An efficient and clean synthesis of pyrido[2,3-d]pyrimidine-4,7-dione derivatives in aqueous media

Article abstract of DOI:10.1002/jhet.223

(Chemical Equation Presented) A series of 2-amino-5-aryl-5,6- dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives were synthesized via the three-component reaction of aromatic aldehyde, 2,6-diaminopyrimidine- 4(3H)-one, and Meldrum's acid in water

Full text of DOI:10.1002/jhet.223

November 2009 An Efficient and Clean Synthesis of Pyrido[2,3-d]pyrimidine-4,7-
dione Derivatives in Aqueous Media
1331
Da-Qing Shi,a* Jing-Wen Shi,b and Shao-Feng Rongb
aCollege of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Organic
Synthesis of Jiangsu Province, Soochow University, Suzhou 215123, People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116,
People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received October 6, 2008
DOI 10.1002/jhet.223
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 2-amino-5-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derivatives were
synthesized via the three-component reaction of aromatic aldehyde, 2,6-diaminopyrimidine- 4(3H)-one,
and Meldrum’s acid in water in the presence of triethylbenzylammonium chloride (TEBAC). This proto-
col has the advantages of easier work-up, milder reaction conditions, and environmentally benign
procedure.
J. Heterocyclic Chem., 46, 1331 (2009).
INTRODUCTION
their wide range of biological activities, which include
antitumor [10], antibacterial [11], anti-inflammatory
[12], antifungal [13], and antileishmaniasis [14] proper-
ties, and also act as cyclin-dependent kinase 4 inhibitors
[15]. Therefore, for the preparation of these complex
molecules large efforts have been directed toward the
synthetic manipulation of uracils. Broom et al. [16] syn-
thesized pyrido[2,3-d]pyrimidines from the reaction of
DMAD and 6-aminouracile in protic solvent but
obtained uncyclized condensed acetylenic adduct when
the reaction was carried in DMF [17]. Bhuyan et al.
[18] reported the synthesis of pyrido[2,3-d]pyrimidines
from the reaction of arylidenemalononitrile with 6-ami-
nouracil in refluxing 1-propanol, but in this reaction,
benzylmalononitrile was obtained as by-product and the
amount of arylidenemalononitrile needed was in excess.
Multicomponent reactions (MCRs), in which multiple
reactions are combined into one synthetic operation,
have been extensively used in synthetic chemistry for
the formation of carbon-carbon and carbon–heteroatom
bonds [1]. Such reactions offer a wide range of possibil-
ities for the efficient construction of highly complex
molecules in a single procedural step, thus avoiding
complication operations and allowing saving both of sol-
vent and of reagents. In the past decade there have been
tremendous developments in three- and four-component
reactions and great efforts continue to be made to de-
velop new MCRs [2]. The need to reduce the amount of
toxic waste and by-product arising from chemical proc-
esses requires increasing emphasis on the use of less
toxic and environmentally compatible materials in the
design of new synthetic methods. One of the most
promising approaches is using water as the reaction me-
dium. Breslow rediscovered the use of water as a sol-
vent in organic synthesis in the 1980s [3]. There has
been growing recognition that water is an attractive me-
dium for many organic reactions [4] and many MCRs in
aqueous media have been reported [5].
