An efficient chemoselective synthesis of pyrido[2,3-d]pyrimidine derivatives under microwave irradiation

Article abstract of DOI:10.1055/s-2008-1032031

A facile and selective synthesis of poly-substituted pyrido[2,3-d] pyrimidines is accomplished via microwave-assisted multicomponent reactions controlled by the nature of solvent. In addition, a possible mechanism accounting for the reaction is proposed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032031

PAPER
369
An Efficient Chemoselective Synthesis of Pyrido[2,3-d]pyrimidine Derivatives
under Microwave Irradiation
Synthesisof
P
h
yrido[2,3-
d
]p
u
yrimidine
D
j
erivativ
i
es und
a
er Microw
a
n
ve Irradiatio
g
n
Tu,* Chunmei Li, Feng Shi, Dianxiang Zhou, Qingqing Shao, Longji Cao, Bo Jiang
School of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou Normal University,
Xuzhou, Jiangsu 221116, P. R. of China
Fax +86(516)83500065; E-mail: laotu@xznu.edu.cn
Received 18 September 2007; revised 31 October 2007
es, and good potency against Cdks has been reported for
Abstract: A facile and selective synthesis of poly-substituted pyri-
representative examples.6–8 Obtaining selectivity for indi-
vidual Cdk enzymes, particularly Cdk4, has been chal-
do[2,3-d]pyrimidines is accomplished via microwave-assisted mul-
ticomponent reactions controlled by the nature of solvent. In
lenging. Many extensive investigations of the structure–
activity relationships for pyrido[2,3-d]pyrimidin-7-one
inhibition of Cdk4 have been initiated. Therefore, to ob-
tain the new potential inhibitors of Cdk4, the synthesis of
pyrido[2,3-d]pyrimidin-7-one should be of great signifi-
cance. For the preparation of these molecules large efforts
have been directed toward the synthetic manipulation of
pyrido[2,3-d]pyrimidine derivatives. As a result, a num-
ber of reports have appeared in the literature9 that gener-
ally require long reaction times and complex synthetic
pathways. Thus, new routes for the synthesis of these mol-
ecules have attracted considerable attention in the search
for a rapid entry to these heterocycles.
addition, a possible mechanism accounting for the reaction is pro-
posed.
Key words: solvent-dependent chemoselectivity, pyrido[2,3-d]py-
rimidines, microwave irradiation, heterocycles, multicomponent re-
action
Selectivity is a key issue to be controlled in organic syn-
thesis. In particular, chemoselectivity is synthetically use-
ful because it gives one of several products selectively
from the same substrate without the need to separate the
product(s) from the product mixture. It continues to be de-
veloped as organic synthesis strives for ever-increasing
levels of efficiency. As a result, many studies have fo-
cused on the chemoselectivity of reactions.1 In recent
years, many reports have dealt with the control of
chemoselectivity reactions with metal catalysts,1a–e while
solvent-dependent chemoselective reactions have been re-
searched in relatively few papers.1g–i Therefore, the devel-
opment of highly solvent-dependent chemoselective
reactions remains a challenge.
In the context of our interest in the design and develop-
ment of useful tactics and strategies for the synthesis of
heterocyclic compounds,10 herein, we wish to report a
new microwave-assisted chemoselective reaction con-
trolled by the nature of solvents for the synthesis of pyri-
do[2,3-d]pyrimidine derivatives using aldehydes 1, 2,6-
diaminopyrimidin-4(3H)-one (2), and 4-hydroxy-2H-
chromen-2-one (3) (Scheme 1). To the best of our knowl-
edge to date, the solvent-dependent chemoselective syn-
thesis of pyrido[2,3-d]pyrimidine derivatives has not yet
been reported.
Pyrido[2,3-d]pyrimidine and its derivatives are useful as
antitumor,2 antibacterial,3 anti-inflammatory,4 and anti-
fungal agents.5 In particular, the pyrido[2,3-d]pyrimidin-
7-one template has been identified previously as a privi-
leged structure for the inhibition of ATP-dependent kinas-
Choosing an appropriate solvent is of crucial importance
not only for successful microwave-promoted (MW) syn-
O
Ar
O
ArCHO
HN
O
DMF
1
O
140 °C
H2N
N
N
H
O
O
HN
4
+
N
H2N
NH2
O
Ar
O
OH
OH
AcOH, DMF
150 °C
HN
2
3
H2N
N
N
O
H
5
Scheme 1
SYNTHESIS 2008, No. 3, pp 0369–0376
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032031; Art ID: F16607SS
© Georg Thieme Verlag Stuttgart · New York

370
S. Tu et al.
PAPER
Table 1 Optimization of Chemoselectivity Conditions in the Syn-
thesis of 4a and 5a
This influence of solvents on product composition in the
reaction is a novel observation and warranted further in-
vestigation. A study on the effect of different ratios of ace-
tic acid to N,N-dimethylformamide was conducted with
the same substrates as described in Table 1 (entries 5–13).
Entry
Solventa
Ratio
Yieldb (%)
4a
5a
0
1
2
H2O
16
0
Surprisingly, totally different chemoselectivity was ob-
served in both solvents (Scheme 1). The products 4a and
5a were generated exclusively in N,N-dimethylform-
amide and the mixed solvent N,N-dimethylformamide–
acetic acid (1:4), respectively. The dramatically different
results from the two reaction conditions highlight the im-
portance of the amount of acetic acid in controlling
chemoselectivity and, thus, the outcome of the reactions.
none
0
3
ethylene glycol
EtOH
81
18
33
28
25
9
0
4
0
5
AcOH
51
54
70
80
88
77
62
32
0
6
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
DMF
1:1
1:2
1:3
1:4
1:5
1:6
1:7
Thus, the question is, why does the selective formation of
5 occur in the mixed solvent acetic acid–N,N-dimethyl-
formamide (1:4) whereas only 4 is obtained in N,N-di-
methylformamide?
7
8
9
0
The chemoselectivity of the reaction should be attributed
to the nature of solvent. In N,N-dimethylformamide, the
reactive position of intermediate 9 is the ketone carbonyl,
which is attracted by the NH2 groups to form product 4,
while in the mixed solvent acetic acid–N,N-dimethyl-
formamide, the reactive position of intermediate 11 is the
ester carbonyl, which is attracted by the NH2 groups to
yield open-ring compound 5. Therefore, the suggested
pathway for the formation of 4 and 5 via route i and route
ii, respectively, is depicted in Scheme 2.
