Microwave-assisted one-pot synthesis of functionalized pyrimidines using ionic liquid

Article abstract of DOI:10.1002/jhet.540

An efficient one-pot multicomponent synthesis of 2,4-diamino-5- pyrimidinecarbonitrile derivatives has been achieved in excellent yields by the condensation of aromatic aldehydes, malononitrile, and guanidine using ionic liquid under controlled microwave irradiation (100 W) at 60°C. This green approach offers a number of advantages in terms of methodology, high-product yield, short reaction time, mild reaction conditions, and easy workup.

Full text of DOI:10.1002/jhet.540

582
Microwave-Assisted One-Pot Synthesis of Functionalized
Pyrimidines Using Ionic Liquid
Vol 48
Dushyant Singh Raghuvanshi and Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
*E-mail: knsinghbhu@yahoo.co.in
Received March 8, 2010
DOI 10.1002/jhet.540
Published online 4 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
An efficient one-pot multicomponent synthesis of 2,4-diamino-5-pyrimidinecarbonitrile derivatives
has been achieved in excellent yields by the condensation of aromatic aldehydes, malononitrile, and
guanidine using ionic liquid under controlled microwave irradiation (100 W) at 60ꢀC. This green
approach offers a number of advantages in terms of methodology, high-product yield, short reaction
time, mild reaction conditions, and easy workup.
J. Heterocyclic Chem., 48, 582 (2011).
INTRODUCTION
pyrimidine-fused compounds are of paramount impor-
tance, particularly in the medicinal and agrochemical
areas [14,15]. Although some pyrimidine synthetic
routes have been known for a long time, the develop-
ment of alternative and more efficient strategies is of
considerable relevance [16–19].
Ionic liquids (ILs) have recently attracted a great deal
of attention as a new class of more sustainable solvent
system in organic synthesis [1]. Being composed
entirely of ions, they possess unique advantages of neg-
ligible vapor pressure, a broad range of room tempera-
ture ionic compositions, excellent thermal and chemical
stabilities, interesting physicochemical characteristics,
and selective dissolvability to many organic and inor-
ganic materials. A wide range of reactions have been
reported using ILs as the reaction media for clean trans-
formations and product selectivity [2,3].
Multicomponent reactions (MCRs) have recently
emerged as valuable tools in the preparation of structur-
ally diverse chemical libraries of drug-like heterocyclic
compounds [20–24]. There is great current interest in
microwave-assisted organic synthesis [25–28], because
such environmentally benign chemical methodologies
are strongly required in light of the paradigm shift to
‘‘Green Chemistry.’’ According to the current synthetic
requirements, environmentally benign multicomponent
procedures using MW methodology are particularly wel-
come due to their intrinsic advantages [29–31].
In recent years, the combination of ‘‘microwaves’’
(MWs) and ‘‘IL’’ is becoming very popular due to the
fact that a great variety of synthetic organic transforma-
tions can be carried out very efficiently and rapidly
under these environmentally benign and green condi-
tions. Consequently, it is highly desirable to develop
environmentally benign MW-assisted processes that can
be conducted in ILs.
In view of the above, an efficient and convenient syn-
thesis of 2,4-diamino-5-pyrimidinecarbonitriles has been
accomplished by the MCR of aromatic aldehydes, malo-
nonitrile, and guanidine using controlled MW irradiation
in the presence of [bmim]OH at an ambient temperature
of 60ꢀC (Scheme 1).
Pyrimidine cores belong to one of the most important
heterocycles and as such make attractive scaffolds in
medicinal chemistry. Pyrimidine derivatives have
diverse biological activities [4–11] and are found in
many medicines as well as genetic materials including
nucleosides and nucleotides. Pyrimidines are also
reported to occur in some pesticides, herbicides, and
plant growth regulators [12,13]. Consequently, synthetic
methodologies for the synthesis of pyrimidines or
RESULTS AND DISCUSSION
Although a few synthetic strategies have been adopted
for the synthesis of pyrimidines using different bases
[16–19]; however, these methods suffer from one or
C
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2011 HeteroCorporation

May 2011
Microwave-Assisted One-Pot Synthesis of Functionalized Pyrimidines Using Ionic Liquid
583
Scheme 1
another drawback such as low-product yield, cumber-
some isolation, and long-reaction time. To develop a
green and efficient approach and to avoid the use of
alkaline catalysts, it was thought worthwhile to exploit
the synthetic potential of [bmim]OH in the synthesis of
of 2,4-diamino-5-pyrimidinecarbonitriles via three com-
ponent reaction of aldehydes, malononitrile, and guani-
dine under controlled MW.
