An efficient synthesis of pyrido[2,3-d]pyrimidine derivatives in ionic liquid

Article abstract of DOI:10.1002/jhet.281

(Chemical Equation Presented) A series of 5,7-diarylpyrido[2,3-d] pyrimidine-2,4(1H,3H)-diones was synthesized via the reaction of 6-aminopyrimidine-2,4-dione and α,β-unsaturated ketones in ionic liquid without using any catalyst. This protocol has the advantages of easier work-up, milder reaction conditions, high yields, and environmentally benign procedure over traditional methods.

Full text of DOI:10.1002/jhet.281

January 2010
An Efficient Synthesis of Pyrido[2,3-d]pyrimidine
Derivatives in Ionic Liquid
131
Da-Qing Shi,a* Yao Zhou,b and Hai Liua
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, 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 August 11, 2009
DOI 10.1002/jhet.281
Published online 5 January 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of 5,7-diarylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was synthesized via the reaction of
6-aminopyrimidine-2,4-dione and a,b-unsaturated ketones in ionic liquid without using any catalyst.
This protocol has the advantages of easier work-up, milder reaction conditions, high yields, and envi-
ronmentally benign procedure over traditional methods.
J. Heterocyclic Chem., 47, 131 (2010).
INTRODUCTION
[15] reported the synthesis of prrido[2,3-d]pyrimidines
by the reaction of 6-amino-2,3-dihydro-2-thioxo-4(1H)-
pyrimidinone and a,b-unsaturated ketones in boiling
DMF. Recently, Bagley et al. [16] reported a new
method for the synthesis of pyrido[2,3-d]pyrimidines by
the reaction of 2,6-diaminopyrimidin-4-one and buty-
nones in a range of different solvents at room tempera-
ture or 60ꢀC. Quiroga et al. [17] reported the synthesis
of pyrido[2,3-d]pyrimidines via a selective cycloconden-
sation reaction between 6-aminopyrimidines and the
Mannich bases, propiophenone hydrochlorides. Devi
et al. [18] reported a novel three-component one-pot
synthesis of pyrido[2,3-d]pyrimidines using microwave
heating. These methods usually require harsh conditions,
using organic solvents, long reaction times and complex
synthetic pathways.
The importance of uracil and its annulated derivatives
is well recognized by synthetic [1] as well as biological
[2] chemists. With the development of clinically useful
anticancer and antiviral drugs [3], there has recently
been remarkable interest in the synthetic manipulations
of uracils [4]. Pyrido[2,3-d]pyrimidines have received
considerable attention over the past years because of
their wide range of biological activities, which include
antitumor [5], antibacterial [6], anti-inflammatory [7],
antifungal [8], and antileishmaniasis [9] properties, and
also act as cyclin-dependent kinase 4 inhibitors [10].
Therefore, for the preparation of these complex mole-
cules large efforts have been directed towards the syn-
thetic manipulation of uracils. Broom et al. [11] synthe-
sized 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 [12]. Wawzonek
reported the synthesis of pyrido[2,3-d]pyrimidine-2,4-
diones by the acid- and base-catalyzed condensation of
6-amino-1,3-dimethyluracil with a,b-unsaturated car-
bonyl compounds [13]. Bhuyan et al. [14] reported the
synthesis of pyrido[2,3-d]pyrimidines from the reaction
of arylidenemalononitrile with 6-aminouracil in reflux-
ing 1-propanol, but in this reaction, benzylmalononitrile
was obtained as by-product and the amount of arylide-
nemalononitrile needed was in excess. Quiroga et al
The ionic liquids have been the subject of consider-
able current interest as environmentally benign reaction
media in organic synthesis because of their unique prop-
erties of nonvolatility, nonflammability, and recyclabil-
ity, among others [19]. Numerous chemical reaction,
such as polymerization [20], hydrogenation [21], regio-
selective alkylation [22], Friedel-Crafts reactions [23],
dimerization of alkenes [24], Diels-Alder reactions [25],
Michael reactions [26], Cross-coupling reactions [27],
and some enzymic reactions [28] can be carried out in
ionic liquid. As part of our current studies on the devel-
opment of new routes to heterocyclic systems [29], we
herein describe
a facile synthesis of pyrido[2,3-
C
V
2010 HeteroCorporation

132
D.-Q. Shi, Y. Zhou, and H. Liu
Vol 47
Scheme 1
ceeded via a reaction sequence of Michael addition, cy-
clization, dehydration and aromatization. First, the Mi-
chael addition reaction of 6-aminopyrimidine- 2,4-dione
1 to a,b-unsaturated ketones 2 give the intermediate
product 4, which on intermolecular cyclization and
dehydration gave rise to 5. In the last step, the interme-
diate product 5 aromatized to product 3.
