Reaction of aliphatic amines with acetoacetanilide in the presence of zeolite catalyst. Solvent-free synthesis of symmetric N,N'-dialkylureas

Full text of DOI:10.1021/jo981109g

1004
J . Org. Chem. 1999, 64, 1004-1006
Sch em e 1
Rea ction of Alip h a tic Am in es w ith
Acetoa ceta n ilid e in th e P r esen ce of Zeolite
Ca ta lyst. Solven t-F r ee Syn th esis of
Sym m etr ic N,N′-Dia lk ylu r ea s
Franca Bigi, Bettina Frullanti, Raimondo Maggi,
Giovanni Sartori,* and Elena Zambonin
Dipartimento di Chimica Organica e Industriale
dell'Universita`, Viale delle Scienze, I-43100 Parma, Italy
Received J une 10, 1998
In tr od u ction
Use of clean heterogeneous catalysts such as clays and
zeolites in organic synthesis has received considerable
attention in the past few years, mainly due to the
minimum production of byproducts and pollutant materi-
als.1
In fact, the possibility of performing efficient chemical
transformations with reusable catalysts avoiding toxic
reagents, large amount of solvents, and expensive puri-
fication methods represents a fundamental target of the
modern organic synthesis.2
As a part of our program aimed at developing new,
selective, and preparatively useful methodologies based
on the use of heterogeneous catalysts as promoters for
fine chemicals preparation,3 we have recently reported
the synthesis of symmetric N,N′-diphenylureas from
aromatic amines and ethyl acetoacetate promoted by
zeolite HSZ-360.4
By considering the mechanism of this reaction, we
found it reasonable that the aromatic amine 1 first reacts
with ethyl acetoacetate 2, giving acetoacetanilide 3
which, in the presence of zeolite catalyst, is converted
into N,N′-diphenylurea 4 and acetone through nuclephilic
attack by a second molecule of aromatic amine (Scheme
1).
On these grounds we attempted the preparation of
unsymmetrical N,N′-disubstituted ureas by reaction of
acetoacetanilide with different aromatic amines under
conditions similar to those employed for the synthesis of
symmetrical ones. However, the process seemed to have
a major drawback: the formation of all three possible
diphenylureas in almost equimolecular amount. On the
other hand, use of aliphatic amines resulted in the
production of mixtures of N-phenyl-N′-alkyl- and N,N′-
dialkylureas as the latter compounds the main reaction
products.
F igu r e 1. 1. Reactivity of acetoacetanilide 3 with benzylamine
5a over dealuninated Y-zeolite HSZ-360 as a function of time.
Here we report results of our studies on the above-
described reaction that allowed us to find a simple and
safe methodology for the synthesis of symmetrical N,N′-
dialkylureas.
Substituted ureas are an industrially important class
of compounds displaying a wide range of applications,
e.g., use as herbicides, antioxidants in gasoline, corrosion
inhibitors, and drugs.5 As most of the applied methods
for the preparation of these compounds are essentially
based on phosgene and isocyanates,6 there is a continuing
interest in their catalytic synthesis via phosgene-free
reactions.
Resu lts a n d Discu ssion
To find out which pathway was operating in the
process, the model reaction between acetoacetanilide 3
(0.01 mol) and benzylamine 5a (0.04 mol) in 1,2-dichlo-
robenzene (5 mL) at 180 °C and in the presence of 0.5 g
of zeolite HSZ-360 (surface acidity7 0.51 mequiv of H+/g,
SiO2/Al2O3 molar ratio 13.9) was analyzed as function of
time.8 It is evident from Figure 1 that acetoacetanilide 3
(Scheme 2, Y ) NHPh) was converted into N,N′-diben-
zylurea 8a via the unsymmetrical N-phenyl-N-benzy-
lurea 7a as the latter was detected in appreciable
amounts at an intermediate stage. The concentration of
7a raised the maximum value (20%) after 1 h, and then,
(1) (a) Ho¨lderich, W. F. Organic Reactions in Zeolites. In Compre-
hensive Supramolecular Chemistry; Atwood, J . L., Ed.; Pergamon: New
York, 1996; Vol. 7, p 671. (b) Balogh, M.; Laszlo, P. Organic Chemistry
Using Clays; Springer-Verlag: New York, 1993. (c) Mizuno, N.; Misono,
M. Chem. Rev. 1998, 98, 199.
(2) (a) Sheldon, R. A. Chem. Ind. (London) 1992, 903. (b) Sheldon,
R. A. J . Mol. Catal., A 1996, 107, 75. (c) Dittmer, D. C. Chem. Ind.
(London) 1997, 779.
(3) (a) Sartori, G.; Bigi, F.; Pastorio, A.; Porta, C.; Arienti, A.; Maggi,
R.; Moretti, N.; Gnappi, G. Tetrahedron Lett. 1995, 36, 9177. (b) Sartori,
G.; Pastorio, A.; Maggi, R.; Bigi, F. Tetrahedron 1996, 52, 8287. (c)
Ballini, R.; Bigi, F.; Carloni, S.; Maggi, R.; Sartori, G. Tetrahedron Lett.
1997, 38, 4169. (d) Ballini, R.; Bosica, G.; Maggi, R.; Sartori, G. Synlett
1997, 795. (e) Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Sartori, G.
J . Org. Chem. 1997, 62, 7024.
(5) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem.
Rev. (Engl. Transl.) 1985, 54, 249.
(6) (a) March, J . Advanced Organic Chemistry; J ohn Wiley & Sons:
New York, 1985; p 370. (b) Kno¨lker, H.-J .; Braxmeier, T.; Schlechtin-
gen, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2497.
(7) Determined in our laboratory by temperature-programmed de-
sorption of ammonia gas (NH3-TPD): Berteau, P.; Delmon, B. Catal.
Today 1989, 5, 121.
(4) Bigi, F.; Maggi, R.; Sartori, G.; Zambonin, E. J . Chem. Soc.,
Chem. Commun. 1998, 513.
(8) Product analyses were carried out by HPLC.
10.1021/jo981109g CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/09/1999

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1005
Ta ble 1. Syn th esis of Va r iou s N,N′-Dia lk ylu r ea s
Sch em e 2
it gradually decreased down to disappearance after 3 h.
In the meantime, the amount of product 8a gradually
increased to a maximum yield of 89% (95% selectivity).
From these results, it can be concluded that production
of N,N′-dibenzylurea 8a involves prior formation of the
N-phenyl-N′-benzylurea 7a through displacement of ac-
etone. Intermediate 7a further reacts with excess ben-
zylamine, giving product 8a with displacement of aniline.
In a comparison experiment, N-phenyl-N′-benzylurea 7a
was reacted with benzylamine 5a under similar reaction
conditions, affording product 8a in 95% yield. Byproduct,
due to the competitive attack on the keto group, was
detected only in traces in the present reaction.
This result is of primary importance since the direct
reaction of ethyl acetoacetate 2 (Scheme 2, Y ) OCH2-
CH3) with benzylamine 5a failed to produce N,N′-diben-
zylurea 8a contrary to what has been previously observed
with aromatic amines;4 in fact, in this case, the nucleo-
philic attack of the nitrogen mainly occurs on the keto
group leading to the production of â-benzylaminocrotonic
acid ethyl ester 6a as reported previously in the litera-
ture.9
Concerning the effect of the solvent, a quite similar
good result was obtained by carrying out the reaction in
decalin in place of the more hazardous 1,2-dichloroben-
zene. However, the best result (95% yield, 97% selectivity)
was achieved by performing the process under solventless
conditions.
Use of typical Lewis acids such as ZnCl2 and AlCl3
resulted in the production of a complex mixture of
compounds, and a comparative experiment with no
catalyst gave the product 8a in 35% yield. These observa-
tions argue in favor of the conclusion that the present
reaction is particularly facilitated by acid zeolites. How-
ever, according to the general statement that the terms
acidity and activity are not interchangeable in zeolite
catalysis,10 we found that the catalyst performance is not
directly related to the overall surface acidity. In fact, use
of the zeolite HSZ-330 with surface area and pore
dimensions similar to those of HSZ-360 but showing
higher overall acidity (surface acidity 1.39 mequiv of
H+/g, SiO2/Al2O3 molar ratio 5.9) afforded the product 8a
in 65% yield and 95% selectivity. The different reactivity
observed could be explained in terms of higher individual
acidity11 of the active sites of zeolite HSZ-36012 with
respect to those of zeolite HSZ-330.13
Then we faced the problem of the catalyst recycling.
In the model reaction with benzylamine, zeolite, simply
recovered by filtration, washed with hot methanol, and
heated overnight at 500 °C was reused four times without
significant loss of efficiency.
The scope of this procedure was expanded to the
synthesis of different N,N′-dialkylureas 8. Synthetic
results from Table 1 reveal that yield and selectivity are
satisfactory or excellent. Most satisfying was the obser-
vation that even acid labile starting materials (entry h)
and chiral amines (entry f) were converted into the
corresponding symmetrical ureas with high selectivity
and with complete retention of the optical activity. Of
particular interest is the synthesis of compound 8i, an
industrial product patented as stabilizer for synthetic
polymers.14 All isolated products were fully characterized
1
by H NMR and IR spectroscopy and MS spectrometry.
The mass recovery and purity of these dialkylureas was
good to excellent in view of the simplicity of our isolation
procedure (see Experimental Section).
Unfortunately, attempts to extend the application to
secondary amines (e.g., dibutylamine) resulted in the
production of almost equimolecular mixtures of both
symmetrical tetrasubstituted (9) and unsymmetrical
trisubstituted (10) ureas.
In conclusion, we have developed a new, efficient,
zeolite-catalyzed, and solvent-free synthesis of sym-
(12) HSZ-360 is a commercial (Tosoh Corp.) HY zeolite with pore
size 7.4 Å, crystal dimension < 0.5 µm, surface area 500 ( 10 m2/g,
and the following chemical composition (wt % dry basis): SiO2 89.0,
Al2O3 10.9, Na2O 0.06.
(9) (a) Werner, W. Tetrahedron 1969, 25, 255. (b) Werner, W.
Tetrahedron 1971, 27, 1755.
(10) Farneth, W. E.; Gorte, R. J . Chem. Rev. 1995, 95, 615.
(11) The characterization of the acidity of both catalyst by NH3-
TPD and FTIR pyridine absorption methods suggests that the acidity
of zeolite HSZ-330 is mainly ascribable to Bro¨nsted sites; on the
contrary, Lewis sites are the most numerous in the zeolite HSZ-360.
(13) HSZ-330 is a commercial (Tosoh Corp.) HY zeolite with pore
size 7.4 Å, crystal dimension < 0.5 µm, surface area 460 ( 10 m2/g,
and the following chemical composition (wt % dry basis): SiO2 77.7,
Al2O3 22.2, Na2O 0.2.
(14) Brandt, S.; Wolf, E. Ger. Offen. 1976, 2,640,409.

1006 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
N,N′-Did ecylu r ea (8e): white solid, mp 93.5-95 °C (lit.17
mp 94-95 °C).
(R,R)-N,N′-Bis[r-m eth ylben zyl]u r ea (8f): pale yellow solid,
mp 202-204.5 °C (lit.18 mp 204.5-206 °C).
N,N′-Dip h en eth ylu r ea (8g): yellow solid, mp 139.5-141 °C
(lit.19 mp 140-1 °C).
metrical N,N′-dialkylureas from readily available ac-
etoaceanilide and primary aliphatic amines. In every
case, good yield and excellent selectivity has been achieved.