10
11
12
13
12
28
66
92
a The volume of solvent was 2.0 mL.
b Isolated yields.
thesis, but also for the effective control of chemoselective
reactions. In order to choose the optimum solvent, the mi-
crowave-assisted reaction of 4-fluorobenzaldehyde (1a),
2,6-diaminopyrimidin-4(3H)-one (2), and 4-hydroxy-2H-
chromen-2-one (3) was examined at 140 °C under sol-
vent-free conditions and using water, ethylene glycol,
N,N-dimethylformamide, acetic acid, and ethanol as sol-
vent. All the reactions were carried out under microwave
irradiation (initial power 100 W and maximum power 200
W). The results of the screening of solvents are presented
in Table 1 (entries 1–5, 13). As can be seen in Table 1,
none of the desired product was detected under solvent-
free conditions, and incomplete reactions were observed
in the case of water and ethanol as the solvent, respective-
ly. When ethylene glycol was selected as the solvent, the
reaction occurred and product 4a (Ar = 4-FC6H4) was ob-
tained in relatively good yield, but the product 4a was ob-
tained with the best yield and the shortest reaction time in
N,N-dimethylformamide, which is an ideal polar aprotic
solvent.11 Furthermore, it was noteworthy that this reac-
tion afforded two products when acetic acid was used as
the solvent. On the basis of the 1H NMR and 13C NMR, the
two compounds were identified as 4a and 5a, and these
were easily distinguished from one another. Compound
5a may give two possible diastereomers, the trans- and
cis-isomers, but only the trans-isomer was obtained. The
1H NMR spectrum of 5a showed two singlets at d = 4.73
and d = 4.34 assigned to C5 and C6, respectively, which
is similar to our recent report.12
The effect of temperature on the reaction using the same
reagents, in N,N-dimethylformamide and the mixed sol-
vent acetic acid–N,N-dimethylformamide (1:4), at tem-
peratures ranging from 100 °C to 170 °C in increments of
10 °C, was investigated respectively. The results are sum-
marized in Table 2.
As can be seen in Table 2, we found that the yield of 4a
improved and the reaction time was shortened as the tem-
perature increased from 100 °C to 140 °C (Table 2, entries
1–5). The yield reached a plateau when the temperature
Table 2 Temperature Optimization for the Synthesis of 4a and 5a
Entry
Temp (°C) Time (min)
Yieldc (%)
4aa
5ab
13
11
10
9
4aa
5ab
69
75
79
82
88
90
90
85
1
2
3
4
5
6
7
8
100
110
120
130
140
150
160
170
15
12
11
8
78
82
87
89
92
92
88
86
5
6
7
6
6
6
6
5
a MW irradiation in DMF.
b MW irradiation in AcOH–DMF (1:4).
c Isolated yields.
Synthesis 2008, No. 3, 369–376 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2,3-d]pyrimidine Derivatives under Microwave Irradiation
371
Ar
O
O
N
O
Ar
O
route i
O
HN
H2N
HN
O
O
NH2
Ar
ArCHO
O
O
H2N
N
N
H
O
Ar
1
9
H2O
4
NH
+ H+
+
+
NH2
+OH
Ar
OH
O
OH
H2N
N
O
O
N
O
N
– H+
2
8
HN
HN
H2N
route ii
O
O
O
H2N
NH2
O
3
NH2
O
10
11
Ar
O
N
Ar
OH
O
N
OH
– H+
HN
HN
H2N
N
H
O
HO
H2N
N
O
H
OH
Ar
12
13
O
N
O
HN
HO
H2N
N
H
O
5
Scheme 2
was further increased from 150 °C to 170 °C (Table 2, en- Furthermore, the volume of solvent was found to be im-
tries 5–8). Therefore, a reaction temperature of 140 °C portant for the yields of the two reactions. The synthesis
was considered to be the most suitable for the synthesis of of 4a [1a (1 mmol), 2 (1 mmol), and 3 (1 mmol)] and 5a
4. In addition, we found that the yield of 5a increased and [1a (1 mmol), 2 (1 mmol), and 3 (1 mmol)] in different
the reaction time was shortened as the temperature was in- volumes of solvent was tested under microwave irradia-
creased from 100 °C to 150 °C (Table 2, entries 1–6). tion conditions. The yield was found to be the highest
However, further increase of the temperature to 160 °C when 2.0 mL of solvent was used for both reactions.
and 170 °C failed to improve the yield of product 5a
(Table 2, entries 7 and 8). Hence, 150 °C was chosen as
the reaction temperature for the synthesis of 5.
Under these optimized reaction conditions, a series of py-
rido[2,3-d]pyrimidine derivatives 4 and 5 were synthe-
sized. The results are presented in Table 3.
Table 3 Synthesis of 4a and 5a under MW Conditions
Entry
4
5
Ar
Time (min)
Yieldc (%)
Mp (°C)
4a
5b
6
5
5
6
6
7
8
8
7
4a
5b
4
5
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
4-FC6H4
5
4
6
5
6
8
7
9
6
92
96
91
92
92
89
88
82
90
90
86
90
90
89
85
86
83
89
295–296
287–289
>300
294–295
4-ClC6H4
4-BrC6H4
3-O2NC6H4
Ph
>300
292–294
>300
>300
286–288
>300
290–291
>300
4-MeOC6H4
4-MeC6H4
3,4-(MeO)2C6H3
2-thienyl
4g
4h
4i
5g
5h
5i
>300
262–263
>300
>300
>300
>300
a MW irradiation in DMF.
b MW irradiation in AcOH–DMF (1:4).
c Isolated yields.
Synthesis 2008, No. 3, 369–376 © Thieme Stuttgart · New York

372
S. Tu et al.
PAPER
In order to expand the scope of the method, we employed Additionally, for comparison, we performed the synthesis
4-hydroxyquinolin-2(1H)-one (6) instead of 4-hydroxy- of some examples of 4, 5, and 7 using classical heating
2H-chromen-2-one (3) in the reaction of 1a and 2,6-di- methods under otherwise identical conditions (reaction
aminopyrimidin-4(3H)-one (2) in different solvents such vessel, temperature, etc.). A comparison of the results for
as acetic acid, N,N-dimethylformamide, and mixtures six compounds are listed in Table 6, which indicated that
thereof. The results are described in Table 4. The reaction the reactions were efficiently promoted by microwave ir-
proceeded smoothly. To our satisfaction, only product 7a radiation and the reaction time was strikingly shortened to
was obtained with the best results in N,N-dimethylform- 4–9 minutes from the several hours required under con-
amide (Scheme 3). With optimized conditions in hand, a ventional heating conditions, the yields were also higher.
series of pyrido[2,3-d]pyrimidine derivatives 7 were syn- In addition, it should be noted that small amounts of 4
thesized. The results are summarized in Table 5.
were detected when compounds 5 were synthesis under
traditional heating conditions in mixed solvents N,N-di-
methylformamide–acetic acid (1:4). Therefore, to some
extent, the reaction chemoselectivity was improved when
the syntheses of 5 were conducted under microwave irra-
diation conditions.
Table 4 Screening Solvents for the Synthesis of 7a
Entry
Solventa
Time (min)
Yieldb (%)
1
2
3
AcOH
9
6
76
90
70
DMF
Table 6 Synthesis of Various 4, 5, and 7 Using Conventional Heat-
ing
AcOH–DMF (1:4)
11
Entry
Product
4a
Time (h)
Yielda (%)
a The volume of solvent is 2.0 mL.
b Isolated yields.
1
4
6
5
6
6
7
68
66
52
49
70
67
2
4g
Table 5 Synthesis of 7 under MW Conditions
3
5a
Entry
7
Ar
Time Yielda Mp (°C)
(min) (%)
4
5g
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
4-FC6H4
6
5
7
6
6
8
9
9
9
90
93
91
92
89
89
88
86
88
298–299
291–292
293–295
273–275
266–268
>300
5
7c
4-HO-3-O2NC6H3
4-ClC6H4
6
7f
a Isolated yields.
3-O2NC6H4
Ph
All the products were characterized by IR spectra and 1H
NMR as well as elemental analyses. Some compounds
were also characterized by 13C NMR and MS. The IR
spectrum of compound 5c showed strong absorptions at
3463, 3326 and 3159 cm–1 due to OH, NH, and NH2
groups and at 1700, 1685, 1635 cm–1 due to C=O func-
tionality. The 1H NMR spectrum of 5c showed two singlet
at d = 4.72 (s, 1 H, CH) and d = 4.31 (s, 1 H, CH) due to
CH, and three singlet at d = 11.19, 10.60, and 10.53 due to
OH and NH protons (exchanged with D2O).
4-MeOC6H4
4-MeC6H4
3,4-(OCH2O)C6H3
2-thienyl
7g
7h
7i
>300
>300
278–279
a Isolated yields.
In conclusion, we have demonstrated an efficient and
practical method for the synthesis of a wide range of pyri-
do[2,3-d]pyrimidine derivatives under microwave irradi-
ation and have shown the effect of the nature of solvent on
chemoselectivity. In addition, efforts to expand the reac-
tion with the help of theoretical and spectroscopic studies
are in progress in our laboratory.
As shown in Tables 3 and 5, this methodology can be ap-
plied not only to aromatic aldehydes either with electron-
withdrawing groups (such as nitro or halide groups) or
with electron-donating groups (such as alkoxy groups),
but also to heterocyclic aldehydes with excellent yields
under the same conditions. Therefore, we concluded that
the electronic nature of the substituents of the aldehydes
had no significant effect on the two reactions.
O
O
N
Ar
O
H
N
O
HN
DMF
HN
NH
+
ArCHO
+
H2N
140 °C
N
NH2
H2N
N
H
OH
1
2
6
7
Scheme 3
Synthesis 2008, No. 3, 369–376 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2,3-d]pyrimidine Derivatives under Microwave Irradiation
373
7.67 (d, J = 7.6 Hz, 1 H, ArH), 7.59 (d, J = 8.0 Hz, 1 H, ArH), 7.48
(d, J = 8.0 Hz, 1 H, ArH), 7.37–7.32 (m, 2 H, ArH), 6.43 (s, 2 H,
NH2), 5.05 (s, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 161.6, 160.4, 154.7, 154.2,
152.5, 148.4, 147.7, 144.5, 134.6, 132.3, 129.7, 124.2, 123.8, 122.3,
121.5, 116.9, 113.2, 104.5, 90.7, 36.0.
Microwave irradiation was performed with microwave oven Emrys
Creator from Personal Chemistry, Uppsala, Sweden. Melting points
were determined in open capillaries and were uncorrected. IR spec-
tra were taken on a FT-IR-Tensor 27 spectrometer in KBr pellets
and reported in cm–1. 1H NMR (13C NMR) spectra were measured
on a Bruker DPX 400 MHz (100 MHz) spectrometer in DMSO-d6
relative to TMS as internal standard. ESI-MS was determined by us-
ing the LCQ Advantage HPLC/MS instrument (Thermo Finnigan).
Elemental analysis was determined by using a Perkin-Elmer 240c
elemental analysis instrument.
MS (ESI): m/z = 402.4 [M – H]–, 353.4, 332.6.
Anal. Calcd for C20H13N5O5: C, 59.56; H, 3.25; N, 17.36. Found: C,
59.44; H, 3.12; N, 17.47.
10-Amino-7-aryl-7,12-dihydro-6H-chromeno[3¢,4¢:5,6]pyri-
do[2,3-d]pyrimidine-6,8(9H)-diones 4; General Procedure
under Microwave Irradiation
7-Phenyl Derivative 4e
IR (KBr): 3479, 3411, 3339, 3228, 2860, 2738, 1664, 1625, 1491,
1446, 1377, 1374, 1352, 1207, 1055, 879, 821, 751, 695 cm–1.
In a 10-mL reaction vial, aldehyde 1 (1 mmol), 2,6-diaminopyrimi-
din-4(3H)-one (2, 126 mg, 1 mmol), 4-hydroxy-2H-chromen-2-one
(3, 162 mg, 1 mmol), and DMF (2.0 mL) were mixed and then the
vial was capped. The mixture was irradiated for the specified time
(Table 3) at 100 W (initial power) and 200 W (maximum power)
and 140 °C. Upon completion (TLC), the mixture was cooled to r.t.
and then poured into cold H2O. The solid product was filtered,
washed with H2O and 95% EtOH, dried, and recrystallized (95%
EtOH) to give the pure product.
1H NMR (400 MHz, DMSO-d6): d = 10.79 (s, 1 H, NH), 10.20 (s, 1
H, NH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H,
ArH), 7.43 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (t, J = 7.6 Hz, 1 H, ArH),
7.24 (t, J = 7.6 Hz, 2 H, ArH), 7.17–7.10 (m, 3 H, ArH), 6.57 (s, 2
H, NH2), 5.51 (s, 1 H, CH).
