Pot, atom and step economic synthesis of fused three heterocyclic ring compounds under microwave irradiation in water

Article abstract of DOI:10.1002/jhet.5570450508

(Chemical Equation Presented) A new series of fused three heterocyclic ring compounds, consisting of a pyrazolo (ring A), a pyridine (ring B), and a pyrimidine (ring C) core, pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives were successfully synthesized by pot, atom and step economic (PASE) method under microwave irradiation in the presence of p-toluene sulphonic acid in water.

Full text of DOI:10.1002/jhet.5570450508

Sep-Oct 2008
1305
Pot, Atom and Step Economic Synthesis of Fused Three
Heterocyclic Ring Compounds under
Microwave Irradiation in Water
Feng Shi, Dianxiang Zhou, Shujiang Tu,* Chunmei Li, Longji Cao, Qingqing Shao
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology
for Medicinal Plant, Xuzhou, Jiangsu, 221116, P. R. China
Received August 7, 2007
R
R
O
O
Ar
N
O
N
N
H2O p-TsOH
R
O
ArCHO
N
N
O
N
MW
N
N
N
R
Ph
NH2
Ph
(a) R = H; (b) R = CH3
A new series of fused three heterocyclic ring compounds, consisting of a pyrazolo (ring A), a pyridine
(ring B), and a pyrimidine (ring C) core, pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine derivatives were
successfully synthesized by pot, atom and step economic (PASE) method under microwave irradiation in
the presence of p-toluene sulphonic acid in water.
J. Heterocyclic Chem., 45, 1305 (2008).
INTRODUCTION
intermediate compounds. Ideally, all the reagents should
also be incorporated into the final product.
Pyrazolo-annelated heterocycles have demonstrated
wide spectrum of agriculture and pharmacological
activities [1,2], such as diagnosis of brain disorders [3],
treatment of coronary heart disease [4], viral diseases [5],
central nervous system diseases [6] and show
pharmacological efficacy [7]. Pyrazolo[4',3':5,6]pyrido-
[2,3-d]pyrimidines showed wide spectrum applications
such as anticonvulsant agents [8], colorants [9],
heat/moisture resistant agents and thermal transfer
printing agent [10], photographic couplers [11]. However,
to the best of our knowledge, there have only been a few
reports of the synthesis of pyrazolopyridopyrimidine
derivatives (Fig. 1) in the literature [12]. Recently,
Hussein [13] et al. disclosed that the condensation of 5-
Ar
O
H
O
N
C
N
H
N
A
N
B
N
We have recently become interested in the development
of facile methods [17] for the synthesis of heterocyclic
compounds. In this paper, we wish to report a simple,
facile and one-pot method for the synthesis of fused three
heterocyclic ring compound, consisting of a pyrazolo
(ring A), a pyridine (ring B), and a pyrimidine (ring C)
core, assisted by p-toluene sulphonic acid (p-TsOH) in
water under microwave (MW) heating (Scheme 1).
amino-3-methyl-1-phenyl-pyrazole-4-carbaldehyde
as
precursors with cyanoacetamide in refluxing ethanolic
piperidine yielded the intermediate compounds of
aminocarboxamide derivatives in moderate yields, then
reacted with urea derivatives to yield the pyrazolo-
pyridopyrimidine derivatives. Jachak and co-workers [14]
reported the synthesis of pyrazolopyrido-pyrimidine
derivatives by multi-step reaction and using organic
solvent.
Scheme 1
O
O
R
R
Ar
O
N
N
H2O p-TsOH
R
O
ArCHO
N
N
O
N
MW
N
N
N
N
R
NH2
Ph
Ph
2
3
1
4
In all these methods a multi-step reaction is needed.
Furthermore, organic solvent is required and the
procedure is not economic and environmentally friendly.
Therefore, the development of a new, pot, atom [15] and
step economic [16] (PASE) method for the synthesis of
pyrazolopyridopyrimidine derivatives is of prime interest.
Pot, atom and step economy aims to combine as many
transformations as possible into a single reaction vessel,
without the need for work-up and isolation of
(a) R = H; (b) R = CH3
RESULTS AND DISCUSSION
We first chose barbituric acid 3a (1.0 mmol) and
searched for the optimized conditions for its reaction with
4-bromobenzaldehyde 1c (1.0 mmol) and 3-methyl-1-
phenyl-1H-pyrazol-5-amine
2 (1.0 mmol) affording

1306
F. Shi, D. Zhou, S. Tu, C. Li, L. Cao, Q. Shao
Vol 45
pyrazolopyridopyrimidines under microwave irradiation
conditions (Scheme 2).
temperature was raised from 150 °C to 160 °C. Therefore,
the temperature of 140 °C was chosen for all further MW-
assisted reactions.