Finally the catalyst could be easily removed from the
reaction mixture and reused several times without loss
of efficiency.
N,N′-Bis[2(1H-in dol-3-yl)eth yl]u r ea (8h ): pale brown solid,
mp 136-138 °C.20
Exp er im en ta l Section
N,N′-Bis[3,3,5,5-tetr a m eth yl-4-p yp er id yl]u r ea (8i): white
solid, mp 225-228 °C.14
Gen er a l. Melting points are uncorrected. 1H NMR spectra
were recorded at 300 MHz. Mass spectra were obtained in EI
mode at 70 eV. TLC analyses were performed on Merck 60 PF254
silica gel plates using mixtures of hexane-ethyl acetate (5-
25%). All the reagents were of commercial quality from freshly
opened containers. Zeolites HSZ-360 and HSZ-330 (Tosoh Corp.)
were utilized without previous thermal or chemical treatment.
Syn th esis of N,N′-Dia lk ylu r ea s 8. Gen er a l P r oced u r e.
To a solution of the selected aliphatic amine (20 mmol) and
zeolite HSZ-360 (0.5 g) at 180 °C was added portionwise the
acetoacetoanilide (5 mmoli, 0.9 g). After 3 h the reaction mixture
was cooled to room temperature, hot methanol (50 mL) was
added, and the catalyst was removed by filtration and washed
with hot methanol (50 mL). After cooling to room temperature,
the N,N′-dialkylurea was precipitated by adding distilled water
(150 mL). The product was isolated by Buchner filtration and
recrystallized from methanol.
N,N,N′,N′-Tetr a bu tylu r ea (9): pale yellow oil, bp 117.5-
118.5 °C/0.5 mmHg (lit.21 bp 119 °C/0.5 mmHg).
N,N-Dibu tyl-N′-p h en ylu r ea (10): white solid, mp 82-83
°C (lit.22 mp 82.7-83 °C).
Ack n ow led gm en t. The authors acknowledge the
support of the Ministero dell′Universita` e della Ricerca
Scientifica e Tecnologica (MURST), Italy, the Consiglio
Nazionale delle Ricerche (CNR), Italy, and the Univer-
sity of Parma (National Project Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni). The
authors are grateful to the Centro Interdipartimentale
Misure (CIM) for the use of NMR and mass instruments
and to Mr. Pier Antonio Bonaldi for technical collabora-
tion.
N,N′-Diben zylu r ea (8a ): pale brown solid, mp 167-168 °C
(lit.15 mp 168 °C).
J O981109G
N,N′-Dicycloh exylu r ea (8b): pale yellow solid, mp 235-
237.5 °C (lit.16 mp 237-238 °C).
(17) Scott, F. L.; Scott, M. T. J . Am. Chem. Soc. 1957, 79, 6077.
(18) Grotjahn, D. B.; J oubran, C. Tetrahedron: Asymmetry 1995,
6, 745.
(19) Moyer, M. I.; McEwen, W. E. J . Am. Chem. Soc. 1951, 73, 3075.
(20) Kayumov, V.; Smushkevich, Y. I.; Suvorov, N. N. Khim.
Geterotsikl. Soedin 1973, 6, 756.
N,N′-Dioctylu r ea (8c): white solid, mp 89-90 °C (lit.15 mp
90 °C).
N,N′-Din on ylu r ea (8d ): white solid, mp 101-102.5 °C (lit.15
mp 101 °C).
(21) Skinner, W. A.; Crawford, H. T.; Rutledge, L. C.; Moussa, M.
A. J . Pharm. Sci. 1979, 68, 391.
(22) Beaver, D. J .; Roman, D. P.; Stoffel, P. J . J . Am. Chem. Soc.
1957, 79, 1236.
(15) Srivastava, S. C.; Shurimal, A. K.; Srivastava, A. J . Organomet.
Chem. 1991, 414, 65.
(16) Ross, S.; Muenster, L. J . Can. J . Chem. 1961, 39, 401.