Synthesis of 1,3-disubstituted symmetrical/unsymmetrical ureas via Cs2CO3-catalyzed transamination of ethylene carbonate and primary amines

Article abstract of DOI:10.1080/00397910802638503

Cs2CO3-catalyzed transamination of primary amines and ethylene carbonate proceeds to form 1,3-disubstituted symmetrical/unsymmetrical ureas in excellent yields. The effect of different reaction parameters such as influences of bases, temperature, and reaction time were investigated for the title reaction.

Full text of DOI:10.1080/00397910802638503

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Synthesis of 1,3-Disubstituted
Symmetrical/Unsymmetrical
Ureas via Cs2CO3-Catalyzed
Transamination of Ethylene
Carbonate and Primary Amines
Sachin R. Jagtap a , Yogesh P. Patil a , Anil G. Panda a
& Bhalchandra M. Bhanage a
a Department of Chemistry , Institute of Chemical
Technology, University of Mumbai , Mumbai, India
Published online: 12 May 2009.
To cite this article: Sachin R. Jagtap , Yogesh P. Patil , Anil G. Panda & Bhalchandra
M. Bhanage (2009) Synthesis of 1,3-Disubstituted Symmetrical/Unsymmetrical Ureas
via Cs2CO3-Catalyzed Transamination of Ethylene Carbonate and Primary Amines,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:12, 2093-2100, DOI: 10.1080/00397910802638503
To link to this article: http://dx.doi.org/10.1080/00397910802638503
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Synthetic Communications1, 39: 2093–2100, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802638503
Synthesis of 1,3-Disubstituted Symmetrical/
Unsymmetrical Ureas via Cs2CO3-Catalyzed
Transamination of Ethylene Carbonate and
Primary Amines
Sachin R. Jagtap, Yogesh P. Patil, Anil G. Panda,
and Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology,
University of Mumbai, Mumbai, India
Abstract: Cs2CO3-catalyzed transamination of primary amines and ethylene
carbonate proceeds to form 1,3-disubstituted symmetrical=unsymmetrical ureas
in excellent yields. The effect of different reaction parameters such as influences
of bases, temperature, and reaction time were investigated for the title reaction.
Keywords: Cesium carbonate, 1,3-disubstituted urea, ethylene carbonate, primary
amine, transamination
INTRODUCTION
Urea and its derivatives find extensive applications in dyes for cellulose
fiber, as antioxidants in gasoline, as corrosion inhibitors, and as inter-
mediates for carbamate synthesis, the raw materials for agrochemicals.[1a]
Their biological activities as plant-growth regulators, agroprotectives,
and tranquillizing and anticonvulsant agents are also important. Recen-
tly, these compounds have attracted interest because substituted ureas
with amino acid groups, have been used for brain cancer treatment and
Received August 18, 2008.
Address correspondence to Prof. Bhalchandra M. Bhanage, Professor of
Industrial and Engineering Chemistry, Department of Chemistry, Institute of
Chemical Technology, N. M. Parekh Marg, Matunga, Mumbai 400 019, India.
E-mail: bhalchandra_bhanage@yahoo.com or bmb@udct.org
2093

2094
S. R. Jagtap et al.
Scheme 1. Synthesis of symmetrical 1,3-disubstituted urea.
have been proven to have a marked inhibitory effect on HIV protease
enzyme.[1b] 1,3-Disubstituted ureas are traditionally synthesized by
methodologies based on the phosgenation of amines, which require use
of the very toxic phosgene.[2] Some nonphosgene-based manufacturing
processes have also been developed to eliminate the use of phosgene.
Oxidative carbonylation of amine with carbon monoxide (CO) is one
of the alternative routes for the synthesis of 1,3-disubstituted ureas.
Various metal catalysts, including gold,[3] palladium,[4] and tungsten,[5]
have been studied for this reaction. Besides the toxicity of CO, these reac-
tions are not ecofriendly because of the risk associated with a potentially
explosive mixture of CO and O2. Another phosgene-free route using
dimethyl carbonate or dimethyl sulfate has also been reported.[6,7] The
direct reaction of carbon dioxide with amines to produce 1,3-disubstituted
urea is one of the best-studied reactions in recent years.[8–13] These meth-
odologies suffer from disadvantages such as use of great pressure, high
temperature,[8,9] and expensive dehydrating reagents such as carbodii-
mides,[11] propargyl alcohols,[12] Me3NSO3,[13] and diorganophosphites.[13]
Herein we report the Cs2CO3-catalyzed synthesis of 1,3-disubstituted
symmetrical=unsymmetrical ureas via transamination of ethylene carbo-
nate (2) and primary amines (1), which proceeds through in situ gener-
ated 2-hydroxycarbamate (3) (Scheme 1).
RESULTS AND DISCUSSION
Preliminary investigations were carried out to optimize the reaction con-
ditions for the synthesis of symmetrical 1,3-disubstituted urea. Initial
screenings of various bases for the synthesis of 1,3-dibutylurea from ethy-
lene carbonate and butyl amine were conducted. Various alkali metal
carbonates=hydroxides were probed for the synthesis of 1,3-dibutylurea
(Table 1). Cesium carbonate was the most effective base and gave 1,3-
dibutylurea with good yield (Table 1, entry 5).
To test the role of the catalyst in the reaction, the reaction was
carried out in the absence of catalyst. This reaction did not lead to urea
formation; however, the formation of 2-hydroxyethylbutylcarbamate (3)