In conclusion, we have developed an efficient synthe-
sis of 5,7-diarylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dio-
nes via the reaction of 6-aminopyrimidine-2,4-dione and
a,b-unsaturated ketones in ionic liquid without any cata-
lyst. This protocol has the advantages of easier work-up,
milder reaction conditions, high yields, and environmen-
tally benign procedure over traditional methods.
d]pyrimidine derivatives by the reaction of 6-aminopyri-
midine-2,4-dione and a,b-unsaturated ketones in ionic
liquid without using any catalyst (Scheme 1).
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of crucial impor-
tance for the successful organic synthesis. To search for
the optimal solvent, the reaction of 6-amino-1,3-dime-
thylpyrimidine-2,4(1H,3H)-dione 1a and 1-(4-chloro-
EXPERIMENTAL
Commercial solvents and reagents were used as received.
Melting points were uncorrected. IR spectra were recorded on
Varian F-1000 spectrometer in KBr with absorptions in cmꢁ1
1H NMR was determined on Varian-400 MHz spectrometer in
DMSO-d6 or CDCl3 solution. J values are in Hz. Chemical
shifts are expressed in ppm downfield from internal standard
TMS. HRMS data were obtained using TOF-MS instrument.
General procedure for the synthesis of pyrido[2,3-d]pyri-
midines derivatives 3. A dry 50 mL flask was charged with
phenyl)-3-(4-methylphenyl)prop-2-en-1-one
2a
was
examined using ionic liquid such as [bmim]Br,
[bmim]BF4, [bmim]PF6, acetone, acetonitrile, ethanol,
chloroform, and DMF as solvent, respectively, at differ-
ent temperature for the synthesis of 3a. The results are
summarized in Table 1.
.
It can be seen from Table 1 that the reactions using
ionic liquids (Table 1, entries 6–8) as the solvents
resulted in higher yields and shorter reaction times than
those using organic solvents (Table 1, entries 1–5). On
the basis of the obtained results, [bmim]Br was found to
be superior in terms of cheap and yield. To optimize the
reaction temperature, the reactions were carried out at
different temperature ranging from room temperature to
90ꢀC. We found that the yield of the product 3a was
improved and the reaction time was shortened, as the
temperature was increased to 90ꢀC (Table 1, entries 8–
12). Therefore, the most suitable reaction temperature is
to 90ꢀC. Under these optimized reaction conditions, a
series of pyrido[2,3-d]pyrimidine derivatives 3 were syn-
thesized. The results are summarized in Table 2.
6-aminopyrimidine-2,4-dione
1 (1 mmol), a,b-unsaturated
ketones 2 (1 mmol), and ionic liquid [bmim]Br (2 mL). The
mixture was stirred at 90ꢀC for 5–7.5 h to complete the reac-
tion (monitored by TLC), then 50 mL H2O was added. The
solid was filtered off and washed with water. The crude prod-
uct was purified by recrystallization from ethanol to give 3.
7-(4-Chlorophenyl)-1,3-dimethyl-5-p-tolylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (3a). Mp: 238–239ꢀC; IR (potassium
bromide): 3074, 2950, 1707, 1665, 1594, 1576, 1545, 1515,
1420, 1403, 1362, 1281, 1257, 1091, 1003, 834, 821, 784, 750
Table 1
Solvent and reaction temperature optimization for
the synthesis of 3aa.