Scheme 2
Table 2
Br
Optimization of the amount of p-TsOH in the synthesis of product 4c in
water at 100°C.
O
O
NH
NH
catalyst
N
CHO
Br
+
+
O
Entry
p-TsOH/ eq.
Time / min
Yielda / %
NH
H2O
MW
N
N
1
2
3
4
5
6
7
8
0.1
0.3
0.6
0.8
0.9
1.0
1.2
1.4
10
10
10
10
10
10
10
10
59
69
72
75
76
80
78
77
Ph
NH2
O
N
Ph
N
N
O
H
1c
2
3a
4c
Different acidic catalysts (1 mmol) were examined. The
results of these comparative experiments are summarized
in Table 1. From the results it is obvious that p-TsOH
(entry 1) demonstrates superior catalytic activity and is
the best catalyst among those examined.
a Crude yields
Table 3
Temperature optimization for the synthesis of product 4c.
Table 1
Optimization of the catalyst in the synthesis of product 4c in water at
100 °C.
Entry
T / °C
Time / min
Yield / %
1
2
3
90
100
110
13
10
9
76
80
82
Entry
Catalyst
Time / min
Yield a / %
1
2
3
4
5
6
7
p-TsOH
10
10
10
10
10
10
10
80
56
35
47
65
74
70
NH2SO3H
H2SO4
4
5
6
7
8
120
130
140
150
160
9
8
6
6
6
83
86
90
88
88
CuSO4·5H2O
FeCl3·6H2O
KH2PO4
H3PO4
a Crude yields
We therefore selected 1.0 equivalent of p-TsOH as the
catalyst, 140 °C for further study. At the beginning of the
search for the aldehyde substrate scope, barbituric acid 3a
and 3-methyl-1-phenyl-1H-pyrazol-5-amine were used as
model substrates (Table 4, entries 1–11), and the results
indicated that aromatic aldehydes bearing either electron-
donating (such as alkoxyl groups) or electron-
withdrawing (such as nitro or halide groups) functional
groups were all suitable to the reaction. Moreover, a
heterocyclic aldehyde, thiophene-2-carbaldehyde (Table
4, entry 12), still showed high reactivity and clean
reaction under these standard conditions. The mechanisms
are similar to that reported in earlier work [18].
In order to further evaluate the influence of p-TsOH
concentration, this reaction was carried out using different
amounts of p-TsOH under microwave irradiation at 100
°C. The results are listed in Table 2. From Table 2 it can
be seen that the reaction proceeded in the presence of 0.1
equivalents of p-TsOH to give the product 4c in 59%
yield under microwave irradiation at 100 °C after 10
minutes of the reaction (entry 1). Increasing the amount of
catalyst to 0.3, 0.6, 0.8 and 0.9 equivalents successively
resulted in the increasing of the yield to 69%, 72%, 75%
and 76%, respectively. Use of just 1.0 equivalent under
microwave irradiation was sufficient to reach the highest
yield (entry 6). Further increases in the amount of catalyst
did not improve the yield (entries 7–8).
Moreover, to further optimize the reaction temperature,
reactions using 4-bromobenzaldehyde (1c, 1.0 mmol), 3-
methyl-1-phenyl-1H-pyrazol-5-amine (2, 1.0 mmol) and
barbituric acid (3a, 1.0 mmol) were carried out in the
range of 90 to 160 °C in increments of 10 °C each time.
The results are shown in Table 3. When the temperature
was increased from 90 °C to 140 °C, the yield of product
4c was improved. However, no significant increase in the
yield of product 4c was observed as the reaction
In order to expand the scope of the present method, we
used different aldehydes and 3-methyl-1-phenyl-1H-
pyrazol-5-amine as model substrates, the replacement of
barbituric acid with 1,3-dimethyl barbituric acid (1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) was also
examined (Scheme 3). In all these cases, the reactions
proceeded smoothly to give the corresponding
pyrazolopyridopyrimidines in good yields. All the
1
products in this study were characterized by IR and H
NMR spectroscopy, as well as by elemental analyses,
some products were characterized by 13C NMR
spectroscopy.

