indus-
trial productions, can be collected into three groups: (i) re-
action of primary amines mainly with phosgene or its less
toxic and less hazardous substitutes; (ii) reaction of prima-
ry and secondary amines with isocyanates, themselves
prepared mainly from phosgene, in organic solvents; and
(iii) reaction of primary and secondary amines with car-
O
O
in H2O, (N2)
60 °C
+
2 R1NH2
+
2 MeSH
MeS
SMe
R1NH
NHR1
1
2
3
4
Scheme 1
As stated above, DMDTC was recently12 employed as a
carbonylating reagent for primary aliphatic amines to give
symmetrical and unsymmetrical N,N¢-dialkylureas. With
regard to the former, the reactions, carried out in methanol
at 60 °C for 24 hours, supplied the products in 72% aver-
age yield (9 examples). With regard to the unsymmetrical
ureas, the authors assert that the reaction between
DMDTC and amines cannot be stopped at the first step,
SYNTHESIS 2007, No. 22, pp 3497–3506
x
x.
x
x
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-990813; Art ID: Z17507SS
© Georg Thieme Verlag Stuttgart · New York

3498
E. Artuso et al.
PAPER
First step
anol. These results demonstrate that the ureas obtained
through reactions carried out in methanol at 60 °C for 24
hours are always impure, and therefore need further puri-
fication by means of crystallization or chromatography. In
this research the same reaction, carried out at 60 °C for 24
hours in water instead of methanol, supplied N,N¢-diben-
zylurea (3j) in 95% yield and 99.2% purity, determined by
GC analysis (Table 1, entry 12). The reaction was repeat-
ed, bubbling nitrogen into the mixture to drive out the
methanethiol (4) as soon as it was formed (entry 13). Un-
der such conditions the reaction time can be shortened to
5 hours and yield and purity of the urea 3j are still high
(93% yield; 100% GC purity). On the basis of these re-
sults, DMDTC was reacted with various primary aliphatic
amines in water at 60 °C, under vigorous stirring and pref-
erably bubbling nitrogen into the reaction mixture
(Scheme 1). The standard DMDTC-to-amine molar ratio
was 1:2. Only in the case of amines with a boiling point
less than 65 °C it was necessary to work with an excess of
amine (entries 1–5,11).
O
O
in H2O
R1NH2
MeSH
+
+
MeS
SMe
R1NH
SMe
20–25 °C
1
2
5
4
R1
R1
5
a
b
c
5
d
e
f
Me
Et
n-C6H13
c-C6H11
Bn
Bu
Second step
O
O
in H2O, (N2)
50–70 °C
R2R3NH
+
+ MeSH
R1NH
SMe
R1NH
9–11
NR2R3
5
6–8
4
R2
R3
6, 9
H
H
H
alkyl
alkyl
7, 10
8, 11
The best conditions were as follows: amine 2 in an aque-
ous solution (concentrations varying between 40% and
70% in weight; entries 1–5, 7, 8, 11–13), or neat when the
amine was not water-soluble (entries 6, 10, 14–16), was
alkyl
Scheme 2
because the substitution of the second methylthio group slowly added to a suspension of DMDTC in water, main-
proceeds more rapidly. Thus, the reaction always leads to tained under vigorous stirring. The mixture was then heat-
symmetrical ureas even when working with a notable re- ed to 60 °C with an oil bath, and heating and stirring were
agent excess. To block the reaction at the first step and to maintained until completion of the reaction, i.e., until the
avoid the successive formation of symmetrical ureas, the disappearance of DMDTC and the S-methyl N-alkylthio-
reactions between DMDTC and amines in an equimolar carbamate 5 intermediate. When the amine had a high
ratio were carried out in anhydrous THF under basic boiling point (above 100 °C) or when it was a solid sub-
conditions (LDA) and nitrogen atmosphere, initially at stance, the reactions were preferably carried out under a
–78 °C and then at room temperature (20 h). Under these nitrogen stream (entries 6, 8, 10, 13–16); under these con-
conditions, the resulting S-methyl N-alkylthiocarbamates ditions the reaction times were considerably shortened
were deprotonated immediately after being formed, giv- (compare entries 8 and 13 with, respectively, entries 7 and
ing the corresponding lithium salts that, being relatively 12). The course of all the reactions was monitored by GC
stable towards nucleophilic substitution, do not react fur- and GC-MS (entries 1–13) or TLC (entries 14–17) analy-
ther to give symmetrical ureas. Later treatment of the N- ses. These analyses highlighted, right from the start and
anions with an acid gave the thiocarbamates. Only two for most of the reaction time, the presence of the S-methyl
compounds were synthesized by this procedure, namely N-alkylthiocarbamate intermediates 5 and the target prod-
S-methyl N-benzylthiocarbamate (62% yield) and N,N¢- ucts N,N¢-dialkylureas 3, alongside the starting com-
(p-xylylene)bis(thiocarbamate) (unreported yield). The pounds, i.e., amines 2 and DMDTC (1). This last reagent
reactions of these two thiocarbamates with various ali- is the first to disappear. Under the best conditions the re-
phatic amines were then carried out in methanol at 60 °C actions reached completion in times between 2 and 12
for 24 hours, resulting in the corresponding unsymmetri- hours. As the ureas 3 are formed, they separated out from
cal N,N¢-dialkylureas in modest yields. The average yield the reaction mixtures as colorless solid substances. At the
of the four examples reported was 47%.
end of the reactions the ureas were collected by different
work-ups: (i) separation by decantation or by filtration un-
der suction with subsequent drying of the products by
treatment with anhydrous toluene or chloroform, and
then, distillation of the toluene/water or chloroform/water
azeotropes under reduced pressure; and (ii) extraction
with an organic solvent that was then dried with sodium
sulfate and evaporated under reduced pressure. All sym-
metrical N,N¢-dialkylureas 3 were obtained in high yields,
between 84 and 98% (the average yield of 13 examples
was 93%) and in very high purity, greater than 99.2% (de-
Recently,14 we revisited the reaction of S,S-dimethyl
dithiocarbonate (1) with benzylamine according to the lit-
erature protocol,12 with a 1:2 molar ratio in methanol at
60 °C for 24 hours. The literature12 reports the exclusive
formation of N,N¢-dibenzylurea in 85% yield. However
our many tests14 showed the complete consumption of
DMDTC, but the resulting N,N¢-dibenzylurea (3j) was ob-
tained only in 72% yield, together with two by-products,
the intermediate S-methyl N-benzylthiocarbamate (5f; 7%
yield), and methyl N-benzylcarbamate (5% yield), the last
being formed by the reaction of 5f with the solvent meth-
1
termined by GC and H NMR analyses). Table 1 shows
Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York

PAPER
Preparation of Mono-, Di-, and Trisubstituted Ureas
3499
the reaction times, yields, purity, and melting points of the With regard to the unsymmetrical ureas, the N-alkyl (9),
symmetrical N,N¢-dialkylureas 3a–m, both crude and N,N¢-dialkyl (10), and N,N,N¢-trialkyl (11) ureas were pre-
crystallized. A further merit of these reactions is that, pared in two steps via the S-methyl N-alkylthiocarbamate
alongside the urea formation, there is also a development intermediates 5 (Scheme 2).
of methanethiol (4) (two moles for each mole of DMDTC,
Scheme 1). This last can be collected in an aqueous sodi-
um hydroxide solution and recovered as sodium meth-
anethiolate in yields higher than 95%.16
Recently,14 we demonstrated that, contrary to previous lit-
erature reports,12 the reactions between S,S-dimethyl
dithiocarbonate (1) and primary aliphatic amines, even in
strong excess, can be stopped at the first step with selec-
tive formation of S-methyl N-alkylthiocarbamates 5,
Table 1 Synthesis and Properties of Symmetrical N,N¢-Dialkylureas 3a–m
Entry R1
Ratio
1/2
Proce- N2
durea
Time
(h)
Product Yield
(%)b
GC
Mp (°C)
purity (%) Crude
Recrystallized
Lit.
