Carboxylic acid-catalyzed one-pot synthesis of cyanoacetylureas and their cyclization to 6-aminouracils in guanidine ionic liquid

Article abstract of DOI:10.1007/s00706-012-0810-9

A novel, one-pot, carboxylic acid-catalyzed synthesis of cyanoacetylureas via in situ generated ureas and their cyclization to 6-aminouracils in the presence of the guanidine-based ionic liquid 1,1,3,3-tetramethylguanidine lactate [TMG][Lac] is described. The ureas were synthesized from amines and potassium cyanate, which on reaction with cyanoacetic acid in the presence of acetic anhydride in the same pot afforded cyanoacetylureas, which undergo cyclization in [TMG][Lac] as solvent as well as catalyst to afford 6-aminouracils. One-pot synthesis of cyanoacetylureas, efficient and rapid cyclization, better yield, shorter reaction time, easy workup procedure, and recyclability of the ionic liquid are some advantages of this procedure.

Full text of DOI:10.1007/s00706-012-0810-9

Monatsh Chem (2013) 144:399–403
DOI 10.1007/s00706-012-0810-9
ORIGINAL PAPER
Carboxylic acid-catalyzed one-pot synthesis of cyanoacetylureas
and their cyclization to 6-aminouracils in guanidine ionic liquid
•
Sunil S. Chavan Rupesh U. Shelke
•
Mariam S. Degani
Received: 17 September 2011 / Accepted: 14 June 2012 / Published online: 27 July 2012
Ó Springer-Verlag 2012
Abstract A novel, one-pot, carboxylic acid-catalyzed
synthesis of cyanoacetylureas via in situ generated ureas
and their cyclization to 6-aminouracils in the presence of
the guanidine-based ionic liquid 1,1,3,3-tetramethylguani-
dine lactate [TMG][Lac] is described. The ureas were
synthesized from amines and potassium cyanate, which on
reaction with cyanoacetic acid in the presence of acetic
anhydride in the same pot afforded cyanoacetylureas,
which undergo cyclization in [TMG][Lac] as solvent as
well as catalyst to afford 6-aminouracils. One-pot synthesis
of cyanoacetylureas, efficient and rapid cyclization, better
yield, shorter reaction time, easy workup procedure, and
recyclability of the ionic liquid are some advantages of this
procedure.
Introduction
Cyanoacetylureas are key intermediates in the synthesis of
6-aminouracils, which possess a number of biological
activities such as anticancer [1], antiviral [2], antihypertensive
[3], insecticidal, herbicidal, and acaricidal [4] activities.
6-Aminouracils (6-aminopyrimidine-2,4(1H,3H)-diones) are
key intermediates in the synthesis of xanthines [5], which
constitute the scaffold of various drugs such as caffeine,
6-mercaptopurine, penciclovir, theophylline, theobromine,
etc. 6-Aminouracils are also used as starting materials for the
synthesis of various fused heterocycles of biological impor-
tance such as pyrido-, pyrazolo-, and pyrimidopyrimidines
[6].
Substituted ureas have been traditionally synthesized by
methodologies mainly based on the use of phosgene and
isocyanates [7]. They have also been synthesized by
reacting primary amines or ammonia with carbon monox-
ide in the presence of transition metal catalysts [8] or by
reacting primary amines with sodium cyanate in the pres-
ence of acid catalysts [9]. These classical methods are not
environmentally safe as they involve the use of corrosive
acid catalysts, hazardous reagents, and volatile organic
solvents; also there is often no recovery of catalysts.
The first synthesis of 6-aminouracils was reported by
Traube [10]. It involves the condensation of urea or
N-mono- or N, N0-disubstituted ureas with cyanoacetic acid in
the presence of phosphorus oxychloride to afford cyano-
acetylureas, which on cyclization in the presence of strong
base afford 6-aminouracils. In a modification, Speer and
Raymond [11] used an excess of acetic anhydride instead
of phosphorus oxychloride to afford intermediate cyano-
acetylureas, which on cyclization in the presence of strong
base afford 6-aminouracils. Another method described the
ring closure of cyanoacetylureas to 6-aminouracils in the
Keywords Cyanoacetylurea ꢀ Carboxylic acid ꢀ
One-pot synthesis ꢀ 6-Aminouracil ꢀ Cyclization ꢀ
Guanidine
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0810-9) contains supplementary
material, which is available to authorized users.
S. S. Chavan ꢀ R. U. Shelke ꢀ M. S. Degani (&)
Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Mumbai, India
e-mail: ms.degani@ictmumbai.edu.in
123