Synthesis of 1,3-Dialkylurea
2095
Table 1. Reaction of butyl amine with ethylene carbonate in the presence of var-
ious bases
Entry
Base
Yielda (%)
1
2
3
4
5
6
7
8
KOH
65
70
26
30
91
75
0
NaOH
K2CO3
Na2CO3
Cs2CO3
NaOMe
KF
NaF
0
aYields refer to isolated pure products characterized by IR, GC-MS, and
1H NMR.
Notes. Reaction ꢀ conditions: butyl amine: 20 mmol, ethylene carbonate:
10 mmol; temp.: 90 C, base: 0.2 mmol, and time: 20 min.
was observed. To study the generality of the reaction, the reaction was
carried out using various aliphatic primary, secondary, and heterocyclic
amines as well as aromatic amines as shown in Table 2.
On the basis of these results, we directed our attention to the
synthesis of unsymmetrical 1,3-disubstituted urea (Scheme 2).
When 20 mmol of ethylene carbonate was allowed to react with
ꢀ
20 mmol of butylamine at 70 C for 1 h in the absence of the catalyst,
99% of ethylene carbonate was selectively converted into 2-hydroxyethyl-
butylcarbamate. After cooling, 20 mmol of benzylamine and 0.2 mmol
of Cs2CO3 were added to the reaction mixture and heated to 100ꢀC for
30min. 1-Butyl-3-benzylurea was formed along with 1,3-dibutylurea and
1,3-dibenzylurea (Table 3, Entry 1).
EXPERIMENTAL
General
Cesium carbonate and ethylene carbonate were purchased from Lancaster.
Infrared (IR) spectra were recorded on a Fourier transform (FT)–IR
1
Perkin-Elmer instrument using KBr. H NMR spectra were recorded on
a Varian-400 NMR spectrometer using tetramethylisilane (TMS) as an
internal standard. Gas chromatography–mass spectra (GC-MS) were
recorded on a Finnigan mass spectrometer (MAT XL95). All compounds
were characterized using these techniques.

2096
S. R. Jagtap et al.
Table 2. Reaction of various amines with ethylene carbonate in the presence
of Cs2CO3
Temp.
(ꢀC)
Yielda
(%)
Entry
1
Amine
Product
90
90
90
87
2
3
93
89
4
5
90
90
76
120
6
7
120
120
83
75
8
100
100
100
76
89
90
9
10
11
100
91
(Continued )

Synthesis of 1,3-Dialkylurea
2097
Table 2. Continued
Temp.
(ꢀC)
Yielda
(%)
Entry
12
Amine
Product
120
78
13
14
120
120
No reaction
No reaction
0
0
aYields refer to isolated pure products characterized by IR, GC-MS, and
1H NMR.
Notes. Reaction conditions: amine: 20 mmol, ethylene carbonate: 10 mmol,
Cs2CO3: 0.2 mmol.
Representative Experimental Procedure for Synthesis of
1,3-Disubstituted Symmetrical Urea
Ethylene carbonate (10 mmol), amine (20 mmol), and Cs2CO3 (0.2 mmol)
were heated to the desired temperature for 20–30 min. The reaction
mixture was cooled, and the solid was filtered. The residue was taken
in 50 ml of water, filtered again, and washed with water. The crude
Scheme 2. Synthesis of unsymmetrical 1,3-disubstituted urea.

2098
S. R. Jagtap et al.
Table 3. Synthesis of unsymmetrical urea
Entry
Amine (1)
Amine (4)
Products (% yield)a
1
2
3
4
5
6
7
Butylamine
Benzylamine
Propylamine
Propylamine
Benzylamine
Butylamine
Benzylamine
Benzylamine
Butylamine
Butylamine
Benzylamine
Cyclohexylamine
Ethanolamine
Ethanolamine
5 (31), 6 (11), 7 (15)
5 (21), 6 (12), 7 (11)
5 (35), 6 (17), 7 (15)
5 (17), 6 (10), 7 (18)
5 (25), 6 (17), 7 (15)
5 (45), 6 (12), 7 (17)
5 (35), 6 (18), 7 (19)
aYields are based on GC analysis.
Notes. Reaction conditions: ethylene carbonate (10 mmol) was reacted with
amine (1; 10 mmol) at 70 ꢀC for 1 h, and then the formed 2-hydroxycarbamate
was reacted with amine (4; 10 mmol) at 100 ꢀC for 30 min using 0.2 mmol Cs2CO3.
product was purified on silica gel by eluting with petroleum ether and
ethyl acetate (70:30).
1,3-Bis-[2-(3,4-dimethoxy-phenyl)-ethyl]-urea (Table 2, Entry 7)
IR (KBr) 3344, 2959, 2870, 1624, 1515, 1510, 1459, 1330, 1260, 1028
(CꢁO str) 845, 810, 765. 1H NMR (400 MHz, CDCl3) d 2.70 (t,
J ¼ 14 Hz, 4H), d 3.44 (q, J ¼ 14 Hz, 4H), d 3.80 (s, 12H), d 4.45 (2H,
–NH), d 6.70 (d, J ¼ 3 Hz, 3H), d 6.80 (m, 3H).
Representative Experimental Procedure for Synthesis of
1,3-Disubstituted Unsymmetrical Urea
Ethylene carbonate (10 mmol) and amine (1) (10 mmol) were heated to
70ꢀC for 1 h. Cs2CO3 (0.2 mmol) and amine (4) (10 mmol) were added
to the sealed tube, and the reaction mixture was heated at the desired
temperature for 30 min. The solid was filtered and washed with water.
CONCLUSION
In conclusion, the synthesis of 1,3-disubstituted symmetrical=
unsymmetrical urea from five-membered cyclic carbonates and the
corresponding amines was performed with excellent yields using cesium
carbonate as a catalyst under mild conditions.

Synthesis of 1,3-Dialkylurea
ACKNOWLEDGMENT
2099
The financial support from the Technical Education Quality Improve-
ment Program (TEQIP), Government of India, is acknowledged.
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