Rapid three-component synthesis of pyrimidine and pyrimidinone derivatives in the presence of Bi(NO3)3·5H2O as a mild and highly efficient catalyst

Article abstract of DOI:10.1007/s11164-013-1172-6

Bismuth(III) nitrate pentahydrate is found as a mild and highly efficient catalyst for the rapid synthesis of 4-amino-5-pyrimidine carbonitrile and pyrimidinone derivatives via three-component reaction of aldehydes, N-unsubstituted amidines, and malononit

Full text of DOI:10.1007/s11164-013-1172-6

Res Chem Intermed
DOI 10.1007/s11164-013-1172-6
Rapid three-component synthesis of pyrimidine
and pyrimidinone derivatives in the presence
of Bi(NO3)3Á5H2O as a mild and highly efficient catalyst
•
Moahboobeh Zahedifar Hassan Sheibani
Received: 2 December 2012 / Accepted: 19 March 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Bismuth(III) nitrate pentahydrate is found as a mild and highly efficient
catalyst for the rapid synthesis of 4-amino-5-pyrimidine carbonitrile and pyrimid-
inone derivatives via three-component reaction of aldehydes, N-unsubstituted
amidines, and malononitrile or ethyl cyanoacetate under thermal aqueous condi-
tions. The reaction protocol is rapid and simple which is followed by formation of
the corresponding pyrimidine and pyrimidinone derivatives in good to excellent
yields with high purity.
Keywords Bismuth(III) nitrate pentahydrate Á Amidines Á Malononitrile Á
4-Amino-5-pyrimidine-carbonitrile and pyrimidinones
Introduction
The discovery of novel synthetic routes towards pyrimidines and dihydropyrimid-
inones (DHPMs) is an area of continuing interest for organic chemists. Pyrimidine
derivatives have occupied an important position in natural and synthetic organic
chemistry, due to their wide range of biological activities, particularly in cancer and
virus research [1]. These compounds often play a fundamental role as analgesic [2],
antihypertensive [3], antipyretic [4], and anti-inflammatory drugs [5], and as
pesticides [6], herbicides, medications, and plant growth regulators [7]. Therefore,
synthetic methodologies for the synthesis of novel pyrimidines or pyrimidine-fused
compounds are of challenging interest to organic chemists [8]. Conventional organic
syntheses are generally based on homogeneous catalysts. However, homogeneous
reactions suffer disadvantages in separation, regeneration, and so forth. From the
M. Zahedifar Á H. Sheibani (&)
Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran
e-mail: hsheibani@mail.uk.ac.ir
123

M. Zahedifar, H. Sheibani
viewpoint of green chemistry, the use of heterogeneous catalysts is desirable. The
consequential advantages of heterogeneous catalysts from the environmental and
economic points of view are clearly understandable, because these procedures allow
money to be saved and the production of waste material to be minimized [9].
Bismuth(III) nitrate pentahydrate is known as a heterogeneous catalyst and
commercially available reagent and requires no special handling. It is a stable
and non-toxic crystalline solid, insensitive to air, and requires no special care during
its handling. This reagent can act as an effective Lewis acid, and it can be used
successfully in the presence of commercially available solvents without any drying
or treatment [10]. The use of bismuth nitrate derivatives as catalysts in organic
synthesis has increased considerably over the years. A literature survey revealed that
bismuth(III) nitrate pentahydrate has been used for conversion of thiocarbonyls to
their carbonyl compounds [11], aromatic nitration [12], protection of carbonyl
compound [13], Michael reactions [14], synthesis of coumarins [15], guanylation of
thiourea [16], etc. In the course of our investigations to develop new synthetic
methods for the preparation of nitrogen-containing heterocycles in the presence of
environmentally friendly base and acid catalysts, in order to reduce the amount of
toxic waste and byproducts arising from chemical processes [17–20], we have
performed the synthesis of 4-amino-5-pyrimidinecarbonitrile and dihydro-5-
pyrimidinonecarbonitrile derivatives through a three-component reaction in the
presence of Bi(NO3)3Á5H2O as a Lewis acid.
Experimental
Melting points were determined on an Gallenkamp melting-point apparatus and are
uncorrected. IR spectra were measured on a Mattson 1000 Fourier transform
1
infrared (FT-IR) spectrometer. H NMR and 13C NMR spectra were determined on
a Bruker DRX-300 Avance spectrometer at 300.13 and 75.47 MHz, respectively.
Mass spectra (MS) were recorded on a Shimadzu QP 1100EX mass spectrometer
operating at an ionization potential of 70 eV. Elemental analyses were performed
using a Heracus CHN-O-Rapid analyzer.
General procedure for the preparation of pyrimidine and pyrimidinone
derivatives
A mixture of the aldehyde (2 mmol), amidines hydrochloride (2 mmol), malono-
nitrile or ethyl cyanoacetate (2 mmol), Bi(NO3)3Á5H2O (5 mol%) and a catalytic
amount of Et3N in CH3CN (5 mL) was refluxed with stirring for the times reported
in Table 1. The progress of the reaction was monitored by thin-layer chromatog-
raphy (TLC), and hexane/ethyl acetate was used as an eluent. After completion of
the reaction, the catalyst was separated from the reaction mixture by centrifugation.
The excess acetonitrile was removed by evaporation and then was poured into ice-
cold water; the crude product was filtered, dried, and recrystallized from 96 %
ethanol.
123