´
Rodrıguez et al. [19] reported the synthesis of 9-aryl
substituted 2-amino-4,7-dioxopyrido[2,3-d]pyrimidines
by refluxing equimolar amounts of 5-arylidene substi-
tuted Meldrum’s acid and 2,6-diamino-4-oxopyrimidine
in acetic acid. Recently, Devi et al. [20] reported a
novel three-component one-pot synthesis of pyrido[2,3-
d]pyrimidines using microwave heating. These methods
usually require forcing conditions, using organic sol-
vents, long reaction times and complex synthetic path-
ways. As part of our current studies on the development
of new routes to heterocyclic systems [21], recently we
have reported the synthesis of pyrido[2,3-d]pyrimidine
derivatives by the three-component reaction of aldehyde,
The importance of uracil and its annulated derivatives
is well recognized by synthetic [6] as well as biological
[7] chemists. With the development of clinically useful
anticancer and antiviral drugs [8], there has recently
been remarkable interest in the synthetic manipulations
of uracils [9]. Pyrido[2,3-d]pyrimidines have received
considerable attention over the past years because of
C
V
2009 HeteroCorporation

1332
D.-Q. Shi, J.-W. Shi, and S.-F. Rong
Vol 46
Scheme 1
Scheme 2
alkyl nitriles, and aminopyrimidines in water [22]. In
this article, we would report an efficient and clean syn-
thetic route to 2-amino-5-aryl-5,6-dihydropyrido[2,3-d]
pyrimidine-4,7(3H,8H)-dione derivatives in aqueous
media catalyzed by TEBAC.
RESULTS AND DISCUSSION
CH2 proton signals at 2.41–2.57 and 2.91–3.17 ppm, the
CH proton signals at 4.05–4.46 ppm, the NH2 proton
signals at 6.53–6.66 ppm, the aromatic proton signals at
6.82–8.16 ppm, and the NH proton signals at 10.10–
10.33 and 10.60–10.90 ppm, respectively.
When the three-components of aromatic aldehyde 1,
2,6-diaminopyrimidine-4(3H)-one 2, and Meldrum’s
acid 3 were treated in water in the presence of TEBAC
at 90ꢀC for a few hours (Scheme 1), the desired 2-
amino-5-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,
8H)-dione 4 were obtained in high yields (Table 1).
As shown in Table 1, this protocol could be applied
not only to the aromatic aldehydes with electron-with-
drawing groups (such as halide and nitro groups), but
also to aromatic aldehydes with electron-donating
groups (such as alkyl and alkoxyl groups). Therefore,
we concluded that the electronic nature of the substitu-
ents of aldehydes has no significant effect on this reac-
tion. However, because some aldehydes were remaining
in the mixture, so some aldehydes gave low yields.
The structures of the compounds 4 were identified by
their spectroscopy analysis. Thus, the IR spectra of com-
pounds 4 measured in potassium bromide pellets show
two bands of the elongation vibrations of the C¼¼O
group at 1703–1646 cmꢁ1, NH2, and NH groups at
Although the detailed mechanism of earlier reaction
remains not to be fully clarified, the formation of com-
pounds 4 could be explained by a reaction sequence pre-
sented in Scheme 2. According to the literature [23], we
proposed that the reaction proceeded via a reaction
sequence of condensation, addition, cyclization, and
elimination. First, the condensation of aldehyde 1 and
Meldrum’s acid 3 gave the intermediate product 5. The
addition of 5 to 2,6-diaminopyrimidine-4(3H)-one 2,
then cyclized to give intermediate product 6. The carbon
dioxide and acetone were losing from the intermediate
product 6 to give the products 4.
In conclusion, we have developed a simple three-
component reaction consisting of an aldehyde, 2,6-dia-
minopyrimidine-4(3H)-one, and Meldrum’s acid for the
synthesis of 2-amino-5-aryl-5,6-dihydropyrido[2,3-d]
pyrimidine-4,7(3H,8H)-dione derivatives in aqueous
media. This method has the advantages of easier work-
up, milder reaction conditions, and environmentally be-
nign procedure.
1
3467–3157 cmꢁ1. In the H NMR spectra of compounds
4 measured in dimethyl-d6 sulfoxide were observed the
Table 1
Synthesis of 2-amino-5-aryl-5,6-dihydropyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione 4 in aqueous media.
EXPERIMENTAL
Entry
Ar
Time (h)
Yield (%)
Melting points are uncorrected. Infrared spectra were
recorded on a Tensor 27 spectrometer in KBr with absorption
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-FC6H4
4-CH3OC6H4
4-BrC6H4
5
3
9
4
6
9
5
4
4
8
6
76
74
69
67
75
65
95
72
69
80
82
in cmꢁ1 1H NMR spectra were recorded on a Bruker DPX
.