400
S. S. Chavan et al.
Scheme 1
O
O
OH
AcOH, Ac2O
60 °C
R1
R1 NH2
+
+
NC
CN
KNCO
N
H
N
H
O
1
2
3
4
Results and discussion
O
O
O
R2
O
N
[TMG][Lac]
95 °C
The condensation of equimolar amounts of butylamine
(1b) and potassium cyanate (2) in the presence of acetic
acid at 60 °C resulted in the formation of butylurea, which
on reaction with 1 M equiv. of cyanoacetic acid and 2 M
equiv. of acetic anhydride at 60 °C afforded N-butylcy-
anoacetylurea (4b) in the same pot. Ring closure of N-
butylcyanoacetylurea (4b) in the presence of [TMG][Lac]
at 95 °C gave 1-butyl-6-aminouracil (5b). The scope and
generality of the reaction as well as the influence of reac-
tion parameters such as amount of [TMG][Lac], reaction
time, and reaction temperature were next investigated.
Initially, N-butylcyanoacetylurea (4b) was prepared via in
situ generated N-butylurea from butylamine and potassium
cyanate in the presence of cyanoacetic acid, acetic anhy-
dride, and acetic acid as solvent using a modification of the
reported method [13]. In this reaction, the catalyst could be
acetic acid or cyanoacetic acid. N-Butylurea was obtained in
optimum yield at 60 °C in a short reaction time of 30 min in
the presence of 2 molar equivalents of acetic acid. The
synthesized N-butylurea was acylated with cyanoacetic acid
in the presence of excess acetic anhydride in the same pot at
60 °C. The best results were obtained with 1 molar equiv-
alent of cyanoacetic acid and 2 molar equivalents of acetic
anhydride at 60 °C with a reaction time of 45 min.
R1
N
CN
N
R2
N
NH2
H
R1
4
5
Scheme 2
presence of hexamethyldisilazane and chlorotrimethylsi-
lane [12]. Similar reports [13–17] are available in the
literature which lack simplicity in the experimental pro-
cedure. Some reactions are multi-step syntheses with
isolation and purification of intermediates at each step,
whereas some reactions are restricted to aliphatic ureas,
some utilize an excess of base, expensive reagents for
cyclization, require dry experimental conditions, and also
have no recovery of catalysts. Therefore, developing a
one-pot carboxylic acid-catalyzed synthetic method for
cyanoacetylureas and their cyclization to 6-aminouracils in
the presence of ionic liquid [TMG][Lac] as an environ-
mentally friendly and recyclable solvent as well as catalyst
is desirable.
This work reports the novel carboxylic acid-catalyzed,
one-pot synthesis of cyanoacetylureas via in situ generated
ureas (Scheme 1) and their cyclization to 6-aminouracils in
the presence of the ionic liquid 1,1,3,3-tetramethylguani-
dine lactate [TMG][Lac] as recyclable solvent and catalyst
(Scheme 2).
With these optimized parameters, reactions of various
aliphatic and aromatic amines with potassium cyanate,
cyanoacetic acid, and acetic anhydride in the presence of acetic
acid were carried out. The results of acid-catalyzed, one-pot
synthesis of cyanoacetylureas are presented in Table 1. Ali-
phatic amines reacted faster than aromatic amines and yields
obtained using aliphatic amines were slightly higher.
The catalyst [TMG][Lac] is safe, easy to handle, envi-
ronmentally benign, and stable in the reaction medium.
Table 1 Acetic acid-catalyzed,
one-pot synthesis of
Entry
R1
Product
Time/min
Yielda/%
M.p./°C
Lit.
m.p./°C
cyanoacetylureas from amine
(1 mmol), potassium cyanate
(1 mmol), cyanoacetic acid
(1 mmol), and acetic anhydride
(2 mmol) at 60 °C (Scheme 1)
1
2
3
4
5
6
7
8
9
n-C3H7
4a
4b
4c
4d
4e
4f
75
90
91
91
88
90
83
85
76
78
168–169
151–153
144–147
208–210
184–185
208–210
181–183
220–224
162–164
169–170 [13]
152–154 [13]
145–146 [13]
209–211 [19]
185 [19]
n-C4H9
75
i-C3H7
75
C6H5CH2
4-CH3OC6H4CH2
C6H5
90
90
120
120
120
120
209–211 [20]
182–184 [10]
224–225 [10]
164 [13]
4-CH3C6H4
4-NO2C6H4
Cyclohexyl
4g
4h
4i
a
Yield of isolated products
123

Carboxylic acid-catalyzed one-pot synthesis of cyanoacetylureas
401
yield significantly (Table 2, entries 5, 8, and 9). There-
after, the reaction was evaluated by varying the reaction
time (0.5–2 h) keeping the ionic liquid quantity of 0.6 g
constant. Better yield was obtained when the reaction was
carried out for 0.5 h (Table 2, entry 4). Further increase in
reaction time and amount of [TMG][Lac] did not improve
the result much (Table 2, entries 8 and 9). These experi-
ments revealed that 0.6 g of [TMG][Lac] and a reaction
time of 0.5 h were optimum for the cyclization of
cyanoacetylurea (4b) to 6-aminouracil (5b) with a yield
of 91 %.
Table 2 Effect of different amounts of [TMG][Lac] on the cycliza-
tion of cyanoacetylurea 4b (2.72 mmol) to 6-aminouracil 5b in the
presence of [TMG][Lac] at 95 °C
Entry
[TMG][Lac]/g
Time/h
Yielda of 5b/%
1
2
3
4
5
6
7
8
9
–
12
0.5
0.5
0.5
0.5
1
NR
63
78
91
91
91
92
92
93
0.2
0.4
0.6
0.8
0.6
0.6
0.8
1.0
2
With these optimized reaction parameters, ring clo-
sures of various aliphatic and aromatic cyanoacetylureas
(4a–4k) to 6-aminouracils (5a–5k) in the presence of
[TMG][Lac] were carried out. The results of [TMG][Lac]-
mediated cyclization of cyanoacetylureas are presented in
Table 3. Aliphatic cyanoacetylureas undergo ring closure
faster than that of aromatic cyanoacetylureas (Table 3,
entries 1–3, 8, 9) and also the yields obtained were
slightly higher. In the case of aromatic cyanoacetylureas,
cyanoacetylureas with electron-donating groups on the
benzene ring reacted smoothly under these reaction con-
ditions (Table 3, entry 7), whereas cyanoacetylureas
with electron-withdrawing groups on the aromatic ring
(Table 3, entry 10) and cyclohexyl cyanoacetyl urea did
not undergo ring closure (Table 3, entry 11) even after
heating at 95 °C for 7 h.
2
2
NR no reaction
a
Isolated yield
In order to optimize the cyclization of cyanoacetylureas
(4a–4k) to 6-aminouracils (5a–5k) in the presence of
[TMG][Lac], cyclization of N-butylcyanoacetylurea (4b) to
1-butyl-6-aminouracil (5b) was selected as a model reac-
tion. To optimize the amount of [TMG][Lac] required for
the ring closure of cyanoacetylurea (4b) to 6-aminouracil
(5b), several experiments were carried out and results are
summarized in Table 2.
The recycling efficiency of catalyst [TMG][Lac] in the
same model reaction was also explored (Table 4). After
completion of the reaction, cold water was added to the
reaction mixture and products were isolated by filtration.
The catalyst [TMG][Lac] was recovered by removing
water under reduced pressure and could be reused at least
five times without appreciable decrease in yield.
Variation of temperature from 70 to 110 °C resulted in
the optimum temperature of 95 °C for the cyclization.
When this reaction was carried out at temperatures below
95 °C, the reaction time was longer and the yield of 5b was
low and when at temperatures above 95 °C, no improve-
ment in the yield of 5b was observed. The yield improved
with increasing the amount of [TMG][Lac] and reached a
maximum of 91 % with 0.6 g of [TMG][Lac] (Table 2,
entry 4) in a fixed reaction time of 0.5 h. However, further
increase in the amount of [TMG][Lac] did not improve the
A tentative reaction mechanism for [TMG][Lac]-cata-
lyzed ring closure of cyanoacetylureas to 6-aminouracils is
proposed in Scheme 3. Formation of hydrogen bonding
Table 3 Cyclization of
Entry
R1
R2
Product Time/h
Yielda/% M.p./°C
Lit. m.p./°C
cyanoacetylureas (1 mmol) to
6-aminouracils in the presence
of 0.6 g [TMG][Lac] at 95 °C
(Scheme 2)
1
n-C3H7
H
5a
5b
5c
5d
5e
5f
0.5
0.5
0.5
1
92
91
91
93
90
84
90
90
89
NR
NR
273–274
265–267
289–291
284–286
276–278
285–286
292–294
304–305
134–136
274–275 [13]
266–267 [13]
290–292 [13]
285–286 [21]
276–278 [14, 15]
285–287 [11]
292–294 [22]
305–306 [21]
135–137 [21]
2
n-C4H9
H
3
CH3
CH3
H
4
C6H5CH2
4-CH3OC6H4CH2
C6H5
5
H
1
6
H
2
7
4-CH3C6H4
CH3
H
5g
5h
2
8
H
0.5
1
9
n-C3H7
n-C3H7 5i
10
11
4-NO2C6H4
Cyclohexyl
H
H
5j
7
NR no reaction
a
Isolated yield
5k
7
123

402
S. S. Chavan et al.
products were compared with those reported in literature
[10–17, 19–22].
Table 4 Recyclability of catalyst [TMG][Lac]
Entry
Cycle number
Yield of 5b/%
1
2
3
4
5
6
Fresh
91
91
90
90
89
88
General procedure for the one-pot synthesis
of cyanoacetylureas 4
1
2
3
4
5
To a 50-cm3 round-bottom flask containing acetic acid
(27.3 mmol) was added amine (13.6 mmol) and potassium
cyanate (13.6 mmol). The reaction mixture was heated at
60 °C for 0.5–2 h. To this, a solution of cyanoacetic acid
(13.6 mmol) in acetic anhydride (27.3 mmol) was added
and heated at 60 °C for 0.75 h to get a clear solution. The
progress of the reaction was monitored by TLC. After the
completion of reaction, the mixture was cooled to room
temperature and product was precipitated. To this, 10 cm3
diethyl ether was added and stirred for 5 min. The pre-
cipitated solid was filtered, washed with 5 cm3 diethyl
ether, and dried to obtain cyanoacetylurea.
between [TMG][Lac] and cyanoacetylureas might facilitate
the nucleophilic attack of the urea nitrogen atom on the
electrophilic carbon of the cyano group to give an inter-
mediate, which tautomerizes to the 6-aminouracils.
Experimental
General procedure for the cyclization
of cyanoacetylureas 4 to 6-aminouracils 5
The ionic liquid was prepared by a previously reported
method without any modifications and characterized by
1
FTIR and H NMR spectroscopy [18]. All chemicals and
To a 10-cm3 round-bottom flask containing cyanoacetylu-
rea (5.46 mmol) was added 0.6 g [TMG][Lac] and the
reaction mixture was stirred at 95 °C for 0.5–2 h (see
Table 3). The progress of the reaction was monitored by
TLC. After completion of the reaction, 5 cm3 cold water
was added and the reaction mixture was stirred for 5 min.
The precipitated solid was filtered and washed with 3 cm3
water to afford 6-aminouracil. The catalyst [TMG][Lac]
was recovered by removing water under reduced pressure
and reused in subsequent catalytic runs. The pure products
reagents were purchased from S. D. Fine and Spectrochem,
India. FTIR spectra were obtained on a Perkin-Elmer
infrared spectrometer with KBr discs (m in cm-1). 1H NMR
ꢀ
spectra were recorded in DMSO-d6 on a JEOL 300 MHz
spectrometer with tetramethylsilane as internal standard (d
in ppm). Melting points were determined on a Kofler
melting point apparatus. Thin-layer chromatography (TLC)
was accomplished on 0.2-mm precoated plates of silica gel
60 F-254 (Merck) and visualization was with ultraviolet
light (254 nm). The physical and spectroscopic data of
N
HO
CH3
H
N
N
OOC
H
O
O
O
O
N
HO
NH
H
N
N
CH3
N
N
R2
N
R2
HN
N
HOOC
R1
R1
4
O
O
R2
R2
O
H
N
N
O
N
NH2
N
NH
R1
R1
5
Scheme 3
123

Carboxylic acid-catalyzed one-pot synthesis of cyanoacetylureas
403
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Acknowledgments Financial support from UGC (SAP), Govt. of
India, is acknowledged by the authors Sunil S. Chavan and Rupesh U.
Shelke.
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