1
2
3
4
5
6
Me
1:3
A
A
B
B
B
C
–
–
–
–
–
+
2
5
3a
3b
3c
3d
3e
3f
97
96
95
95
86
96
100
100
107.4–108.0
107.8–108.3
(toluene)
10617
Et
1:4
110.0–111.2
73.6–74.1
111–112
(toluene)
11117
Bu
1:2.1
1:2.1
1:3
8
99.8
74.1–75.0
(pentane)
7117
i-Bu
10
12
6
99.8
132.8–133.4
136.7–137.6
76.4–76.9
133.9–134.8
(Et2O)
13417
s-Bu
n-C6H13
c-C6H11
100
137.1–137.5
(Et2O)
134.86b
76.16b
232–23317
1:2
99.7
77.5–78.6
(MeOH)
7
8
9
1:2
B
–
+
+
16
5
3g
3g
3g
85
84
84
99.5
99.8
99.2
232.1–232.9
232.5–232.9
232.4–232.9
232.6–233.2
(CHCl3)
C
Ec
5
d
10
11
n-C10H21
CH2=CHCH2
Bn
1:2
1:4
1:2
C
B
+
–
4
6
3h
3i
98
97
–
99.9–101.4
96.5–97.4
99.9–101.4
(CHCl3)
101.16b
100
96.8–97.5
(toluene–pentane)
92–9412
172-17317
12
13
B
C
–
24
5
3j
3j
95
93
99.6
169.7–170.3
170.9–171.5
171.7–172.8
(EtOH)
+
100
e
14
15
4-MeC6H4CH2
4-ClC6H4CH2
1:2
1:2
D
D
+
+
7
8
3k
3l
91
88
–
224.4–224.9
245.5–246.5
225.3–225.6
(MeOH)
215–21618b
242-24319
200–20212
e
–
246.4–247.3
(MeOH)
f
16
17
4-H2NC6H4CH2 1:2
D
Ec
+
+
6
6
3m
3m
80
90
–
203.5–204.3
203.5–204.3
203.5–204.3
(MeOH)
f
–
a All reactions were carried out in H2O at 60 °C, under vigorous stirring.
b Based on the starting DMDTC (1).
c The first step was carried out at r.t. and the second step at 60 °C.
d GC and 1H NMR analyses of compound 10h are less significant because of its poor solubility in organic solvents; however, comparison of
the mp of the crude product with that of the recrystallized one confirmed its purity.
e Purity was confirmed by TLC analysis (SiO2; CHCl3).
f Purity was confirmed by TLC analysis (SiO2; CHCl3–MeOH, 1:1).
Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York

3500
E. Artuso et al.
PAPER
working at ambient (20–25 °C) or lower temperatures. In At the end of the reactions, the solvents were removed un-
accordance with the reported protocol,14 the reactions be- der reduced pressure, and the residues were dried by treat-
tween DMDTC (1) and several primary aliphatic amines ment with anhydrous toluene or chloroform and then, by
2 (R1 = Me, Et, n-Bu, n-C6H13, c-C6H11, Bn), in a 1:2 mo- under reduced pressure distillation of the toluene/water or
lar ratio, were carried out in water at room temperature chloroform/water azeotropes. Subsequent washings with
(Scheme 2, first step). The aim of the excess amine is two- small amounts of cold ethyl acetate (for 9b–e) or 1,4-di-
fold: to shorten the reaction time and to obtain purer prod- oxane (for 9a) or toluene (for 9f) afforded the pure (GC,
ucts in higher yields. After the disappearance of DMDTC, GC-MS, 1H NMR) ureas 9a–f in overall yields, based on
the reaction mixtures consisting of the formed thiocar- the starting DMDTC, varying from 92% to 96% (Table 2;
bamates 5 and the unreacted amines were extracted with 6 examples, average overall yield 94%).
dichloromethane. The organic solutions were then washed
with aqueous 5% hydrochloric acid to separate out the ex-
cess amine, which was later recovered almost quantita-
tively. Evaporation of the solvent left the crude S-methyl
To prepare unsymmetrical N,N¢-dialkylureas 10 and
N,N,N¢-trialkylureas 11 the crude S- methyl N- alkylthio-
carbamates 5 obtained in the first step were directly react-
ed in the second step with amines, both primary (7:
N-alkylthiocarbamates 5a–f in 95–100% yield and greater
R2 = H; R3 = alkyl) and secondary (8: R2, R3 = alkyl), in
than 99% purity (determined by GC and 1H NMR analy-
water and at temperatures varying between 50 and 60 °C.
ses). The crude products obtained in this first step were
The reactions were monitored by GC and GC-MS analy-
then reacted directly in the second step with ammonia or
ses, and all went to completion in 1 to 16 hours. The slow-
different amines, in water and at temperatures varying be-
est reactions were also carried out under nitrogen, and this
tween 50 °C and 70 °C.
shortened the reaction times to 2–4 hours (compare entries
The best conditions for the synthesis of N-alkylureas 9 8 and 12 with, respectively, entries 7 and 11). Work-up as
were as follows: a 30% aqueous solution of ammonia (6: described above for symmetrical N,N¢-dialkylureas 3, led
R2 = R3 = H) was added with stirring to the crude S-meth- also to the ureas 10 and 11, practically pure (GC purity
yl N-alkylthiocarbamates obtained in the first step, either 99.2–100%) and in overall yields of 93% to 100%, based
as such (5a–c) or to their solutions in 1,4-dioxane (5d–f). on the starting DMDTC. The average yield of the nine ex-
The molar ratio ammonia: 5 varied from 9:1 to 12:1. amples considered was 96%. Table 2 shows the reaction
These mixtures were heated to 60–70 °C in an oil bath. conditions, overall yields of the two steps, purity, and the
GC and GC-MS analyses of the obtained solutions melting points of the unsymmetrical ureas 10a–f and 11a–
showed the progressive decrease of the starting thiocar- c, both crude and crystallized. These reactions allowed
bamates 5 and the progressive increase in the formed N- also the recovery of the formed methanethiol (4) (2 moles
alkylureas 9. The reaction times varied from 3 to 6 hours. for each mole of starting DMDTC).
Table 2 Synthesis and Properties of N-Alkylureas 9a–f, Unsymmetrical N,N¢-Dialkylureas 10a–e, and N,N,N¢-Trialkylureas 11a–c
Entry R1
R2
H
H
H
H
H
H
H
R3
Ratio
5/6–8
N2
–
Temp Time Product Yield GC purity Mp (°C)
(°C)a (h)
(%)b (%)
Crude
Recrystallized
Lit.