400-MHz spectrometer as DMSO-d6 solution. J values are in
Hz. Chemical shifts are expressed in d downfield from internal
tetramethylsilane.
General procedure for the synthesis of 2-amino-5-aryl-
5,6-dihydropyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione deriv-
atives 4 in aqueous media. A suspension of a mixture of aro-
matic aldehyde 1 (2 mmol), 2,6-diaminopyrimidine-4(3H)-one
2 (2 mmol), Meldrum’s acid 3 (2 mmol) and TEBAC (0.15 g)
was stirred in water (10 mL) at 90ꢀC for several hours. After
4-ClC6H4
2-NO2C6H4
4-CH3C6H4
3-NO2C6H4
3-ClC6H4
2-ClC6H4
3,4-OCH2OC6H3
4-NO2C6H4
4j
4k
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
An Efficient and Clean Synthesis of Pyrido[2,3-d]pyrimidine-4,7-dione
Derivatives in Aqueous Media
1333
completion monitored by TLC, the reaction mixture was
allowed to cool to room temperature. The crystalline powder
formed recrystallized from DMF and water to give pure 4.
2-Amino-5-(4-fluorophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H, 8H)-dione (4a). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium
bromide): 3325, 3167, 1691, 1652, 1591, 1537, 1508, 1485,
1361, 1305, 1264, 1211, 1158, 1099, 1015, 973, 906, 838, 794
1H NMR (DMSO-d6): d 2.23 (s, 3H, CH3), 2.45 (d, J ¼ 16
Hz, 1H, CH), 2.93 (dd, J1 ¼ 7.6 Hz, J2 ¼ 16 Hz, 1H, CH),
4.07 (d, J ¼ 7.6 Hz, 1H, CH), 6.55 (br., s, 2H, NH2), 7.02 (d,
J ¼ 8.0 Hz, 2H, ArH), 7.15 (d, J ¼ 8.0 Hz, 2H, ArH), 10.10
(s, 1H, NH), 10.60 (s, 1H, NH).
2-Amino-5-(3-nitrophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4g). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium
bromide): 3450, 3317, 3163, 1691, 1652, 1588, 1530, 1470,
1405, 1353, 1301, 1266, 1020, 977, 929, 894, 826, 807, 790,
1
cmꢁ1; H NMR (DMSO-d6): d 2.48 (d, J ¼ 16 Hz, 1H, CH),
2.96 (dd, J1 ¼ 7.6 Hz, J2 ¼ 16 Hz, 1H, CH), 4.13 (d, J ¼ 7.6
Hz, 1H, CH), 6.59 (br., s, 2H, NH2), 7.07–7.12 (m, 2H, ArH),
7.16–7.20 (m, 2H, ArH), 10.16 (s, 1H, NH), 10.64 (s, 1H,
NH).
1
737 cmꢁ1; H NMR (DMSO-d6): d 2.57 (d, J ¼ 16.4 Hz, 1H,
CH), 3.05 (dd, J1 ¼8.0 Hz, J2 ¼ 16.4 Hz, 1H, CH), 4.30 (d, J
¼ 8.0 Hz, 1H, CH), 6.66 (br, s, 2H, NH2), 7.58ꢂ7.67 (m, 2H,
ArH), 8.01 (s, 1H, ArH), 8.06–8.11 (m,1H, ArH), 10.28 (s,
1H, NH), 10.71 (s, 1H, NH).
2-Amino-5-(4-methoxylphenyl)-5,6-dihydropyrido[2,3-d]
pyrimidine-4,7(3H,8H)-dione (4b). This compound was
obtained as solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR
(potassium bromide): 3464, 3315, 3159, 1691, 1652, 1596,
1559, 1539, 1511, 1488, 1457, 1396, 1361, 1310, 1251, 1220,
2-Amino-5-(3-chlorophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4h). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300 ꢀC); IR (potassium
bromide): 3325, 3169, 1683, 1652, 1585, 1539, 1477, 1391,
1
1178, 1033, 907, 831, 793, 699 cmꢁ1; H NMR (DMSO-d6): d
1
2.45 (d, J ¼ 16 Hz, 1H, CH), 2.91 (dd, J1 ¼ 7.6 Hz, J2 ¼ 16
Hz, 1H, CH), 3.70 (s, 3H, CH3O), 4.06 (d, J ¼ 7.6 Hz, 1H,
CH), 6.53 (br., s, 2H, NH2), 6.82 (d, J ¼ 8.4 Hz, 2H, ArH),
7.06 (d, J ¼ 8.4 Hz, 2H, ArH), 10.08 (s, 1H, NH), 10.80 (s,
1H, NH).
1264, 1212, 953, 907, 840, 786, 781 cmꢁ1; H NMR (DMSO-
d6): d 2.49 (d, J ¼ 16 Hz, 1H, CH), 2.97(dd, J1 ¼ 7.6 Hz, J2
¼ 16 Hz, 1H, CH), 4.14(d, J ¼ 7.6 Hz, 1H, CH), 6.62 (br., s,
2H, NH2), 7.12 (d, J ¼ 7.6 Hz, 1H, ArH), 7.17 (s, 1H, ArH),
7.25–7.34 (m, 2H, ArH), 10.17 (s, 1H, NH), 10.67 (s, 1H,
NH).
2-Amino-5-(4-bromophenyl)-5,6-dihydro[2,3-d] pyrimidine-4,
7(3H,8H)-dione (4c). This compound was obtained as solid
with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium bro-
mide): 3325, 3159, 1688, 1646, 1588, 1539, 1486, 1398, 1362,
2-Amino-5-(2-chlorophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4i). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium
bromide): 3327, 3174, 1703, 1670, 1621, 1540, 1487, 1440,
1395, 1359, 1325, 1098, 1048, 1035, 1005, 975, 909, 813, 753
1307, 1262, 1212, 1158, 1074, 1010, 972, 907, 817, 793 cmꢁ1
;
1H NMR (DMSO-d6): d 2.47 (d, J ¼ 16.4 Hz, 1H, CH), 2.97
(dd, J1 ¼ 8.0 Hz, J2 ¼ 16.4 Hz, 1H, CH), 4.11 (d, J ¼ 8.0
Hz, 1H, CH), 6.60 (br., s, 2H, NH2), 7.11 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.47 (d, J ¼ 8.4 Hz, 2H, ArH), 10.18 (s, 1H, NH),
10.66 (s, 1H, NH).
1
cmꢁ1; H NMR (DMSO-d6): d 2.37 (d, J ¼ 16.4 Hz, 1H, CH),
3.04 (dd, J1 ¼ 8.4 Hz, J2 ¼ 16.4 Hz, 1H, CH), 4.46 (d, J ¼
8.4 Hz, 1H, CH), 6.61 (br, s, 2H, NH2), 6.89–6.93 (m, 1H,
ArH), 7.21–7.28 (m, 2H, ArH), 7.45–7.49 (m, 1H, ArH), 10.20
(s, 1H, NH), 10.68 (s, 1H, NH).
2-Amino-5-(4-chlorophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4d). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300 ꢀC); IR (potassium
bromide): 3460, 3319, 3158, 1698, 1650, 1591, 1539, 1487,
1398, 1361, 1307, 1261, 1211, 1159, 1091, 1014, 973, 907,
2-Amino-5-(benzo[d][1,3]dioxol-6-yl)-5,6-dihydropyrido
[2,3-d]pyrimidine-4,7-(3H,8H)-dione (4j). This compound
was obtained as solid with mp > 300ꢀC (Lit. [24] > 300ꢀC);
IR (potassium bromide): 3467, 3320, 3164, 1694, 1639, 1591,
1540, 1502, 1486, 1438, 1405, 1356, 1311, 1242, 1212, 1121,
1
819, 793 cmꢁ1; H NMR (DMSO-d6): d 2.47 (d, J ¼ 16 Hz,
1H, CH), 2.97 (dd, J1 ¼ 8.0 Hz, J2 ¼ 16 Hz, 1H, CH), 4.12
(d, J ¼ 8.0 Hz, 1H, CH), 6.59 (br., s, 2H, NH2), 7.17 (d, J ¼
8.4 Hz, 2H, ArH), 7.34 (d, J ¼ 8.4 Hz, 2H, ArH), 10.16 (s,
1H, NH), 10.65 (s, 1H, NH).
967, 934, 811, 807, 790 cmꢁ1 1H NMR (DMSO-d6): d 2.45
;
(d, J ¼ 16 Hz, 1H, CH), 2.91 (dd, J1 ¼ 7.6 Hz, J2 ¼ 16 Hz,
1H, CH), 4.05 (d, J ¼ 7.6 Hz, 1H, CH), 5.95 (s, 2H, OCH2O),
6.50–6.62 (m, 3H, NH2þArH), 6.73 (s, 1H, ArH), 6.79 (d, J ¼
8.0 Hz, 1H, ArH), 10.12 (s, 1H, NH), 10.62 (s, 1H, NH).
2-Amino-5,6-dihydro-5-(4-nitrophenyl)pyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4k). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium
bromide): 3360, 3308, 3186, 1693, 1675, 1588, 1513, 1482,
1412, 1347, 1305, 1262, 1180, 1058, 1022, 966, 905, 826,
2-Amino-5-(2-nitrophenyl)-5,6-dihydropyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4e). This compound was obtained as
solid with mp > 300ꢀC (Lit. [19] > 300ꢀC); IR (potassium
bromide): 3433, 3319, 3167, 1698, 1652, 1588, 1536, 1519,
1477, 1408, 1340, 1281, 1259, 1233, 1213, 1165, 1018, 967,
930, 904, 862, 824, 794, 744, 700 cmꢁ1 1H NMR (DMSO-
;
1
d6): d 2.41 (d, J ¼ 16.4 Hz, 1H, CH), 3.17 (dd, J1 ¼ 8.8 Hz,
J2 ¼ 16.4 Hz, 1H, CH), 4.49 (d, J ¼ 8.8 Hz, 1H, CH), 6.65
(br., s, 2H, NH2), 7.16 (d, J ¼ 7.6 Hz, 1H, ArH), 7.49 (t, J ¼
7.6 Hz, 1H, ArH), 7.63 (t, J ¼ 7.6 Hz, 1H, ArH), 7.93 (d, J ¼
8.0 Hz, 1H, ArH), 10.33 (s, 1H, NH), 10.67 (s, 1H, NH).
2-Amino-5-(4-methylphenyl)-5,6-dihydro-pyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione (4f). This compound was obtained as
solid with mp > 300ꢀC (Lit. [24] > 300ꢀC); IR (potassium
bromide): 3315, 3157, 1698, 1653, 1636, 1600, 1559, 1540,
791, 701 cmꢁ1; H NMR (DMSO-d6): d 2.53 (d, J ¼ 16.4 Hz,
1H, CH), 3.06 (dd, J1 ¼ 8.0 Hz, J2 ¼ 16.4 Hz, 1H, CH), 4.27
(d, J ¼ 8.0 Hz, 1H, CH), 6.64 (br., s, 2H, NH2), 7.44 (d, J ¼
8.4 Hz, 2H, ArH), 8.16 (d, J ¼ 8.4 Hz, 2H, ArH), 10.27 (s,
1H, NH), 10.70 (s, 1H, NH).
Acknowledgments. The authors are grateful to the Foundation
of Key Laboratory of Organic Synthesis of Jiangsu Province and
Key Laboratory of Biotechnology on Medical Plants of Jiangsu
Province for financial support.
1487, 1457, 1395, 1362, 1309, 1264, 948, 904, 835, 809 cmꢁ1
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1334
D.-Q. Shi, J.-W. Shi, and S.-F. Rong
Vol 46
Anticancer Res 1986, 6, 549; (e) Jones, A. S.; Verhalst, G.; Walker,
R. T. Tetrahedron Lett 1979, 20, 4415.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet