Reaction of aromatic amines and ethyl acetoacetate promoted by zeolite HSZ-360. Phosgene-free synthesis of symmetric diphenylureas

Article abstract of DOI:10.1039/a708019k

Reaction of aromatic amines 1 with ethyl acetoacetate 2 in the presence of the commercially available acid zeolite HSZ-360 gives symmetric diphenylureas 3 in good yields and excellent selectivities.

Full text of DOI:10.1039/a708019k

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Reaction of aromatic amines and ethyl acetoacetate promoted by zeolite
HSZ-360. Phosgene-free synthesis of symmetric diphenylureas
Franca Bigi, Raimondo Maggi, Giovanni Sartori*† and Elena Zambonin
Dipartimento di Chimica Organica e Industriale dell’Universita`, Viale delle Scienze, I-43100 Parma, Italy
Reaction of aromatic amines 1 with ethyl acetoacetate 2 in
the presence of the commercially available acid zeolite HSZ-
360 gives symmetric diphenylureas 3 in good yields and
excellent selectivities.
aminocrotonates or acetoacetoanilides,8 depending on the
temperature. We found that DPUs could be obtained as the sole
reaction products by heating the same mixture in the presence of
different solid acids (Table 1).
The reaction of p-anisidine, selected as the model substrate,
with 2 in the presence of zeolite HSZ-3609 in o-dichlorobenzene
at 180 °C for 5 h gave N,NA-bis(4-methoxyphenyl)urea which
was isolated in 60% yield and 93% selectivity (entry g). Zeolite
HSZ-330,10 with higher acidity and comparable surface area,
was less effective (entry f). The use of two montmorillonites,
K10 and KSF,11 gave the product with lower yield and similar,
high selectivity independent of surface area and acidity (entries
d and e).
The acidity of the catalyst is likely to play an important role
in the activation of 2. Note that the present system seems to
require an optimum acidity level with respect to both strength
and nature of the individual Brønsted and Lewis sites. Indeed,
the more active zeolite HSZ-360 has a lower concentration of
acid sites than HSZ-330, but the individual sites are more
strongly acidic.9,10 Moreover the use of typical hard Brønsted
and Lewis acids such as TsOH, ZnCl2 and AlCl3 results in the
production of untractable mixtures of compounds (entries a, b
and c).
Zeolites and other solid acids have opened new perspectives in
synthetic organic chemistry not only in terms of yield and
selectivity, but also concerning the work-up and the effluent
pollution.1 The use of both solid acids and non-toxic reagents
leads to a substantial reduction in cost and environmental
impact of the production processes.2 Here we report preliminary
results of our study concerning the synthesis of symmetric
diphenylureas (DPUs) from aromatic amines and ethyl aceto-
acetate under solid acid catalysis.
Substituted ureas have received considerable attention due to
their wide range of applications, e.g. for use as antidiabetic and
tranquillizing drugs, antioxidants in gasoline, corrosion in-
hibitors and herbicides.3 The conventional methods reported for
the urea synthesis are essentially based on phosgene and
isocyanates,4 phosgene substitutes,5 carbonates and carba-
mates6 or carboxylic acid derivatives.7 However, phosgene and
isocyanates are toxic and expensive to handle and the above
methods are often difficult to apply. There is, thus, a continuing
interest in the catalytic synthesis of ureas via phosgene-free
reactions. Our strategy, utilizing ethyl acetoacetate as carbox-
ylating agent in place of phosgene and solid acids as catalysts
represents an efficient, innovative and environmentally safe
method for the synthesis of DPUs.
The best result was achieved by carrying out the reaction with
zeolite HSZ-360 under solventless conditions (76% yield, 95%
selectivity) (entry h). This result is of particular interest since
o-dichlorobenzene is on the ‘black list’ of the environmentally
incompatible solvents.12. In the control experiment with no
zeolite catalyst only p-methoxyacetoacetanilide was recovered
as reported above.8 The general applicability of the present
The reaction of aromatic amines 1 with ethyl acetoacetate 2
has been described in the literature to produce ethyl b-aryl-
Table 1 Formation of DPUs in the presence of different solid acid catalysts
NH2
H
N
H
N
O
O
Catalyst
+
O
180 °C, 5 h
OEt
R
R
R
1
2
3
Surface
Surface
area/
m2 g21
acidity/
mequiv.
H+ g21
Yield
(%)
Selectivity
(%)
Entry
R
Catalyst
Solvent
a
b
c
d
e
f
g
h
i
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
H
TsOH
ZnCl2
AlCl3
KSF
1,2-Cl2C6H4
1,2-Cl2C6H4
1,2-Cl2C6H4
a
a
a
—
—
—
92
90
94
93
95
95
93
94
96
15 ± 10
200 ± 10
460 ± 10
500 ± 10
500 ± 10
500 ± 10
500 ± 10
500 ± 10
500 ± 10
0.85 ± 0.03 1,2-Cl2C6H4
0.70 ± 0.03 1,2-Cl2C6H4
1.39 ± 0.03 1,2-Cl2C6H4
0.51 ± 0.03 1,2-Cl2C6H4
0.51 ± 0.03 None
0.51 ± 0.03 None
0.51 ± 0.03 None
0.51 ± 0.03 None
0.51 ± 0.03 None
43
45
52
60
76
66
77
73
58
K10
HSZ-330
HSZ-360
HSZ-360
HSZ-360
HSZ-360
HSZ-360
HSZ-360
j
k
l
3-CH3
4-CH3
4-Cl
a Untractable mixture of compounds.
Chem. Commun., 1998
513

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2 J. M. Thomas and K. I. Zamaraev, Angew. Chem., Int. Ed. Engl., 1994,
33, 308; New. J. Chem., 1996, 20, issue dedicated to the ‘Environmen-
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Chem. Ind. (London), 1997, 12.
DPU synthesis was demonstrated by extending the reaction to
different aromatic amines 1 and recovering the products 3 with
good yields and excellent selectivities (entries h–l).
A representative procedure for the preparation of DPUs is as
follows: a flask containing a mixture of the selected aromatic
amine 1 (10 mmol) and zeolite HSZ-360 (0.5 g) was placed in
a hot oil bath (180 °C) and 2 (0.8 g, 0.8 ml, 6 mmol) was added
dropwise during 1 min. The mixture was efficiently stirred at the
same temperature for 5 h.13 After cooling to room temp. the
slurry was washed with boiling MeOH containing 5% water (2
3 100 ml). After filtration the product was recovered from the
solution by addition of more water and cooling.14 Alternatively,
hot DMSO could be successfully utilized under the same
conditions.
The formation of compounds 3 could be attributed to the
initial production of acetoacetanilides and their subsequent
reaction with a second molecule of aromatic amine to give
DPUs and acetone. This hypothesis was in part confirmed by
quantitative production of diphenylurea by heating a 1:1
mixture of acetoacetanilide and aniline in the presence of zeolite
HSZ-360. We then estimated the catalyst activity on reuse. Our
results confirmed that the activity of HSZ-360 recovered by
filtration, washed with acetone and reactivated by heating at
500 °C for 8 h was the same for 5 runs.
In conclusion the above reported method of utilizing 2 as
carboxylating agent, zeolite HSZ-360 as solid catalyst and
avoiding the use of any solvent, represents an innovative
phosgene-free route for the selective synthesis of symmetric
diphenylureas.
Thanks are due to the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica (MURST), Italy, and the
Consiglio Nazionale delle Ricerche (CNR), Italy, for financial
support. The authors are also grateful to the Centro Interfacolta`
Misure (C.I.M.) for the use of NMR and mass spectrometry
instruments and to Mr Pier Antonio Bonaldi for technical
assistance.
3 T. P. Vishnyakova, I. A. Golubeva and E. V. Glebova, Russ. Chem. Rev.
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9 Zeolite HSZ-360 is a commercial (Tosoh Corp.) acid faujasitic-type
catalyst with 13.9 SiO2–Al2O3 molar ratio, pore size 7.4 Å, surface area
500 ± 10 m2 g21 (determined in our laboratory by the BET method:
S. Brunauer, P. H. Emmett and E. Teller, J. Am. Chem. Soc., 1938, 60,
309), acidity 0.51 mequiv. H+ g21 [determined in our laboratory by
temperature programmed desorption of ammonia gas (NH3-TPD):
P. Berteau and B. Delmon, Catal. Today, 1989, 5, 121] and with the
following chemical composition (wt% dry basis): SiO2 89.0, Al2O3
10.9, Na2O 0.06.
10 Zeolite HSZ-330 is a commercial (Tosoh Corp.) acid faujasitic-type
catalyst with 5.9 SiO2–Al2O3 molar ratio, pore size 7.4 Å, surface area
460 ± 10 m2 g21 (determined in our laboratory by the BET method),
acidity 1.59 mequiv. H+ g21 [determined in our laboratory by
temperature programmed desorption of ammonia gas (NH3-TPD)] and
with the following chemical composition (wt% dry basis): SiO2 86.1,
Al2O3 13.7, Na2O 0.19.
11 KSF is a commercial (Fluka) montmorillonite with surface area 15 ± 10
m2 g21, acidity 0.85 mequiv. H+ g21 [determined in our laboratory by
temperature programmed desorption of ammonia gas (NH3-TPD)] and
with the following chemical composition (average value): SiO2
(54.0%), Al2O3 (17.0%), Fe2O3 (5.2%), CaO (1.5%), MgO (2.5%),
Na2O (0.4%), K2O (1.5%); K10 is a commercial (Fluka) montmor-
illonite with surface area 200 ± 10 m2 g21, acidity 0.70 mequiv. H+ g21
[determined in our laboratory by temperature programmed desorption of
ammonia gas (NH3-TPD)] and with the following chemical composition
(average value): SiO2 (73.0%), Al2O3 (14.0%), Fe2O3 (2.7%), CaO
(0.2%), MgO (1.1%), Na2O (0.6%), K2O (1.9%).
Notes and References
† E-mail: sartori@ipruniv.cce.unipr.it
12 See for example: R. A. Sheldon, Chem. Ind. (London), 1992, 903;
R. A. Sheldon, J. Mol. Catal., A, 1996, 107, 75; D. C. Dittmer, Chem.
Ind. (London), 1997, 779.
13 By carrying out the reaction for longer times the same value of yield
( ~ 70%) was observed.
14 A. F. M. Iqbal, Helv. Chim. Acta, 1976, 59, 655. 3g: pale brown solid,
mp 237–238 °C (lit., 236–238 °C); 3h: pale brown solid, mp
237–283.5 °C (lit., 239 °C); 3i: pale brown solid, mp 218–220 °C (lit.,
219–220 °C); 3j: pale brown solid, mp 263–264 °C (lit., 263–265 °C);
3k: pale brown solid, mp 283–284.5 °C (lit., 284 °C).
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Received in Liverpool, UK, 6th November 1997; 7/08019K
514
Chem. Commun., 1998