1
2
3
4
5
6
Me
H
1:12
1:12
1:12
1:12
1:9
65
70
70
70
70
60
3
6
4
6
6
6
9a
9b
9c
9d
9e
9f
96c
90d
95d
95d
92e
93
100
100
100
101–102
101.9–102.1
(EtOH)
10217
Et
H
–
93.2–93.3
96.6–96.8
93.3
(EtOH)
9217
Bu
H
–
96.8
(EtOH)
9617
n-C6H13
c-C6H11
Bn
H
–
99.5
110.3–111.2 110.8–111.2
(H2O)
107–10920
192–19317
147–14817
157–15921
H
–
100
100
193.6–194.5 193.8–194.5
(EtOH)
H
1:9
–
149.1–149.7 150.4–150.8
(EtOH)
7
8
Me
c-C6H11
1:1.2
–
60
60
16
2
10a
10a
94
94
99.7
99.4
157.7–158.1 158.1–159.0
157.0–157.6 (MeOH)
1:1.05
+
9
Me
H
Bn
1:1.2
+
60
4
10b
95
100
97.4–99.3
98.4–99.5
(EtOH)
97–9822
Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York

PAPER
Preparation of Mono-, Di-, and Trisubstituted Ureas
3501
Table 2 Synthesis and Properties of N-Alkylureas 9a–f, Unsymmetrical N,N¢-Dialkylureas 10a–e, and N,N,N¢-Trialkylureas 11a–c
(continued)
Entry R1
R2
H
R3
Ratio
5/6–8
N2
–
Temp Time Product Yield GC purity Mp (°C)
(°C)a (h)
(%)b (%)
Crude
Recrystallized
Lit.
10
Et
Me
Bn
1:10
50
1
10c
97
100
54.0–54.5
54.3–54.7
(Et2O)
52–5317
11
12
Bu
H
1:1
–
60
60
9
3
10d
10d
100
97
99.2
100.3–101.1 103.1–104.2
9823
1:1.1
+
99.6
101–102
(EtOAc)
13
14
15
n-C6H13
Bn
H
Bn
Bu
Et
1:1
+
+
–
60
60
60
2
7
7
10e
10d
11a
99
95
94
99.5
77.2–78.7
79.2–79.6
(CHCl3–pentane)
77–7824
9823
H
1:3
99.6
102.5–103.4 103.1–104.2
(EtOAc)
f
Me
Et
Bu
1:1.2
100
–
36.5–37.5
(pentane)
34–3525
46–4717
16
17
Me
Bu
1:1.1
1:1.1
–
60
60
9
2
11b
11b
95
95
99.2
99.5
44.2–44.9
44.3–45.3
46.6-48.2
(pentane)
+
18
Et
Pr
Pr
1:1.6
+
60
5
11c
93
99.9
62.7–63.6
63.4–64.1
(pentane)
a The temperatures reported refer to the second reaction step; whereas the first step was carried out at r.t. (20–25 °C).
b Overall yield of the two steps, based on the starting DMDTC (1).
c Crude product, washed with 1,4-dioxane.
d Crude product, washed with EtOAc.
e Crude product, washed with anhyd toluene.
f Oily colorless crystals, as reported.25
In conclusion, this research has confirmed the validity of vantages, these new set-up procedures adapt well for use
S,S-dimethyl dithiocarbonate (1) as an efficient phosgene on both laboratory and industrial scales.
substitute in the carbonylation of aliphatic amines to pro-
duce mono-, di-, and trisubstituted ureas 3,9–11. Indeed,
the advantages of the set-up procedures, with respect to
traditional ones using phosgene and isocyanates (prepared
mostly from phosgene), can be summarized as follows: (i)
use of an easily available reagent, low-cost, nontoxic and
hazard-free, and therefore easy and safe to handle; (ii) use
of a liquid reagent with the consequent simplification of
its measurement and the equipment needed; (iii) exclusive
formation of ureas in high yields and nearly pure, usually
>84% and >99.2%; (iv) easy isolation of the ureas that,
being mostly not soluble in the water in which they are
formed, they are easily collected by simple decantation or
by suction filtration; and (v) formation of a co-product of
industrial interest, methanethiol (4), in an amount of two
moles for each mole of DMDTC. Methanethiol spontane-
ously goes out from the reaction mixtures and, when
working on a large scale,16 it can be recovered almost
quantitatively as sodium methanethiolate. Consequently,
the new procedures exploit all of the DMDTC, with evi-
dent economic and ecological advantages. Furthermore,
differently from methodologies using carbon dioxide or
carbon monoxide/oxygen that usually require rather harsh
conditions and sometimes the presence of catalysts, the
new methodologies based on the use of DMDTC are very
simple and call for neither solvents nor catalysts. Thus,
given their simplicity and economic and ecological ad-
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
200 spectrometer at 200 MHz and 50 MHz, respectively, in CDCl3
or DMSO-d6, unless otherwise noted. Mass spectra were recorded
on an AT 5973N mass selective detector connected to an AT 6890N
GC, cross-linked methyl silicone capillary column. Details for the
1
reactions and yields for the pure (GC, GC-MS, TLC, H NMR)
products are listed in Tables 1 and 2. The molecular structures of all
products were confirmed by comparison of their physical (mp or
bp) and spectral data (MS, 1H NMR) with those reported in the lit-
erature, or with those of authentic samples of analytical purity. All
the amines were purchased from Aldrich and used without further
purification. S,S-Dimethyl dithiocarbonate (1, DMDTC) was ob-
tained from Oxon Italia S.p.A. (Italy)8 or prepared as described in
the literature.7
N,N¢-Dialkylureas 3a–m; Typical Procedures
N,N¢-Dimethylurea (3a)
Procedure A; Table 1, Entry 1: An aq 40% soln of MeNH2 (2,
R1 = Me; 2.33 g, 30 mmol; Aldrich) was added dropwise over a pe-
riod of 5 min to DMDTC (1; 1.22 g, 10 mmol), previously heated in
an oil bath to 60 °C, and maintained under stirring. The reaction was
exothermic, the temperature raised at once to 67–68 °C and a color-
less solution was obtained. Heating at about 60 °C was maintained
until completion of the reaction that was monitored by GC and GC-
MS analyses. After 1 h, the products were S-methyl N-alkylthiocar-
bamate (5a) and the title compound 3a, in a GC ratio of 1:3. After 2
h, the intermediate 5a disappeared and 3a was the only product. The
solvent was removed under reduced pressure and the colorless solid
residue was dried by addition of anhydrous toluene (4–5 mL) and
subsequent distillation under reduced pressure of the toluene/H2O
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3502
E. Artuso et al.
PAPER
azeotrope; yield: 0.85 g (97%); 100% purity (GC analysis); mp
107.6–107.9 °C; mp 107.8–108.3 °C (recrystallized from toluene)
(Lit.17 mp 106 °C).
ture easier, successive portions of H2O (2 × 5 mL) were added after
2 and 4 h. The progress of the reaction was monitored by TLC
(SiO2; CHCl3). After 1 h, DMDTC disappeared and two products
were present, the intermediate S-methyl N-(4-methylbenzyl)thio-
carbamate and the urea 3k, the first as the major product. After 7 h,
the intermediate disappeared and 3k was the only product. The solid
substance was separated by decantation and first treated, under stir-
ring, with a 5% aq soln of HCl (20 mL) and then with H2O (20 mL).
After filtration under reduced pressure, the solid substance was
dried by subsequent additions of anhyd toluene or CHCl3 (3 × 20
mL) and distillation under reduced pressure of the toluene/H2O or
chloroform/H2O azeotropes. The residue was the pure title com-
pound 3k; yield: 2.44 g (91%); mp 224.4–224.9 °C; mp 225.4–
225.6 °C (recrystallized from MeOH) (Lit.18amp 204–205 °C;
Lit.18b mp 215–216 °C).
When the reaction was carried out in the presence of a great excess
of MeNH2 (molar ratio of 1:amine = 1:10), the reaction was com-
plete after 10–15 min. Yield and GC purity of 3a were as above.
N,N¢-Diethylurea (3b; entry 2) was also prepared according to Pro-
cedure A, using an aq 70% soln of EtNH2 (2, R1 = Et; Aldrich); the
molar ratio of 1:EtNH2 was 1:4.
N,N¢-Dibenzylurea (3j)
Procedure B; Table 1, Entry 12: The reaction was carried out ac-
cording to Procedure A, starting from DMDTC (1; 1.22 g, 10 mmol)
and an aq 40% soln of benzylamine (2, R1 = Bn; 2.14 g, 20 mmol)
in H2O (5.35 mL). The mixture was maintained at 60 °C under vig-
orous stirring. After 2 h, GC and GC-MS analyses showed the dis-
appearance of DMDTC. Beside the starting benzylamine, two
products were present, the intermediate S-methyl N-benzylthiocar-
bamate (5j) and N,N¢-dibenzylurea (3j), in a ratio of about 1:1. Dur-
ing the reaction the target product 3j separated out from the mixture
as a colorless solid; subsequent addition of H2O (ca. 3 × 3 mL)
made the stirring easier. The reaction was complete after 24 h, when
compound 5j disappeared, and 3j was the only product. The solid
substance was separated by decantation and first treated with a 5%
aq soln of HCl (10 mL) to remove traces of the unreacted benzyl-
amine and then with H2O (10 mL). After filtration under reduced
pressure, the solid was dried by subsequent addition of anhyd tolu-
ene or CHCl3 (3 × 20 mL) and distillation under reduced pressure of
the toluene/H2O or CHCl3/H2O azeotropes; yield: 2.28 g (95%);
99.2% purity (GC analysis); mp 169.7–170.3 °C; mp 171.7–
172.8 °C (recrystallized from EtOH); (Lit.17 mp 172–173 °C).
N,N¢-Bis(4-chlorobenzyl)urea (3l) and N,N¢-bis(4-aminoben-
zyl)urea (3m) were also prepared according to Procedure D (entries
15 and 16).
N,N¢-Bis(4-aminobenzyl)urea (3m)
Procedure E; Table 1, Entry 17: The reaction was carried out in two
steps. According to the procedure previously reported,14 in the first
step S-methyl N-(4-aminobenzyl)thiocarbamate was prepared start-
ing from DMDTC (1; 1.22 g, 10 mmol) and 4-aminobenzylamine
(2.44 g, 20 mmol) in H2O (15–20 mL) at 20–25 °C for 16 h, under
stirring. After this time, the starting DMDTC disappeared and S-
methyl N-(4-aminobenzyl)thiocarbamate [MS: m/z = 196 (M+)]
was the only product formed. Then N2 was bubbled through the
mixture at 60 °C. After 6 h, the intermediate thiocarbamate disap-
peared and urea 3m was the only product (TLC analysis: CHCl3–
MeOH, 1:1). After a work-up similar to that reported in Procedure
D, the pure title compound 3m was obtained; yield: 2.43 g (90%);
mp 203.6–204.4 °C; mp 203.6–204.4 °C (recrystallized from
MeOH) (Lit.12 mp 200–202 °C).
Alternatively, the solid substance was collected by filtration under
reduced pressure and then dissolved in CH2Cl2–EtOAc (8:1; 160
mL). The organic solution was washed successively with an aq 5%
soln of HCl (20 mL) and H2O (50 mL), dried (Na2SO4) and then
evaporated under reduced pressure. The crude residue was the title
compound 3j; yield and purity were as above.
N,N¢¢-Dicyclohexylurea (3g) was also prepared (entry 9) according
to Procedure E.
Details for the reactions of entries 1–17 are reported in Table 1;
spectral data are given below.
Ureas 3c–e,g,i were also prepared (entries 3–5,7,11) according to
Procedure B. It should be noted that under the adopted conditions
(H2O, 60 °C, with stirring) ureas 3c–e,i emulsified as soon as they
were formed. Instead, when the reaction mixtures were allowed to
cool to r.t., the ureas separated out as colorless solids.
N,N¢-Dimethylurea (3a)
1H NMR (CDCl3): d = 2.73 (d, J = 4.6 Hz, 6 H, 2 × CH3), 5.41 (m,
2 H, 2 × NH); identical to that reported.26
MS (EI, 70 eV): m/z (%) = 88 (100, [M+]), 58 (68, [CH3NHCO]), 44
Procedure C; Table 1, Entry 13: A stream of N2 was bubbled
through the mixture, prepared as described in Procedure B (entry
12) and maintained at 60 °C under stirring, to remove the meth-
anethiol (4) as it was formed. This can be collected in an aq 50%
soln of NaOH and recovered as sodium methanethiolate. The
progress of the reaction was monitored by GC analysis: DMDTC
(1) disappeared after 1 h and the intermediate 5j after 5 h. When the
reaction was complete, the mixture was worked up as described for
Procedure B. The crude title compound 3j was obtained in 93%
yield (2.23 g); 99.6% purity (GC analysis); mp 170.9–171.5 °C.
(7), 31 (19), 30 (54), 28 (17); identical to that reported.26
N,N¢-Diethylurea (3b)
1H NMR (400 MHz, CDCl3): d = 1.05 (t, J = 7.0 Hz, 6 H, 2 × CH3),
3.09 (dq, J = 7.0 Hz, 4 H, 2 × CH2), 5.40 (m, 2 H, 2 × NH); identi-
cal to that reported.26
MS (EI, 70 eV): m/z (%) = 116 (100, [M+]), 101 (12, [M+ – CH3]),
72 (11), 44 (75), 30 (66), 29 (15); identical to that reported.26
N,N¢-Dibutylurea (3c)
According to Procedure C, ureas 3f–h were also prepared (entries
6,8,10). When the amines were not water-soluble (2, R1 = n-C6H13,
n-C10H21), they were added neat (respectively 2.02 g and 3.14 g, 20
mmol) to a suspension of DMDTC (1; 1.22 g, 10 mmol) in H2O (5–
10 mL), under vigorous stirring (entries 6,10).
1H NMR (CDCl3): d = 0.91 (t, J = 7.2 Hz, 6 H, 2 × CH3), 1.25–1.54
[m, 8 H, 2 × CH2(CH2)2CH3], 3.15 (t, J = 6.6 Hz, 4 H, 2 × CH2NH),
4.60 (m, 2 H, 2 × NH); identical to that reported.6b
MS (EI, 70 eV): m/z (%) = 172 (42, [M+]), 130 (16), 129 (14), 101
(17), 100 (13), 87 (11), 72 (11), 57 (19), 44 (41), 41 (22), 30 (100);
identical to that reported.6b
N,N¢-Bis(4-methylbenzyl)urea (3k)
Procedure D; Table 1, Entry 14: 4-Methylbenzylamine (2.42 g, 20
mmol) was added in one portion to a suspension of DMDTC (1;
1.22 g, 10 mmol) in H2O (15 mL) maintained at 60 °C, under vigor-
ous stirring. Then N2 was bubbled through the mixture. After 15–20
min, a colorless solid began to separate out. The amount of precip-
itate increased during the reaction; to make the stirring of the mix-
N,N¢-Diisobutylurea (3d)
1H NMR (CDCl3): d = 0.89 (d, J = 6.7 Hz, 12 H, 4 × CH3), 1.62–
1.82 (m, 2 H, 2 × CH), 2.97 (d, J = 6.8 Hz, 4 H, 2 × CH2), 5.18 (m,
2 H, 2 × NH); identical to that reported.12
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PAPER
Preparation of Mono-, Di-, and Trisubstituted Ureas
3503
MS (EI, 70 eV): m/z (%) = 172 (60, [M+]), 157 (18), 129 (16), 72
(11), 58 (29), 57 (23), 56 (13), 41 (25), 30 (100), 29 (10); identical
to that reported.12
MS (EI, 70 eV): m/z (%) = 268 (38, [M+]), 163 (28), 147 (14), 132
(22), 121 (13), 120 (100), 118 (12), 106 (20), 105 (50), 104 (18), 93
(18), 91 (26), 79 (11), 77 (21).
N,N¢-Di(sec-butyl)urea (3e)
N,N¢-Bis(4-chlorobenzyl)urea (3l)
1H NMR (CDCl3): d = 0.91 (t, J = 7.4 Hz, 6 H, 2 × CH3CH2), 1.12
(d, J = 6.5 Hz, 6 H, 2 × CH3CH), 1.38–1.52 (m, 4 H, 2 × CH2),
3.59–3.72 (m, 2 H, 2 × CH), 4.09 (m, 2 H, 2 × NH); identical to that
reported.6b
1H NMR (DMSO-d6): d = 4.20 (d, J = 6.1 Hz, 4 H, 2 × CH2), 6.53
(t, J = 6.1 Hz, 2 H, 2 × NH), 7.25 (d, J = 8.4 Hz, 4 H, 2 × ArH), 7.37
(d, J = 8.4 Hz, 4 H, 2 × ArH); similar to that reported.27
MS (EI, 70 eV): m/z (%) = 308 (19, [M+]), 183 (19), 167 (29), 142
(32), 140 (100), 138 (24), 132 (92), 127 (23), 125 (75), 106 (46), 89
(25), 77 (38), 75 (23), 32 (22).
MS (EI, 70 eV): m/z (%) = 172 (6, [M+]), 143 (32), 72 (9), 58 (25),
44 (100); identical to that reported.6b
N,N¢-Dihexylurea (3f)
N,N¢-Bis(4-aminobenzyl)urea (3m)
1H NMR (CDCl3): d = 0.88 (d, J = 5.6 Hz, 6 H, 2 × CH3), 1.30 [m,
12 H, 2 × CH2(CH2)3CH2], 1.46–1.52 (m, 4 H, 2 × CH2CH3), 3.15
(app t, J = 6.5 Hz, 4 H, 2 × CH2NH), 4.42 (m, 2 H, 2 × NH); identi-
cal to that reported.6b
1H NMR (DMSO-d6): d = 4.01 (d, J = 5.5 Hz, 4 H, 2 × CH2), 4.91
(br s, 4 H, 2 × NH2), 6.02 (t, J = 5.5 Hz, 2 H, 2 × NH), 6.49 (d,
J = 8.3 Hz, 4 H, 2 × ArH), 6.89 (d, J = 8.3 Hz, 4 H, 2 × ArH); iden-
tical to that reported.12
MS (EI, 70 eV): m/z (%) = 228 (40, [M+]), 199 (30), 185 (41), 158
(14), 128 (18), 115 (12), 102 (20), 101 (19), 100 (11), 56 (11), 55
(13), 44 (36), 43 (33), 41 (22), 30 (100), 29 (11); identical to that re-
ported.6b
MS (direct, 70 eV): m/z (%) = 270 (75, [M+]), 177 (79), 164 (100),
121 (94), 106 (92), 94 (83); identical to that reported.12
S-Methyl N-Alkylthiocarbamates 5a–f; S-Methyl N-Hexylthio-
carbamate (5d); Typical Procedure
N,N¢-Dicyclohexylurea (3g)
According to the procedure previously reported,14 hexylamine (2.02
g, 20 mmol) was added dropwise over a period of 10 min to a sus-
pension of S,S-dimethyl dithiocarbonate (1; 1.22 g, 10 mmol) in
H2O (5 mL), under vigorous stirring. The reaction was mildly exo-
thermic, and during the addition the temperature of the mixture was
maintained at 20–25 °C with an ice-water bath. The progress of the
reaction was monitored by GC and GC-MS analyses. During the re-
action an emulsion was formed. Stirring at r.t. (20–25 °C) was
maintained until disappearance of 1 (2 h). The mixture was then
treated with cold CH2Cl2/aq 5% HCl (2:1, 100 mL). The aqueous
soln was separated and extracted with CH2Cl2 (30 mL). The com-
bined organic extracts were washed with H2O (30 mL), dried
(Na2SO4), and evaporated under reduced pressure to give crude 5d;
yield: 1.75 g (ca. 100%); 99.9% purity (GC analysis); mp 56.5–
57.5 °C (pentane). Studies regarding biological activities of com-
pound 5d are reported in the literature,28 but its physical and spectral
data are not reported.
1H NMR (CDCl3): d = 0.85 (t, J = 6.7 Hz, 3 H, CH3CH2), 1.29 [m,
6 H, CH3CH2(CH2)3CH2], 1.45–1.51 (m, 2 H, CH3CH2), 2.35 (s, 3
H, SCH3), 3.24–3.30 (m, 2 H, CH2NH), 5.42 (m, 1 H, NH).
13C NMR (CDCl3): d = 13.74 (CH3CH2), 15.41 (CH3S), 23.94,
27.85, 31.12, 32.83, 43.00 (CH2), 168.91 (C=O).
MS (EI, 70 eV): m/z (%) = 175 (2, [M+]), 128 (78, [M+ – SCH3]),
112 (24), 99 (100), 85 (81), 75 (20), 56 (58), 43 (86), 29 (16).
1H NMR (DMSO-d6): d = 0.99–1.27, 1.57–1.84 (2 m, 10.5:9.5, 20
H, 10 × CH2), 3.34–3.49 (m, 2 H, 2 × CH), 5.57 (d, J = 7.3 Hz, 2 H,
2 × NH); identical to that reported.6b
MS (EI, 70 eV): m/z (%) = 224 (53, [M+]), 143 (44), 100 (11), 99
(44), 98 (29), 70 (19), 61 (28), 56 (100), 43 (13), 41 (14); identical
to that reported.6b
N,N¢-Didecylurea (3h)
1H NMR (CDCl3): d = 0.88 (t, J = 6.7 Hz, 6 H, 2 × CH3), 1.26–1.72
(m, 32 H, 2 × CH3(CH2)8], 3.12–3.14 (m, 4 H, 2 × CH2NH), 4.37
(m, 2 H, 2 × NH); NMR data are not reported, as measurement of
NMR spectra was difficult because of the very low solubility of 3h
in organic solvents.6b
MS (EI, 70 eV): m/z (%) = 340 (23, [M+]), 255 (26), 241 (27), 158
(19), 112 (21), 99 (42), 57 (20), 56 (21), 55 (33), 44 (30), 43 (40),
41 (34), 30 (100); identical to that reported.6b
N,N¢-Diallylurea (3i)
1H NMR (CD3OD): d = 3.76 (app d, J = 5.1 Hz, 4 H, 2 × CH2NH),
5.07 (dd, J = 10.3, 1.3 Hz, 2 H, 2 × CH), 5.17 (dd, J = 17.2, 1.3 Hz,
2 H, 2 × CH), 5.77–5.96 (m, 2 H, 2 × CH); identical to that report-
ed.6i
MS (EI, 70 eV): m/z (%) = 140 (4, [M+]), 99 (8), 98 (13), 85 (14),
57 (80), 56 (100), 54 (8), 41 (43), 39 (20), 30 (20), 28 (17).
The aqueous layers were collected and evaporated under reduced
pressure. Usual work-up afforded pure (GC and GC-MS analyses)
hexylamine. Its yield, based on excess amine, was 98% (0.99 g).
N,N¢-Dibenzylurea (3j)
1H NMR (DMSO-d6): d = 4.22 (d, J = 5.9 Hz, 4 H, 2 × CH2), 4.34
(t, J = 5.9 Hz, 2 H, 2 × NH), 7.17–7.35 (m, 10 H, 2 × C6H5); similar
to that reported.6b
According to the literature,14 the other S-methyl N-alkylthiocarbam-
ates 5a–c,e,f were also prepared in excellent yields and with a high
degree of purity. Reaction times, yields and GC purity of the crude
products are reported in brackets: S-methyl N-methylthiocarbamate
(5a) (15 min, ca. 100%, 99.8%), S-methyl N-ethylthiocarbamate
(5b) (2 h, 97%, 99.9%), S-methyl N-butylthiocarbamate (5c) (2 h,
ca. 100%, 100%), S-methyl N-cyclohexylthiocarbamate (5e) (24 h,
95%, 99%) and S-methyl N-benzylthiocarbamate (5f) (15 h, 98%,
99.7%). All the thiocarbamates 5a–f were directly used in the next
steps, without further purification.
MS (EI, 70 eV): m/z (%) = 240 (50, [M+]), 149 (21), 107 (11), 106
(100), 91 (51), 79 (18), 77 (12), 65 (12); identical to that reported.6b
N,N¢-Bis(4-methylbenzyl)urea (3k)
1H NMR (DMSO-d6): d = 2.26 (s, 6 H, 2 × CH3), 4.16 (d, J = 6.0
Hz, 4 H, 2 × CH2), 6.33 (t, J = 6.0 Hz, 2 H, 2 × NH), 7.09 (d, J = 8.6
Hz, 4 H, 2 × ArH), 7.13 (d, J = 8.6 Hz, 4 H, 2 × ArH). The title com-
pound is known,18a,b but the spectral data are not reported.
13C NMR (CDCl3): d = 22.55 (2 × CH3), 44.58 (2 × CH2), 128.87,
130.63 (4 × CH, ArH), 137.42, 139.70 (4 × C, ArH), 159.92 (C=O).
N-Alkylureas 9a–f; N-Hexylurea (9d); Typical Procedure
The reaction mixture containing the crude S-methyl N-hexylthiocar-
bamate obtained in the previous step (5d; 1.75 g, 10 mmol), 1,4-di-
oxane (5 mL), and an aq 30% soln of NH3 (6, R1 = R2 = H; 4.53 g,
80 mmol) was heated in an oil-bath to 70 °C, under stirring. A col-
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3504
E. Artuso et al.
PAPER
orless solution was obtained. Progress of the reaction was moni-
tored by GC and GC-MS analyses. Two portions of NH3, each of
1.13 g (20 mmol), were added after 2 and 4 h (the GC ratio 5d:9d
was about 1:1 after 2 h and 1:3 after 4 h). The reaction was complete
after a total of 6 h. The solvents (H2O and 1,4-dioxane) were then
removed under reduced pressure. A colorless solid substance was
obtained in ca. 100% yield (1.44 g); mp 106.8–108.0 °C; GC purity
98.6% [the by-product present was N,N¢-dihexylurea; MS: m/z =
228 (M+)]. The crude product was washed with cold (0 °C) EtOAc
(1–2 mL). The title compound 9d was obtained pure (GC analysis)
in 95% (1.36 g) overall yield for the two steps, based on the starting
DMDTC (1); mp 110.3–111.2 °C; mp 110.8–111.2 °C (recrystal-
lized from H2O) (Lit.20 mp 107–109 °C).
N-Benzyl-N¢-hexylurea (10e); Typical Procedure
A suspension of crude S-methyl N-hexylthiocarbamate (5d; 1.75 g,
10 mmol), obtained in the first step as described above, in H2O (5
mL) was heated to 60 °C in an oil-bath, under vigorous stirring. An
aq 40% soln of benzylamine (1.07 g, 10 mmol) in H2O (2.7 mL) was
added dropwise and then N2 was flushed through the mixture. At
once 5d became an oil that emulsified in the reaction medium.
Progress of the reaction was monitored by GC and GC-MS analy-
ses. After 1 h, a colorless solid separated out from the mixture. To
make the stirring easier, another portion of H2O (5 mL) was added.
The reaction was complete after 2 h when 5d disappeared and 10e
was the only product. The mixture was extracted with CH2Cl2
(2 × 80 mL); the organic layers were collected and washed with aq
5% HCl (50 mL) and then with H2O (50 mL), dried (Na2SO4), and
evaporated under reduced pressure. The crude residue was the title
compound 10e; overall yield of the two steps, based on the starting
DMDTC (1): 2.32 g (99%); 99.5% purity (GC analysis); mp 77.2–
78.7 °C; mp 79.2–79.6 °C (recrystallized from CHCl3–pentane)
(Lit.24 mp 77–78 °C).
Details for the reactions are given in Table 2, entries 1–6 for ureas
9a–f; spectral data are reported below.
N-Methylurea (9a)
1H NMR (400 MHz, DMSO-d6): d = 2.46 (d, J = 5.0 Hz, 3 H, CH3),
5.49 (br s, 2 H, NH2), 5.85 (br s, 1 H, NH); identical to that of an
authentic sample (Aldrich) of analytical purity.
According to the same procedure, N,N¢-dialkylureas 10a–d and
N,N,N¢-trialkylureas 11a–c were also prepared. Ureas could be sep-
arated from the reaction medium by extraction with CH2Cl2, as
above, or by decantation, or by filtration under suction. In these two
last work-ups, the products were then dried by treatments with an-
hyd toluene or CHCl3 and subsequently under reduced pressure
evaporation of the toluene/H2O or CHCl3/H2O azeotropes.
MS (EI, 70 eV): m/z (%) = 74 (100, [M+]), 58 (15), 44 (32), 31 (22),
30 (47), 28 (21); identical to that of an authentic sample (Aldrich)
of analytical purity.
N-Ethylurea (9b)
1H NMR (400 MHz, CDCl3): d = 1.16 (t, J = 7.0 Hz, 3 H, CH3),
3.20 (dq, J = 7.0 Hz, 2 H, CH2), 5.01 (br s, 2 H, NH2), 5.55 (m, 1 H,
NH); identical to that of an authentic sample (Aldrich) of analytical
purity.
Details for the reactions are given in Table 2, entries7–18 for ureas
10a–e and 11a–c; spectral data are reported below.
N-Cyclohexyl-N¢-methylurea (10a)
MS (EI, 70 eV): m/z (%) = 88 (100, [M+]), 73 (88), 44 (90), 43 (18),
42 (16), 30 (82), 29 (14), 28 (19); identical to that of an authentic
sample (Aldrich) of analytical purity.
1H NMR (CDCl3): d = 1.07–1.44, 1.65–1.74, 1.84–1.95 (3 m, 3:1:1,
10 H, 5 × CH2), 2.77 (d, J = 4.9 Hz, 3 H, CH3), 3.43–3.57 (m, 1 H,
CH), 4.55 (m, 2 H, 2 × NH); the title compound is known,21 but the
spectral data are not reported.
N-Butylurea (9c)
1H NMR (400 MHz, CDCl3): d = 0.75–1.15 (m, 3 H, CH3), 1.20–
1.72 [m, 4 H, CH3(CH2)2CH2], 2.96–3.38 (m, 2 H, CH2NH), 5.00
(br s, 2 H, NH2), 7.75 (m, 1 H, NH); identical to that of an authentic
sample (Aldrich) of analytical purity.
13C NMR (CDCl3): d = 26.42 (2 × CH2), 27.07 (CH2), 28.37 (CH3),
35.41 (2 × CH2), 50.34 (CH), 160.30 (C=O).
MS (EI, 70 eV): m/z (%) = 156 (53, [M+]), 113 (18), 98 (13), 75
(50), 70 (14), 58 (16), 56 (100), 55 (12), 43 (16), 41 (10).
MS (EI, 70 eV): m/z (%) = 116 (19, [M+]), 87 (24), 74 (41), 73 (69),
44 (44), 43 (14), 41 (13), 30 (100), 29 (10), 28 (11); identical to that
of an authentic sample (Aldrich) of analytical purity.
N-Benzyl-N¢-methylurea (10b)
1H NMR (CDCl3): d = 2.63 (br s, 3 H, CH3), 4.25 (d, J = 5.0 Hz, 2
H, CH2), 5.21 (m, 1 H, NH), 5.55 (m, 1 H, NH), 7.23–7.27 (m, 5 H,
C6H5); similar to that reported.29
N-Hexylurea (9d)
1H NMR (DMSO-d6): d = 0.85 (t, J = 6.9 Hz, 3 H, CH3), 1.23–1.31
[m, 8 H, CH3(CH2)4CH2], 2.91 (m, 2 H, CH2NH), 5.34 (br s, 2 H,
NH2), 5.87 (m, 1 H, NH); similar to that reported.20
MS (EI, 70 eV): m/z (%) = 164 (84, [M+]), 107 (13), 106 (100), 104
(15), 91 (56), 79 (22), 77 (19), 65 (12), 58 (11).
MS (EI, 70 eV): m/z (%) = 144 (18, [M+]), 115 (24), 101 (26), 88
(10), 87 (19), 74 (48), 73 (96), 61 (14), 44 (35), 30 (100); identical
to that reported.20
N-Ethyl-N¢-methylurea (10c)
1H NMR (400 MHz, CDCl3): d = 1.12 (t, J = 7.0 Hz, 3 H, CH2CH3),
2.75 (d, J = 5.0 Hz, 3 H, CH3NH), 3.17 (dq, J = 7.0 Hz, 2 H, CH2);
identical to that reported.30
N-Cyclohexylurea (9e)
MS (EI, 70 eV): m/z (%) = 102 (100, [M+]), 87 (22), 58 (30), 44
(44), 31 (10), 30 (49), 29 (10), 28 (12).
1H NMR (DMSO-d6): d = 0.96–1.32, 1.48–1.74 (2 m, 1:1, 10 H,
5 × CH2), 3.26 (m, 1 H, CH), 5.30 (br s, 2 H, NH2), 5.82 (d, J = 7.7,
1 H, NH); similar to that reported.20
N-Benzyl-N¢-butylurea (10d)
MS (EI, 70 eV): m/z (%) = 142 (23, [M+]), 99 (40), 70 (11), 61 (43),
1H NMR (CDCl3): d = 0.85 (t, J = 6.8 Hz, 3 H, CH3), 1.23–1.35 [m,
4 H, CH3(CH2)2], 2.99–3.04 (m, 2 H, CH2NH), 4.21 (d, J = 5.0 Hz,
2 H, CH2C6H5), 5.34 (m, 1 H, NH), 5.68 (m, 1 H, NH), 7.20–7.25
(m, 5 H, C6H5); identical to that reported.23
56 (100), 43 (28), 41 (10); identical to that reported.20
N-Benzylurea (9f)
1H NMR (400 MHz, DMSO-d6): d = 4.15 (d, J = 6.0 Hz, 2 H, CH2),
5.42 (br s, 2 H, NH2), 6.35 (m, 1 H, NH), 7.05–7.25 (m, 5 H, C6H5);
identical to that reported.26
MS (EI, 70 eV): m/z (%) = 206 (100, [M+]), 107 (16), 106 (87), 104
(10), 91 (72), 79 (12), 77 (12), 65 (12), 44 (12), 30 (21).
MS (EI, 70 eV): m/z (%) = 150 (65, [M+]), 107 (20), 106 (100), 105
(10), 104 (15), 91 (30), 79 (32), 78 (12), 77 (25), 51 (11); identical
to that reported.26
N-Benzyl-N¢-hexylurea (10e)
1H NMR (DMSO-d6): d = 0.86 (t, J = 6.4 Hz, 3 H, CH3), 1.24–1.35
[m, 8 H, CH3(CH2)4CH2], 4.18 (d, J = 5.8 Hz, 2 H, CH2NH), 5.90
(t, J = 4.6 Hz, 1 H, NH), 6.26 (t, J = 5.8 Hz, 1 H, NH), 7.20–7.34
Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York

PAPER
Preparation of Mono-, Di-, and Trisubstituted Ureas
3505
(m, 5 H, C6H5); the title compound is known,24 but the spectral data
are not reported.
13C NMR (CDCl3): d = 15.43 (CH3), 23.99, 27.96, 31.58, 32.50,
42.02 (CH2), 45.89 (CH2C6H5), 128.65 (CH, ArH), 128.82, 130.01
(2 × CH, ArH), 140.80 (C, ArH), 159.85 (C=O).
(3) For a plentiful recent literature (until 2003) on the synthesis
and applications of substituted ureas see: Gabriele, B.;
Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004, 69,
4741; and references cited therein.
(4) Some recent references (after 2003) on new applications of
substituted ureas: (a) Martinez Gil, A.; Medina Padilla, M.;
Castro Morera, A.; Alonso Cascon, M.; Martin Aparicio, E.;
Fuertes Huerta, A.; Navarro Rico, M. L.; Perez Puerto, M. J.
Neuropharma S. A., Spain, EP 1749523, 2007; Chem. Abstr.
2007, 146, 206112. (b) Bhalay, G.; Dunstan, A.; Glen, A.;
Howe, T. J.; McCarthy, C. Novartis AG Switzerland,
Novartis Pharma GmbH, WO 015852, 2006; Chem. Abstr.
2006, 144, 232805. (c) Dasseux, J.-L. H.; Oniciu, D. C.
Esperion Therapeutics Inc. USA, WO 068420, 2005; Chem.
Abstr. 2005, 143, 172557. (d) Carruthers, N. I.; Shah, C. R.;
Swanson, D. M. Janssen Pharmaceutica, N. V., Belgium,
WO 014580, 2005; Chem. Abstr. 2005, 142, 240468.
(e) Defossa, E.; Kadereit, D.; Klabunde, T.; Burger, H.-J.;
Herling, A.; Wendt, K.-U.; Von Roedern, E.; Schoenafinger,
K.; Enhsen, A. Aventis Pharma Deutschland GmbH,
Germany, WO 065356, 2004; Chem. Abstr. 2004, 141,
173980.
MS (EI, 70 eV): m/z (%) = 234 (100, [M+]), 191 (13), 164 (10), 106
(78), 107 (18), 91 (72), 79 (11), 65 (10), 44 (12), 30 (23).
N,N-Diethyl-N¢-methylurea (11a)
1H NMR (CDCl3): d = 1.09 (t, J = 7.1 Hz, 6 H, 2 × CH2CH3), 2.77
(d, J = 4.0 Hz, 3 H, CH3NH), 3.22 (q, J = 7.1 Hz, 4 H,
2 × CH2CH3), 4.46 (m, 1 H, NH); identical to that reported.25
MS (EI, 70 eV): m/z (%) = 130 (47, [M+]), 115 (33), 72 (27), 58
(100), 44 (24).
N,N-Dibutyl-N¢-methylurea (11b)
1H NMR (CDCl3): d = 0.93 (t, J = 7.1 Hz, 6 H, 2 × CH2CH3), 1.21–
1.40 and 1.40–1.59 (2 m, 1:1, 8 H, 2 × CH2(CH2)2CH3], 2.80 (d,
J = 4.5 Hz, 3 H, CH3NH), 3.16 [app t, J = 7.5 Hz, 4 H,
N(CH2CH2CH2CH3)2], 4.26 (m, 1 H, NH); identical to that report-
ed.30
(5) Some recent references (after 2003) on the use of
monoalkyl-, dialkyl-, and trialkylureas in organic synthesis:
(a) Fritz, J. A.; Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006, 8,
2531. (b) Sigachev, A. S.; Kravchenko, A. N.; Gazieva, G.
A.; Belyakov, P. A.; Kolotyrkina, N. G.; Lebedev, O. V.;
Makhova, N. N.; Lyssenko, K. A. J. Heterocycl. Chem.
2006, 43, 1295. (c) Gel’mbol’dt, V. O.; Koroeva, L. V.;
Filinchuk Ya, E. Russ. J. Coord. Chem. 2005, 31, 775.
(d) Natarajan, A.; Guo, Y.; Arthanari, H.; Wagner, G.;
Halperin, J. A.; Chorev, M. J. Org. Chem. 2005, 70, 6362.
(e) Hansen, A. L.; Skrydstrup, T. J. Org. Chem. 2005, 70,
5997. (f) Kravchenko, A. N.; Sigachev, A. S.; Maksareva, E.
Y.; Gazieva, G. A.; Trunova, N. S.; Lozhkin, B. V.; Pivina,
T. S.; Il’in, M. M.; Lyssenko, K. A.; Nelyubina, Y. V.;
Davankov, V. A.; Lebedev, O. V.; Makhova, N. N.;
Tartakovsky, V. A. Russ. Chem. Bull. 2005, 54, 691.
(g) Zhou, X.; Chen, Y.; Liu, B. Faming Zhuanli Shenqing
Gongkai Shuomingshu, CN 1515540 A, 2004; Chem. Abstr.
2005, 143, 77851.
MS (EI, 70 eV): m/z (%) = 186 (18, [M+]), 143 (32), 87 (10), 86
(100), 58 (13), 57 (10), 44 (31).
N,N-Dipropyl-N¢-ethylurea (11c)
1H NMR (CDCl3): d = 0.89 (t, J = 7.4 Hz, 6 H, 2 × CH2CH2CH3),
1.13 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.55 (app q, J = 7.5 Hz, 4 H,
2 × CH2CH2CH3), 3.13 [app t, J = 7.5 Hz, 4 H, N(CH2CH2CH3)2],
3.20–3.33 (m, 2 H, CH2NH), 4.24 (m, 1 H, NH).
13C NMR (CDCl3): d = 12.80 (2 × CH2CH2CH3), 17.14 (CH2CH3),
23.19
(2 × CH2CH2CH3),
37.01
(CH2CH3),
50.46
(2 × CH2CH2CH3), 159.14 (C=O).
MS (EI, 70 eV): m/z (%) = 172 (19, [M+]), 143 (24), 72 (100), 43
(10).
Anal. Calcd for C9H20N2O: C, 62.75; H, 11.70; N, 16.26. Found: C,
62.82; H, 11.74; N, 16.31.
Acknowledgment
(6) Some recent references (after 2003) on the synthesis of
monoalkyl-, dialkyl-, and trialkylureas: (a) Peng, X.; Li, F.;
Xia, C. Synlett 2006, 1161; and references cited therein.
(b) Mizuno, T.; Mihara, M.; Iwai, T.; Ito, T.; Ishino, Y.
Synthesis 2006, 2825; and references cited therein. (c) Zhu,
B.; Angelici, R. J. J. Am. Chem. Soc. 2006, 128, 14460.
(d) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.;
Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71, 5951;
and references cited therein. (e) Fan, X.; Rui, B.; Yan, L.;
Li, C. Faming Zhuanli Shenqing Gongkai Shuomingshu,
CN 1827594 A, 2006; Chem. Abstr. 2006, 145, 397096.
(f) Wang, C.; Li, Y.; Du, M.; Xu, S.; Zheng, C.; Wang, C.;
Yang, X.; Shi, L.; Wang, W. Faming Zhuanli Shenqing
Gongkai Shuomingshu, CN 1740140 A, 2006; Chem. Abstr.
2006, 145, 10086. (g) Li, Z.; Wang, Z.-Y.; Zhu, W.; Xing,
Y.-L.; Zhao, Y.-L. Synth. Commun. 2005, 35, 2325.
(h) Nishiyama, Y.; Kawamatsu, H.; Sonoda, N. J. Org.
Chem. 2005, 70, 2551. (i) Perveen, S.; Abdul Hai, S. M.;
Khan, R. A.; Khan, K. M.; Afza, N.; Sarfaraz, T. B. Synth.
Commun. 2005, 35, 1663. (j) Enquist, P.-A.; Nilsson, P.;
Edin, J.; Larhed, M. Tetrahedron Lett. 2005, 46, 3335.
(k) Fujita, S.; Bhanage, B. M.; Kanamaru, H.; Arai, M. J.
Mol. Catal. A: Chem. 2005, 230, 43; and references cited
This work was supported by the Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (MURST) and the National
Research Council (CNR), Italy, National Project ‘New synthetic
methodologies for industrial intermediates and products’ and by the
University of Turin.
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Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York

3506
E. Artuso et al.
PAPER
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Synthesis 2007, No. 22, 3497–3506 © Thieme Stuttgart · New York