Reaction
temperature (ꢀC)
Time
(h)
Yield
(%)
As shown in Table 2, this protocol can be applied not
only to the aromatic rings of a,b-unsaturated ketones
with electron-withdrawing groups (such as halide and
nitro groups), but also to a,b-unsaturated ketones with
electron-donating groups (such as alkyl and alkoxyl
groups). Therefore, we concluded that the electronic na-
ture of the substituents of aromatic rings of a,b-unsatu-
rated ketones has no significant effect on this reaction.
In this study, all the products 3 were characterized by
Entry
Solvent
1
2
acetone
acetonitrile
ethanol
chloroform
DMF
reflux
reflux
reflux
reflux
100
90
90
90
r.t.
40
15
10
8.5
13
7
43
58
72
52
88
96
90
88
47
62
73
81
3
4
5
6
7
[bmim]Br
[bmim]BF4
[bmim]PF6
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
5
6
8
9
6.5
18
16
10
6.5
1
mp, IR, and H NMR spectral data as well as HRMS
analysis.
10
11
12
60
80
Although the detailed mechanism of above reaction
remains not to be fully clarified, the formation of com-
pounds 3 could be explained by a reaction sequence pre-
sented in Scheme 2. We proposed that the reaction pro-
a 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1 mmol), 1-(4-
chlorophenyl)-3-(4-methylphenyl)prop-2-en-1-one (1 mmol), and 2 mL
solvent.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
An Efficient Synthesis of Pyrido[2,3-d]pyrimidine Derivatives in Ionic Liquid
133
Table 2
Synthesis of pyrido[2,3-d]pyrimidine derivatives 3 in ionic liquid.
Entry
R1
R2
Ar1
Ar2
Time (h)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
4-CH3C6H4
3,4-Cl2C6H3
4-NO2C6H4
4-BrC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
5
6
96
92
92
90
93
88
87
90
90
96
92
98
98
6
6.5
7.5
5
3,4-Cl2C6H3
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
6
4-MeC6H4
3,4-OCH2OC6H3
4-ClC6H4
3,4-OCH2OC6H3
4-ClC6H4
4-MeC6H4
5
5
3j
3k
3l
H
H
5
5
H
H
6
3m
H
H
Naphthalene-2-yl
7
1
cmꢁ1; H NMR (DMSO-d6) d: 2.38 (s, 3H, CH3), 3.18 (s, 3H,
CH3), 3.68 (s, 3H, CH3), 7.21–7.29 (m, 4H, ArH), 7.55–7.61
(m, 3H, ArH), 8.þ27 (d, J ¼ 8.4 Hz, 2H, ArH). HRMS [Found:
m/z: 391.1089(M ); Calcd for C22H3185ClN3O2: M 391.1088].
5-(3,4-Dichlorophenyl)-7-(4-methoxyphenyl)-1,3-dimethylpyr-
ido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3b). Mp: 295–296ꢀC;
IR (potassium bromide): 1706, 1670, 1578, 1543, 1472, 1422,
Hz, 2H, ArH), 7.59 (d, J ¼ 8.4 Hz, 2H, ArH), 8.07 (d, J ¼
8.8 Hz, 2H, ArH). HRMS [Found: m/z: 455.0039 (Mþ); Calcd
for C21H7195Br35ClN3O2: M 455.0036].
5-(3,4-Dichlorophenyl)-7-(4-chlorophenyl)-1,3-dimethylpyrido
[2,3-d]pyrimidine-2,4(1H,3H)-dione (3e). Mp: 254–256ꢀC; IR
(potassium bromide): 1710, 1672, 1575, 1548, 1475, 1421,
1
1365, 1218, 1089, 1008, 841, 753 cmꢁ1; H NMR (DMSO-d6)
1367, 1253, 1221, 1178, 1132, 1027, 832, 753 cmꢁ1; H NMR
d: 3.20 (s, 3H, CH3), 3.72 (s, 3H, CH3), 7.39 (dd, J1 ¼ 2.0
Hz, J2 ¼ 8.4 Hz, 1H, ArH), 7.61 (d, J ¼ 8.8 Hz,2H, ArH),
7.69–7.71 (m, 2H, ArH), 7.76 (s, 1H, ArH), 8.23 (d, J ¼ 8.8
Hz, 2H, ArH). HRMS [Found: m/z: 445.0152 (Mþ); Calcd for
C21H3154Cl3N3O2: M 445.0152].
