Efficient and facile synthesis of 2,4-diamino-6-arylpyrimidine-5- carbonitrile under solvent-free conditions

Article abstract of DOI:10.1080/00397910902987784

An efficient and convenient method for the preparation of 2,4-diamino-6-arylpyrimidine-5-carbonitrile derivatives by the one-pot reaction of aromatic aldehydes, malononitrile, and guanidine carbonate, in the presence of sodium hydroxide under solvent-free

Full text of DOI:10.1080/00397910902987784

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Efficient and Facile Synthesis of 2,4-
Diamino-6-arylpyrimidine-5-carbonitrile
Under Solvent-Free Conditions
Liangce Rong a b , Hongxia Han a , Lijiu Gao a , Yisi Dai a , Minxia Cao
a & Shujiang Tu a b
a College of Chemistry and Chemical Engineering, Xuzhou Normal
University , Xuzhou, China
b Key Laboratory of Biotechnology for Medicinal Plants, Jiangsu
Province of Xuzhou , Jiangsu, China
Published online: 03 Feb 2010.
To cite this article: Liangce Rong , Hongxia Han , Lijiu Gao , Yisi Dai , Minxia Cao & Shujiang Tu (2010)
Efficient and Facile Synthesis of 2,4-Diamino-6-arylpyrimidine-5-carbonitrile Under Solvent-Free
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:4, 504-509, DOI: 10.1080/00397910902987784
To link to this article: http://dx.doi.org/10.1080/00397910902987784
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Synthetic Communications1, 40: 504–509, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902987784
EFFICIENT AND FACILE SYNTHESIS OF
2,4-DIAMINO-6-ARYLPYRIMIDINE-5-CARBONITRILE
UNDER SOLVENT-FREE CONDITIONS
Liangce Rong,1,2 Hongxia Han,1 Lijiu Gao,1 Yisi Dai,1
Minxia Cao,1 and Shujiang Tu1,2
1College of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou, China
2Key Laboratory of Biotechnology for Medicinal Plants, Jiangsu
Province of Xuzhou, Jiangsu, China
An efficient and convenient method for the preparation of 2,4-diamino-6-arylpyrimidine-5-
carbonitrile derivatives by the one-pot reaction of aromatic aldehydes, malononitrile, and
guanidine carbonate, in the presence of sodium hydroxide under solvent-free conditions,
was reported. This method has the advantages of excellent yields, mild reaction conditions,
easy work up, and environmental friendliness over the existing procedures.
Keywords: Aromatic aldehyde; guanidine carbonate; malononitrile; pyrimidine; solvent-free condition;
synthesis
In organic synthesis, the synthesis of heterocyclic compounds has been a subject of
great interest because of the wide applicability of those compounds. Heterocyclic
compounds occur very widely in nature and are essential to life. Nitrogen-containing
heterocyclic molecules constitute the largest portion of chemical entities, which are
part of many natural products, fine chemicals, and biologically active pharmaceuti-
cals, which are vital for enhancing quality of life.[1–10] Pyrimidines, as the most
important nitrogen-containing heterocyclic compounds, are of chemical and phar-
macological interest,[11,12] and compounds containing the pyrimidine ring system
have been shown to possess antitumor, antibacterial, antifungal, antimalarial, and
anticonvulsant activities.[11–13] Some are valuable drugs for the treatment of
hyperthyroidism, acute leukemia in children, and adult granulocytic leukemia.[12]
Furthermore, several pyrimidines are used in polymer and supramolecular chemis-
try.[14,15] Conjugated molecules that have a pyrimidine core as the key unit have
received much attention, and they are prospective candidates for light-emitting
devices[16] and molecular wires.[17]
Recently, there has been a surge of interest in performing chemical transforma-
tions in a solvent-free environment.[18] In comparison to methods employing
Received January 21, 2009.
Address correspondence to Liangce Rong, College of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou, 221116, China. E-mail: lcrong2005@yahoo.com
504

2,4-DIAMINO-6-ARYLPYRIMIDINE
505
Scheme 1. Synthesis of 2,4-diamino-6-arylpyrimidine-5-carbonitrile.
molecular solvents, the solvent-free approach proceeds more cleanly and provided
better yields. A great number of organic reactions can be carried out in shorter times,
in milder conditions, or with better selectivity under solvent-free conditions. As part
of our continued interest in the development of green methods for the synthesis of
organic compounds,[19] we report here a very simple and efficient method for the
synthesis of 2,4-diamino-6-arylpyrimidine-5-carbonitrile derivatives via a one-pot
cyclocondensation reaction using simple and inexpensive sodium hydroxide as the
catalyst in solvent-free conditions.
The synthetic strategy can be carried out as follows: the mixture of aromatic
aldehydes 1, malononitrile 2, guanidine carbonate 3, and 1.0 equivalents NaOH
was put into a reaction flask, then the reactive reagent was heated at 70ꢀC for a
certain time, and the reaction could be completed (Scheme 1). The results of reaction
was listed in Table 1.
As can be seen from Table 1, aromatic aldehydes, malononitrile, and guanidine
carbonate in the presence of sodium hydroxide (NaOH) gave the corresponding
2,4-diamino-6-arylpyrimidine-5-carbonitrile under solvent-free conditions in good
yields. In this reaction, the NaOH was absolutely necessary. If the NaOH was lack-
ing, the reaction could not be carried out. We thought the NaOH took the more
important role in the reaction. On one side, as the catalyst, the NaOH promoted
the reagents to react with each other: on the other side, NaOH is the base and
reacted with carbonic acid, so the carbamidine could release from organic salt. It
then took part in the reaction. We also investigated the reaction of different aromatic
aldehydes with malononitrile and guanidine carbonate. We found that aromatic
aldehydes, carrying either electron-donating or electron-withdrawing substituent
groups, could react well in the reaction and gave the product with excellent yields.
Table 1. Synthetic results of compounds 4
Entry
Ar
Product
Yield (%)
Mp (ꢀC)
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
85
80
88
82
89
85
90
91
92
237–239
255–257
236–238
233–235
260–262
253–255
265–266
264–266
235–237
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3)2C6H3
4-BrC6H4
3-ClC6H4
4-ClC6H4
4g
4h
4i
3,4-Cl2C6H3
4-FC6H4

506
L. RONG ET AL.
In summary, we have developed an economically and environmentally friendly
procedure for the synthesis of 2,4-diamino-6-arylpyrimidine-5-carbonitrile with good
yields. This involves the use of NaOH, as a very inexpensive and easily available
catalyst, and solvent-free conditions.
EXPERIMENTAL
Melting points were determined on a XT-5 microscopic melting-point
spectrometer and were uncorrected. Infrared (IR) spectra were recorded on a
Fourier transform (FT)–IR-8101 spectrometer. 1H NMR spectra were obtained
from solution in dimethylsulfoxide (DMSO-d6) with Me4Si as internal standard
using a Bruker-400 spectrometer. High-resolution mass spectra (HRMS) were
obtained with a Bruker MicroTOF-Q 134 instrument.
General Procedure for the Synthesis of 2,4-Diamino-6-
arylpyrimidine-5-carbonitrile
The mixture of aromatic aldehydes 1 (2 mmol), malononitrile 2 (3 mmol),
guanidine carbonate 3 (1 mmol), and 1.0 equivalents of NaOH was put in a reaction
flask and kept at 70ꢀC. After completion of the reaction, as indicated by thin-layer
chromatography (TLC; acetone=petroleum ether, 1:3), the reaction mixture was
poured into water and then washed with 0.5% HCl=water thoroughly. The product
was filtered, dried, and recrystallized from 95% ethanol.
Selected Data
2,4-Diamino-6-phenylpyrimidine-5-carbonitrile (4a). IR (KBr) v: 3466,
3324, 3219, 2979, 2933, 2226, 1623, 1586, 1345, 1189, 1017, 770, 700 cmꢁ1 1H
.
NMR (400 MHz, DMSO-d6) d: 7.13 (2H, s, NH2), 7.25 (2H, s, NH2), 7.48–7.55
(3H, m, ArH), 7.75 (2H, dd, J ¼ 2.0 Hz, J ¼ 2.0 Hz, ArH). HRMS m=z calc. for
C11H9N5 [M þ H]: 212.0931; found: 212.0930.
2,4-Diamino-6-p-tolylpyrimidine-5-carbonitrile (4b). IR (KBr) v: 3463,
1
3427, 3379, 3156, 2204, 1682, 1614, 1543, 1489, 1275, 1040, 792 cmꢁ1. H NMR
(400 MHz, DMSO-d6) d: 2.38 (3H, s, CH3), 7.03–7.10 (4H, br, s, 2 ꢂ NH2), 7.30
(2H, d, J ¼ 8.0 Hz, ArH), 7.67 (2H, d, J ¼ 8.0 Hz, ArH). HRMS m=z calcd. for
C12H11N5 [M þ H]: 226.1087; found: 226.1096.
2,4-Diamino-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (4c). IR
(KBr) v: 3506, 3425, 3378, 2936, 2203, 1609, 1549, 1444, 1257, 1169, 1026, 842,
1
797 cmꢁ1. H NMR (400 MHz, DMSO-d6) d: 3.83 (3H, s, OCH3), 7.10–7.21 (4H,
br, s, 2 ꢂ NH2), 7.05 (2H, d, J ¼ 8.8 Hz, ArH), 7.78 (2H, d, J ¼ 8.8 Hz, ArH). HRMS
m=z calcd. for C12H11N5O [M þ H]: 242.1036; found: 242.1041.
2,4-Diamino-6-(3,4-dimethylphenyl)pyrimidine-5-carbonitrile (4d). IR
1
(KBr) v: 3437, 3332, 3138, 2200, 1635, 1538, 1445, 1276, 1121, 1023, 797 cmꢁ1. H
NMR (400MHz, DMSO-d6) d: 2.78 (6H, s, 2 ꢂ CH3), 6.92–7.09 (4H, br, s, 2 ꢂ NH2),

2,4-DIAMINO-6-ARYLPYRIMIDINE
507
7.25 (1H, d, J ¼ 7.6 Hz, ArH), 7.51 (1H, d, J ¼ 8.0 Hz, ArH), 7.55 (1H, s, ArH).
HRMS m=z calc. for C13H13N5 [M þ H]: 240.124; found: 240.1250.
2,4-Diamino-6-(4-bromophenyl)pyrimidine-5-carbonitrile (4e). IR (KBr)
v: 3508, 3427, 3377, 3151, 2206, 1683, 1614, 1549, 1448, 1281, 1180, 1072, 1012, 888,
1
836, 793 cmꢁ1. H NMR (400 MHz, DMSO-d6) d: 6.96–7.24 (4H, br, s, 2 ꢂ NH2),
7.71 (4H, s, ArH). HRMS m=z calcd. for C11H8N5Br [M þ H]: 290.0036; found:
290.0031.
2,4-Diamino-6-(3-chlorophenyl)pyrimidine-5-carbonitrile (4f). IR (KBr)
1
v: 3496, 3434, 3378, 3316, 3221, 3143, 2203, 1682, 1623, 1549, 1286, 781 cmꢁ1. H
NMR (400 MHz, DMSO-d6) d: 7.12–7.25 (4H, br, s, 2 ꢂ NH2), 7.54 (1H, t,
J ¼ 7.6 Hz, J ¼ 8.0 Hz, ArH), 7.59 (1H, d, J ¼ 1.6 Hz, ArH), 7.73 (1H, d, J ¼ 7.6 Hz,
ArH), 7.77 (1H, s, ArH). HRMS m=z calcd. for C11H8N5Cl [M þ H]: 246.0541;
found: 246.0540.
2,4-Diamino-6-(4-chlorophenyl)pyrimidine-5-carbonitrile (4g). IR (KBr)
v: 3509, 3427, 3378, 3152, 2206, 1685, 1615, 1550, 1447, 1274, 1094, 836, 792 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6) d: 7.1–7.20 (4H, br, s, 2 ꢂ NH2), 7.58 (2H, d,
J ¼ 8.4 Hz, ArH), 7.78 (2H, d, J ¼ 8.4 Hz, ArH). HRMS m=z calcd. for C11H8N5Cl
[M þ H]: 246.0541; found: 246.0536.
2,4-Diamino-6-(3,4-dichlorophenyl)pyrimidine-5-carbonitrile
(4h). IR
(KBr) v: 3496, 3439, 3379, 3137, 2203, 1681, 1622, 1576, 1410, 1031, 792 cmꢁ1. H
NMR (400 MHz, DMSO-d6) d: 7.19–7.28 (4H, br, s, 2 ꢂ NH2), 7.78 (2H, t,
J ¼ 1.6 Hz, J ¼ 6.4 Hz, ArH), 7.99 (1H, d, J ¼ 1.6 Hz, ArH). HRMS m=z calc. for
C11H7N5Cl2 [M þ H]: 280.0151; found: 280.0156.
1
2,4-Diamino-6-(4-fluorophenyl)pyrimidine-5-carbonitrile (4i). IR (KBr)
v: 3509, 3422, 3380, 3152, 2205, 1686, 1616, 1547, 1518, 1453, 1239, 1160, 843,
1
793 cmꢁ1. H NMR (400 MHz, DMSO-d6) d: 7.06–7.17 (4H, br, s, 2 ꢂ NH2), 7.34
(2H, t, J ¼ 8.8 Hz, J ¼ 8.8 Hz, ArH), 7.82 (2H, dd, J ¼ 5.6 Hz, J ¼ 5.6 Hz, ArH).
HRMS m=z calc. for C11H8N5F [M þ H]: 230.0837; found: 230.0836.
ACKNOWLEDGMENTS
We thank the Natural Science Foundation of Jiangsu Education Department
(No. 08KJB150017) and the Pei Yu Foundation (No. 07PYL06) of Xuzhou Normal
University for financial support.
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