Rapid three-component synthesis of pyrimidine and pyrimidinone
Table 1 Synthesis of compounds 4a–s and 5a–f in the presence of base and acid catalysts
Compd. Ar
no.
R
Thermal
conditions
Commercially High surface
available MgO area MgO
Bi(NO3)3Á5H2O
Time Yield Time
(h)
Yield Time
(%)
Yield Time
(%)
Yield
(%)
(%)
(min)
(min)
(min)
4a
4b
4c
4d
4e
4f
C6H5
Ph
6
78
81
79
64
60
78
60
55
65
60
70
90
83
86
81
84
80
80
20
15
20
22
30
40
85
88
83
86
82
83
5
4
86
83
82
86
80
83
C6H5
NH2
Ph
5
4-MeC6H4
4-MeC6H4
4
5
NH2
5
7
4-MeOC6H4 Ph
8
12
15
4-
Me2NC6H4
Ph
12
4g
Ph
6
46
70
65
30
70
11
71
S
4h
4i
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
4-FC6H4
3-FC6H4
3-FC6H4
3-FC6H4
4-CF3C6H4
4-CF3C6H4
4-CF3C6H4
C6H5
Ph
4
3
4
4
4
4
3
4
5
2
4
5
–
–
–
–
–
–
73
82
80
78
63
66
80
68
60
70
72
60
–
50
45
87
90
84
87
88
91
87
92
83
83
87
80
80
84
84
82
86
87
15
13
18
15
14
12
10
8
89
91
87
89
90
92
90
96
85
88
90
83
82
85
86
84
88
89
4
4
90
90
85
89
88
91
90
96
83
88
92
81
80
85
82
81
89
89
NH2
Ph
4j
58
5
4k
4l
NH2
NH2
Ph
52
4
48
3
4m
4n
4o
4p
4q
4r
4s
45
3
Ph
50
2
NH2
Me
Ph
45
2
60
20
17
15
25
40
35
33
36
33
33
5
53
6
NH2
Me
Ph
50
4
65
10
20
16
15
16
14
13
5a
5b
5c
5d
5e
5f
120
110
100
110
105
100
4-ClC6H4
3-FC6H4
4-CF3C6H4
2,4-ClC6H3
4-NO2C6H4
Ph
–
Ph
–
Ph
–
Ph
–
Ph
–
6-Oxo-2,4-diphenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4a)
Yellow crystals; mp 105 °C. IR (KBr, tmax/cm-1): 3,329 (NH), 2,212 (CN), 1,691
(C=O), 1,617 (C=N), 1,542, 1,492 (C=C); 1H NMR (300 MHz, DMSO-d6): 9.62 (s,
1H, NH), 8.32–7.29 (m, 10H, Ar). 13C NMR (75 MHz, DMSO-d6): 173.50, 168.29,
166.51, 138.96, 138.55, 130.72, 130.34, 129.40, 128.89, 128.66, 128.63, 120.88
(CN), 91.47 (C5). MS (m/z): 273 (M?) (30), 245 (35), 170 (50), 142 (15), 120 (60),
104 (87), 77 (50), 53 (25). Anal. calcd. for C17H11N3O: C, 74.71; H, 4.06; N,
15.38 %. Found: C, 74.37; H. 3.92; N; 15.05 %.
123

M. Zahedifar, H. Sheibani
4-(4-Chlorophenyl)-6-oxo-2phenyl-1,6dihydro-5-pyrimidinecarbonitrile (4b)
Yellow crystals; mp 210–212 °C. IR (KBr, tmax/cm-1): 3,478 (NH), 2,212 (CN),
1
1,690 (C=O), 1,617 (C=N), 1,542 (C=C). H NMR (300 MHz, DMSO-d6): 9.35 (s,
1H, NH); 8.31–7.33 (m, 9H, Ar). 13C NMR (75 MHz, DMSO-d6): 173.29, 167.00,
164.95, 138.82, 137.23, 135.16, 130.81, 130.61, 128.76, 128.60, 128.54, 120.12
(CN), 91.37 (C5). MS (m/z): 307 (M?) (40), 272 (45), 145 (60), 104 (60), 77 (55),
51 (35). Anal. calcd. for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65 %. Found: C,
66.12; H. 3.08; N; 13.31 %.
4-(3-Fluorophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4c)
White crystals; mp 105 °C. IR (KBr, tmax/cm-1): 3,329 (NH), 2,212 (CN), 1,691
(C=O), 1,617 (C=N), 1,542, 1,492 (C=C). H NMR (300 MHz, DMSO-d6): 9.35 (s,
1H, NH); 8.32–7.36 (m, 9H, Ar). 13C NMR (75 MHz, DMSO-d6) 169.92, 166.81,
163.48, 162.30 (d,1J=C–F 241.50 Hz), 140.27 (d,3J=C–F 7.50 Hz), 137.01, 131.48,
130.88 (d,3J=C–F 7.50 Hz), 128.76, 128.74, 125.03, 119.13 (CN), 117.58 (d,2J=C–F
21 Hz),115.59 (d,2J=C–F 22.50 Hz), 92.79 (C5). MS (m/z): 291 (M?) (60), 263 (65),
188 (90), 160 (25), 138 (20), 104 (75), 77 (80), 51 (35). Anal. calcd. for
C17H10FN3O: C, 70.10; H, 3.46; N, 14.43 %. Found: C, 69.86; H, 3.22; N; 14.05 %.
6-Oxo-2-phenyl-4-[4-(trifluoromethyl)phenyl]-1,6-dihydro-5-
pyrimidinecarbonitrile (4d)
Yellow crystals; mp 125 °C. IR (KBr, tmax/cm-1): 3,503 (NH), 2,212 (CN),
1,641(C=O), 1,592 (C=N), 1,567 (C=C). H NMR (300 MHz, DMSO-d6) 9.55 (s,
1
1H, NH), 8.32–7.44 (m, 9H, Ar). 13C NMR (75 MHz, DMSO-d6): 172.72, 166.83,
2
165.04, 142.64, 139.06, 131.81 (q, J=C–F 22.50 Hz), 130.01, 129.58, 128.01 (q,
3
1J=C–F 270.75 Hz, CF3), 125.86 (q, J=C–F 3.75 Hz), 120.04 (CN), 91.91 (C5). MS
(m/z): 341 (M?) (60), 313 (65), 238 (80), 221 (15), 194 (10), 172 (10), 145 (40), 104
(85), 77 (90), 51 (50). Anal. calcd. for C18H10F3N3O: C, 63.35; H, 2.95; N, 12.31 %.
Found: C, 63.01; H. 2.90; N; 12.18 %.
4-(2,4-Dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4e)
Yellow crystals; mp 110 °C. IR (KBr, tmax/cm-1): 3,379 (NH), 2,212 (CN), 1,690
(C=O), 1,617 (C=N), 1,542, 1,492 (C=C). 1H NMR (300 MHz, DMSO-d6): 9.37 (s,
1H, NH), 8.20–7.41 (m, 9H, Ar). 13C NMR (75 MHz, DMSO-d6): 171.84, 167.26,
166.29, 138.94, 137.19, 134.59, 132.82, 132.13, 130.64, 129.51, 129.42, 128.78,
127.88, 119.15 (CN), 94.13 (C5). MS (m/z): 341 (M?) (90), 313 (75), 238 (85), 221
(60), 194 (25), 171 (20), 145 (65), 104 (80), 77 (90), 51 (40). Anal. calcd. For
C17H9Cl2N3O: C, 59.67; H, 2.65; N, 12.28 %. Found: C, 59.35; H. 2.56; N;
12.14 %.
123

Rapid three-component synthesis of pyrimidine and pyrimidinone
4-(4-Nitrophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4f)
Brown crystals; mp 105 °C. IR (KBr, tmax/cm-1): 3,379 (NH), 2,212 (CN), 1,680
1
(C=O), 1,592 (C=N), 1,517 (C=C). H NMR (300 MHz, DMSO-d6): 9.52 (s, 1H,
NH); 8.34–7.44 (m, 9H, Ar). 13C NMR (75 MHz, DMSO-d6): 172.53, 166.16,
165.03, 148.47, 144.81, 138.95, 130.74, 130.14, 128.54, 123.88, 120.04 (CN), 91.91
(C5). MS (m/z): 318 (M?) (10), 215 (10), 176 (15), 136 (70), 103 (7), 77 (75), 63
(90), 45 (40). Anal. calcd. For C17H10N4O3: C, 64.15; H, 3.17; N, 17.60 %. Found:
C, 64.03; H. 3.02; N; 17.45 %.
Results and discussion
The versatility of the bismuth(III) nitrate pentahydrate reagent encouraged us to
study its utility for the Knoevenagel condensation and Michael addition. We have
observed that Bi(NO3)3Á5H2O can be utilized efficiently for the synthesis of
4-amino-5-pyrimidinecarbonitrile and dihydro-5-pyrimidinonecarbonitrile deriva-
tives with three-component reaction of aromatic aldehydes 1, malononitrile or ethyl
cyanoacetate 2, and amidines 3 in acetonitrile at reflux, and in the presence of an
equivalent amount of bismuth(III) nitrate pentahydrate for a short experimental time
in good to excellent yields with high purity (Scheme 1).
To optimize the reaction conditions for preparing compounds 4 and 5, the effect
of catalysts under different reaction conditions was investigated. We examined
three-component reactions of aromatic aldehydes 1, malononitrile or ethylcyanoac-
etate 2, and amidines 3 in different solvents, such as water, ethanol, and acetonitrile
at the thermal condition without catalyst and in the presence of catalysts, such as
magnesium oxide MgO [commercial MgO (CM-MgO), high surface area MgO
(HSA-MgO)] and bismuth(III) nitrate pentahydrate. As shown in Table 1, thr yield
of the reaction is markedly affected by the catalyst and solvent, and optimum results
were obtained when reactions were treated in acetonitrile and in the presence of
bismuth(III) nitrate pentahydrate. We also optimized the quantity of catalyst, the
best results being obtained when the reaction was carried out in the presence of
5 mol% catalyst.
In order to confirm the reactivity of bismuth(III) nitrate pentahydrate
(Bi(NO3)3Á5H2O) in the mentioned reactions, we separately studied Knoevenagel
Ar
Ar
O
Ar
H
CN
O
CN
NH
NH2.HCl
N
Bi(NO3)3.5H2O
Et3N , CH3CN
CN
N
1
+
or
R
R
N
H
X
R
N
NH2
2
X= CO2Et
5a-f
X= CN
4a-s
3
Scheme 1 Three-component reaction of aromatic aldehydes 1, malononitrile or ethyl cyanoacetate 2,
and amidines 3 in the presence of Bi(NO3)3Á5H2O
123

M. Zahedifar, H. Sheibani
Table 2 Knoevenagel condensation of aldehydes with malononitrile or ethyl cyanoacetate catalyzed by
Bi(NO3)3Á5H2O in CH3CN
Ar
CN
CN
Bi(NO3)3.5H2O
+
ArCHO
X
Et3N , CH3CN
H
X
2a: X=CN
2b: X=CO2Et
1a-f
6a-f
Compound
Ar
X
Time (s)
Yield (%)
6a
6b
6c
6d
6e
6f
C6H5
C6H5
CN
5
70
2
94
92
97
93
98
92
CO2Et
CN
4-ClC6H4
4-ClC6H4
CO2Et
CN
20
2
4-O2NC6H4
4-O2NC6H4
CO2Et
25
condensations of malononitrile or ethyl cyanoacetate as active methylene
compounds with aromatic aldehydes 1a–f. The catalyst plays a crucial role in the
success of the reaction in terms of the rate and the yields. Our observations are
reported in Table 2.
We also separately studied the Michael addition of arylidenemalononitriles or
arylidene cyanoacetate 6 with amidines in the presence bismuth(III) nitrate
pentahydrate. As shown in Table 3, the rates of these reactions are fast.
The one-pot and sequential steps reaction is often referred to as a tandem or
cascade reaction in which reagents and catalysts are mixed together and
experimental conditions are set up in such a way as to promote the reaction
cascade. Thus, the arylidenemalononitrile or arylidenecyanoacetate 6 containing the
electron-poor C=C double bond is quantitatively produced by fast Knoevenagel
Table 3 Michael additions of compounds 6 with amidines in the presence of Bi(NO3)3Á5H2O
Ar
Ar
CN
O
CN
N
Ar
CN
X
NH
NH2.HCl
N
Bi(NO3)3.5H2O
Et3N , CH3CN
or
+
R
N
H
R
R
N
NH2
H
X= CO2Et
5
X= CN
4
2
6
Compound
Ar
R
Time (min)
Yield (%)
4a
4b
5a
5b
4h
4i
C6H5
C6H5
NH2
4
6
91
92
96
96
97
94
C6H5
C6H5
C6H5
C6H5
C6H5
NH2
18
15
2
4-ClC6H4
4-ClC6H4
4-ClC6H4
4
123

Rapid three-component synthesis of pyrimidine and pyrimidinone
addition of malononitrile to an aromatic aldehyde in the presence bismuth(III)
nitrate pentahydrate. The second step is followed by Michael addition, cycload-
dition, isomerization, and aromatizetion to afford the 4-amino-5-pyrimidinecarbo-
nitrile and dihydro-5-pyrimidinone carbonitrile derivatives. Structures 4a–s were
established on the basis of infrared (IR), which showed the presence of a C=N group
in the region of 2,235–2,238 cm-1 and two sharp bands at 3,500–3,450 and
3,390–3,380 cm-1, due to the asymmetric and symmetric vibrations of NH2 group.
1
The H and 13C NMR spectroscopic data were comparable with the reported data
[17]. The structures of 5a–f were determined on the basis of their elemental
1
analyses, mass spectra, H and 13C NMR data, and IR spectral data.
Conclusion
In summary, Bi(NO3)3Á5H2O is reported as an efficient Lewis acid for the synthesis
of 4-amino-5-pyrimidinecarbonitrile and pyrimidinones derivatives in a three-
component reaction containing aldehydes, amidin systems, or malononitrile or ethyl
cyanoacetate. Advantages of the strategy include mild reaction temperature, easy
recovery, and reusability of the catalyst with consistent activity and short reaction
times.
Acknowledgment The authors express appreciation to the Shahid Bahonar University of Kerman
Faculty Research Committee Fund for its support of this investigation.
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