1
(DMSO-d6) d: 3.20 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.85 (s,
3H, OCH3), 7.09 (d, J ¼ 8.8 Hz,2H, ArH), 7.38 (dd, J1 ¼ 2.0
Hz, J2 ¼ 8.4 Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.69 (d, J ¼
8.4 Hz, 2H, ArH), 8.28 (dþ, J ¼ 8.8 Hz, 2H, ArH). HRMS
[Found: m/z: 441.0646 (M ); Calcd for C22H3175Cl2N3O3: M
441.0647].
7-(4-Methoxyphenyl)-1,3-dimethyl-5-(4-nitrophenyl) pyrido
[2,3-d]pyrimidine-2,4-(1H,3H)-dione (3c). Mp: >300ꢀC; IR
(potassium bromide): 1705, 1665, 1587, 1548, 1510, 1418,
1368, 1268, 1245, 1178, 1130, 838, 752 cmꢁ1 1H NMR
;
(DMSO-d6) d: 3.19 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.85 (s,
3H, OCH3), 7.09 (d, J ¼ 8.8 Hz, 2H, ArH), 7.65–7.68 (m, 3H,
ArH), 7.66 (s, 1H, ArH), 8.27–8.30 (m, 4H, ArH). HRMS
[Found: m/z: 418.1276 (Mþ); Calcd for C22H18N4O5: M
418.1277].
5-(4-Bromophenyl)-7-(4-chlorophenyl)-1,3-dimethyl-pyrido
[2,3-d]pyrimidine-2,4(1H,3H)- dione (3d). Mp: 264–266ꢀC;
IR (potassium bromide): 1707, 1668, 1593, 1576, 1547, 1490,
1420, 1363, 1282, 1258, 1178, 1003, 832, 804, 752 cmꢁ1; H
7-(4-Methoxyphenyl)-1,3-dimethyl-5-p-tolylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (3f). Mp: 259–260ꢀC; IR (potassium
bromide): 1700, 1655, 1604, 1554, 1519, 1423, 1367, 1246,
1
1225, 1176, 1036, 834, 818, 751 cmꢁ1; H NMR (DMSO-d6)
d: 2.38 (s, 3H, CH3), 3.18 (s, 3H, CH3), 3.72 (s, 3H, CH3),
3.84 (s, 3H, OCH3), 7.04–7.09 (m, 2H, ArH), 7.20–7.30 (m,
4H, ArH), 7.53 (s, 1H, ArH), 8.20–8.27 (m, 2H, ArH). HRMS
[Found: m/z: 387.1583 (Mþ); Calcd for C23H21N3O3: M
387.1583].
5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-1,3-dimethylpyrido
[2,3-d]pyrimidine-2,4(1H,3H)-dione (3g). Mp: 279–280ꢀC; IR
(potassium bromide): 1702, 1657, 1607, 1579, 1557, 1519,
1
1423, 1366, 1249, 1226, 1174, 1087, 1029, 833, 751 cmꢁ1; H
NMR (DMSO-d6) d: 3.19 (s, 3H, CH3), 3.72 (s, 3H, CH3),
3.84 (s, 3H, OCH3), 7.08 (d, J ¼ 8.0 Hz, 2H, ArH), 7.41 (dd,
J1 ¼ 2.0 Hz, J2 ¼ 7.6 Hz, 2H, ArH), 7.48 (dd, J1 ¼ 2.0 Hz,
J2 ¼ 7.6 Hz, 2H, ArH), 7.59 (s, 1H, ArH), 8.26 (dd, J1 ¼ 2.0
Hz, J2 ¼ 8.0 Hz, 2H, ArH). HRMS [Found: m/z: 407.1037
(Mþ); Calcd for C22H1385ClN3O3: M 407.1037].
1
NMR (CDCl3) d: 3.38 (s, 3H, CH3), 3.87 (s, 3H, CH3), 7.22
(d, J ¼ 8.8 Hz, 2H, ArH), 7.39 (s, 1H, ArH), 7.48 (d, J ¼ 8.8
Scheme 2
1,3-Dimethyl-5,7-di(p-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,
3H)-dione (3h). Mp: 217–219ꢀC; IR (potassium bromide):
1704, 1661, 1590, 1546, 1515, 1418, 1363, 1260, 1220, 819,
755 cmꢁ1
;
1H NMR (DMSO-d6) d: 2.43 (s, 6H, 2 ꢂ CH3),
3.39 (s, 3H, CH3), 3.88 (s, 3H, CH3), 7.27–7.32 (m, 6H, ArH),
7.44 (s, 1H, ArH), 8.03 (d, J ¼ 8.0 Hz, 2H, ArH). HRMS
[Found: m/z: 371.1634 (Mþ); Calcd for C23H21N3O2: M
371.1634].
5-(3,4-Methylenedioxyphenyl)-7-(4-methoxyphenyl)-1-methyl-
pyrido[2,3-d]pyrimidine-2,4 (1H, 3H)-dione (3i). Mp: 308–
309ꢀC; IR (potassium bromide): 3299, 1707, 1687, 1577,
1550, 1502, 1484, 1441, 1376, 1255, 1229, 1180, 1106, 1028,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

134
D.-Q. Shi, Y. Zhou, and H. Liu
Vol 47
931, 842, 765 cm-1; 1H NMR (DMSO-d6) d: 3.68 (s, 3H,
CH3), 3.84 (s, 3H, OCH3), 6.08 (s, 2H, OCH2O), 6.91 (d, J ¼
8.0 Hz, 1H, ArH), 6.96 (d, J ¼ 8.0 Hz, 1H, ArH), 7.00 (s, 1H,
ArH), 7.08 (d, J ¼ 8.0 Hz, 2H, ArH), 7.52 (s, 1H, ArH), 8.24
(d, J ¼ 8.0 Hz, 2H, ArH), 11.39 (s, 1H, NH). HRMS [Found:
m/z: 403.1166 (Mþ); Calcd for C22H17N3O5: M 403.1168].
5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-1-methyl-pyrido[2,
3-d]pyrimidine-2,4(1H,3H)-dione (3j). Mp: >300ꢀC; IR (po-
tassium bromide): 3172, 1707, 1692, 1579, 1543, 1485, 1448,
268; (e) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249,
1533; (f) Pontikis, R.; Monneret, C. Tetrahedron Lett 1994, 35, 4351.
[3] (a) Heidelberger, C.; Arafield, F. J Cancer Res 1963, 23,
1226; (b) Baba, M.; Pauwels, R.; Herdwig, P.; Clercq, E. D.; Desmy-
ster, J.; Vandepulfe, M. Biochem Biophys Res Commun 1987, 142,
128; (c) Clercq, E. D. J Med Chem 1986, 29, 1561; (d) Clercq, E. D.
Anticancer Res 1986, 6, 549; (e) Jones, A. S.; Verhalst, G.; Walker,
R. T. Tetrahedron Lett 1979, 20, 4415.
[4] (a) Hirota, K.; Kitade, Y.; Senda, S.; Halat, M. J.; Wata-
nabe, K. A.; Fox, J. J. J Org Chem 1981, 46, 846; (b) Su, T. L.;
Huang, J. T.; Burchanal, J. H.; Watanabe, K. A.; Fox, J. J. J Med
Chem 1986, 29, 709; (c) Prajapati, D.; Sandhu, J. S. Synthesis 1988,
342.
1
1386, 1363, 1262, 1242, 1179, 1032, 981, 833 cmꢁ1; H NMR
(DMSO-d6) d: 3.65 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.06–
7.10 (m, 2H, ArH), 7.41–7.50 (m, 4H, ArH), 7.56 (s, 1H,
ArH), 8.23–8.28 (m, 2H, ArH), 11.44 (s, 1H, NH). HRMS
[Found: m/z: 393.0881 (Mþ); Calcd for C21H3156ClN3O3: M
393.0880].
[5] (a) Broom, A. D.; Shim, J. L.; Anderson, G. L. J Org Chem
1976, 41, 1095; (b) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D.
S.; Nichol, C. A. J Med Chem 1980, 23, 327.
5-(3,4-Methylenedioxyphenyl)-7-(4-methoxyphenyl)pyrido[2,
3-d]pyrimidine-2,4(1H,3H)-dione (3k). Mp: 317–318ꢀC; IR
(potassium bromide): 3294, 1723, 1705, 1593, 1578, 1549,
1441, 1406, 1362, 1253, 1183, 1094, 1037, 932, 871, 827, 804
[6] (a) Matsumoto, J.; Minami, S. J Med Chem 1975, 18, 74;
(b) Suzuki, N. Chem Pharm Bull 1980, 28, 761; (c) Oakes, V.; Rydon,
H. N. J Chem Soc 1956, 4433; (d) Degraw, J. I.; Kisliuk, R. L.; Gau-
mont, Y.; Baugh, C. M. J Med Chem 1974, 17, 470; (e) Zakharov, A.
V.; Gavrilov, M. Y.; Novoselova, G. N.; Vakhrin, M. I.; Konshin, M.
E. Khim Farm Zh 1996, 30, 39.
cmꢁ1 1H NMR (DMSO-d6) d: 3.83 (s, 3H, OCH3), 6.07 (s,
;
2H, OCH2O), 6.91–6.96 (m, 2H, ArH), 7.01 (s, 1H, ArH),
7.06 (d, J ¼ 8.4 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 8.17 (d, J
¼ 8.4 Hz, 2H, ArH), 11.13 (s, 1H, NH), 11.59 (s, 1H, NH).
HRMS [Found: m/z: 389.1024 (Mþ); Calcd for C21H15N3O5:
M 389.1012].
7-(4-Bromophenyl)-5-(4-chlorophenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (3l). Mp: >300ꢀC; IR (potassium bromide):
3180, 1714, 1590, 1575, 1553, 1484, 1403, 1361, 1260, 1008,
828, 766 cmꢁ1 1H NMR (DMSO-d6) d: 7.46–7.48 (m, 4H,
;
[7] Deyanov, A. B.; Niyazov, R. K.; Nazmetdinov, F. Y.; Syro-
pyatov, B. Y.; Kolla, V. E.; Konshin, M. E. Khim Farm Zh 1991, 25,
26.
[8] Heckler, R. E.; Jourdan, G. P.; Eur. Pat. Appl. EP 414386
A1 27, 1991; Chem Abstr 1991, 115, 71630.
[9] Agarwal, A.; Ashutosh, R.; Goyal, N.; Chauhan, P. M. S.;
Gupta, S. Bioorg Med Chem 2005, 13, 6678.
[10] Vander Wel, S. N.; Harvey, P. J.; McNamara, D. J.; Repine,
J. T.; Keller, P. R.; Quin, J., III; Booth, R. J.; Elliott, W. L.; Dobrusin,
E. M.; Fry, D. W.; Toogood, P. L. J Med Chem 2005, 48, 2371.
[11] Broom, A. D.; Shim, J. L.; Anderson, C. L. J Org Chem
1976, 41, 1095.
ArH), 7.59 (s, 1H, ArH), 7.75 (dd, J1 ¼ 1.2 Hz, J2
¼
8.4Hz,2H, ArH), 8.17 (dd, J1 ¼ 1.2 Hz, J2 ¼ 8.8 Hz, 2H,
ArH), 11.28 (s, 1H, NH), 11.77 (s, 1H, NH). HRMS [Found:
M
m/z: 426.9724 (Mþ); Calcd for C19H7119Br35ClN3O2:
426.9723].
[12] Shim, J. L.; Neiss, R.; Broom, A. D. J Org Chem 1972, 37,
578.
7-(Naphthalen-2-yl)-5-p-tolylpyrido[2,3-d]pyrimidine-2,4(1H,
3H)-dione (3m). Mp: 302–304ꢀC; IR(potassium bromide):
3412, 3170, 3056, 1721, 1692, 1594, 1553, 1506, 1409, 1389,
[13] Wawzonek, S. J Org Chem 1976, 41, 3149.
[14] Bhuyan, P.; Boruah, R. C.; Sandhu, J. S. J Org Chem 1990,
55, 568.
1262, 1197, 860, 747 cmꢁ1 1H NMR (DMSO-d6) d: 2.40 (s,
;
[15] Quiroga, J.; Insuasty, B.; Sanchez, A.; Nogueras, M.; Meier,
H. J Heterocycl Chem 1992, 29, 1045.
3H, CH3), 7.25 (d, J ¼ 7.6 Hz, 2H, ArH), 7.38 (dd, J1 ¼ 1.2
Hz, J2 ¼ 8.0 Hz, 2H, ArH), 7.59–7.63 (m, 2H, ArH), 7.70 (d,
J ¼ 1.6 Hz, 1H, ArH), 7.99 (d, J ¼ 8.0 Hz, 1H, ArH), 8.04–
8.09 (m, 2H, ArH), 836 (d, J ¼ 8.8 Hz, 1H, ArH), 8.83 (s,
1H, ArH), 11.22 (s, 1H, NH), 11.74 (s, 1H, NH). HRMS
[Found: m/z: 379.1345 (Mþ); Calcd for C24H17N3O2: M
379.1321].
[16] Bagley, M. C.; Hughes, D. D.; Lloyd, R.; Powers, V. E. C.
Tetrahedron Lett 2001, 42, 6585.
´
[17] Quiroga, J.; Insuasty, H.; Insuasty, B.; Abonıa, R.; cobo, J.;
´
Sanchez, A.; Nogueras, M. Tetrahedron 2002, 58, 4873.
[18] Devi, I.; Kumar, B. S. D.; Bhuyan, P. J. Tetrahedron Lett
2003, 44, 8307.
[19] (a) Welton, T. Chem Rev 1999, 99, 2071; (b) Wassersc-
heid, P.; Keim, W. Angew Chem Int Ed 2000, 39, 3773; (c) Shel-
don, R. Chem Commun 2001, 2399; (d) Wilkes, J. S. Green Chem
2002, 4, 73; (e) Yao, Q. Org Lett 2002, 4, 2197; (f) Zerth, H. M.;
Leonard, N. M.; Mohan, R. S. Org Lett 2003, 5, 55; (g) Su, C.;
Chen, Z. C.; Zheng, Q. G. Synthesis 2003, 555; (h) Rajagopal, R.;
Jarikote, D. V.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Tetrahe-
dron Lett 2003, 44, 1815; (i) Kumar, A.; Pawar, S. S. J Org Chem
2004, 69, 1419.
Acknowledgment. We are grateful to the Key Laboratory of Or-
ganic Synthesis of Jiangsu Province for financial support.
REFERENCES AND NOTES
[1] (a) Bradshaw, T. K.; Hutchison, D. W. Chem Soc Rev
1977, 6, 43; (b) Sasaki, T.; Minamoto, K.; Suzuki, T.; Yamashita, S.
Tetrahedron 1980, 36, 865; (c) Prajapati, D.; Bhuyan, P. J.; Sandhu, J.
S. J Chem Soc Perkin Trans I 1988, 607; (d) Bhuyan, P. J.; Borah, H.
N.; Sandhu, J. S. J Chem Soc Perkin Trans I 1999, 3083.
[20] Abdul-Sada, A. A. K.; Ambler, P. W.; Hodgson, P. K. G.;
Seddon, K. R.; Stewark, N. J. World Pat. WO9521871, 1995.
[21] (a) Chauvin, Y.; Mussman, L.; Olivier, H. Angew Chem Int
Ed Engl 1995, 38, 3097; (b) Fisher, T.; Sethi, A.; Wellton, T.; Woolf,
J. Tetrahedron Lett 1999, 40, 293; (c) Asams, C. J.; Earle, M. J.; Sed-
don, K. R. Chem Commun 1999, 25; (d) Dyson, P. J.; Ellis, D. J.;
Parker, D. G.; Welton, T. Chem Commun 1999, 1043; (e) Monteiro,
A. L.; Zimn, F. K.; de Souza, R. F.; Dupont, J. Tetrahedron:
[2] (a) Marumoto, R.; Furukawa, Y. Chem Pharm Bull 1997,
25, 2974; (b) Griengl, R.; Wack, E.; Schwarz, W.; Streicher, W.;
Rosenwirth, B.; Clercq, E. D. J Med Chem 1987, 30, 1199; (c) Clercq,
E. D.; Bernaerts, R. J Biol Chem 1987, 262, 14905; (d) Jones, A. S.;
Sayers, J. R.; Walker, R. T.; Clercq, E. D. J Med Chem 1988, 31,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
An Efficient Synthesis of Pyrido[2,3-d]pyrimidine Derivatives in Ionic Liquid
135
Asymmetry 1997, 8, 177; (f) Suarez, P. A. Z.; Dullius, J. E. L.;
Einloft, S.; de Souza, R. F.; Dupont, J. Polyhedron 1996, 15,
1217.
Souza, R. F.; Dupont, J.; Monteiro, A. L. Tetrahedron Lett. 1998, 39,
7071; (e) Song, L. E.; Roh, E. J Chem Commun 2000, 837.
[28] Schoefer, S. H.; Kaftzik, N.; Wasserscheid, P.; Kragl, U.
Chem Commun 2001, 425.
[22] (a) Badri, M.; Brunet, J. J.; Perron, R. Tetrahedron Lett
1992, 33, 4435; (b) Earle, M. J.; McCormac, P. B.; Seddon, K. R.
Chem Commun 1998, 2245.
[29] (a) Shi, D. Q.; Dou, G. L.; Li, Z. Y.; Ni, S. N.; Li, X. Y.;
Wang, X. S.; Wu, H.; Ji, S. J. Tetrahedron 2007, 63, 9764; (b) Shi, C.
L.; Shi, D. Q.; Kim, S. H.; Huang, Z. B.; Ji, S. J.; Ji, M. Tetrahedron
2008, 64, 2425; (c) Shi, D. Q.; Dou, G. L.; Shi, C. L.; Li, Z. Y.; Ji, S.
J. Synthesis 2007, 3117; (d) Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J.
W.; Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J. Synlett 2007, 2509; (e)
Shi, D. Q.; Niu, L. H.; Shi, J. W.; Wang, X. S.; Ji, S. J. J Heterocycl
Chem 2007, 44, 1083; (f) Shi, D. Q.; Ni, S. N.; Yang, F.; Shi, J. W.;
Dou, G. L.; Li, X. Y.; Wang, X. S. J Heterocycl Chem 2008, 45, 653;
(g) Shi, D. Q.; Ni, S. N.; Yang, F.; Shi, J. W.; Dou, G. L.; Li, X. Y.;
Wang, X. S.; Ji, S. J. J Heterocycl Chem 2008, 45, 693; (h) Shi, D.
Q.; Yang, F.; Ni, S. N. J Heterocycl Chem 2009, 46, 469; (i) Dou, G.
L.; Wang, M. M.; Huang, Z. B.; Shi, D. Q. J Heterocycl Chem 2009,
46, 645; (j) Shi, D. Q.; Niu, L. H.; Yao, H.; Jiang, H. J Heterocycl
Chem 2009, 46, 237.
[23] (a) Boon, J. A.; Levisky, J. A.; Pflug, J. L.; Wilkes, J. S. J
Org Chem 1986, 54, 480; (b) Luer, G. D.; Bartalk, D. E. J Org Chem
1982, 47, 1238; (c) Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon,
K. R. Chem Commun 1998, 2097.
[24] Ellis, B.; Keim, W.; Wasserscheid, P. Chem Commun
1999, 337.
[25] Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem 1999,
1, 23.
[26] Corey, E. J.; Zhang, F. Y. Org Lett 2000, 2, 1097.
[27] (a) Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett
1996, 1091; (b) Bohm, V. P. W.; Herrmann, W. A. Chem Eur J 2000,
6, 1017; (c) Carmichael, A. J.; Earle, M. J.; Holberey, J. D.; McCor-
mac, P. B.; Seddon, K. R. Org Lett 1999, 1, 997; (d) Zim, D.; de
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet