One-pot synthesis of pyrido[2,3-d]pyrimidines via efficient three-component reaction in aqueous media

Article abstract of DOI:10.1002/jhet.5570440517

(Chemical Equation Presented) A short and facile synthesis of pyrido[2,3-d]pyrimidine derivatives was accomplished in good yields via the three-component reaction of aldehydes, alkyl nitriles and aminopyrimidines in water in the presence of triethylbenzyl

Full text of DOI:10.1002/jhet.5570440517

Sep-Oct 2007
1083
One-pot Synthesis of Pyrido[2,3-d]pyrimidines via Efficient
Three-component Reaction in Aqueous Media
Daqing Shi,*1,2 Lihui Niu2, Jingwen Shi2, Xiangshan Wang2, Shunjun Ji1
1 College of Chemistry and Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou University, Suzhou 215123, P. R. China
2 Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. China
E-mail: dqshi@suda.edu.cn
Received November 9, 2006
CN
O
R
CN
NH2
CN
CN
HN
H2N
TEBAC,H2O, 90oC
O
N
N
O
N
R
HN
CN
R
CHO
+
NH2
COOCH3
H2N
HN
H2N
TEBAC,H2O, 90oC
N
N
H
O
A short and facile synthesis of pyrido[2,3-d]pyrimidine derivatives was accomplished in good yields via
the three-component reaction of aldehydes, alkyl nitriles and aminopyrimidines in water in the presence of
triethylbenzylammonium chloride (TEBAC). The structures of these compounds were characterized by
1
elemental analysis, IR and H NMR spectra and further confirmed by single crystal X-ray diffraction
analysis.
J. Heterocyclic Chem., 44, 1083 (2007).
INTRODUCTION
for the synthesis of these molecules have attracted
considerable attention in search for a rapid entry to these
heterocycles.
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 represent a hetero-
cyclic ring system of considerable interest because of
several biological activities associated with this scaffold.
Some analogues have been found to act as anticancer
agents inhibiting dihydrofolate reductases or tyrosine
kinases [5], while others are known antiviral agents [6].
Therefore, for the preparation of these complex molecules
large efforts have been directed towards the synthetic
manipulation of uracils. As a result, a number of reports
have appeared in the literature. Broom et al. [7]
synthesized pyrido[2,3-d]pyrimidines from the reaction of
DMAD and 6-aminouracil in protic solvent but obtained
uncyclized condensed acetylenic adduct [8] when the
reaction was carried in dimethylformamide. Bhuyan et al.
[9] reported the synthesis of pyrido[2,3-d]pyrimidines
from the reaction of arylidenemalononitrile with 6-
aminouracil in refluxing 1-propanol, but in this reaction,
benzylmalononitrile was obtained as by-product and the
amount of arylidenemalononitrile needed was in excess.
Recently Devi et al. [10] 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 solvents, long reaction
times and complex synthetic pathways. Thus new routes
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry. The first
MCR was described by Strecker in 1850 for the synthesis
of amino acids [11]. However, in the past decade there
have been tremendous developments in three- and four-
component reactions and great efforts continue to be
made to develop new MCRs [12]. The need to reduce the
amount of toxic waste and by-product arising from
chemical processes 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 media. Breslow [13], who showed that hydro-
phobic effects could strongly enhance the rate of several
organic reactions, rediscovered the use of water as a
solvent in organic chemistry in the 1980’s. There has been
growing recognition that water is an attractive medium for
many organic reactions [14] and many MCRs in aqueous
medium have been reported [15]. As part of our current
studies on the development of new routes to heterocyclic
systems [16], we now report an efficient and clean
synthetic route to pyrido[2,3-d]pyrimidine derivatives in
aqueous media catalyzed by TEBAC.
RESULTS AND DISCUSSION
When the reaction of 4-chlorobenzaldeyhde 1a,
malononitrile 2 and 1,3-dimethyl-6-aminouracile 3a was

1084
D. Shi, L. Niu, Jingwen Shi, X. Wang, S. Ji
Vol 44
oxo-5-arylpyrido[2,3-d]-pyrimidine-6-carbonitrile 6
(Scheme 2) and the results are summarized in Table 3.
performed in water in the presence of TEBAC at 90 °C, in
a 96% yield of 2-amino-6,8-dimethyl-5,7-dioxo-4-(4-
chlorophenyl)pyrido[2,3-d]pyrimidine-3-carbonitrile (4a)
was obtained (Scheme 1). We tested this reaction in
different organic solvents and the yields were lower
(Table 1). When substituted aldehydes 1b-z and 6-
aminouraciles 3b-z were employed, the same products
4b-z were obtained (Table 2).
Scheme 2
O
O
N
R
N
CN
CN
TEBAC
H2O, 90oC
HN
HN
H2N
+
R
CHO
+
CN
N
NH2
NH2
H2N
1
6
2
5
Scheme 1
Table 3
Synthesis of pyrido[2,3-d]pyrimidine derivatives 6 in aqueous medium
O
O
R
N
R2
O
R2
O
CN
TEBAC
CN
CN
N
N
R
CHO
+
+
H2O, 90oC
Entry
6a
R
Time (h)
Yield (%)
N
R1
3
NH2
N
R1
NH2
4-NO2C6H4
4-HOC6H4
2-ClC6H4
6
10
6
93
84
80
76
78
81
86
77
6b
6c
1a-z
2
4
6d
6e
6f
6g
2,4-Cl2C6H3
4-BrC6H4
3,4-(CH3)2C6H3
4-ClC6H4
5
8
7
6
10
Table 1
Synthesis of 7-amino-1,3-dimethyl-2,4-dioxo-5-(4-chlorophenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (4a) in different solvents
6h
n-C4H9
Entry
Solvent
Time (h)
Temperature
Yield (%)
(°C)
90
78
55
80
40
However, the reaction of aldehyde 1, methyl cyano-
acetate 7 and 2,4-diamino-6-hydroxypyrimidine 5 in the
same reaction conditions afforded 2-amino-3,4,7,8-tetra-
hydro-4,7-dioxo-5-arylpyrido[2,3-d]pyrimidine-6-carbo-
nitrile 8, which is different from the reaction reported by
Bhuyan et al. [9]. The desired product methyl 2,7-
diamino-3,4-dihydro-4-oxo-5-arylpyrido[2,3-d]pyrim-
idine-6-carboxy late 9 was not obtained (Scheme 3). The
results are summarized in Table 4. Recently, Tu et al. [17]
reported a three-component synthesis of compound 8
under microwave irradiation. The spectra data of 8g are
matching the literature data.
4a
4a
4a
4a
4a
4a
water
ethanol
acetone
1,2-dichloroethane
dichloromethane
DMF
12
18
24
17
19
24
96
55
42
38
60
20
90
Table 2
Synthesis of pyrido[2,3-d]pyrimidine derivatives 4 in aqueous medium
Entry
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
R
R1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
R2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Time (h)
12
12
13
14
10
8
12
20
8
12
18
16
20
20
20
14
12
15
10
9
Yield (%)
96
71
4-ClC6H4
2-NO2C6H4
4-CH3C6H4
3-NO2C6H4
3-ClC6H4
4-HOC6H4
4-NO2C6H4
4-CH3OC6H4
4-BrC6H4
3-ClC6H4
4-BrC6H4
3-NO2C6H4
4-CH3OC6H4
4-HOC6H4
4-NO2C6H4
3-Pyridyl
4-Pyridyl
n-C4H9
90
89
76
86
89
91
74
95
86
97
95
96
92
86
88
82
90
96
92
77
97
80
94
80
Scheme 3
O
N
R
CN
HN
H2N
O
N
H
CN
O
TEBAC
H2O, 90oC
HN
R
CHO
+
+
8
9
O
R
COOCH3
N
NH2
H2N
COOCH3
NH2
HN
H2N
7
1
5
N
N
Table 4
Synthesis of pyrido[2,3-d]pyrimidine derivatives 8 in aqueous medium
2,4-Cl2C6H3
4-BrC6H4
4-FC6H4
3,4-Cl2C6H3
3-NO2C6H4
2-ClC6H4
4t
Entry
8a
8b
8c
8d
8e
R
Time (h)
Yield (%)
4u
4v
4w
4x
4y
4z
12
8
10
10
4
4-CH3C6H4
3,4-Cl2C6H3
3-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
C6H5
4-CH3OC6H4
3,4-(CH3)2C6H3
4-FC6H4
12
12
16
16
8
11
8
9
96
91
92
90
95
89
89
87
95
93
4-NO2C6H4
4-ClC6H4
16
8f
8g
8h
8i
Similarly, the reaction of aldehyde 1, malononitrile 2
and 2,4-diamino-6-hydroxypyrimidine 5 in the same
reaction conditions afforded 2,7-diamino-3,4-dihydro-4-
8
10
8j
3-Pyridyl

Sep-Oct 2007
One-pot Synthesis of Pyrido[2,3-d]pyrimidines via Efficient
1085
All the products 4, 6 and 8 were characterized by IR, 1H
NMR and elemental analysis. The structure of 4g was
further confirmed by single crystal X-ray diffraction
analysis. Figure 1 shows the molecular structure of 4g.
The crystallographic data of this compound is
summarized in Table 5.
Though the detailed mechanism of these reactions has not
been clarified yet, the formation of 4 can be explained by
the possible mechanism presented in Scheme 4. The
reaction occurs via an initial formation of the cyano-
olefin, from the condensation of aldehyde and alkyl
nitriles as shown in Scheme 4, which suffers nucleophilic
attack to give the Michael adduct [A]. The intermediate
[A] then cyclizes and subsequently losses a hydrogen
molecule to afford the fully aromatized compound. This
type of hydrogen loss is well documented [18].
Scheme 4
CN
CN
CN
R
C
C
R
CHO
+
H
CN
1
2
O
O
R
O
R
N
R2
R2
R2
O
CN
CN
C
N
N
N
C
C
N
C
C
N
R
C
H
C
CN
O
N
R1
N
R1
NH
N
R1
NH2
O
NH
O
R
O
R
H
R2
CN
R2
CN
NH2
-H2
N
N
N
R1
N
NH2
N
R1
N
H
O
O
4
Figure 1. X-ray structure of 4g.
In conclusion, a series of pyrido[2,3-d]pyrimidine
derivatives were synthesized via novel three-component
reaction of aldehyde, alkyl nitrile and aminopyrimidine in
water in the presence of TEBAC. Compared to other
methods, this new method has the advantages of high
yields, mild reaction conditions, easy work-up,
inexpensive reagents and an environmentally friendly
procedure.
Table 5
Crystallographic Data for 4g
Empirical formula
Formula weight
Wave length (Å)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
ꢀ (˚)
ꢁ (˚)
C16H12N6O4
352.32
0.71070
Monoclinic
P21/n
9.6209(9)
11.7064(12)
14.5493(16)
90
106.939(3)
90
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. IR spectra were measured on a FTIR-8101
ꢂ (˚)
V (Å3)
Z
1
spectrometer. H NMR spectra were measured on an Inova-400
1567.5(3)
4
MHz spectrometer using TMS as internal standard, DMSO-d6 as
solvent. Microanalyses were carried out on Perkin-Elmer 2400 II
instruments. X-ray diffraction was recorded on a Rigaku
Mercury diffractometer.
Dcalc. (Mg/m3)
Absorption coefficient(mm-1)
F(000)
1.493
0.112
728
Crystal size (mm)
ꢃ Range (˚)
Limiting indices
0.60 ꢀ 0.40 ꢀ 0.32
3.41 to 27.48
-12 ꢀ h ꢀ 10
-15 ꢀ k ꢀ 14
-18 ꢀ l ꢀ 18
17123
General Procedure for the Synthesis of pyrido[2,3-d]-
pyrimidine derivatives 4. A suspension of a mixture of aldehyde
1 (2 mmol), malononitrile 2 (2 mmol), 6-aminouracile 3 (2 mmol)
and TEBAC (0.15 g) was stirred in water (10 mL) at 90°C for
several hours. After completion monitored by TLC, the reaction
mixture was allowed to cool to room temperature. The crystalline
powder formed recrystallized from DMF to give pure 4.
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2 ꢄ(I)]
3595
3595/0/246
1.107
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-chlorophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4a). This compound was
obtained as solid with mp 280-281 °C; ir (potassium bromide):
3416, 3314, 3220, 2215, 1715, 1667, 1623, 1573, 1549, 1508,
1494, 1439, 1369, 1278, 1229, 1165, 1014, 974, 847, 831, 805,
R1 = 0.0458
wR = 0.1177
R1 = 0.0516
wR = 0.1217
0.238 and -0.250
R indices (all data )
1
Largest diff. Peak and hole (e.Å-3)
753 cm-1; H nmr (DMSO-d6): ꢀ 3.09 (s, 3H, CH3), 3.51 (s, 3H,

1086
D. Shi, L. Niu, Jingwen Shi, X. Wang, S. Ji
Vol 44
CH3), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.51 (d, J = 8.4 Hz, 2H,
ArH), 7.92 (s, 2H, NH2). Anal. Calcd. for C16H12ClN5O2: C,
56.23; H, 3.54; N, 20.49. Found: C, 56.38; H, 3.41; N, 20.64.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(2-nitrophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4b). This compound was
obtained as solid with mp 290-291 °C; ir (potassium bromide):
3459, 3350, 3233, 2221, 1708, 1668, 1636, 1578, 1522, 1439,
1371, 1347, 1310, 1278, 1234, 1146, 1102, 1060, 973, 850, 804,
788, 769, 749, 735, 720 cm-1; 1H nmr (DMSO-d6): ꢀ 3.06 (s, 3H,
CH3), 3.53 (s, 3H, CH3), 7.43 (d, J = 7.6 Hz, 1H, ArH), 7.74-
7.78 (m, 1H, ArH), 7.87-7.91 (m, 1H, ArH), 8.03 (s, 2H, NH2),
8.32 (d, J = 8.0 Hz, 1H, ArH). Anal. Calcd. for C16H12N6O4: C,
54.55; H, 3.43; N, 23.85. Found: C, 54.73; H, 3.26; N, 23.68.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-methylphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4c). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3457, 3310, 3219, 2212, 1715, 1667, 1621, 1562, 1508, 1439,
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-methoxyphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4h). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3458, 3306, 3218, 2213, 1716, 1666, 1616, 1580, 1509, 1439,
1366, 1292, 1254, 1178, 1096, 1064, 1034, 973, 932, 838, 807,
1
770, 754, 725 cm-1; H nmr (DMSO-d6): 3.09 (s, 3H, CH3), 3.51
(s, 3H, CH3), 3.83 (s, 3H, CH3O), 6.98 (d, J = 8.4 Hz, 2H, ArH),
7.18 (d, J = 8.4 Hz, 2H, ArH), 7.79 (s, 2H, NH2). Anal. Calcd.
for C17H15N5O3: C, 60.53; H, 4.48; N, 20.76. Found: C, 60.75; H,
4.58; N, 20.57.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-bromophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4i). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3460, 3313, 3220, 2960, 2215, 1714, 1660, 1623, 1568, 1547,
1509, 1492, 1438, 1369, 1278, 1229, 1164, 1096, 1011, 973,
1
830, 805, 753 cm-1; H nmr (DMSO-d6): 3.09 (s, 3H, CH3), 3.51
(s, 3H, CH3), 7.21 (d, J = 8.0 Hz, 2H, ArH), 7.64 (d, J = 8.0 Hz,
2H, ArH), 7.90 (s, 2H, NH2), Anal. Calcd. for C16H12BrN5O2: C,
49.76; H, 3.13; N, 18.13. Found: C, 49.51; H, 3.26; N, 18.37.
7-Amino-1-methyl-2,4-dioxo-5-(3-chlorophenyl)pyrido[2,3-
d]pyrimidine-6-carbonitrile (4j). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3392, 3295,
3165, 3032, 2845, 2217, 1702, 1650, 1618, 1558, 1513, 1483,
1439, 1411, 1373, 1242, 1204, 1190, 1100, 1085, 1054, 868,
803, 784, 693 cm-1; 1H nmr (DMSO-d6): 3.44 (s, 3H, CH3), 7.20-
7.22 (m, 1H, ArH), 7.35 (s, 1H, ArH), 7.44-7.50 (m, 2H, ArH),
7.87 (s, 2H, NH2), 11.22 (s, 1H, NH). Anal. Calcd. for
C15H10ClN5O2: C, 54.97; H, 3.08; N, 21.37. Found: C, 55.08; H,
3.12; N, 21.15.
7-Amino-1-methyl-2,4-dioxo-5-(4-bromophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4k). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3459, 3334, 3179, 3043, 2832, 2223, 1721, 1681, 1633, 1575,
1550, 1507, 1484, 1451, 1434, 1379, 1371, 1303, 1238, 1189,
1073, 1010, 990, 963, 877, 828, 806, 793, 774, 667 cm-1; 1H nmr
(DMSO-d6): 3.43 (s, 3H, CH3), 7.22 (d, J = 8.4 Hz, 2H, ArH),
7.63 (d, J = 8.4 Hz, 2H, ArH), 7.90 (s, 2H, NH2), 11.22 (s, 1H,
NH). Anal. Calcd. for C15H10BrN5O2: C, 48.41; H, 2.71; N,
18.82. Found: C, 48.67; H, 2.50; N, 18.69.
1
1368, 1307, 1278, 1229, 1096, 960, 825, 805, 754 cm-1; H nmr
(DMSO-d6): 2.38 (s, 3H, CH3), 3.08 (s, 3H, CH3), 3.51 (s, 3H,
CH3), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.23 (d, J = 8.0 Hz, 2H,
ArH), 7.83 (s, 2H, NH2). Anal. Calcd. for C17H15N5O2: C, 63.54;
H, 4.71; N, 21.79. Found: C, 63.85; H, 4.61; N, 21.94.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(3-nitrophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4d). This compound was
obtained as solid with mp 298-299 °C; ir (potassium bromide):
3460, 3337, 3235, 3093, 2225, 1713, 1668, 1638, 1565, 1530,
1442, 1393, 1368, 1350, 1280, 1231, 1095, 1068, 981, 805, 752,
1
722, 698 cm-1; H nmr (DMSO-d6): 3.09 (s, 3H, CH3), 3.53 (s,
3H, CH3), 7.76-7.80 (m, 2H, ArH), 7.96 (s, 2H, NH2), 8.18 (s,
1H, ArH), 8.32-8.33 (m, 1H, ArH). Anal. Calcd. for C16H12N6O4:
C, 54.55; H, 3.43; N, 23.85. Found: C, 54.81; H, 3.24; N, 23.97.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(3-chlorophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4e). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3465, 3337, 3235, 3074, 2224, 1712, 1674, 1638, 1558, 1509,
1481, 1436, 1416, 1367, 1307, 1279, 1228, 1090, 980, 898, 808,
1
789, 753, 710 cm-1; H nmr (DMSO-d6): 3.10 (s, 3H, CH3), 3.52
(s, 3H, CH3), 7.21-7.22 (m, 1H, ArH), 7.34 (s, 1H, ArH), 7.45-
7.51 (m, 2H, ArH), 7.90 (s, 2H, NH2). Anal. Calcd. for
C16H12ClN5O2: C, 56.23; H, 3.54; N, 20.49. Found: C, 56.40; H,
3.32; N, 20.27.
7-Amino-1-methyl-2,4-dioxo-5-(3-nitrophenyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4l). This compound was obtained as
solid with mp > 300 °C; ir (potassium bromide): 3455, 3347,
3224, 3081, 2811, 2229, 1699, 1629, 1562, 1445, 1359, 1241,
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-hydroxyphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4f). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3465, 3309, 3140, 2958, 2217, 1710, 1654, 1612, 1574, 1514,
1436, 1372, 1269, 1226, 1172, 1098, 1066, 974, 839, 823, 806,
1
1206, 1051, 848, 817, 800, 753, 736, 701, 686 cm-1; H nmr
(DMSO-d6): 3.45 (s, 3H, CH3), 7.74-7.77 (m, 2H, ArH), 7.96 (s,
2H, NH2), 8.19 (s, 1H, ArH), 8.31-8.33 (m, 1H, ArH), 11.28 (s,
1H, NH). Anal. Calcd. for C15H10N6O4: C, 53.26; H, 2.98; N,
24.84. Found: C, 53.52; H, 2.77; N, 24.68.
1
755 cm-1; H nmr (DMSO-d6): 3.10 (s, 3H, CH3), 3.50 (s, 3H,
CH3), 6.79 (d, J = 8.0 Hz, 2H, ArH), 7.05 (d, J = 8.0 Hz, 2H,
ArH), 7.77 (s, 2H, NH2), 7.96 (s, 1H, OH). Anal. Calcd. for
C16H13N5O3: C, 59.44; H, 4.05; N, 21.66. Found: C, 59.68; H,
3.81; N, 21.74.
7-Amino-1-methyl-2,4-dioxo-5-(4-methoxyphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4m). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3482, 3351, 3189, 3064, 2835, 2214, 1709, 1671, 1613, 1575,
1557, 1512, 1459, 1427, 1368, 1309, 1292, 1254, 1231, 1201,
1175, 1114, 1077, 1049, 1025, 963, 837, 798, 779, 754, 705, 669
cm-1; 1H nmr (DMSO-d6): 3.43 (s, 3H, CH3), 3.82 (s, 3H,
CH3O), 6.97 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d, J = 8.4 Hz, 2H,
ArH), 7.80 (s, 2H, NH2), 11.13 (s, 1H, NH). Anal. Calcd. for
C16H13N5O3: C, 59.44; H, 4.05; N, 21.66. Found: C, 59.61; H,
3.94; N, 21.79.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(4-nitrophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4g). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3457, 3342, 3112, 2225, 1718, 1654, 1559, 1512, 1431, 1373,
1342, 1286, 1252, 1216, 1148, 1093, 1070, 1014, 975, 860, 847,
1
811, 785, 753, 728, 694 cm-1; H nmr (DMSO-d6): 3.08 (s, 3H,
CH3), 3.51 (s, 3H, CH3), 7.57 (d, J = 8.8 Hz, 2H, ArH), 8.02 (s,
2H, NH2), 8.32 (d, J = 8.8 Hz, 2H, ArH). Anal. Calcd. for
C16H12N6O4: C, 54.55; H, 3.43; N, 23.85. Found: C, 54.72; H,
3.29; N, 23.60.
7-Amino-1-methyl-2,4-dioxo-5-(4-hydroxyphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (4n). This compound was

Sep-Oct 2007
One-pot Synthesis of Pyrido[2,3-d]pyrimidines via Efficient
1087
obtained as solid with mp > 300 °C; ir (potassium bromide):
3433, 3334, 3224, 3071, 2222, 1703, 1635, 1610, 1560, 1516,
1437, 1373, 1271, 1241, 1204, 1175, 1105, 882, 843, 805 cm-1;
1H nmr (DMSO-d6): 3.43 (s, 3H, CH3), 6.78 (d, J = 8.4 Hz, 2H,
ArH), 7.06 (d, J = 8.4 Hz, 2H, ArH), 7.75 (s, 2H, NH2), 9.60 (s,
1H, OH), 11.10 (s, 1H, NH). Anal. Calcd. for C15H11N5O3: C,
58.25; H, 3.58; N, 22.64. Found: C, 58.10; H, 3.74; N, 22.83.
7-Amino-1-methyl-2,4-dioxo-5-(4-nitrophenyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4o). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3414, 3329,
3238, 3048, 2836, 2223, 1727, 1678, 1639, 1558, 1515, 1442,
1374, 1351, 1287, 1239, 1205, 1107, 1051, 1014, 967, 887, 859,
10.95 (s, 1H, NH), 11.50 (s, 1H, NH). Anal. Calcd. for
C14H8BrN5O2: C, 46.95; H, 2.25; N, 19.55. Found: C, 47.08; H,
2.11; N, 19.36.
7-Amino-2,4-dioxo-5-(4-fluorophenyl)pyrido[2,3-d]pyrimi-
dine-6-carbonitrile (4u). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3362, 3334, 3147,
3015, 2802, 2229, 1734, 1703, 1674, 1646, 1606, 1566, 1512,
1440, 1387, 1302, 1224, 1160, 1097, 1028, 877, 832, 808, 756
1
cm-1; H nmr (DMSO-d6): 7.24-7.27 (m, 2H, ArH), 7.30-7.35
(m, 2H, ArH), 7.66 (s, 2H, NH2), 10.94 (s, 1H, NH), 11.48 (s,
1H, NH). Anal. Calcd. for C14H8FN5O2: C, 56.57; H, 2.71; N,
23.56. Found: C, 56.70; H, 2.52; N, 23.38.
1
847, 806, 753, 719, 692 cm-1; H nmr (DMSO-d6): 3.44 (s, 3H,
7-Amino-2,4-dioxo-5-(3,4-dichlorophenyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4v). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3396, 3328,
3187, 3090, 2818, 2223, 1715, 1699, 1645, 1592, 1560, 1478,
1440, 1372, 1302, 1261, 1203, 1138, 1103, 1033, 947, 899, 803,
733, 702, 685 cm-1; 1H nmr (DMSO-d6): 7.30 (d, J = 8.0 Hz, 1H,
ArH), 7.63 (s, 1H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.74 (s,
2H, NH2), 11.01 (s, 1H, NH), 11.54 (s, 1H, NH). Anal. Calcd.
for C14H7Cl2N5O2: C, 48.30; H, 2.03; N, 20.12. Found: C, 48.44;
H, 2.17; N, 20.02.
CH3), 7.58 (d, J = 8.4 Hz, 2H, ArH), 8.00 (s, 2H, NH2), 8.30 (d,
J = 8.4 Hz, 2H, ArH), 11.32 (s, 1H, NH). Anal. Calcd. for
C15H10N6O4: C, 53.26; H, 2.98; N, 24.84. Found: C, 53.47; H,
2.76; N, 24.63.
7-Amino-1-methyl-2,4-dioxo-5-(3-pyridyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4p). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3490, 3323,
3222, 3050, 2219, 1694, 1650, 1561, 1514, 1442, 1413, 1374,
1
1246, 1208, 1061, 1041, 960, 827, 806, 791, 754, 709 cm-1; H
nmr (DMSO-d6): 3.44 (s, 3H, CH3), 7.74-7.77 (m, 2H, ArH),
7.96 (s, 2H, NH2), 8.19 (s, 1H, ArH), 8.31 (d, J = 7.2 Hz, 1H,
ArH), 11.27 (s, 1H, NH). Anal. Calcd. for C14H10N6O2: C, 57.14;
H, 3.43; N, 28.56. Found: C, 57.29; H, 3.25; N, 28.63.
7-Amino-2,4-dioxo-5-(3-nitrophenyl)pyrido[2,3-d]pyrimi-
dine-6-carbonitrile (4w). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3401, 3326, 3188,
3090, 2803, 2227, 1724, 1702, 1646, 1598, 1560, 1532, 1485,
1447, 1370, 1340, 1304, 1205, 1099, 1030, 924, 847, 803, 737,
7-Amino-1-methyl-2,4-dioxo-5-(4-pyridyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4q). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3384, 3318,
3166, 3052, 2219, 1703, 1667, 1567, 1530, 1509, 1437, 1369,
1310, 1243, 1220, 1205, 1182, 1073, 1055, 1004, 960, 889, 836,
1
703, 682 cm-1; H nmr (DMSO-d6): 7.74-7.81 (m, 4H, ArH and
NH2), 8.21-8.22 (m, 1H, ArH), 8.30-8.32 (m, 1H, ArH), 11.02
(s, 1H, NH), 11.56 (s, 1H, NH). Anal. Calcd. for C14H8N6O4: C,
51.86; H, 2.49; N, 25.92. Found: C, 51.95; H, 2.23; N, 25.78.
7-Amino-2,4-dioxo-5-(2-chlorophenyl)pyrido[2,3-d]pyrimi-
dine-6-carbonitrile (4x). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3386, 3325, 3164,
2921, 2223, 1717, 1673, 1648, 1598, 1563, 1484, 1439, 1381,
1306, 1258, 1204, 1154, 1100, 1057, 1028, 808, 763, 707 cm-1;
1H nmr (DMSO-d6): 7.28-7.31 (m, 1H, ArH), 7.39-7.46 (m, 2H,
ArH), 7.52-7.54 (m, 1H, ArH), 7.76 (s, 2H, NH2), 11.01 (s, 1H,
NH), 11.55 (s, 1H, NH). Anal. Calcd. for C14H8ClN5O2: C,
53.60; H, 2.57; N, 22.33. Found: C, 53.52; H, 2.46; N, 22.57.
7-Amino-2,4-dioxo-5-(4-nitrophenyl)pyrido[2,3-d]pyrimi-
dine-6-carbonitrile (4y). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3609, 3535, 3321,
3199, 3081, 2848, 2227, 1706, 1666, 1589, 1553, 1522, 1450,
1381, 1348, 1208, 1151, 1108, 1018, 926, 887, 852, 812, 770,
1
806, 790, 757 cm-1; H nmr (DMSO-d6): 3.44 (s, 3H, CH3), 7.29
(d, J = 5.2 Hz, 2H, ArH), 7.95 (s, 2H, NH2), 8.64 (d, J = 5.2 Hz,
2H, ArH), 11.28 (s, 1H, NH). Anal. Calcd. for C14H10N6O2: C,
57.14; H, 3.43; N, 28.56. Found: C, 57.24; H, 3.59; N, 28.36.
7-Amino-2,4-dioxo-5-butylpyrido[2,3-d]pyrimidine-6-
carbonitrile (4r). This compound was obtained as solid with mp
> 300 °C; ir (potassium bromide): 3384, 3329, 3170, 2954,
2810, 2229, 1697, 1654, 1606, 1556, 1448, 1436, 1376, 1259,
1187, 1156, 1023, 822, 800, 756, 720 cm-1; 1H nmr (DMSO-d6):
0.93 (t, J = 7.2 Hz, 3H, CH3), 1.38-1.54 (m, 4H, 2 x CH2), 3.21
(t, J = 7.6 Hz, 2H, CH2), 7.51 (s, 2H, NH2), 11.04 (s, 1H, NH),
11.33 (s, 1H, NH). Anal. Calcd. for C12H13N5O2: C, 55.59; H,
5.05; N, 27.01. Found: C, 55.72; H, 4.95; N, 27.27.
