Ionic liquid mediated one-pot synthesis of 6-aminouracils

Article abstract of DOI:10.1039/c1gc15940b

A novel, one-pot synthesis of 6-aminouracils via in situ generated ureas and cyanoacetylureas in the presence of an ionic liquid catalyst, 1,1,3,3-tetramethylguanidine acetate, is described. The catalyst can be recycled for five consecutive runs without loss of activity. The mechanism for the ring closure of cyanoacetylurea to 6-aminouracil is also discussed.

Full text of DOI:10.1039/c1gc15940b

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Ionic liquid mediated one-pot synthesis of 6-aminouracils†
Sunil S. Chavan and Mariam S. Degani*
Received 2nd August 2011, Accepted 26th October 2011
DOI: 10.1039/c1gc15940b
A novel, one-pot synthesis of 6-aminouracils via in situ
generated ureas and cyanoacetylureas in the presence of an
ionic liquid catalyst, 1,1,3,3-tetramethylguanidine acetate,
is described. The catalyst can be recycled for five consecutive
runs without loss of activity. The mechanism for the
ring closure of cyanoacetylurea to 6-aminouracil is also
discussed.
Uracil has been found to be a common structural moiety of sev-
eral bioactive compounds known for anticancer,1 antiviral,2 anti-
hypertensive,3 insecticidal, herbicidal, acaricidal4 activity etc. 6-
Aminouracils (6-aminopyrimidine-2,4(1H,3H)-diones) are key
intermediates in the synthesis of xanthines5 which constitute
the basic nucleus of various drugs such as caffeine, 6-mercapto
purine, penciclovir, theophylline, theobromine etc (Fig. 1). 6-
Aminouracils are also used as starting materials for the synthesis
of various fused heterocycles with biological importance, such
as pyrido-, pyrazolo- and pyrimido-pyrimidines.6
Ureas have been traditionally synthesized using methodolo-
gies mainly based on the use of phosgene and isocyanates.7
They are also synthesized by reacting primary amines or
ammonia with carbon monoxide in presence of transition metal
catalysts8 or by reacting primary amines with sodium cyanate
in presence of acid catalysts.9 These classical methods are not
environmentally safe as it involves the use of corrosive acid
Fig. 1 Xanthine drugs obtained from 6-aminouracils.
catalysts, hazardous reagents, volatile organic solvents and also
there is often no recovery of the catalysts.
which lack simplicity in their experimental procedure. Some
reactions are multi-step syntheses with isolation and purification
of intermediates at each step, some reactions are restricted to
aliphatic ureas and have no recovery of catalysts. Therefore,
developing a synthetic method for a one-pot synthesis of 6-
aminouracils using an ionic liquid as an environmentally friendly
and recyclable solvent as well as catalyst is desirable.
Ionic liquids (ILs) have attracted much attention as an
environmentally friendly alternative to conventional organic
solvents in chemical processes, due to their physicochemical
properties, such as negligible vapor pressure, excellent chemical
and thermal stability, good solvating ability, ease of recyclabil-
ity, non-flammability and their potential to enhance reaction
rates.17,18 Over the past few years, a number of reactions have
been successfully conducted using ionic liquids as solvents or
catalysts. As new generation ionic liquids, a wide range of
guanidine ionic liquids (GILs) have been synthesized and used
in many organic reactions such as the Henry reaction, aldol
The first synthesis of 6-aminouracils was reported by Traube.10
It involves the condensation of either urea, N-mono- or N,N¢-
disubstituted ureas with cyanoacetic acid (CAA) in the presence
of phosphorous oxychloride to afford cyanoacetylureas, which
on cyclization in the presence of a strong base affords 6-
aminouracils. In a modification of this method, Speer and
Raymond11 used acetic anhydride in acetic acid instead of phos-
phorous oxychloride to afford intermediate cyanoacetylureas
which on cyclization in the presence of a strong base also afford
6-aminouracils. Similar reports12–16 are available in the literature
Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, N. Parekh Marg, Matunga, Mumbai, 400019,
India. E-mail: ms.degani@ictmumbai.edu.in, m_degani@yahoo.com;
Fax: +9122 2414 5614; Tel: +9122 3361 2231
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, spectral data and spectra of compounds. See DOI:
10.1039/c1gc15940b
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reaction and Heck reaction.19–22 In the quest of developing
simple, mild and environmentally friendly synthetic protocols,
Table 1 Effect of the amount of [TMG] [Ac] on the yield of the
productsa
we have previously reported a hetero-Michael reaction,23
a
Amount of
[TMG] [Ac] (g)
Knoevenagel condensation,24 a Biginelli reaction25 and a Heck
reaction26 using cost-effective ionic liquids as the recyclable
solvent as well as the catalyst.
Sr. No.
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
—
12
NR
26
41
60
72
84
84
85
88
88
89
0.2
0.4
0.6
0.8
1.0
1.2
1.5
1.0
1.2
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
3.5
5.0
In the present work, for the first time, a one-pot synthesis of
6-aminouracils via in situ generated ureas and cyanoacetylureas
(Scheme 1) using ionic liquid, 1,1,3,3-tetramethylguanidine
acetate [TMG] [Ac] as the recyclable solvent and catalyst has
been developed. The ionic liquid [TMG] [Ac] was prepared
by the previously reported method (Scheme 2) without any
modifications.27
9
10
11
a Reaction conditions: amine 1g (4.6 mmol), cyanate 2g (4.6 mmol),
[TMG] [Ac], water (0.3 ml) at 60 ◦C, for 30 min, cyanoacetic acid
(4.6 mmol) and acetic anhydride (9.2 mmol) at 60 ◦C, for 60 min, and at
90 ◦C, for 60 min. b Isolated yield. NR: no reaction.
Scheme 1 One-pot synthesis of 6-aminouracils in the ionic liquid
[TMG] [Ac].
equivalents of acetic anhydride at 60 ◦C in 60 min to afford
cyanoacetylurea 4g. In order to cyclize cyanoacetylurea 4g to
6-aminouracil 5g, a range of reaction temperatures, from 60 ◦C
to 120 ◦C, were tested. Results determined that an optimum
temperature of 90 ◦C was required for the cyclization. Thus,
when the reaction was performed with 0.2 g [TMG] [Ac], 6-
aminouracil 5g was obtained with a yield of 26% (entry 2, Table
1). The yield improved from 26% to 84% with increasing the
amount of [TMG] [Ac] and reached a maximum with 1.0 g of
[TMG] [Ac] (entry 6, Table 1) in a fixed reaction time of 2 h.
However, further increase in the amount of [TMG] [Ac] did not
affect the yields to a great extent (entries 7 and 8, Table 1).
Thereafter, the reaction was evaluated by varying the reaction
time (2 to 5 h.) while keeping the ionic liquid quantity (1.0 g)
constant. An improved yield was obtained when the reaction
was carried out for 2.5 h (entry 9, Table 1). Further increases in
the reaction times and amounts of [TMG] [Ac] did not improve
the result to a great extent (entries 10 and 11, Table 1). These
experiments revealed that 1.0 g of [TMG] [Ac] and a reaction
time of 2.5 h were the optimum parameters for the one-pot
synthesis of 6-aminouracil 5g with yield of 88%.
Scheme 2 Synthesis of the ionic liquid [TMG] [Ac].
A one-pot reaction of equi-molar amounts of amine 1g and
cyanate 2g in the presence of [TMG] [Ac] at 60 ◦C resulted
in the formation of urea 3g, which on reaction with 1 molar
equivalent of cya◦noacetic acid and 2 molar equivalents of acetic
anhydride at 60 C afforded cyanoacetylurea 4g. Ring closure
of cyanoacetylurea 4g at 90 ◦C gave 6-aminouracil 5g in the
same pot (Scheme 3). The scope and generality of the reaction
as well as the influence of reaction parameters such as amount of
[TMG] [Ac], reaction time and reaction temperature were next
investigated. Also, the mechanism of [TMG] [Ac] mediated ring
closure of cyanoacetylurea to 6-aminouracil was discussed.
With these optimized reaction parameters, reactions of var-
ious aliphatic and aromatic amines 1a–1w with cyanate 2a–
2w, cyanoacetic acid and acetic anhydride in [TMG] [Ac] were
carried out. The results of the [TMG] [Ac] mediated one-pot
synthesis of 6-aminouracils are presented in Table 2. Aliphatic
amines reacted faster as compared to aromatic amines and also,
the yields obtained were slightly higher. In the case of aromatic
amines, amines with electron-donating groups on the benzene
ring reacted smoothly under these reaction conditions (entries
10–13, 16, Table 2); whereas amines with electron-withdrawing
groups on the aromatic ring did not undergo cyclization to give
6-aminouracils (entries 17–22, Table 2); only cyanoacetylureas
were isolated, even after heating at 90 ◦C for 7–8 h. In the
case of the perfluorinated alkylamine, only cyanoacetylurea
was isolated (entry 23, Table 2). In addition, 1-phenyl-3-allyl-
6-aminouracil and 1-benzyl-3-allyl-6-aminouracil were synthe-
sized from allylamine and the corresponding isocyanates under
the optimized reaction conditions (entries 14, 15, Table 2).
Scheme 3 One-pot reaction of amine 1g and cyanate 2g.
To optimize the amount of [TMG] [Ac] required for the one-
pot synthesis of 6-aminouracil 5g, several experiments were
carried out using amine 1g, cyanate 2g, cyanoacetic acid and
acetic anhydride as the substrates , the results are summarized
in Table 1.
Initially, urea 3g was prepared by the reaction of amine 1g
and cyanate 2g in the presence of 0.2 g [TMG] [Ac] at room
temperature. The reaction resulted in urea formation with a
moderate yield. This could be due to the low solubility of
cyanate. Use of water as the co-solvent in the reaction resulted
in an increase in the yield of urea, probably due to the increase
in solubility of the cyanate. Best results were obtained at 60 ◦C
with a short reaction time of 30 min. Synthesized urea 3g was
acylated with 1 molar equivalent of cyanoacetic acid and 2 molar
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Table 2 Ionic liquid mediated one-pot synthesis of 6-aminouracilsae
Sr. No.
Substrate
Amines (1) R1
Cyanate (2) R3
6-Aminouracil
Time (h)
Isolated yield (%)
1
2
a
b
c
d
e
f
CH3
—
—
—
CH3
n-C3H7
—
—
—
5a
5b
5c
5d
5e
5f
2.0
2.0
2.0
2.0
2.0
5
87
85
86
91
83
89
88
90
n-C3H7
3
n-C4H9
4b
5b
6
CH3
n-C3H7
C6H5
7
8
g
h
C6H5CH2
4-(MeO)-
C6H4CH2
C6H5CH2CH2
4-(MeO)–C6H4
4-(Me)–C6H4
3-(Me)–C6H4
2-(Me)–C6H4
5g
5h
2.5
4
9
i
j
k
l
m
n
—
—
5i
5j
5k
5l
5m
5n
2.5
3
3
3
3
84
86
87
86
87
80
10
11
12
13
14c
—
—
C6H5
2.5
15d
o
C6H5CH2
5o
2.5
81
16
17
18
19
20
21
22
23
p
q
r
4-N(Me)2–C6H4
4-NO2–C6H4
3-NO2–C6H4
2-NO2–C6H4
4-F–C6H4
3-F–C6H4
2-F–C6H4
—
—
—
5p
5q
5r
5s
5t
5u
5v
5w
3.0
7
8
8
8
8
8
7
73
NR
NR
NR
NR
NR
NR
NR
s
t
u
v
w
CF3CH2
a Reaction conditions: amine 1 (1 mmol), cyanate 2 (1 mmol), [TMG] [Ac] (1 g), water (0.3 ml) at 60 ◦C, for 0.5 h, cyanoacetic acid (1 mmol) and
acetic anhydride (2 mmol) at 60 ◦C, for 1 h, and at 90 ◦C, for 0.5–3.5 h. b Dimethylurea and dipropylurea were directly used for the synthesis of
6-aminouracils 5d and 5e, respectively. c Reaction conditions: amine 1 (1 mmol), cyanate 2 (1 mmol), [TMG] [Ac] (1 g), at RT, for 0.5 h, cyanoacetic
acid (1 mmol) and acetic anhydride (2 mmol) at 60 ◦C, for 1 h, and at 90 ◦C, for 1 h. d Reaction conditions: amine 1 (1 mmol), cyanate 2 (1 mmol),
[TMG] [Ac] (1 g), at RT, for 0.5 h, cyanoacetic acid (1 mmol) and acetic anhydride (2 mmol) at 60 ◦C, for 1 h, and at 90 ◦C, for 1 h. e All products
were identified by their melting point, IR and 1H-NMR spectra, according to the literature10,12,14,15,16 and references cited therein. NR: no formation
of 6-aminouracil; only cyanoacetylureas were isolated.
Table 3 Results for recyclability of the ionic liquid catalyst [TMG] [Ac]
for the synthesis of 6-aminouracil 5g
could be explained by the formation of hydrogen bonding
between [TMG] [Ac] and the cyanoacetylureas (Scheme 4).
This facilitates the nucleophilic attack of the nitrogen on the
electrophilic carbon of the cyano group to give an intermediate,
which on migration of a proton gives the corresponding 6-
aminouracil.
Sr. No.
Cycle number
Yield (%)
1
2
3
4
5
6
1
2
3
4
5
6
88
88
87
86
85
85
The recycling efficiency of [TMG] [Ac] in the same model
reaction was also explored (Table 3). After the completion of
the reaction, cold water was added to the reaction mixture
and the products were isolated by filtration. The ionic liquid
was recovered by removing the water under reduced pressure
and could be reused at least five times without any appreciable
decrease in yield.
The proposed reaction mechanism for the [TMG] [Ac]
mediated cyclization of cyanoacetylureas to 6-aminouracils
Scheme 4 Proposed mechanism for cyclization of cynoacetylureas to
6-aminouracils.
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In summary, for the first time, a facile and efficient [TMG] [Ac]
mediated one-pot synthesis of 6-aminouracils from aromatic, as
well as aliphatic, amines is described. In this procedure, three
C–N bonds are formed in the one-pot process. Thus, the con-
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were replaced by a one-pot catalytic system, which provides a
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General procedure for Table 2 and Table 3
To a stirred mixture of [TMG] [Ac] (1 g) and water (0.3 ml)
was added amine (1 mmol) followed by cyanate (1 mmol) and
the mixture was heated to 60 ◦C for 30 min. To this, a solution
of cyanoacetic acid (1 m◦mol) in acetic anhydride (2 mmol) was
added and heated at 60 C for 60 min to give a ◦clear solution,
then the reaction temperature was raised to 90 C and stirred
for a further 60 min. The progress of the reaction was monitored
by TLC. After completion of the reaction, cold water (5 ml) was
added and stirred for 5 min. The precipitated solid was collected
by filtration, washed with water (5 ml) and dried to obtain the
corresponding 6-aminouracil. The ionic liquid was recovered
by removing the water under reduced pressure and could be
reused at least five times without any appreciable decrease in
yield.
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Acknowledgements
Financial support of this research by the Univer-
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©