Anal. Calcd for C20H14N4O3: C, 67.03; H, 3.94; N, 15.63. Found: C,
67.17; H, 3.81; N, 15.56.
7-(4-Methoxyphenyl) Derivative 4f
IR (KBr): 3451, 3343, 3198, 2838, 1657, 1635, 1591, 1509, 1441,
7-(4-Fluorophenyl) Derivative 4a
1363, 1249, 1181, 1033, 835, 761 cm–1.
IR (KBr): 3472, 3417, 3343, 3233, 3052, 2856, 1662, 1626, 1607,
1536, 1507, 1468, 1380, 1301, 1245, 1199, 1038, 909, 791, 752
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.80 (s, 1 H, NH), 10.09 (s, 1
H, NH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.63 (t, J = 7.6 Hz, 1 H,
ArH), 7.43 (d, J = 8.0 Hz, 1 H, ArH), 7.36 (t, J = 7.6 Hz, 1 H, ArH),
7.15–7.03 (m, 4 H, ArH), 6.58 (s, 2 H, NH2), 5.48 (s, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 161.8, 160.6, 159.4, 153.8,
152.2, 147.8, 135.4, 132.3, 128.4, 128.3, 124.2, 123.9, 117.8, 116.2,
114.9, 114.7, 104.9, 89.8, 35.0.
1H NMR (400 MHz, DMSO-d6): d = 10.76 (s, 1 H, NH), 9.81 (s, 1
H, NH), 7.89–7.83 (m, 1 H, ArH), 7.63 (t, J = 8.0 Hz, 1 H, ArH),
7.43–7.34 (m, 1 H, ArH), 7.14 (d, J = 7.6 Hz, 1 H, ArH), 7.00 (d,
J = 8.4 Hz, 2 H, ArH), 6.80 (d, J = 8.4 Hz, 2 H, ArH), 6.56 (s, 2 H,
NH2), 5.45 (s, 1 H, CH), 3.71 (s, 3 H, OCH3).
Anal. Calcd for C21H16N4O4: C, 64.94; H, 4.15; N, 14.43. Found: C,
65.21; H, 3.98; N, 14.48.
7-(4-Methylphenyl) Derivative 4g
IR (KBr): 3462, 3326, 3203, 2921, 1660, 1629, 1592, 1573, 1479,
Anal. Calcd for C20H13FN4O3: C, 63.83; H, 3.48; N, 14.89. Found:
C, 63.78; H, 3.62; N, 14.97.
1437, 1356, 1190, 1043, 795, 759 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.77 (s, 1 H, NH), 10.11 (s, 1
H, NH), 7.83 (d, J = 7.6 Hz, 1 H, ArH), 7.64 (t, J = 7.6 Hz, 1 H,
ArH), 7.42 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (t, J = 7.6 Hz, 1 H, ArH),
7.04 (t, J = 7.6 Hz, 2 H, ArH), 6.98 (d, J = 8.0 Hz, 2 H, ArH), 6.56
(s, 2 H, NH2), 5.46 (s, 1 H, CH), 2.25 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.2, 160.0, 157.9, 153.7,
152.2, 147.6, 138.9, 134.5, 132.2, 128.8, 126.4, 123.9, 121.8, 113.9,
112.2, 104.9, 90.5, 35.1, 20.7.
7-(4-Chlorophenyl) Derivative 4b
IR (KBr): 3490, 3463, 3195, 2962, 1661, 1633, 1570, 1485, 1454,
1356, 1284, 1042, 900, 784, 767 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.72 (s, 1 H, NH), 10.16 (s, 1
H, NH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H,
ArH), 7.42 (d, J = 8.4 Hz, 3 H, ArH), 7.36 (t, J = 7.6 Hz, 1 H, ArH),
7.07 (d, J = 8.4 Hz, 2 H, ArH), 6.63 (s, 2 H, NH2), 5.46 (s, 1 H, CH).
MS (ESI): m/z = 389.9 [M + NH4]+.
Anal. Calcd for C20H13ClN4O3: C, 61.16; H, 3.34; N, 14.26. Found:
C, 59.94; H, 3.48; N, 14.18.
Anal. Calcd for C21H16N4O3: C, 67.73; H, 4.33; N, 15.05. Found: C,
67.70; H, 4.41; N, 15.11.
7-(4-Bromophenyl) Derivative 4c
IR (KBr): 3492, 3423, 3357, 3231, 3066, 2980, 1662, 1625, 1580,
7-(3,4-Dimethoxyphenyl) Derivative 4h
1489, 1447, 1373, 1345, 1280, 1052, 877, 792, 751 cm–1.
IR (KBr): 3495, 3413, 3358, 2934, 1699, 1645 1520, 1450, 1391,
1262, 1192, 1137, 1022, 768 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.68 (s, 1 H, NH), 10.10 (s, 1
H, NH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.65 (t, J = 7.6 Hz, 1 H,
ArH), 7.43 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (t, J = 7.6 Hz, 1 H, ArH),
7.27 (d, J = 8.4 Hz, 2 H, ArH), 7.12 (d, J = 8.4 Hz, 2 H, ArH), 6.60
(s, 2 H, NH2), 5.48 (s, 1 H, CH).
1H NMR (400 MHz, DMSO-d6): d = 10.66 (s, 1 H, NH), 10.02 (s, 1
H, NH), 8.45 (d, J = 8.0 Hz, 1 H, ArH), 7.62 (t, J = 7.6 Hz, 1 H,
ArH), 7.39–7.36 (m, 2 H, ArH), 6.96 (s, 1 H, ArH), 6.78 (d, J = 8.0
Hz, 1 H, ArH), 6.64 (d, J = 8.0 Hz, 1 H, ArH), 6.41 (s, 2 H, NH2),
4.93 (s, 1 H, CH), 3.67 (s, 6 H, OCH3).
13C NMR (100 MHz, DMSO-d6): d = 161.7, 160.6, 154.3, 154.1,
152.3, 148.3, 147.5, 143.7, 139.2, 132.0, 124.2, 123.5, 119.3, 116.9,
113.4, 112.2, 111.9, 100.6, 91.7, 55.7, 55.6, 34.6.
Anal. Calcd for C20H13BrN4O3: C, 54.94; H, 3.00; N, 12.81. Found:
C, 55.07; H, 3.16; N, 12.86.