7-Amino-2,4-dioxo-5-(2,4-dichlorophenyl)pyrido[2,3-d]-
pyrimidine-6-carbonitrile (4s). This compound was obtained
as solid with mp > 300 °C; ir (potassium bromide): 3385, 3334,
3156, 3081, 2924, 2820, 2223, 1717, 1651, 1636, 1598, 1560,
1485, 1440, 1383, 1306, 1257, 1205, 1145, 1100, 1056, 1026,
906, 877, 826, 802, 756, 711 cm-1; 1H nmr (DMSO-d6): 7.36 (d, J
= 8.4 Hz, 1H, ArH), 7.52 (d, J = 8.4 Hz, 2H, ArH), 7.74 (s, 1H,
ArH), 7.81 (s, 2H, NH2), 11.05 (s, 1H, NH), 11.60 (s, 1H, NH).
Anal. Calcd. for C14H7Cl2N5O2: C, 48.30; H, 2.03; N, 20.12.
Found: C, 48.45; H, 2.09; N, 20.37.
1
750, 696 cm-1; H nmr (DMSO-d6): 7.59 (d, J = 6.8 Hz, 2H,
ArH), 7.80 (s, 2H, NH2), 8.29 (d, J = 6.8 Hz, 2H, ArH), 11.03 (s,
1H, NH), 11.56 (s, 1H, NH). Anal. Calcd. for C14H8N6O4: C,
51.86; H, 2.49; N, 25.92. Found: C, 51.98; H, 2.31; N, 26.02.
7-Amino-2,4-dioxo-5-(4-chlorophenyl)pyrido[2,3-d]pyrimi-
dine-6-carbonitrile (4z). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3398, 3330, 3169,
3090, 2224, 1706, 1645, 1590, 1556, 1495, 1442, 1409, 1375,
1299, 1260, 1200, 1144, 1092, 1018, 877, 803, 771, 680 cm-1;
7.30 (d, J = 8.4 Hz, 2H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH),
7.66 (s, 2H, NH2), 10.95 (s, 1H, NH), 11.47 (s, 1H, NH). Anal.
Calcd. for C14H8ClN5O2: C, 53.60; H, 2.57; N, 22.33. Found: C,
53.47; H, 2.39; N, 22.46.
7-Amino-2,4-dioxo-5-(4-bromophenyl)pyrido[2,3-d]pyrim-
idine-6-carbonitrile (4t). This compound was obtained as solid
with mp > 300 °C; ir (potassium bromide): 3400, 3329, 3172,
3080, 2931, 2803, 2221, 1716, 1698, 1645, 1592, 1545, 1491,
1441, 1410, 1374, 1298, 1264, 1199, 1143, 1105, 1073, 1014,
General Procedure for the Synthesis of pyrido[2,3-d]-
pyrimidine derivatives 6. A suspension of a mixture of
aldehyde 1 (2 mmol), malononitrile 2 (2 mmol), 2,4-diamino-6-
1
876, 801, 768, 706 cm-1; H nmr (DMSO-d6): 7.24 (d, J = 8.4
Hz, 2H, ArH), 7.62 (d, J = 8.4 Hz, 2H, ArH), 7.68 (s, 2H, NH2),

1088
D. Shi, L. Niu, Jingwen Shi, X. Wang, S. Ji
Vol 44
hydroxypyrimid-ine 5 (2 mmol) and TEBAC (0.15g) was stirred
in water (10 mL) at 90°C for several hours. After completion
monitored by TLC, the reaction mixture was allowed to cool to
room temperature. The crystalline powder formed recrystallized
from DMF to give pure 6.
2,7-Diamino-3,4-dihydro-4-oxo-5-(4-chlorophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (6g). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3501, 3394, 3318, 3056, 2214, 1681, 1668, 1615, 1549, 1492,
1
1428, 1309, 1195, 1088, 1016, 916, 877, 812, 683 cm-1; H nmr
2,7-Diamino-3,4-dihydro-4-oxo-5-(4-nitrophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (6a). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3446, 3343, 3187, 2170, 1670, 1550, 1515, 1472, 1439, 1385,
(DMSO-d6): 6.82 (s, 2H, NH2), 7.22 (s, 2H, NH2), 7.27 (d, J =
8.4 Hz, 2H, ArH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 10.64 (s, 1H,
NH). Anal. Calcd. for C14H9ClN6O: C, 53.77; H, 2.90; N, 26.87.
Found: C, 53.86; H, 2.73; N, 26.59.
2,7-Diamino-3,4-dihydro-4-oxo-5-butylpyrido[2,3-d]pyrimi-
dine-6-carbonitrile (6h). This compound was obtained as solid
with mp > 300 °C; 3401, 3341, 3118, 2959, 2215, 1697, 1665,
1617, 1556, 1467, 1429, 1397, 1367, 1258, 1205, 1193, 1128,
1054, 1028, 855, 815, 736 cm-1; 0.94 (t, J = 7.6 Hz, 3H, CH3),
1.37-1.55 (m, 4H, 2 x CH2), 3.22 (t, J = 7.6 Hz, 2H, CH2), 6.74
(s, 2H, NH2), 7.06 (s, 2H, NH2), 10.72 (s, 1H, NH). Anal. Calcd.
for C12H14N6O: C, 55.80; H, 5.46; N, 32.54. Found: C, 55.63; H,
5.38; N, 32.69.
General Procedure for the Synthesis of pyrido[2,3-d]-
pyrimidine derivatives 8. A suspension of a mixture of
aldehyde 1 (2 mmol), methyl cyanoacetate 7 (2 mmol), 2,4-
diamino-6-hydroxypyrimidine 5 (2 mmol) and TEBAC (0.15 g)
was stirred in water (10 mL) at 90°C for several hours. After
completion monitored by TLC, the reaction mixture was allowed
to cool to room temperature. The crystalline powder formed
recrystallized from DMF to give pure 8.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(4-methylphenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (8a). This compound
was obtained as solid with mp > 300 °C; 3348, 3130, 2225,
1714, 1671, 1617, 1575, 1545, 1471, 1368, 1255, 1165, 1059,
916, 880, 797, 729, 683 cm-1; 2.36 (s, 3H, CH3), 6.68 (s, 2H,
NH2), 7.13 (d, J = 7.6 Hz, 2H, ArH), 7.21 (d, J = 7.6 Hz, 2H,
ArH), 10.90 (s, 1H, NH), 12.30 (s, 1H, NH). Anal. Calcd. for
C15H11N5O2: C, 61.43; H, 3.78; N, 23.88. Found: C, 61.58; H,
3.61; N, 23.73.
1
1346, 1301, 1216, 1106, 916, 885, 851, 816, 742 cm-1; H nmr
(DMSO-d6): 6.95 (s, 2H, NH2), 7.35 (s, 2H, NH2), 7.55 (d, J =
8.8 Hz, 2H, ArH), 8.26 (d, J = 8.8 Hz, 2H, ArH), 10.70 (s, 1H,
NH). Anal. Calcd. for C14H9N7O3: C, 52.02; H, 2.81; N, 30.33.
Found: C, 52.25; H, 2.67; N, 30.59.
2,7-Diamino-3,4-dihydro-4-oxo-5-(4-hydroxyphenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (6b). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3381, 3181, 3140, 2800, 2213, 1696, 1667, 1636, 1613, 1549,
1515, 1425, 1388, 1309, 1266, 1223, 1196, 1173, 1106, 917,
877, 835, 813 cm-1; 1H nmr (DMSO-d6): 6.75 (d, J = 8.0 Hz, 2H,
ArH), 6.91 (s, 2H, NH2), 7.04 (d, J = 8.0 Hz, 2H, ArH), 7.08 (s,
2H, NH2), 9.55 (s, 1H, OH), 10.58 (s, 1H, NH). Anal. Calcd. for
C14H10N6O2: C, 57.14; H, 3.43; N, 28.56. Found: C, 57.36; H,
3.24; N, 28.70.
2,7-Diamino-3,4-dihydro-4-oxo-5-(2-chlorophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (6c). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3463, 3333, 3177, 2189, 1661, 1556, 1458, 1389, 1300, 1205,
1
1135, 1035, 811, 786, 755 cm-1; H nmr (DMSO-d6): 6.92 (s,
2H, NH2), 7.25-7.28 (m, 1H, ArH), 7.33 (s, 2H, NH2), 7.36-7.44
(m, 2H, ArH), 7.50-7.52 (m, 1H, ArH), 10.78 (s, 1H, NH). Anal.
Calcd. for C14H9ClN6O: C, 53.77; H, 2.90; N, 26.87. Found: C,
53.85; H, 2.73; N, 26.69.
2,7-Diamino-3,4-dihydro-4-oxo-5-(2,4-dichlorophenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (6d). This compound
was obtained as solid with mp > 300 °C; ir (potassium bromide):
3368, 3190, 3098, 2886, 2222, 1673, 1626, 1555, 1479, 1433,
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(3,4-dichlorol-
phenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8b). This
compound was obtained as solid with mp > 300 °C; 3326, 3129,
2226, 1715, 1668, 1573, 1561, 1467, 1382, 1250, 1200, 1172,
1132, 1104, 1032, 944, 878, 794, 718, 686 cm-1; 6.72 (s, 2H,
NH2), 7.29 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H, ArH), 7.60 (d, J =
2.0 Hz, 1H, ArH), 7.69 (d, J = 8.4 Hz, 1H, ArH), 10.96 (s, 1H,
NH), 12.41 (s, 1H, NH). Anal. Calcd. for C14H7Cl2N5O2: C,
48.30; H, 2.03; N, 20.12. Found: C, 48.52; H, 1.96; N, 20.35.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(3-chlorolphenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (8c). This compound
was obtained as solid with mp > 300 °C; ir (potassium bromide):
3392, 3132, 2228, 1713, 1669, 1620, 1573, 1541, 1466, 1365,
1
1340, 1199, 1143, 1104, 1054, 921, 878, 816, 797 cm-1; H nmr
(DMSO-d6): 6.90 (s, 2H, NH2), 7.33 (d, J = 8.4 Hz, 1H, ArH),
7.35 (s, 2H, NH2), 7.49 (d, J = 8.4 Hz, 1H, ArH), 7.70 (s, 1H,
ArH), 10.76 (s, 1H, NH). Anal. Calcd. for C14H8Cl2N6O: C,
48.44; H, 2.32; N, 24.21. Found: C, 48.61; H, 2.16; N, 24.42.
2,7-Diamino-3,4-dihydro-4-oxo-5-(4-bromophenyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (6e). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3389, 3330, 3197, 3150, 3078, 2214, 1685, 1667, 1615, 1546,
1489, 1428, 1309, 1195, 1071, 1012, 916, 876, 810 cm-1; 1H nmr
(DMSO-d6): 6.62 (s, 2H, NH2), 7.21 (d, J = 8.0 Hz, 2H, ArH),
7.28 (s, 2H, NH2), 7.59 (d, J = 8.0 Hz, 2H, ArH), 10.70 (s, 1H,
NH). Anal. Calcd. for C14H9BrN6O: C, 47.08; H, 2.54; N, 23.53.
Found: C, 47.23; H, 2.37; N, 23.66.
2,7-Diamino-3,4-dihydro-4-oxo-5-(3,4-dimethylphenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (6f). This compound
was obtained as solid with mp > 300 °C; ir (potassium bromide):
3510, 3407, 3195, 3031, 2878, 2206, 1694, 1665, 1612, 1547,
1500, 1472, 1423, 1306, 1188, 1099, 961, 878, 832, 811 cm-1; 1H
nmr (DMSO-d6): 2.24 (s, 3H, CH3), 2.28 (s, 3H, CH3), 6.78 (s,
2H, NH2), 6.93 (d, J = 8.4 Hz, 1H, ArH), 6.98 (s, 1H, ArH),
7.11-7.17 (m, 3H, NH2 and ArH), 10.56 (s, 1H, NH). Anal.
Calcd. for C16H14N6O: C, 62.74; H, 4.61; N, 27.44. Found: C,
62.91; H, 4.58; N, 27.64.
1
1252, 1196, 1163, 1083, 938, 877, 803, 784, 728, 689 cm-1; H
nmr (DMSO-d6): 6.70 (s, 2H, NH2), 7.22-7.24 (m, 1H, ArH),
7.35-7.36 (m, 1H, ArH), 7.42-7.48 (m, 2H, ArH), 10.91 (s, 1H,
NH), 12.39 (s, 1H, NH). Anal. Calcd. for C14H8ClN5O2: C,
53.60; H, 2.57; N, 22.33. Found: C, 53.81; H, 2.44; N, 22.48.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(2,4-dichlorol-
phenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8d). This
compound was obtained as solid with mp > 300 °C; ir
(potassium bromide): 3333, 3103, 2227, 1712, 1682, 1636,
1583, 1559, 1470, 1384, 1247, 1201, 1173, 1102, 1055, 919,
877, 801, 754, 727 cm-1; 6.81 (s, 2H, NH2), 7.35 (d, J = 8.0 Hz,
1H, ArH), 7.50 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H, ArH), 7.71 (d,
J = 2.0 Hz, 1H, ArH), 11.04 (s, 1H, NH), 12.45 (s, 1H, NH).

Sep-Oct 2007
One-pot Synthesis of Pyrido[2,3-d]pyrimidines via Efficient
1089
Anal. Calcd. for C14H7Cl2N5O2: C, 48.30; H, 2.03; N, 20.12.
Found: C, 48.49; H, 2.15; N, 20.36.
Natural Science Foundation of Jiangsu Province (BK2006048)
and the Natural Science Foundation of Jiangsu Education
Department (06KJA15007) for financial support.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(4-bromophenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (8e). This compound
was obtained as solid with mp > 300 °C (Lit. [17] mp > 300 °C);
ir (potassium bromide): 3341, 3154, 3088 , 2225, 1717, 1676,
1617, 1561, 1473, 1369, 1257, 1166, 1073, 1012, 915, 897, 820,
798, 731, 684 cm-1; 1H nmr (DMSO-d6): 6.72 (s, 2H, NH2), 7.23
(d, J = 8.0 Hz, 2H, ArH), 7.61 (d, J = 8.0 Hz, 2H, ArH), 10.92
(s, 1H, NH), 12.35 (s, 1H, NH). Anal. Calcd. for C14H8BrN5O2:
C, 46.95; H, 2.25; N, 19.55. Found: C, 47.10; H, 2.08; N, 19.72.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-phenylpyrido[2,3-d]-
pyrimidine-6-carbonitrile (8f). This compound was obtained as
solid with mp > 300 °C; ir (potassium bromide): 3305, 3114,
2219, 1699, 1659, 1578, 1545, 1470, 1438, 1379, 1254, 1198,
1170, 1152, 1106, 913, 895, 804, 761, 736, 721, 701, 667 cm-1;
1H nmr (DMSO-d6): 6.68 (s, 2H, NH2), 7.23-7.25 (m, 2H, ArH),
7.38-7.40 (m, 3H, ArH), 10.89 (s, 1H, NH), 12.34 (s, 1H, NH).
Anal. Calcd. for C14H9N5O2: C, 60.21; H, 3.25; N, 25.08. Found:
C, 60.46; H, 3.21; N, 25.24.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(4-methoxyphenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (8g). This compound
was obtained as solid with mp > 300 °C (Lit. [17] mp > 300 °C);
ir (potassium bromide): 3376, 3132, 2225, 1714, 1674, 1629,
1605, 1575, 1545, 1518, 1469, 1368, 1303, 1254, 1180, 1116,
1060, 1027, 915, 879, 800, 756, 733, 685 cm-1; 1H nmr (DMSO-
d6): 3.81 (s, 3H, CH3O), 6.82 (s, 2H, NH2), 6.94 (d, J = 8.4 Hz,
2H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 10.91 (s, 1H, NH),
12.25 (s, 1H, NH). Anal. Calcd. for C15H11N5O3: C, 58.25; H,
3.58; N, 22.64. Found: C, 58.12; H, 3.68; N, 22.85.
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2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(3,4dimethyl-
phenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8h). This
compound was obtained as solid with mp > 300 °C; ir
(potassium bromide): 3393, 3134, 2227, 1719, 1673, 1606,
1537, 1470, 1366, 1260, 1225, 1203, 1164, 1124, 1060, 960,
880, 800, 727, 681 cm-1; 1H nmr (DMSO-d6): 2.23 (s, 3H, CH3),
2.27 (s, 3H, CH3), 6.65 (s, 2H, NH2), 6.95 (d, J = 8.0 Hz, 1H,
ArH), 7.00 (s, 1H, ArH), 7.15 (d, J = 8.0 Hz, 1H, ArH), 10.86 (s,
1H, NH), 12.30 (s, 1H, NH). Anal. Calcd. for C16H13N5O2: C,
62.53; H, 4.26; N, 22.79. Found: C, 62.67; H, 4.12; N, 22.90.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(4-fluorophenyl)-
pyrido[2,3-d]pyrimidine-6-carbonitrile (8i). This compound was
obtained as solid with mp > 300 °C (Lit. [17] mp > 300 °C); ir
(potassium bromide): 3401, 3092, 2229, 1696, 1670, 1600, 1585,
1561, 1503, 1474, 1437, 1382, 1255, 1216, 1167, 1102, 1062, 1022,
917, 879, 838, 802, 760, 728, 691 cm-1; 1H nmr (DMSO-d6): 6.72 (s,
2H, NH2), 7.21-7.26 (m, 2H, ArH), 729-7.33 (m, 2H, ArH), 10.92
(s, 1H, NH), 12.35 (s, 1H, NH). Anal. Calcd. for C14H8FN5O2: C,
56.57; H, 2.71; N, 23.56. Found: C, 56.74; H, 2.45; N, 23.68.
2-Amino-3,4,7,8-tetrahydro-4,7-dioxo-5-(3-pyridyl)pyrido-
[2,3-d]pyrimidine-6-carbonitrile (8j). This compound was
obtained as solid with mp > 300 °C; ir (potassium bromide):
3338, 3132, 2223, 1712, 1667, 1636, 1581, 1553, 1469, 1416,
1375, 1260, 1197, 1106, 1056, 1028, 916, 876, 798, 771, 724,
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1
675 cm-1; H nmr (DMSO-d6): 6.81 (s, 2H, NH2), 7.45 (dd, J1 =
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4.8 Hz, J2 = 7.6 Hz, 1H, ArH), 7.73 (d, J = 7.6 Hz, 2H, ArH),
8.47 (s, 1H, ArH), 8.59 (d, J = 4.8 Hz, 2H, ArH), 10.96 (s, 1H,
NH), 12.40 (s, 1H, NH). Anal. Calcd. for C13H8N6O2: C, 55.72;
H, 2.88; N, 29.99. Found: C, 55.93; H, 2.72; N, 30.07.
Acknowledgement. We are grateful to the National Natural
Science Foundation of China (20472062 and 20672079), the
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