As is evident from the table, the use of [bmim]OH as
solvent without any catalyst stands best under the inves-
tigated set of reaction conditions affording 4a in 72%
yield under conventional conditions (Table 1, entry 12).
Application of monomode MW irradiation at the same
temperature, moreover, brought about a tremendous
increase in the yield (94%) and a dramatic reduction in
the reaction time. A further increase in the MW power
and temperature starts diminishing the product yield
(Table 1, entries 13).
To optimize the reaction conditions, the catalytic ac-
tivity of a number of catalysts viz., K2CO3, NaHCO3,
KF/alumina, NaOH, DBU and [bmim]OH in ethanol
were observed in a typical MCR of benzaldehyde 1a,
malononitrile, and guanidine under conventional as well
as MW irradiation conditions. The outcome is given in
Table 1. The use of NaOH, DBU, KF/alumina, and
[bmim]OH (Table 1, entries 7–10 and 14–17) in ethanol
also promoted the reaction to a reasonable extent, but
the other catalysts such as, K2CO3, NaHCO3 in same
solvent ethanol did not work well (Table 1, entries 3–6).
Under the optimized set of controlled MW reaction
conditions (100 W and 60ꢀC), a number of aromatic
aldehydes 1a–i were allowed to undergo MCR with
malononitrile and guanidine in a molar ratio of 1:1:1 in
IL [bmim]OH (1 mL)affording 2,4-diamino-5-pyrimidi-
necarbonitriles 4a–i in excellent yields in 2–3 min
(Table 2). The physical and spectral data of all the prod-
ucts are in full agreement with the assigned structures.
It is worthwhile to mention that the IL [bmim]OH was
Table 1
Optimization of reaction conditions for the multicomponent synthesis of 4a.
Microwave
Conventional
S.NO.
Catalyst
Solvent
MW (W) Temperature (ꢀC) Time (min) Yield (%)a Temperature (ꢀC) Time (min) Yield (%)a
1
–
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
bmim[OH]
bmim[OH]
bmim[OH]
EtOH
EtOH
EtOH
EtOH
80
100
80
100
80
100
80
100
80
60
60
60
80
60
80
60
80
60
80
60
60
70
60
80
60
80
20
10
15
10
10
15
15
10
10
10
05
02
05
10
15
10
15
–
Trace
37
55
25
45
50
69
52
70
85
94
93
42
58
43
62
60
Reflux
60
Reflux
60
Reflux
60
Reflux
60
120
120
120
120
120
90
–
2
–
3
4
K2CO3
K2CO3
NaHCO3
NaHCO3
NaOH
NaOH
bmim[OH]
bmim[OH]
–
28
45
20
35
40
58
45
65
20
72
71
30
54
35
56
5
6
7
8
120
120
60
9
10
11
12
13
14
15
16
17
100
80
Reflux
RT
60
80
60
Reflux
60
Reflux
60
60
–
100
110
80
100
80
90
90
–
DBU
DBU
KF/Al2O3
KF/Al2O3
60
120
120
120
100
a Isolated yield based on aldehyde.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

584
D. S. Raghuvanshi and K. N. Singh
Vol 48
Table 2
which was recrystallized from ethanol to afford pure 2,4-dia-
mino-5-pyrimidinecarbonitriles 4. After isolation of the prod-
uct, the remaining aqueous layer containing the IL was washed
with ether (10 mL) to remove any organic impurity, dried
under vacuum at 90ꢀC to afford [bmim]OH, which was used
in subsequent runs without further purification.
[bmim]OH-mediated synthesis of 2,4-diamino-5-
pyrimidinecarbonitriles (4a–i).
Microwave
(100 W, 80ꢀC)
Physical and spectral data of the products.
mino-6-phenyl-5-pyrimidinecarbonitrile (4a). Yellow crystals;
2,4-Dia-
Time
(min)
Yield
(%)a
M.p.
(ꢀC)
Entry Product
R1
M.p.: 235–237ꢀC; IR (KBr): 3426, 3377, 2203, 1691, 1617,
1548 cmꢂ1
;
1H-NMR (300 MHz, DMSO-d6): d ¼ 7.12
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
4-FC6H4
4-BrC6H4
2
2
3
2
3
3
2
3
2
94
96
93
235–237
243–245
263–265
(4H, broad, 2NH2), 7.53–7.76 (5H, m, Ar) ppm; 13C-NMR
(DMSO-d6): d ¼ 79.21, 116.25, 128.03, 128.56, 130.72,
136.18, 162.87, 164.92, 169.05 ppm; Anal. Calcd. for
C11H9N5: C, 62.55; H, 4.29; N, 33.16. Found: C, 62.43; H,
4.32; N, 33.02.
2-Furyl
4-MeOC6H4
4-ClC6H4
92b 265–267
90
87
90
91
96
238–240
233–235
263–265
228–230
190–192
4-N(CH3)2C6H4
4-MeC6H4
3,4,5-(OMe)3C6H2
2,4-Diamino-6-(4-fluorophenyl)-5-pyrimidinecarbonitrile
(4b). Yellow shining crystals; M.p.: 243–245ꢀC; IR (KBr):
;
3413, 3383, 3145, 2202, 1678, 1615, 1550 cmꢂ1 1H-NMR
a Isolated yield based on aldehyde.
b Average yield of five recycles.
(300 MHz, DMSO-d6): d ¼ 7.05–7.85 (m, Ar and NH2) ppm;
13C-NMR (DMSO-d6): d ¼ 75.84, 115.07, 115.36, 117.92,
130.57, 133.61, 162.96, 165.02, 168.31 ppm; Anal. Calcd. for
C11H8FN5: C, 57.64; H, 3.52; N, 30.55. Found: C, 57.49; H,
3.43; N, 30.48.
recycled up to five times with no loss and diminution in
its amount and efficacy (cf. Table 2, entry 4). After
each and every recycle, the purity of the IL was
affirmed by spectroscopic data.
2,4-Diamino-6-(4-bromophenyl)-5-pyrimidinecarbonitrile
(4c). Yellow crystals; M.p.: 263–265ꢀC; IR (KBr): 3425,
3375, 3152, 2203, 1680, 1614, 1548 cmꢂ1 1H-NMR (300
;
In conclusion, this report demonstrates an efficient
use of [bmim]OH and MW combination for a conven-
ient multicomponent synthesis of 2,4-diamino-5-pyrimi-
dinecarbonitriles by the condensation of aromatic alde-
hydes, malononitrile, and guanidine. The advantages
include excellent yields, easier work-up, lesser reaction
time, and application of green methodology.
MHz, DMSO-d6): d ¼ 7.16–7.71 (m, Ar and NH2) ppm; 13C-
NMR (DMSO-d6): d ¼ 76.05, 118.12, 128.45, 130.47, 134.79,
136.32, 163.23, 165.50, 168.56 ppm; Anal. Calcd. for
C11H8BrN5: C, 45.54; H, 2.78; N, 24.14. Found: C, 45.38; H,
2.69; N, 23.97.
2,4-Diamino-6-(2-furyl)-5-pyrimidinecarbonitrile (4d). Brown
crystals; M.p.: 265–267ꢀC IR (KBr): 3419, 3369, 3154, 2204,
1
1678, 1628, 1542 cmꢂ1. H-NMR (300 MHz, DMSO-d6): d ¼
6.71–7.93 (m, Ar and NH2) ppm; 13C-NMR (DMSO-d6): d ¼
72.51, 112.28, 114.16, 117.43, 145.57, 150.15, 157.22, 162.96,
165.02 ppm; Anal. Calcd. for C9H7N5O: C, 53.73; H, 3.51; N,
34.81. Found: C, 53.56; H, 3.46; N, 34.69.
EXPERIMENTAL
IR spectra were recorded on a JASCO FT/IR-5300 spectro-
photometer, whereas NMR was run on a JEOL AL300
FTNMR spectrometer. The chemical shifts are given in d ppm
with respect to TMS as internal standard. Elemental analysis
(C, H, and N) of final compounds were performed on a Model
CE-440 CHN Analyzer. The TLC spots were detected using
iodine chamber. MW irradiation was made using a CEM Dis-
cover single mode MW reactor (Benchmate Model, USA) with
infrared temperature probe and adjustable 0–300 W output
power. All the chemicals used were purchased from Aldrich
and E. Merck. The IL [bmim]OH was prepared adopting a
literature report [3], and its purity was checked by IR and
1H-NMR.
General microwave procedure for 2,4-diamino-5-pyrimi-
dinecarbonitriles (4a–h). Aromatic aldehyde (1 mmol), malo-
nonitrile (1 mmol), guanidine (1 mmol), and [bmim]OH (1
mL) were put in a pressure regulation 10-mL pressurized vial
‘‘snap-on’’ cap, and the reaction mixture was subjected to irra-
diation in a single-mode MW synthesis system at 100 W
power and 60ꢀC for 2–3 min. After completion of the reaction
as indicated by TLC, 10 mL of water was added and the prod-
uct was extracted with EtOAc (3 ꢁ 10 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and were
evaporated under reduced pressure to afford the crude product,
2,4-Diamino-6-(4-methoxyphenyl)-5-pyrimidinecarbonitrile
(4e). Yellow crystals; M.p.: 238–240ꢀC; IR (KBr): 3422,
3379, 3160, 2201, 1670, 1610, 1550 cmꢂ1 1H-NMR (300
.
MHz, DMSO-d6): d ¼ 6.94–7.78 (m, Ar and NH2) ppm; 13C-
NMR (DMSO-d6): d ¼ 55.31, 75.21, 113.51, 118.32, 129.33,
129.85, 160.94, 162.94, 165.21, 168.56; Anal. Calcd. for
C12H11N5O: C, 59.74; H, 4.60; N, 29.03. Found: C, 59.63; H,
4.48; N, 28.94.
2,4-Diamino-6-(4-chlorophenyl)-5-pyrimidinecarbonitrile (4f). White
crystals; M.p.: 233–235ꢀC; IR (KBr): 3482, 3370, 3182, 2210,
1
1675, 1612, 1553 cmꢂ1; H-NMR (300 MHz, DMSO-d6): d ¼
7.15–7.76 (m, Ar and NH2) ppm; 13C-NMR (DMSO-d6): d ¼
76.15, 117.23, 128.52, 131.04, 135.51, 136.72, 163.30, 165.28,
168.65 ppm; Anal. Calcd. for C11H8ClN5: C, 53.78; H, 3.28;
N, 28.51. Found: C, 53.61; H, 3.19; N, 28.38.
2,4-Diamino-6-[4-(dimethylamino)phenyl]-5-pyrimidinecar-
bonitrile (4g). Yellow crystals; M.p.: 263–265ꢀC; IR (KBr):
;
3410, 3300, 2924, 2197, 1688, 1622, 1545 cmꢂ1 1H-NMR
(300 MHz, DMSO-d6): d ¼ 3.05 (s, 6H, NA(CH3)2), 6.74–
7.78 (m, Ar and NH2) ppm; 13C-NMR (DMSO-d6): d ¼ 40.50,
75.8, 110.87, 120.20, 123.75, 129.42, 151.70, 162.86, 165.44,
169.50 ppm; Anal. Calcd. for C13H14N6: C, 61.40; H, 5.55; N,
33.05. Found: C, 61.51; H, 5.43; N, 32.92.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Microwave-Assisted One-Pot Synthesis of Functionalized Pyrimidines Using Ionic Liquid
585
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;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet