An environmentally benign access to carbamates and ureas

Article abstract of DOI:10.1016/S0040-4039(00)01051-0

Ureas were synthesized from methyl carbamates which were obtained by reaction of amines with dimethylcarbonate. Both reactions were catalyzed by γ-A1₂O₃. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01051-0

Tetrahedron Letters 41 (2000) 6347±6350
An environmentally benign access to carbamates and ureas
Isabelle Vauthey, Frederic Valot, Christel Gozzi, Fabienne Fache
 Â
and Marc Lemaire*
Laboratoire de Catalyse et SyntheÁse Organique, Unit e Mixte de Recherches 5622, Universite Claude Bernard Lyon I,
B aà t. 308 CPE, 43 Bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France
Received 14 March 2000; accepted 20 June 2000
Abstract
Ureas were synthesized from methyl carbamates which were obtained by reaction of amines with
dimethylcarbonate. Both reactions were catalyzed by g-Al O . # 2000 Elsevier Science Ltd. All rights
reserved.
2
3
Keywords: carbamate synthesis; urea synthesis; heterogeneous catalysis; dimethylcarbonate.
The carbamate and urea functions are widely encountered in the structure of biologically active
3,4
1,2
compounds. These compounds are generally prepared from phosgene, phosgene derivatives
5
or isocyanates in reaction with alcohols in the case of carbamates and amines in the case of
ureas. Nevertheless, none of these methods are environmentally benign (use of toxic reagents and
generation of by-products).
In the case of carbamates, numerous methods have been described to avoid such drawbacks.
6
Tetraethylammonium hydrogen carbonate (Et NHCO ) was recently described as a safe reagent
4
3
to obtain carbamates from amines but this method generates salts as by products. Hofmann rear-
rangement7 also allowed the synthesis of carbamates from amides. Mono- and di-substituted
ureas were obtained by reductive alkylation of aromatic ureas using an aldehyde with NaBH and
,8
4
9
TMSCl. Nevertheless, this is only suitable for aromatic aldehydes. Solid-phase synthesis is used
0
10
more and more for the obtention of urea libraries using thiophenoxy carbonyl linker or 1,1 -
carbonylbisbenzotriazole.11 Heterogeneous catalysis has also been reported for carbamate and
urea synthesis. For example, platinum group metals have been developed to catalyze the
alkoxycarbonylation of amines leading to carbamates.1
2,13
Nevertheless, this reaction requires the
use of carbon monoxide. Zinc, as well, promoted the synthesis of carbamates starting from
chloroformates and amines.14 Dimethylcarbonate was used with lead derivatives as catalysts for
the synthesis of methyl-N-phenylcarbamate from aniline.15 Tin derivatives were also patented for
*
Corresponding author. Fax: 33 (0) 4 72 43 14 08; e-mail: marc.lemaire@univ-lyon1.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01051-0

6
348
the same purpose.16 Symmetric diphenyl ureas were synthesized from primary amines and ethyl
acetoacetate17 using zeolite HSZ-360. Recently, phenyl carbamates were also used as
intermediates but DMSO was required as solvent and the synthesis of phenyl carbamates
generates salt.18
In the course of our studies on the use of heterogeneous catalysis in ®ne organic chemistry, we
developed a method which allows the direct synthesis of methyl carbamates from amines and
dimethylcarbonate (DMC). Furthermore, the resulting carbamates could be transformed into
symmetrical or unsymmetrical ureas after reaction with amines. These reactions are theoretically
possible without catalysts but are too slow to be useful preparative methods. We have tested
various inorganic catalysts (zeolites and alumina). Best results were obtained with g-alumina
which was used as a catalyst for both reactions (Fig. 1).
Figure 1. Synthesis of carbamates and ureas using g-alumina
The typical procedure for the synthesis of carbamates was as follows: 4.16 mmol of amine and
19
the same weight of g-alumina were mixed in dimethyl carbonate ([amine]=0.28 M) and
re¯uxed. The reaction mixture was ®ltered on Celite and carbamate was obtained without further
puri®cation after the evaporation of DMC. Reacting amine and dimethylcarbonate without
catalyst does not yield signi®cative amounts of carbamate except in the case of piperidine.
Isolated yields were good to excellent because only small amounts of by-products were formed
(
N-methylated amine) (Table 1). In the case of product 5, only the dicarbamate was detected and
0
it was noticeable that the 4,4 -methylenedianiline was more reactive than aniline (1 day for the
formation of 5 instead of 2 for the formation of 2). The importance of the procedure lies in the
fact that the carboxyalkylating agent is dimethyl carbonate which is easy to handle, cheap and a
clean reagent. Furthermore, the only by-product is methanol.
The typical procedure for the synthesis of ureas was as follows: 16.8 mmol of carbamate, the
same weight of g-alumina and 2 equivalents of amine were mixed in toluene ([carbamate]=1.68
M) and put under re¯ux. The reaction mixture was ®ltered on Celite and the urea was obtained
without further puri®cation after evaporation of toluene. Without alumina, there is no reaction.
Two equivalents of amine were necessary to ensure a reasonable reaction time for total
conversion. In the case of 5, only the diurea 11 was obtained (Table 2). The reactivity of 5 was
higher than the reactivity of the other carbamates, since it was completely transformed into 11 in
only 1 day. After 2 days, the conversion of 4 into product 10 was not complete and puri®cation
over SiO was necessary. This explains the moderate isolated yield compared to the others.
2
For both reactions, we have investigated the possibility to decrease the quantity of alumina,
but the reaction time thus considerably increased. Nevertheless, the catalyst is also cheap and safe
and could be reused after thermal activation.
In conclusion, we present here a very simple method which seems to be particularly valuable
from both an economic and an environmental point of view.

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349
Table 1
Preparation of carbamate from di€erent amines
Table 2
Synthesis of ureas from carbamates

6
350
References
1
2
. Norwick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha, G. J. Org. Chem. 1992, 57, 7364±7366.
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Weinheim, 1986; p. 51.
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. Inesi, A.; Mucciante, V.; Rossi, L. J. Org. Chem. 1998, 63, 1337±1338.
. Matsumura, Y.; Maki, T.; Satoh, Y. Tetrahedron Lett. 1997, 38, 8879±8882.
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. Xu, D.; Ciszewski, L.; Li, T.; Repic, O.; Blacklock, T. Tetrahedron Lett. 1998, 39, 1107±1110.
1
1
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2
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0. Dressman, B.; Singh, U.; Kaldor, S. Tetrahedron Lett. 1998, 39, 3631±3634.
1. Nieuwenhuijzen, J.; Conti, P.; Ottenheijm, H.; Linders, J. Tetrahedron Lett. 1998, 39, 7811±7814.
2. Fukuoka, S.; Masazumi, C.; Kohno, M. J. Org. Chem. 1984, 49, 1460±1461.
3. Alper, H.; Hartstock, F. J. Chem. Soc., Chem. Commun. 1985, 1141±1142.
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8. Thavonekham, B. Synthesis 1997, 1189±1194.
2
9. g-Al
2
O
3
was purchased from Degussa (oxid C (g), 100 m /g, d=60 g/l).
0. Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahedron: Asymmetry 1994, 5, 363±370.
1. Aresta, M.; Berloco, C.; Quaranta, E. Tetrahedron 1995, 51, 8073±8088.
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1
3. Hirsch, J. A.; Augustine, R. L.; Koletar, G.; Wolf, H. G. J. Org. Chem. 1975, 40, 3547. Product 3: H NMR
(
CDCl ): 3.78 (s, 3H, OCH ), 7.05 (bs, 1H, NH), 7.39 (d, J=8.3 Hz, 1H), 7.61 (dd, J=8.7, 6.4 Hz, 1H), 7.72 (s,
3 3
1
H); 13C NMR: 52.73, 117.70 (q, J=174 Hz, CF
3
), 122.62, 126.05, 128.85 (d, J=31.6 Hz), 132.03, 136.90, 153.95
): 3.76 (s, 3H, OCH ), 3.88 (s, 2H, CH ), 7.09 (m, 4H), 7.26
ꢀ
1
(
(
7
2
3
1
CˆO), mp=100±101 C. Product 5: H NMR (CDCl
3
3
2
1
3
m, 4H); C NMR (d DMSO): 39.76 (CH ), 51.46 (CH ), 118.35, 128.80, 135.46, 137.01, 153.97 (CˆO). Product
6
2
3
1
: H NMR (CDCl ): 0.81 (t, 3H, J=6.3 Hz, CH
H, CH N), 3.59 (s, 3H, OCH
2
3
3
), 1.21 (s, 10H, 5CH
2
), 1.40 (m, 2H, CH
): 13.93 (CH ), 22.54, 26.66, 29.12, 29.92, 31.70,
2
), 3.09 (q, J=6.5 Hz,
), 4.97 (s, NH); 13C NMR (CDCl
3
3
3
1
1.74, 41.00 (CH ), 51.76 (OCH ), 157.08 (CˆO). Product 8: H NMR (CDCl ): 0.88 (t, 3H, J=6.4 Hz, CH ),
2
3
3
3
.24 (m, 12H, CH
2
), 1.41 (d, 2H, J=6.9 Hz, CH
3
), 3.1 (m, 2H, N-CH
2
), 4.8 (q, 1H, J=6.6 Hz, CH), 4.9 (bs, 1H,
NH), 5.4 (bs, 1H, NH), 7.29 (m, 5H aro); 13C NMR: 14.12 (CH
), 22.69 (CH
3
2 3
), 23.47 (CH ), 26.90, 29.29, 29.74,
1
3
NMR (CDCl
0.25, 31.86, 40.42 (6CH ), 50.04 (CH), 125.90, 127.12, 128.65 (C ), 144.57 (C ), 158.17 (CˆO). Product 9: H
2
aro
q
3
): 0.91 (t, 3H, J=7 Hz, CH
3
), 1.15 (m, 11H, CH
3
+4CH
2
), 2.6 (t, 2H, J=7 Hz, CH
), 14.05 (CH ), 20.23, 20.56 (CH
), 51.38 (CH), 126.04, 126.96, 128.56 (Caro), 144.87 (C
2
N), 3.17 (t, 2H,
J=6.8 Hz, N-CH
2
2
), 5.00 (m, 1H, CH), 7.30 (m, 5H aro); 13C NMR: 13.92 (CH
3
3
2
),
),
2.79 (CH
3
), 30.83, 32.23, 47.09, 49.80 (4CH
2
q
ꢀ
1
56.93(CˆO). Product 10: mp=130 C; 1H NMR (d6 DMSO): 0.86 (t, 3H, J=6.8 Hz, CH ), 1.26 (m, 10H,
3
2 2 2
CH ), 1.40 (m, 2H, CH ), 3.05 (m, 2H, N-CH ), 6.15 (t, 1H, J=5.6 Hz, NH), 7.26 (m, 2H aro), 7.40 (m, 2H aro),
8
1
4
.5 (s, 1H, NH); 13C NMR: 13.89 (CH
3 2
), 22.03, 26.32, 28.64, 28.69, 29.64, 31.19, 39.01 (7CH ), 118.98, 124.27,
1
28.38, 139.57 (Caro), 154.98 (CˆO). Product 11: H NMR (CDCl ): 1.27 (s, 20H, CH ), 1.42 (s, 4H, CH ), 1.49 (t,
3
2
2
2 2
H, J=6.8 Hz, N-CH ), 1.59 (s, 2H, NH), 3.89 (s, 2H, CH ), 7.12 (m, 4H), 7.26 (m, 4H). All products gave the
expected elemental analyses within 0.2%.