7-(3-Nitrophenyl) Derivative 4d
IR (KBr): 3498, 3433, 3373, 3231, 3066, 2974, 1662, 1621, 1592,
MS (ESI): m/z = 419.3 [M + H]+, 383.4, 363.3.
1520, 1491, 1351, 1247, 1109, 899, 842, 792, 751 cm–1.
Anal. Calcd for C22H18N4O5: C, 63.15; H, 4.34; N, 13.39. Found: C,
63.03; H, 4.51; N, 13.44.
1H NMR (400 MHz, DMSO-d6): d = 10.62 (s, 1 H, NH), 10.11 (s, 1
H, NH), 8.45 (d, J = 8.0 Hz, 1 H, ArH), 8.03–7.95 (m, 2 H, ArH),
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S. Tu et al.
PAPER
7-(2-Thienyl) Derivative 4i
5-(3-Nitrophenyl) Derivative 5d
IR (KBr): 3469, 3339, 3185, 2872, 1625, 1528, 1479, 1439, 1358,
IR (KBr): 3411, 3338, 3227, 3022, 1706, 1624, 1491, 1447, 1352,
1206, 758, 698 cm–1.
1312, 1248, 1208, 1159, 1010, 863, 791, 751 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.47 (s, 1 H, NH), 10.11 (s, 1
H, NH), 7.87 (d, J = 8.4 Hz, 1 H, ArH), 7.65 (t, J = 8.0 Hz, 1 H,
ArH), 7.44–7.35 (m, 3 H, ArH), 7.27–7.24 (m, 1 H, ArH), 6.87–6.86
(m, 1 H, ArH), 6.65 (s, 2 H, NH2), 5.63 (s, 1 H, CH).
1H NMR (400 MHz, DMSO-d6): d = 11.21 (s, 1 H, OH), 10.64 (s, 1
H, NH), 10.60 (s, 1 H, NH), 8.12 (d, J = 8.4 Hz, 2 H, ArH), 7.85 (d,
J = 7.6 Hz, 1 H, ArH), 7.66 (t, J = 7.6 Hz, 1 H, ArH), 7.45–7.35 (m,
4 H, ArH), 6.65 (s, 2 H, NH2), 4.78 (s, 1 H, CH), 4.46 (s, 1 H, CH).
Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N, 15.38; S, 8.80.
Found: C, 59.19; H, 3.47; N, 15.43; S, 8.92.
Anal. Calcd for C20H15N5O6: C, 57.01; H, 3.59; N, 16.62. Found: C,
57.20; H, 3.66; N, 16.49.
2-Amino-5-aryl-6-(2-hydroxybenzoyl)-5,8-dihydropyrido[2,3-
d]pyrimidine-4,7(3H,6H)-dione 5; General Procedure under
Microwave Irradiation
5-Phenyl Derivative 5e
IR (KBr): 3434, 3317, 3174, 2906, 2862, 1652, 1601, 1537, 1490,
1451, 1393, 1359, 1276, 1159, 932, 791, 750, 698 cm–1.
In a 10-mL reaction vial, aldehyde 1 (1 mmol), 2,6-diaminopyrimi-
din-4(3H)-one (2, 126 mg, 1 mmol), 4-hydroxy-2H-chromen-2-one
(3, 162 mg, 1 mmol), AcOH (0.4 mL), and DMF (1.6 mL) were
mixed and then the vial was capped. The mixture was irradiated for
the specified time (Table 3) at 100 W (initial power) and 200 W
(maximum power) and 150 °C. Upon completion (TLC), the subse-
quent workup was the same as that given for the general procedure
under microwave irradiation for 4.
1H NMR (400 MHz, DMSO-d6): d = 11.14 (s, 1 H, OH), 10.55 (s, 1
H, NH), 10.45 (s, 1 H, NH), 7.66 (d, J = 7.6 Hz, 1 H, ArH), 7.53–
7.49 (m, 1 H, ArH), 7.34–7.22 (m, 5 H, ArH), 7.04 (d, J = 8.8 Hz, 1
H, ArH), 6.95 (t, J = 8.0 Hz, 1 H, ArH), 6.58 (s, 2 H, NH2), 4.75 (s,
1 H, CH), 4.34 (s, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 197.5, 169.0, 161.5, 158.5,
157.1, 155.3, 142.6, 135.6, 130.9, 128.8, 126.9, 126.8, 121.5, 119.8,
119.9, 117.7, 89.7, 60.5, 37.4.
5-(4-Fluorophenyl) Derivative 5a
Anal. Calcd for C20H16N4O4: C, 63.82; H, 4.28; N, 14.89. Found: C,
63.61; H, 4.11; N, 14.97.
IR (KBr): 3443, 3337, 3177, 2913, 1700, 1647, 1507, 1453, 1359,
1301, 1241, 1159, 840, 754 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.18 (s, 1 H, OH), 10.60 (s, 1
H, NH), 10.51 (s, 1 H, NH), 7.66 (d, J = 7.2 Hz, 1 H, ArH), 7.51 (t,
J = 7.2 Hz, 1 H, ArH), 7.30–7.26 (m, 2 H, ArH), 7.16 (t, J = 8.8 Hz,
2 H, ArH), 7.04 (d, J = 8.0 Hz, 1 H, ArH), 6.95 (t, J = 7.6 Hz, 1 H,
ArH), 6.63 (s, 2 H, NH2), 4.73 (s, 1 H, CH), 4.34 (s, 1 H, CH).
5-(4-Methoxyphenyl) Derivative 5f
IR (KBr): 3433, 3343, 3199, 2938, 2840, 1699, 1637, 1537, 1510,
1485, 1363, 1299, 1250, 1177, 997, 825, 798, 757 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.17 (s, 1 H, OH), 10.56 (s, 1
H, NH), 10.46 (s, 1 H, NH), 7.65 (d, J = 8.0 Hz, 1 H, ArH), 7.51 (t,
J = 7.6 Hz, 1 H, ArH), 7.16 (d, J = 8.4 Hz, 2 H, ArH), 7.04 (d,
J = 8.0 Hz, 1 H, ArH), 6.95 (t, J = 7.6 Hz, 1 H, ArH), 6.87 (t, J = 8.4
Hz, 2 H, ArH), 6.59 (s, 2 H, NH2), 4.71 (s, 1 H, CH), 4.28 (s, 1 H,
CH), 3.71 (s, 3 H, OCH3).
Anal. Calcd for C20H15FN4O4: C, 60.91; H, 3.83; N, 14.21. Found:
C, 60.77; H, 3.62; N, 14.29.
5-(4-Chlorophenyl) Derivative 5b
13C NMR (100 MHz, DMSO-d6): d = 197.6, 169.0, 161.5, 158.6,
158.3, 156.9, 155.2, 135.6, 134.5, 130.9, 127.9, 121.5, 119.8, 117.7,
114.1, 90.1, 60.7, 55.3, 36.7.
IR (KBr): 3460, 3322, 3182, 2934, 1698, 1644, 1536, 1488, 1456,
1485, 1355, 1299, 1214, 1158, 1092, 997, 931, 815, 791, 754 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.19 (s, 1 H, OH), 10.62 (s, 1
H, NH), 10.52 (s, 1 H, NH), 7.65 (d, J = 7.2 Hz, 1 H, ArH), 7.51 (t,
J = 8.0 Hz, 1 H, ArH), 7.40 (d, J = 8.0 Hz, 2 H, ArH), 7.26 (d,
J = 8.4 Hz, 2 H, ArH), 7.04 (d, J = 8.0 Hz, 1 H, ArH), 6.94 (t,
J = 8.4 Hz, 1 H, ArH), 6.65 (s, 2 H, NH2), 4.72 (s, 1 H, CH), 4.33
(s, 1 H, CH).
Anal. Calcd for C21H18N4O5: C, 62.06; H, 4.46; N, 13.79. Found: C,
61.84; H, 4.61; N, 13.84.
5-(4-Methylphenyl) Derivative 5g
IR (KBr): 3421, 3321, 3163, 2915, 2770, 1689, 1651, 1540 1487,
1451, 1357, 1241, 1158, 795, 751 cm–1.
MS (ESI): m/z = 409.4 [M – H]–.
1H NMR (400 MHz, DMSO-d6): d = 11.15 (s, 1 H, OH), 10.55 (s, 1
H, NH), 10.45 (s, 1 H, NH), 7.64 (d, J = 8.0 Hz, 1 H, ArH), 7.50 (t,
J = 8.0 Hz, 1 H, ArH), 7.15–7.10 (m, 4 H, ArH), 7.04 (d, J = 8.0 Hz,
1 H, ArH), 6.95 (t, J = 7.6 Hz, 1 H, ArH), 6.59 (s, 2 H, NH2), 4.71
(s, 1 H, CH), 4.30 (s, 1 H, CH), 2.26 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 197.6, 169.0, 161.5, 158.5,
157.0, 155.2, 140.0, 136.0, 135.6, 130.9, 129.3, 126.7, 121.5, 119.8,
117.7, 89.9, 60.6, 37.1, 20.7.
Anal. Calcd for C20H15ClN4O4: C, 58.47; H, 3.68; N, 13.64. Found:
C, 58.33; H, 3.79; N, 13.75.
5-(4-Bromophenyl) Derivative 5c
IR (KBr): 3463, 3326, 3159, 2942, 1700, 1685, 1635, 1536, 1486,
1457, 1353, 1296, 1243, 1159, 1009, 997, 813, 789, 754 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.19 (s, 1 H, OH), 10.60 (s, 1
H, NH), 10.53 (s, 1 H, NH), 7.66 (d, J = 7.6 Hz, 1 H, ArH), 7.52 (t,
J = 8.4 Hz, 2 H, ArH), 7.51–7.49 (m, 1 H, ArH), 7.21 (d, J = 8.4 Hz,
2 H, ArH), 7.04 (d, J = 8.4 Hz, 1 H, ArH), 6.95 (t, J = 7.6 Hz, 1 H,
ArH), 6.64 (s, 2 H, NH2), 4.72 (s, 1 H, CH), 4.31 (s, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 197.1, 168.7, 161.4, 158.5,
157.1, 155.4, 142.1, 135.6, 131.7, 131.0, 129.1, 121.5, 120.0, 119.9,
117.7, 89.3, 60.2, 36.9.
MS (ESI): m/z = 389.7 [M – H]–, 352.7, 339.0.
Anal. Calcd for C21H18N4O4: C, 64.61; H, 4.65; N, 14.35. Found: C,
64.72; H, 4.82; N, 14.09.
5-(3,4-Dimethoxyphenyl) Derivative 5h
IR (KBr): 3420, 3306, 3187, 2939, 1691, 1638, 1561 1514, 1455,
1420, 1321, 1123, 1002, 782, 757 cm–1.
MS (ESI): m/z = 455.5 [M]+, 387.8.
1H NMR (400 MHz, DMSO-d6): d = 11.13 (s, 1 H, OH), 10.42 (s, 1
H, NH), 10.37 (s, 1 H, NH), 7.78 (d, J = 7.6 Hz, 1 H, ArH), 7.46 (t,
J = 8.0 Hz, 1 H, ArH), 7.39–7.35 (m, 2 H, ArH), 6.71 (d, J = 8.0 Hz,
1 H, ArH), 6.64–6.62 (m, 2 H, ArH), 6.37 (s, 2 H, NH2), 4.69 (s, 1
H, CH), 4.21 (s, 1 H, CH), 3.71 (s, 6 H, OCH3).
Anal. Calcd for C20H15BrN4O4: C, 52.76; H, 3.32; N, 12.31. Found:
C, 52.71; H, 3.21; N, 12.39.
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Synthesis of Pyrido[2,3-d]pyrimidine Derivatives under Microwave Irradiation
375
13C NMR (100 MHz, DMSO-d6): d = 197.7, 168.9, 161.2, 158.8,
154.7, 154.2, 152.3, 149.8, 135.6, 134.3, 131.1, 129.7, 126.6, 121.3,
119.8, 117.7, 114.5, 90.4, 60.7, 55.8, 55.6, 36.6.
1H NMR (400 MHz, DMSO-d6): d = 13.76 (s, 1 H, NH), 11.71 (s, 1
H, NH), 10.65 (s, 1 H, NH), 8.05 (s, 1 H, ArH), 7.86–7.83 (m, 2 H,
ArH), 7.55–7.52 (m, 3 H, ArH), 7.36 (d, J = 8.4 Hz, 1 H, ArH), 7.20
(t, J = 7.6 Hz, 1 H, ArH), 6.51 (s, 2 H, NH2), 5.83 (s, 1 H, CH).
Anal. Calcd for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C,
60.59; H, 4.47; N, 12.77.
Anal. Calcd for C20H14N6O4: C, 59.70; H, 3.51; N, 20.89. Found: C,
59.78; H, 3.29; N, 20.61.
5-(2-Thienyl) Derivative 5i
IR (KBr): 3489, 3339, 3194, 3065, 2956, 1689, 1633, 1542, 1491,
7-Phenyl Derivative 7e
1439, 1359, 1206, 1106, 899, 758 cm–1.
IR (KBr): 3419, 3344, 3182, 3025, 2997, 2929, 1658, 1637, 1608,
1491, 1437, 1385, 1257, 1100, 875,825, 793, 755 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.15 (s, 1 H, OH), 10.78 (s, 1
H, NH), 10.45 (s, 1 H, NH), 7.84 (d, J = 7.6 Hz, 1 H, ArH), 7.57 (t,
J = 8.0 Hz, 1 H, ArH), 7.41–7.28 (m, 3 H, ArH), 6.83 (s, 1 H, ArH),
6.71–6.83 (m, 1 H, ArH), 6.43 (s, 2 H, NH2), 4.73 (s, 1 H, CH), 4.28
(s, 1 H, CH).
1H NMR (400 MHz, DMSO-d6): d = 13.79 (s, 1 H, NH), 11.61 (s, 1
H, NH), 10.50 (s, 1 H, NH), 7.82 (d, J = 8.0 Hz, 1 H, ArH), 7.51 (t,
J = 7.6 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.23–7.06 (m,
6 H, ArH), 6.43 (s, 2 H, NH2), 5.74 (s, 1 H, CH).
Anal. Calcd for C18H14N4O4S: C, 56.54; H, 3.69; N, 14.65; S, 8.39.
Found: C, 56.70; H, 3.86; N, 14.59; S, 8.27.
13C NMR (100 MHz, DMSO-d6): d = 165.5, 164.0, 161.0, 153.7,
140.3, 137.5, 130.5, 128.0, 126.5, 125.3, 123.4, 121.6, 116.7, 115.2,
110.8, 90.3, 34.2.
10-Amino-7-aryl-7,12-dihydrobenzo[h]pyrimido[4,5-
b][1,6]naphthyridine-6,8(5H,9H)-dione 7; General Procedure
under Microwave Irradiation
Anal. Calcd for C20H15N5O2: C, 67.22; H, 4.23; N, 19.60. Found: C,
67.10; H, 4.33; N, 19.87.
In a 10-mL reaction vial, aldehyde 1 (1 mmol), 2,6-diaminopyrimi-
din-4-one (2, 126 mg, 1 mmol), 4-hydroxyquinolin-2(1H)-one (6,
160 mg, 1 mmol), and DMF (2.0 mL) were mixed and then the vial
was capped. The mixture was irradiated for the specified time
(Table 5) at 100 W (initial power) and 200 W (maximum power)
and 140 °C. Upon completion (TLC), the subsequent workup was
the same as that given for the general procedure under microwave
irradiation for 4.
7-(4-Methoxyphenyl) Derivative 7f
IR (KBr): 3423, 3337, 3172, 2835, 1645, 1607, 1508, 1438, 1387,
1247, 1177, 1032, 841, 803, 758 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.77 (s, 1 H, NH), 11.57 (s, 1
H, NH), 10.46 (s, 1 H, NH), 7.81 (d, J = 8.4 Hz, 1 H, ArH), 7.52–
7.33 (m, 1 H, ArH), 7.33 (d, J = 8.4 Hz, 1 H, ArH), 7.17 (t, J = 7.6
Hz, 1 H, ArH), 6.95 (d, J = 8.4 Hz, 2 H, ArH), 6.77 (d, J = 8.0 Hz,
2 H, ArH), 6.40 (s, 2 H, NH2), 5.68 (s, 1 H, CH), 3.71 (s, 3 H,
OCH3).
7-(4-Fluorophenyl) Derivative 7a
IR (KBr): 3436, 3345, 3160, 2902, 1652, 1633, 1506, 1444, 1387,
1292, 1222, 1157, 1098, 1062, 862, 844, 807, 782, 760, 667 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.80 (s, 1 H, NH), 11.65 (s, 1
H, NH), 10.54 (s, 1 H, NH), 7.82 (d, J = 8.0 Hz, 1 H, ArH), 7.53–
7.44 (m, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.19–7.01 (m, 5
H, ArH), 6.45 (s, 2 H, NH2), 5.71 (s, 1 H, CH).
Anal. Calcd for C21H17N5O3: C, 65.11; H, 4.42; N, 18.08. Found: C,
64.98; H, 4.27; N, 18.16.
7-(4-Methylphenyl) Derivative 7g
IR (KBr): 3402, 3342, 3177, 2923, 1640, 1633, 1508, 1490, 1369,
1254, 1099, 1010, 841, 801, 757 cm–1.
Anal. Calcd for C20H14FN5O2: C, 64.00; H, 3.76; N, 18.66. Found:
C, 64.06; H, 3.59; N, 18.73.
1H NMR (400 MHz, DMSO-d6): d = 13.77 (s, 1 H, NH), 11.61 (s, 1
H, NH), 10.49 (s, 1 H, NH), 7.81 (d, J = 8.4 Hz, 1 H, ArH), 7.50 (t,
J = 7.6 Hz, 1 H, ArH), 7.33 (d, J = 8.4 Hz, 2 H, ArH), 7.17 (t,
J = 7.6 Hz, 1 H, ArH), 7.01 (d, J = 8.0 Hz, 1 H, ArH), 6.94 (d,
J = 8.0 Hz, 2 H, ArH), 6.41 (s, 2 H, NH2), 5.68 (s, 1 H, CH), 2.24
(s, 3 H, CH3).
7-(4-Hydroxy-3-nitrophenyl) Derivative 7b
IR (KBr): 3426, 3340, 3328, 3149, 2928, 1689, 1638, 1533, 1487,
1341, 1248, 1155, 1100, 791, 752 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.78 (s, 1 H, NH), 11.66 (s, 1
H, NH), 10.69 (s, 1 H, OH), 10.61 (s, 1 H, NH), 7.82 (d, J = 7.6 Hz,
1 H, ArH), 7.54–7.50 (m, 2 H, ArH), 7.34 (d, J = 8.4 Hz, 1 H, ArH),
7.25 (d, J = 8.0 Hz, 1 H, ArH), 7.19 (t, J = 7.6 Hz, 1 H, ArH), 7.02
(d, J = 8.4 Hz, 1 H, ArH), 6.47 (s, 2 H, NH2), 5.68 (s, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 165.5, 165.4, 163.9, 160.9,
153.6, 137.5, 137.2, 134.0, 130.5, 128.6, 126.4, 123.3, 121.6, 116.7,
115.2, 111.2, 90.4, 33.9, 20.7.
MS (ESI): m/z = 388.7 (M + NH4)+.
Anal. Calcd for C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C,
68.11; H, 4.68; N, 18.77.
Anal. Calcd for C20H14N6O5: C, 57.42; H, 3.37; N, 20.09. Found: C,
57.46; H, 3.49; N, 20.16.
7-[3,4-(Methylenedioxy)phenyl] Derivative 7h
7-(4-Chlorophenyl) Derivative 7c
IR (KBr): 3416, 3345, 3180, 2929, 2742, 1636, 1631, 1608, 1486,
IR (KBr): 3430, 3335, 3178, 3095, 2908, 1673, 1636, 1605, 1487,
1439, 1322, 1235, 1010, 928, 828, 783, 762 cm–1.
1436, 1385, 1272, 1094, 875, 847, 792, 755 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.77 (s, 1 H, NH), 11.54 (s, 1
H, NH), 10.46 (s, 1 H, NH), 7.83 (d, J = 8.0 Hz, 1 H, ArH), 7.50 (t,
J = 7.6 Hz, 1 H, ArH), 7.33 (d, J = 8.0 Hz, 1 H, ArH), 7.17 (t,
J = 7.6 Hz, 1 H, ArH), 6.74 (d, J = 8.0 Hz, 1 H, ArH), 6.56–6.52 (m,
2 H, ArH), 6.52 (s, 2 H, NH2), 5.94 (s, 2 H, CH2), 5.67 (s, 1 H, CH).
1H NMR (400 MHz, DMSO-d6): d = 13.77 (s, 1 H, NH), 11.64 (s, 1
H, NH), 10.54 (s, 1 H, NH), 7.82 (d, J = 7.6 Hz, 1 H, ArH), 7.52 (t,
J = 7.6 Hz, 1 H, ArH), 7.33 (d, J = 8.0 Hz, 1 H, ArH), 7.27 (d,
J = 8.0 Hz, 2 H, ArH), 7.20–7.12 (m, 1 H, ArH), 7.07 (d, J = 8.0 Hz,
2 H, ArH), 6.45 (s, 2 H, NH2), 5.70 (s, 1 H, CH).
Anal. Calcd for C21H15N5O4: C, 62.84; H, 3.77; N, 17.45. Found: C,
62.58; H, 3.88; N, 17.29.
Anal. Calcd for C20H14ClN5O2: C, 61.31; H, 3.60; N, 17.87. Found:
C, 61.26; H, 3.51; N, 17.79.
7-(2-Thienyl) Derivative 7i
7-(3-Nitrophenyl) Derivative 7d
IR (KBr): 3432, 3342, 3178, 2873, 1637, 1603, 1485, 1431, 1373,
IR (KBr): 3411, 3344, 3190, 3091, 2918, 1665, 1631, 1526, 1493,
1267, 828, 757, 695, 670 cm–1.
1445, 1349, 1258, 1094, 862, 793 cm–1.
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PAPER
1H NMR (400 MHz, DMSO-d6): d = 14.08 (s, 1 H, NH), 11.62 (s, 1
H, NH), 10.57 (s, 1 H, NH), 7.85 (d, J = 8.0 Hz, 1 H, ArH), 7.52 (d,
J = 7.6 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.24–7.16 (m,
2 H, ArH), 6.85–6.83 (m, 1 H, ArH), 6.57 (s, 1 H, ArH), 6.47 (s, 2
H, NH2), 5.86 (s, 1 H, CH).
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Anal. Calcd for C18H13N5O2S: C, 59.49; H, 3.61; N, 19.27; S, 8.82.
Found: C, 59.43; H, 3.39; N, 19.20; S, 8.65.
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J. Med. Chem. 1974, 17, 470. (e) Zakharov, A. V.;
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Syropyatov, B. Y.; Kolla, V. E.; Konshin, M. E. Khim.-
Farm. Zh. 1991, 25, 26.
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Keller, P. R.; Wu, Z.; Dobrusin, E.; Leopold, W. R.; Fattaey,
A.; Garrett, M. D. J. Biol. Chem. 2001, 276, 16617.
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Heterocycl. Commun. 2000, 6, 275. (b) Quiroga, J.; Cruz,
S.; Insuasty, B.; Abonia, R.; Nogueras, M.; Sanchez, A.;
Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2001, 38, 53.
(c) Thankur, A. J.; Saikia, P.; Prajapati, D.; Sandhu, J. S.
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Synthesis of 4 and 7 with Conventional Heating; General Proce-
dure
A mixture containing aldehyde 1 (1 mmol), 4-hydroxy-2H-
chromen-2-one (3, 162 mg, 1 mmol) [or 4-hydroxyquinolin-2(1H)-
one (6, 160 mg, 1 mmol)], 2,6-diaminopyrimidin-4(3H)-one (2, 126
mg, 1 mmol), and DMF (2.0 mL) was introduced into a 10-mL Em-
rys reaction vial, the vial was capped, and the mixture was then
stirred at 140 °C (oil-bath temperature) for the specified time. When
the reaction was completed (TLC), workup was the same as that
given for the general procedure under microwave irradiation for 4.
Synthesis of 5 under Classical Heating Conditions; General
Procedure
A mixture containing aldehyde 1 (1 mmol), 4-hydroxy-2H-
chromen-2-one (3, 162 mg, 1 mmol), 2,6-diaminopyrimidin-4(3H)-
one (2, 126 mg, 1 mmol), AcOH (0.4 mL), and DMF (1.6 mL) were
mixed into a 10-mL Emrys reaction vial, the vial was capped, and
the mixture was then stirred at 150 °C (oil-bath temperature) for the
specified time. When the reaction was completed (TLC), workup
was the same as that given for the general procedure under micro-
wave irradiation for 4.
Acknowledgment
We are grateful to financial support from the National Science
Foundation of China (No. 20672090), Natural Science Foundation
of the Jiangsu Province (No. BK2006033), Six Kinds of Professio-
nal Elite Foundation of the Jiangsu Province (No. 06-A-039)
References
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Synthesis 2008, No. 3, 369–376 © Thieme Stuttgart · New York