Efficient and facile three-component reaction for the synthesis of 2-amine-4,6-diarylpyrimidine under solvent-free conditions

Article abstract of DOI:10.1080/00397910802399932

An efficient and convenient multicomponent reaction for the preparation of 2-amine-4,6-diarylpyrimidine by aromatic aldehydes, aromatic ketones, and guanidine carbonate in the presence of sodium hydroxide under solvent-free conditions is reported. The sho

Full text of DOI:10.1080/00397910802399932

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Efficient and Facile Three-
Component Reaction for the
Synthesis of 2-Amine-4,6-
diarylpyrimidine Under
Solvent-Free Conditions
Qiya Zhuang a , HongXia Han a , Suhui Wang a ,
Shuajiang Tu a b & Liangce Rong a b
a College of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou, Jiangsu, China
b Key Laboratory of Biotechnology for Medicinal
Plant, Xuzhou, Jiangsu, China
Version of record first published: 08 Jan 2009
To cite this article: Qiya Zhuang, HongXia Han, Suhui Wang, Shuajiang Tu &
Liangce Rong (2009): Efficient and Facile Three-Component Reaction for the
Synthesis of 2-Amine-4,6-diarylpyrimidine Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:3, 516-522
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Synthetic Communications1, 39: 516–522, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802399932
Efficient and Facile Three-Component Reaction
for the Synthesis of 2-Amine-4,6-diarylpyrimidine
Under Solvent-Free Conditions
Qiya Zhuang,1 HongXia Han,1 Suhui Wang,1 Shuajiang Tu,1,2
and Liangce Rong1,2
1College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu, China
2Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou, Jiangsu, China
Abstract: An efficient and convenient multicomponent reaction for the
preparation of 2-amine-4,6-diarylpyrimidine by aromatic aldehydes, aromatic
ketones, and guanidine carbonate in the presence of sodium hydroxide under
solvent-free conditions is reported. The short reaction time coupled with the
simplicity of the reaction procedure make this method one of the most efficient
methods for the synthesis of this class of compounds.
Keywords: One-pot reactions, pyrimidine, solvent-free, synthesis
Synthesis of polysubstituted pyrimidines received strong attention
because of several biological activities associated with this scaffold.[1]
Some reports in the literature describe the application of these substrates
for the treatment of hypoxemia,[2] neuronosis,[3] and neuropathy.[4]
Preclinical data from several research laboratories indicate continuing
interest in polysubstituted pyrimidines as potential antitumor agents.[5]
Pyrimidine derivatives have been also used in coordination chemistry,
specifically as ligands for metal-cage complexes, in particular with
lanthanides[6], and ruthenium.[7]
Multicomponent reactions (MCRs) are of increasing importance
in organic and medicinal chemistry.[8] MCRs leading to interesting
Received June 3, 2008.
Address correspondence to Liangce Rong, College of Chemistry and Chemical
Engineering, Xuzhou Normal University, Xuzhou, Jiangsu, 22116, China.
E-mail: Icrong2005@yahoo.com
516

2-Amine-4,6-diarylpyrimidine
517
Scheme 1. The reaction of aromatic aldehydes, aromatic ketones, and guanidine
carbonate.
heterocyclic scaffolds are particularly useful for the creation of diverse
chemical libraries of ‘‘drug-like’’ molecules for biological screening,
because the combination of three or more small-molecular-weight build-
ing blocks in a single operation leads to high combinatorial efficacy.
Because they avoid using toxic organic solvents in the reaction, solvent-
free organic reactions[9] have attracted more attention. The advantages of
these methods are that they provide greater selectivity, enhanced reaction
rates, cleaner products, and manipulative simplicity. Herein we report a
novel three-component synthesis of multifunctionalized 2-amine-4,6-
diarylpyrimidine scaffolds employing one-pot condensations of aromatic
aldehydes, aromatic ketones, and guanidine carbonate building blocks
under solvent-free conditions.
Our synthetic strategy was as follows: aromatic aldehydes, aromatic
ketones, guanidine carbonate, and a small quantity of NaOH were
blended together, and the mixture was put into a round-bottomed flask.
The reactant was heated up slowly and reacted at 70 ꢀC. The reactions
could be completed within 25 min (Scheme 1). The results of reactions
are listed in Table 1. As shown in Table 1, the corresponding products
Table 1. Synthesis of 2-amine-4,6-diarylpyrimidine
Entry
Ar1
Ar2
Product
Yield
1
2
3
4
5
6
7
8
9
4-CH3C6H4
4-FC6H4
4-ClC6H4
C6H5
4-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
4-ClC6H4
4-CH3C6H4
4-ClC6H4
4-CH3OC6H4
4-CH3C6H4
C6H5
C6H5
C6H5
4-ClC6H4
C6H5
C6H5
4a
4b
4c
4c
4d
4e
4f
4g
4h
4i
90
95
96
94
92
88
90
95
90
92
90
90
C6H5
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-ClC6H4
4-CH3OC6H4
10
11
12
4i
4j

518
Q. Zhuang et al.
were obtained in 88–96% yields. Different kinds of substituted
benzaldehydes or acetophenones, bearing either electron-releasing or
electron-withdrawing substituents, were all carried out smoothly in the
reactions. The reaction time was very short, and the yield of product was
quite high. In our study, we found if we prepared chalcone using the corres-
ponding aromatic aldehydes and aromatic ketones in advance, then used it to
react with guanidine carbonate under the same reaction conditions, we
gained corresponding 2-amine-4,6-diarylpyrimidin with very low yields
(not more than 15%). So, the one-pot synthesis of 2-amine-4,6-diarylpyrimi-
dine reaction was more efficient than the corresponding multistep reaction.
1
The structure of 4 was confirmed by IR, H NMR, and elemental
analysis. To confirm the product structure of 4, we did a contrapositive
experiment. When benzaldehyde and 1-(4-chlorophenyl)ethanone were
chosen to react with guanidine carbonate, simultaneously 4-chloro-
benzaldehyde and acetophenone were chosen to react with guanidine
carbonate too, and the same product [2-amine 4-(4-chlorophenyl)-6-
phenylpyrimidine] was obtained. The reaction result showed the structure
that we presented was right.
In conclusion, we have developed a new, rapid, and simple multicom-
ponent cyclocondensation protocol for the synthesis of biologically active
2-amine-4,6-diarylpyrimidine. The cheapness and the availability of the
reagents, easy and clean workup, and good yields make the method att-
ractive for the synthesis of various 2-amine-4,6-diarylpyrimidine. Further-
more, because it to avoids using organic solvent, this method contributes
to the promotion of economical and environmentally friendly experi-
mental procedures.
EXPERIMENTAL
Melting points were uncorrected. IR spectra were recorded on a Tensor 27
1
spectrometer in KBr. H NMR spectra were obtained in DMSO-d6 sol-
ution with Me4Si as internal standard using a Bruker-400 spectrometer.
Elemental analyses were carried out using Perkin-Elmer 240 II analyzer.
General Procedure for the Synthesis of 2-Amine-4,6-diarylpyrimidine
The mixture of aromatic aldehydes 1 (2 mmol), aromatic ketones 2
(2 mmol), guanidine carbonate 3 (3 mmol), and NaOH (2 mmol) was
ꢀ
put in a reaction flask at 70 C for about 25 min.
After completing the reaction, the reaction mixture was poured into
water, and then washed with water thoroughly. The product was filtered,
dried, and recrystallized from 95% ethanol.

2-Amine-4,6-diarylpyrimidine
519
Spectral Data
2-Amine-4-phenyl-6-p-tolylpyrimidine (4a)
This compound was obtained as yellow crystals, mp 120–121 ꢀC; IR
(KBr, n, cmꢁ1): 3312, 3198, 1633, 1568, 1453, 1365, 1221, 1185, 1115,
1075, 1019, 990, 925, 852, 837, 820, 801, 769, 697, 651, 589; H NMR
1
(400 MHz, DMSO-d6) (d, ppm): 8.22 (1H, d, J ¼ 3.6 Hz, ArH), 8.20
(1H, d, J ¼ 2.8 Hz, ArH), 8.13 (2H, d, J ¼ 8.0 Hz, ArH), 7.68 (1H, s,
C5-H), 7.53 (2H, d, J ¼ 3.6 Hz, ArH), 7.52 (1H, d, J ¼ 2.8 Hz, ArH),
7.33 (2H, d, J ¼ 8.0 Hz, ArH), 6.71 (2H, s, NH2), 2.39 (3H, s, CH3). Anal.
calcd. for C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C, 78.02; H,
5.83; N, 16.15.
2-Amine-4-(4-fluorophenyl)-6-phenylpyrimidine (4b)
This compound was obtained as yellow crystals, mp 118–120 ꢀC; IR
(KBr, n, cmꢁ1): 3496, 3329, 3199, 1638, 1604, 1560, 1509, 1459, 1359,
1227, 1157, 1096, 1015, 845, 820, 768, 695, 652; H NMR (400 MHz,
1
DMSO-d6) (d, ppm): 8.13 (1H, d, J ¼ 2.4 Hz, ArH), 8.11 (1H, d,
J ¼ 3.6 Hz, ArH), 7.58–7.62 (2H, m, ArH), 7.48–7.53 (5H, m, ArH),
7.33 (1H, s, C5-H), 6.86 (2H, s, NH2). Anal. calcd. for C16H12FN3: C,
72.44; H, 4.56; N, 15.84. Found: C, 72.50; H, 4.48; N, 15.73.
2-Amine-4-(4-chlorophenyl)-6-phenylpyrimidine (4c)
This compound was obtained as yellow crystals, mp 147–149 ꢀC; IR
(KBr, n, cmꢁ1): 3493, 3312, 3192, 1634, 1596, 1583, 1542, 1493, 1458,
1397, 1360, 1235, 1220, 1175, 1127, 1094, 1018, 849, 824, 812, 770, 697,
1
644; H NMR (400 MHz, DMSO-d6) (d, ppm): 8.27 (2H, d, J ¼ 8.8 Hz,
ArH), 8.22 (2H, t, J ¼ 3.2 Hz, ArH), 7.75 (1H, s, C5-H), 7.59 (2H, d,
J ¼ 8.8 Hz, ArH), 7.53 (3H, t, J ¼ 3.2 Hz, ArH), 6.81 (2H, s, NH2). Anal.
calcd. for C16H12ClN3: C, 68.21; H, 4.29; N, 14.91. Found: C, 68.07; H,
4.33; N, 15.03.
2-Amine-4-(4-bromophenyl)-6-phenylpyrimidine (4d)
This compound was obtained as yellow crystals, mp 152–154 ꢀC; IR
(KBr, n, cmꢁ1): 3493, 3310, 3190, 1633, 1591, 1566, 1536, 1488, 1457,
1359, 1235, 1219, 1177, 1072, 1012, 925, 846, 824, 812, 769, 695, 640;
1H NMR (400 MHz, DMSO-d6) (d, ppm): 8.22 (2H, t, J ¼ 2.8 Hz,
ArH), 8.20 (2H, d, J ¼ 8.8 Hz, ArH), 7.73 (1H, s, C5-H), 7.72 (2H, d,

520
Q. Zhuang et al.
J ¼ 8.8 Hz, ArH), 7.52 (3H, d, J ¼ 2.8Hz, ArH), 6.81 (2H, s, NH2). Anal.
calcd. for C16H12BrN3: C, 58.91; H, 3.71; N, 12.88. Found: C, 58.82; H,
3.76; N, 12.97.
2-Amine-4-(2-chlorophenyl)-6-phenylpyrimidine (4e)
This compound was obtained as yellow crystals, mp 121–123 ꢀC; IR
(KBr, n, cmꢁ1): 3500, 3311, 3187, 1628, 1600, 1577, 1536, 1456, 1436,
1364, 1264, 1215, 1182, 1128, 1060, 1035, 954, 842, 831, 160, 714, 685,
625, 587; 1H NMR (400 MHz, DMSO-d6) (d, ppm): 8.12 (2H, dd,
J ¼ 3.6 Hz, ArH), 7.58–7.63 (2H, m, ArH), 7.47–7.52 (5H, m, ArH),
7.33 (1H, s, C5-H), 6.84 (2H, s, NH2). Anal. calcd. for C16H12ClN3: C,
68.21; H, 4.29; N, 14.91. Found: C, 68.34; H, 4.36; N, 14.76.
2-Amine-4-(2,4-dichlorophenyl)-6-phenylpyrimidine (4f)
This compound was obtained as yellow crystals, mp 134–136 ꢀC; IR
(KBr, n, cmꢁ1): 3491, 3321, 3195, 1627, 1594, 1574, 1558, 1538, 1479,
1455, 1434, 1384, 1353, 1255, 1216, 1184, 1105, 1059, 863, 841, 824,
1
767, 730, 682; H NMR (400 MHz, DMSO-d6) (d, ppm): 8.11 (2H, t,
J ¼ 3.6 Hz, ArH), 7.78 (1H, d, J ¼ 2.0 Hz, ArH), 7.65 (1H, d, J ¼ 8.0 Hz,
ArH), 7.57 (1H, dd, J ¼ 2.0, 2.0 Hz, ArH), 7.52 (1H, d, J ¼ 2.0 Hz, ArH),
7.51 (2H, d, J ¼ 3.6 Hz, ArH), 7.35 (1H, s, C5-H), 6.91 (2H, s, NH2).
Anal. calcd. for C16H11Cl2N3: C, 60.78; H, 3.51; N, 13.29. Found: C,
60.62; H, 3.57; N, 13.38.
2-Amine-4,6-bis(4-chlorophenyl)pyrimidine (4g)
This compound was obtained as yellow crystals, mp 203–204 ꢀC; IR (KBr, n,
cmꢁ1): 3475, 3310, 3193, 1639, 1597, 1581, 1537, 1491, 1458, 1397, 1363,
1230, 1176, 1128, 1093, 1015, 969, 848, 833, 805, 731, 585; 1H NMR
(400MHz, DMSO-d6) (d, ppm): 8.27 (2H, d, J ¼ 8.0 Hz, ArH), 8.15 (2H,
d, J ¼ 8.0 Hz, ArH), 7.72 (1H, s, C5-H), 7.60 (2H, d, J ¼ 8.0 Hz,
ArH), 7.35 (2H, d, J ¼ 8.0 Hz, ArH), 6.91 (2H, s, NH2). Anal. calcd. for
C16H11Cl2N3: C, 60.78; H, 3.51; N, 13.29. Found: C, 60.63; H, 3.43; N, 13.13.
2-Amine-4-(4-chlorophenyl)-6-p-tolylpyrimidine (4h)
This compound was obtained as yellow crystals, mp 163–164 ꢀC; IR
(KBr, n, cmꢁ1): 3490, 3310, 3191, 1641, 1596, 1581, 1538, 1491, 1454,
1396, 1363, 1232, 1219, 1175, 1089, 1013, 838, 829, 802, 781; H NMR
1
(400 MHz, DMSO-d6) (d, ppm): 8.25 (2H, d, J ¼ 8.0 Hz, ArH), 8.13

2-Amine-4,6-diarylpyrimidine
521
(2H, d, J ¼ 8.0 Hz, ArH), 7.71 (1H, s, C5-H), 7.58 (2H, d, J ¼ 8.0 Hz,
ArH), 7.33 (2H, d, J ¼ 8.0 Hz, ArH), 6.76 (2H, s, NH2), 2.38 (3H, s,
CH3). Anal. calcd. for C17H14ClN3: C, 69.03; H, 4.77; N, 14.21. Found:
C, 69.15; ,H 4.71; N, 14.38.
2-Amine-4-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidine (4i)
This compound was obtained as yellow crystals, mp 149–150 ꢀC; IR
(KBr, n, cmꢁ1): 3330, 3209, 1645, 1608, 1596, 1561, 1532, 1514, 1491,
1439, 1359, 1301, 1258, 1239, 1175, 1125, 1107, 1088, 1033, 1010, 838,
1
815, 681, 593, 578; H NMR (400 MHz, DMSO-d6) (d, ppm): 8.22 (4H,
q, J ¼ 8.8 Hz, ArH), 7.68 (1H, s, C5-H), 7.59 (2H, d, J ¼ 8.8 Hz, ArH),
7.07 (2H, d, J ¼ 8.8 Hz, ArH), 6.70 (2H, s, NH2), 2.84 (3H, s, OCH3).
Anal. calcd. for C17H14ClN3O: C, 65.49; H, 4.53; N, 13.48. Found: C,
65.60; H, 4.61; N, 13.38.
4-(4-Methoxyphenyl)-6-p-tolylpyrimidin-2-amine (4j)
This compound was obtained as yellow crystals, mp 126–128 ꢀC; IR
(KBr, n, cmꢁ1): 3466, 3287, 3171, 1609, 1568, 1535, 1511, 1435, 1364,
1309, 1242, 1178, 1109, 1036, 941, 833, 817, 786, 648, 609, 587; 1H
NMR (400 MHz, DMSO-d6) (d, ppm): 8.19 (2H, d, J ¼ 8.4 Hz, ArH),
8.11 (2H, d, J ¼ 8.0 Hz, ArH), 7.62 (1H, s, C5-H), 7.32 (2H, d, J ¼ 8.0 Hz,
ArH), 7.06 (2H, d, J ¼ 8.4 Hz, ArH), 6.63 (2H, s, NH2), 2.84 (3H, s,
OCH3), 2.38 (3H, s, CH3). Anal. calcd. for C18H17N3O: C, 74.20; H,
5.88; N, 14.42. Found: C, 74.05; H, 5.90; N, 14.50.
ACKNOWLEDGMENTS
We thank the Natural Science Foundation of Jiangsu Education Depart-
ment (No. 08KJB150017) and the Pei Yu Foundation (No. 07PYL06) of
Xuzhou Normal University for financial support.
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