Sep-Oct 2008
Pot, Atom and Step Economic Synthesis of Fused Three Heterocyclic Ring Compounds
1307
Table 4
Synthesis of compounds 4 in water under microwave irradiation at 140 °C.
Entry
Ar
3
R
Product
Time / min
Yield / %
Mp / °C
1
2
4-FC6H4
4-ClC6H4
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
H
H
4a
4b
4c
4d
4e
4f
7
7
6
8
9
9
6
7
7
9
7
7
8
7
7
6
7
6
9
7
9
9
7
8
88
86
90
85
84
82
92
86
87
88
90
91
87
85
86
89
88
88
86
88
84
85
87
85
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
3
4-BrC6H4
H
4
4-NO2C6H4
4-CH3OC6H4
4-CH3C6H4
3-NO2C6H4
C6H5
H
5
H
6
H
7
H
4g
4h
4i
8
H
9
2,4-Cl2C6H3
3,4-(CH3O)2C6H3
4-OH-3-NO2C6H3
thiophen-2-yl
4-FC6H4
H
10
11
12
13
14
15
16
17
18
19
H
4j
H
4k
4l
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4m
4n
4o
4p
4q
4r
4s
4-ClC6H4
4-BrC6H4
4-CH3C6H4
3-NO2C6H4
3-BrC6H4
2-ClC6H4
20
21
22
23
24
C6H5
3b
3b
3b
3b
3b
CH3
CH3
CH3
CH3
CH3
4t
2,4-Cl2C6H3
4u
4v
4w
4x
3,4-OCH2OC6H3
4-OH-3-NO2C6H3
thiophen-2-yl
was determined with a Perkin-Elmer 240c elemental analysis
instrument.
General procedure for the one-pot synthesis of compounds
Scheme 3
O
Ar
O
N
N
p-TsOH
H2O
derivatives
4 in water under microwave irradiation
ArCHO
N
N
O
condition. Typically, in a 10-mL EmrysTM reaction vial, an
aldehyde 1 (1 mmol), 3-methyl-1-phenyl-1H-pyrazol-5-amine 2
(1 mmol), and barbituric acids 3 (1 mmol), water (1 mL), p-
TsOH (1 mmol) were mixed and then capped. The mixture was
irradiated for a given time at 140 °C under microwave
irradiation (initial power 100 W and maximum power 250 W).
Upon completion, monitored by TLC, the reaction mixture was
cooled to room temperature and then poured into cold water.
The solid product was collected by Büchner filtration, which
was further purified by recrystallization from EtOH (95%) to
give the pure product.
N
MW
N
N
N
N
O
Ph
NH2
O
Ph
1
2
3b
4
In conclusion, a pot, atom, and step economic (PASE)
method for the synthesis of pyrazolo[4',3':5,6]pyrido[2,3-
d]pyrimidine derivatives, important classes of building
blocks in natural products and pharmaceuticals, was
accomplished via a three-component reaction in water
under microwave heating. Obtaining good to excellent
product yields, avoiding multi-step reactions to construct
useful heterocycles, and eliminating the use of organic
solvent are some of the salient features of this approach.
4-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo-[4',3':
5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4a). ir (KBr):
1
3185 (NH), 1720 (C=O), 1695 (C=O) cm-1; H nmr: ꢀ 11.81 (s,
1H, NH), 11.21 (s, 1H, NH), 8.26 (d, 2H, J = 8.0 Hz, ArH), 7.56
(t, 2H, J = 8.0 Hz, ArH), 7.42-7.30 (m, 5H, ArH), 1.81 (s, 3H,
CH3). 13C nmr: ꢀ 161.7, 153.0, 150.4, 150.0, 149.9, 145.1, 138.7,
132.4, 130.0, 129.3, 126.2, 120.6, 114.8, 114.6, 113.9, 104.1,
14.5. Anal. calcd for C21H14FN5O2: C, 65.11; H, 3.64; N, 18.08.
Found: C, 65.18; H, 3.60; N, 18.14.
EXPERIMENTAL
Microwave irradiation was carried out with an EmrysTM
Creator microwave oven from Personal Chemistry, Uppsala,
Sweden. Melting points were determined in open capillaries and
were uncorrected. IR spectra were taken with a FT-IR-Tensor 27
4-(4-Chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo-[4',3':
5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4b). ir (KBr):
1
3185 (NH), 1716 (C=O), 1701 (C=O) cm-1; H nmr: ꢀ 11.82 (s,
spectrometer in KBr pellets and are reported in cm-1. H NMR
1
and 13C NMR spectra were measured with a Bruker DPX 400
MHz spectrometer in DMSO-d6 with chemical shifts (ꢀ) given in
ppm relative to TMS as internal standard. Elemental analysis
1H, NH), 11.22 (s, 1H, NH), 8.25 (d, 2H, J = 7.6 Hz, ArH),
7.58-7.54 (m, 4H, ArH), 7.40-7.36 (m, 3H, ArH), 1.82 (s, 3H,
CH3). 13C nmr: ꢀ 161.7, 152.9, 150.4, 150.0, 149.4, 145.0,

1308
F. Shi, D. Zhou, S. Tu, C. Li, L. Cao, Q. Shao
Vol 45
104.2, 14.3. Anal. calcd for C21H15N5O2: C, 68.28; H, 4.09; N,
18.96. Found: C, 68.22; H, 4.13; N, 18.88.
138.7, 135.1, 132.9, 129.7, 129.4, 127.8, 126.2, 120.6, 113.6,
104.0, 14.3. Anal. calcd for C21H14ClN5O2: C, 62.46; H, 3.49; N,
17.34. Found: C, 62.39; H, 3.45; N, 17.39.
4-(2,4-Dichlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4i). ir
4-(4-Bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo-[4',3':
5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4c). ir (KBr):
1
(KBr): 3178 (NH), 1716 (C=O), 1701 (C=O) cm-1; H nmr: ꢀ
1
3186 (NH), 1713 (C=O), 1699 (C=O) cm-1; H nmr: ꢀ 11.82 (s,
11.95 (s, 1H, NH), 11.36 (s, 1H, NH), 8.24 (d, 2H, J = 8.0 Hz,
ArH), 7.83-7.82 (m, 1H, ArH), 7.57 (t, 3H, J = 8.0 Hz, ArH),
7.45 (d, 1H, J = 8.4 Hz, ArH), 7.37 (t, 1H, J = 7.6 Hz, ArH),
1.85 (s, 3H, CH3). 13C nmr: ꢀ 161.5, 153.0, 150.4, 150.3, 145.8,
144.6, 138.6, 134.3, 133.8, 132.1, 130.8, 129.4, 128.5, 127.3,
126.3, 120.7, 113.0, 104.2, 15.1. Anal. calcd for C21H13Cl2N5O2:
C, 57.55; H, 2.99; N, 15.98. Found: C, 57.46; H, 2.95; N, 15.90.
4-(3,4-Dimethoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4j). ir
(KBr): 3200 (NH), 1719(C=O), 1704(C=O) cm-1; 1H nmr: ꢀ
11.76 (s, 1H, NH), 11.16 (s, 1H, NH), 8.25 (d, 2H, J = 8.0 Hz,
ArH), 7.56 (t, 2H, J = 8.0. Hz, ArH), 7.35 (t, 1H, J = 7.6 Hz,
ArH), 7.05 (d, 1H, J = 8.4 Hz, ArH), 6.96-6.95 (m, 1H, ArH),
6.85 (dd, 1H, J1 = 8.4 Hz, J2 = 1.6 Hz, ArH), 3.85 (s, 3H, OCH3),
3.73 (s, 3H, OCH3), 1.86 (s, 3H, CH3). 13C nmr: ꢀ 161.8, 153.3,
151.3, 150.7, 150.3, 149.0, 148.5, 145.7, 139.1, 129.6, 128.6,
126.4, 120.8, 120.5, 114.4, 112.4, 111.3, 104.4, 56.1, 56.0, 14.5.
Anal. calcd for C23H19N5O4: C, 64.33; H, 4.46; N, 16.31. Found:
C, 64.26; H, 4.44; N, 16.24.
1H, NH), 11.22 (s, 1H, NH), 8.25 (d, 2H, J = 8.4 Hz, ArH), 7.69
(d, 2H, J = 8.0 Hz, ArH), 7.56 (t, 2H, J = 8.0 Hz, ArH), 7.38-
7.32 (m, 3H, ArH), 1.82 (s, 3H, CH3). 13C nmr: ꢀ 161.7, 152.9,
150.3, 150.0, 149.4, 145.0, 138.7, 135.5, 130.7, 130.0, 129.3,
126.2, 121.4, 120.6, 113.5, 103.9, 14.4. Anal. calcd for
C21H14BrN5O2: C, 56.27; H, 3.15; N, 15.62. Found: C, 56.20; H,
3.18; N, 15.69.
3-Methyl-4-(4-nitrophenyl)-1-phenyl-1H-pyrazolo-[4',3':5,
6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4d). ir (KBr):
1
3195 (NH), 1729 (C=O), 1686 (C=O) cm-1; H nmr: ꢀ 11.91 (s,
1H, NH), 11.31 (s, 1H, NH), 8.36 (d, 2H, J = 8.8 Hz, ArH), 8.25
(d, 2H, J = 8.0 Hz, ArH), 7.68 (d, 2H, J = 8.4 Hz, ArH), 7.57 (t,
2H, J = 8.0 Hz, ArH), 7.38 (t, 1H, J = 7.6 Hz, ArH), 1.79 (s, 3H,
CH3). 13C nmr: ꢀ 161.8, 152.9, 150.4, 150.1, 148.1, 147.4, 144.8,
143.6, 138.6, 129.4, 126.3, 122.9, 120.7, 113.1, 104.5, 103.9,
14.7. Anal. calcd for C21H14N6O4: C, 60.87; H, 3.41; N, 20.28.
Found: C, 60.80; H, 3.38; N, 20.22.
4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo-[4',
3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4e). ir
4-(4-Hydroxy-3-nitrophenyl)-3-methyl-1-phenyl-1H-pyraz-
olo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4k).
1
(KBr): 3190 (NH), 1722 (C=O), 1703 (C=O) cm-1; H nmr: ꢀ
1
11.77 (s, 1H, NH), 11.16 (s, 1H, NH), 8.25 (d, 2H, J = 8.0 Hz,
ArH), 7.55 (t, 2H, J = 7.6 Hz, ArH), 7.34 (t, 1H, J = 7.6 Hz,
ArH), 7.26 (d, 2H, J = 8.0 Hz, ArH), 7.03 (d, 2H, J = 8.0 Hz,
ArH,), 3.85 (s, 3H, OCH3), 1.81 (s, 3H, CH3). 13C nmr: ꢀ 161.6,
159.2, 153.0, 151.1, 150.4, 150.0, 145.3, 138.8, 129.3, 129.2,
128.0, 126.1, 120.6, 114.2, 113.1, 104.1, 55.3, 14.4. Anal. calcd
for C22H17N5O3: C, 66.16; H, 4.29; N, 17.53. Found: C, 66.10; H,
4.24; N, 17.47.
ir (KBr): 3209 (NH), 1721 (C=O), 1706 (C=O) cm-1; H nmr: ꢀ
11.84 (s, 1H, NH), 11.29 (s, 1H, OH), 11.26 (s, 1H, NH), 8.25
(d, 2H, J = 8.0 Hz, ArH), 7.92-7.91 (m, 1H, ArH), 7.58-7.54 (m,
3H, ArH), 7.36 (t, 1H, J = 7.6 Hz, ArH), 7.24 (d, 1H, J = 8.8 Hz,
ArH), 1.92 (s, 3H, CH3). 13C nmr: ꢀ 162.1, 153.3, 152.3, 150.6,
150.4, 148.5, 145.3, 139.0, 136.7, 135.3, 129.7, 127.1, 126.5,
125.0, 120.9, 118.8, 114.2, 104.5, 15.0. Anal. calcd for
C21H14N6O5: C, 58.61; H, 3.28; N, 19.53. Found: C, 58.52; H,
3.24; N, 19.59.
3-Methyl-4-(4-methylphenyl)-1-phenyl-1H-pyrazolo-[4',3':
5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4f). ir (KBr):
3-Methyl-1-phenyl-4-thien-2-yl-1H-pyrazolo[4',3':5,6]pyr-
ido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4l). ir (KBr): 3183
1
3185 (NH), 1723 (C=O), 1708 (C=O) cm-1; H nmr: ꢀ 11.77 (s,
1
(NH), 1715 (C=O), 1698 (C=O) cm-1; H nmr: ꢀ 11.82 (s, 1H,
1H, NH), 11.16 (s, 1H, NH), 8.25 (d, 2H, J = 8.0 Hz, ArH), 7.55
(t, 2H, J = 8.0 Hz, ArH), 7.34 (t, 1H, J = 7.6 Hz, ArH), 7.29 (d,
2H, J = 8.0 Hz, ArH), 7.21 (d, 2H, J = 8.0 Hz, ArH), 2.42 (s, 3H,
CH3), 1.76 (s, 3H, CH3). 13C nmr: ꢀ 161.6, 152.9, 151.2, 150.4,
150.0, 145.2, 138.8, 137.2, 133.2, 129.3, 128.2, 127.6, 126.0,
120.5, 113.9, 104.0, 21.2, 18.7. Anal. calcd for C22H17N5O2: C,
68.92; H, 4.47; N, 18.27. Found: C, 68.98; H, 4.44; N, 18.20.
3-Methyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo-[4',3':5,
6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4g). ir (KBr):
NH), 11.25 (s, 1H, NH), 8.24 (d, 2H, J = 8.0 Hz, ArH), 7.80-
7.79 (m, 1H, ArH), 7.56 (t, 2H, J = 8.0 Hz, ArH), 7.36 (t, 1H, J
= 7.6 Hz, ArH), 7.21-7.19 (m, 1H, ArH), 7.13-7.12 (m, 1H,
ArH), 1.92 (s, 3H, CH3). 13C nmr: ꢀ 161.2, 152.9, 150.3, 149.8,
145.1, 143.7, 138.6, 135.0, 129.3, 127.6, 127.4, 126.8, 126.2,
120.6, 114.8, 105.3, 18.7. Anal. calcd for C19H13N5O2S: C,
60.79; H, 3.49; N, 18.66; S, 8.54. Found: C, 60.71; H, 3.44; N,
18.59; S, 8.62.
1
3184 (NH), 1710 (C=O), 1695 (C=O) cm-1; H nmr: ꢀ 11.89 (s,
4-(4-Fluorophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4m). ir
1H, NH), 11.29 (s, 1H, NH), 8.37 (d, 1H, J = 7.6 Hz, ArH), 8.26
(t, 3H, J = 8.0 Hz, ArH), 7.88 (d, 1H, J = 7.2 Hz, ArH), 7.80 (t,
1H, J = 8.0 Hz, ArH), 7.57 (t, 2H, J = 7.6 Hz, ArH), 7.36 (t, 1H,
J = 7.6 Hz, ArH), 1.79 (s, 3H, CH3). 13C nmr: ꢀ 162.2, 153.2,
150.7, 150.4, 147.9, 147.7, 145.1, 138.9, 138.2, 134.9, 129.7,
129.6, 126.5, 123.4, 123.2, 120.9, 113.8, 104.4, 14.7. Anal. calcd
for C21H14N6O4: C, 60.87; H, 3.41; N, 20.28. Found: C, 60.94; H,
3.44; N, 20.19.
1
(KBr): 1712 (C=O), 1667 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H, J
= 8.0 Hz, ArH), 7.60 (t, 2H, J = 8.0 Hz, ArH), 7.41-7.32 (m, 5H,
ArH), 3.71 (s, 3H, NCH3), 3.19 (s, 3H, NCH3), 1.82 (s, 3H,
CH3). 13C nmr: ꢀ 161.2, 151.1, 151.0, 150.5, 149.3, 145.3, 138.5,
132.0, 128.8, 128.6, 125.8, 120.3, 115.2, 114.9, 114.0, 103.7,
30.4, 28.2, 14.1. Anal. calcd for C23H18FN5O2: C, 66.50; H, 4.37;
N, 16.86. Found: C, 66.44; H, 4.35; N, 16.74.
4-(4-Chlorophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4n). ir
3-Methyl-1,4-diphenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]-
pyrimidine-5,7(6H,8H)-dione (4h). ir (KBr): 3183 (NH), 1712
(C=O), 1697 (C=O) cm-1; 1H nmr: ꢀ 11.80 (s, 1H, NH), 11.18 (s,
1H, NH), 8.26 (d, 2H, J = 8.0 Hz, ArH), 7.56 (t, 2H, J = 8.0 Hz,
ArH), 7.49-7.48 (m, 3H, ArH), 7.37-7.33 (m, 3H, ArH), 1.75 (s,
3H, CH3). 13C nmr: ꢀ 161.9, 153.3, 150.7, 145.5, 139.0, 136.5,
129.6, 128.0, 127.9, 126.5, 126.4, 125.3, 123.7, 120.9, 114.1,
1
(KBr): 1708 (C=O), 1664 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H, J
= 8.4 Hz, ArH), 7.63-7.57 (m, 5H, ArH), 7.39-7.37 (m, 2H,
ArH), 3.72 (s, 3H, NCH3), 3.19 (s, 3H, NCH3), 1.85 (s, 3H,
CH3). Anal. calcd for C23H18ClN5O2: C, 63.96; H, 4.20; N, 16.22.
Found: C, 63.90; H, 4.23; N, 16.29.

Sep-Oct 2008
Pot, Atom and Step Economic Synthesis of Fused Three Heterocyclic Ring Compounds
1309
4-(4-Bromophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4o). ir
calcd for C23H17Cl2N5O2: C, 59.24; H, 3.67; N, 15.02. Found: C,
59.18; H, 3.63; N, 15.10.
1
(KBr): 1709 (C=O), 1664 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H, J
4-(1,3-Benzodioxol-5-yl)-3,6,8-trimethyl-1-phenyl-1H-pyr-
azolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione
(4v). ir (KBr): 1711 (C=O), 1668 (C=O) cm-1; 1H nmr: ꢀ 8.25 (d,
2H, J = 8.4 Hz, ArH), 7.60 (t, 2H, J = 8.0 Hz, ArH), 7.36 (t, 1H,
J = 7.6 Hz, ArH), 7.04 (d, 1H, J = 8.0 Hz, ArH), 6.92 (s, 1H,
ArH), 6.77 (d, 1H, J = 8.0 Hz, ArH), 6.15-6.14 (m, 2H, CH2),
3.70 (s, 3H, NCH3), 3.20 (s, 3H, NCH3), 1.93 (s, 3H, CH3). 13C
nmr: ꢀ 160.4, 151.2, 151.1, 150.9, 149.3, 147.4, 147.3, 145.5,
138.6, 129.5, 128.8, 125.7, 120.2, 120.1, 114.2, 107.9, 107.8,
103.8, 101.1, 30.3, 28.2, 14.1. Anal. calcd for C24H19N5O4: C,
65.30; H, 4.34; N, 15.86. Found: C, 65.23; H, 4.38; N, 15.78.
4-(4-Hydroxy-3-nitrophenyl)-3-methyl-1-phenyl-1H-pyraz-
olo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4w).
ir (KBr): 1714 (C=O), 1667 (C=O) cm-1; 1H nmr: ꢀ 11.29 (s, 1H,
OH), 8.22 (d, 2H, J = 8.0 Hz, ArH), 7.91-7.90 (m, 1H, ArH),
7.59-7.51 (m, 3H, ArH), 7.34 (t, 1H, J = 7.6. Hz, ArH), 7.26 (d,
1H, J = 8.4 Hz, ArH), 3.69 (s, 3H, NCH3), 3.18 (s, 3H, NCH3),
1.90 (s, 3H, CH3). 13C nmr: ꢀ 160.3, 152.0, 151.3, 150.9, 149.2,
148.5, 145.0, 138.5, 136.5, 134.7, 129.5, 127.2, 126.1, 124.3,
120.1, 118.7, 113.5, 104.5, 30.5, 28.2, 14.6. Anal. calcd for
C23H18N6O5: C, 60.26; H, 3.96; N, 18.33. Found: C, 60.33; H,
3.98; N, 18.39.
= 8.0 Hz, ArH), 7.71 (d, 2H, J = 8.0 Hz, ArH), 7.61 (t, 2H, J =
8.0 Hz, ArH), 7.38 (t, 1H, J = 7.6 Hz, ArH), 7.31 (d, 2H, J = 8.4
Hz, ArH), 3.72 (s, 3H, NCH3), 3.19 (s, 3H, NCH3), 1.85 (s, 3H,
CH3). Anal. calcd for C23H18BrN5O2: C, 58.00; H, 3.81; N,
14.70. Found: C, 58.08; H, 3.85; N, 14.64.
3,6,8-Trimethyl-4-(4-methylphenyl)-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4p). ir
1
(KBr): 1709 (C=O), 1665 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H, J
= 8.4 Hz, ArH), 7.60 (t, 2H, J = 8.0 Hz, ArH), 7.37 (t, 1H, J =
7.6 Hz, ArH), 7.31 (d, 2H, J = 8.0 Hz, ArH), 7.21 (d, 2H, J = 8.0
Hz, ArH), 3.71 (s, 3H, NCH3), 3.18 (s, 3H, NCH3), 2.44 (s, 3H,
CH3), 1.80 (s, 3H, CH3). 13C nmr: ꢀ 160.6, 152.0, 151.2, 151.0,
149.3, 145.7, 138.6, 137.7, 133.2, 128.8, 128.5, 126.5, 125.7,
120.3, 114.1, 103.7, 30.3, 28.2, 21.3, 14.0. Anal. calcd for
C24H21N5O2: C, 70.06; H, 5.14; N, 17.02. Found: C, 70.00; H,
5.16; N, 17.09.
3,6,8-Trimethyl-4-(3-nitrophenyl)-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4q). ir
1
(KBr): 1716 (C=O), 1667 (C=O) cm-1; H nmr: ꢀ 8.39 (d, 1H, J
= 7.2 Hz, ArH), 8.26 (d, 3H, J = 8.0 Hz, ArH), 7.87-7.81 (m,
2H, ArH), 7.62 (t, 2H, J = 8.0 Hz, ArH), 7.39 (t, 1H, J = 7.2 Hz,
ArH), 3.74 (s, 3H, NCH3), 3.19 (s, 3H, NCH3), 1.82 (s, 3H,
CH3). 13C nmr: ꢀ 160.5, 151.6, 150.9, 149.4, 148.0, 147.6, 144.5,
138.3, 137.9, 133.0, 128.9, 126.0, 125.3, 123.0, 122.1, 120.4,
113.4, 103.4, 30.4, 28.2, 14.3. Anal. calcd for C23H18N6O4: C,
62.44; H, 4.10; N, 19.00. Found: C, 62.49; H, 4.13; N, 19.06.
4-(3-Bromophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4r). ir
3,6,8-Trimethyl-1-phenyl-4-thien-2-yl-1H-pyrazolo-[4',3':
5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4x). ir (KBr):
1
1710 (C=O), 1660 (C=O) cm-1; H nmr: ꢀ 8.28-8.27 (m, 2H,
ArH), 7.58-7.56 (m, 3H, ArH), 7.35-7.33 (m, 3H, ArH), 3.66 (s,
3H, NCH3), 3.20 (s, 3H, NCH3), 1.91 (s, 3H, CH3). Anal. calcd
for C21H17N5O4S: C, 62.52; H, 4.25; N, 17.36; S, 7.95. Found: C,
62.45; H, 4.28; N, 17.43; S, 7.85.
1
(KBr): 1713 (C=O), 1667 (C=O) cm-1; H nmr: ꢀ 8.26-8.24 (m,
Acknowledgements We are grateful to the financial support
from the National Natural Science Foundation of China (No.
20672090), the Natural Science Foundation of the Jiangsu
Province (No. BK2006033), Six Kinds of Professional Elite
Foundation of the Jiangsu Province (No. 06-A-039).
2H, ArH), 7.73-7.70 (m, 1H, ArH), 7.63-7.59 (m, 3H, ArH),
7.50-7.46 (m, 1H, ArH), 7.40-7.35 (m, 2H, ArH), 3.72 (s, 3H,
NCH3), 3.20 (s, 3H, NCH3), 1.84 (s, 3H, CH3). Anal. calcd for
C23H18BrN5O2: C, 58.00; H, 3.81; N, 14.70. Found: C, 58.11; H,
3.84; N, 14.59.
4-(2-Chlorophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo-
[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4s). ir
REFERENCES
1
(KBr): 1713 (C=O), 1666 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H, J
= 8.4 Hz, ArH), 7.65-7.59 (m, 3H, ArH), 7.51-7.48 (m, 2H,
ArH), 7.40-7.36 (m, 2H, ArH), 3.73 (s, 3H, NCH3), 3.21 (s, 3H,
NCH3), 1.82 (s, 3H, CH3). Anal. calcd for C23H18ClN5O2: C,
63.96; H, 4.20; N, 16.22. Found: C, 63.84; H, 4.26; N, 16.15.
3,6,8-Trimethyl-1,4-diphenyl-1H-pyrazolo[4',3':5,6]pyrido-
[2,3-d]pyrimidine-5,7(6H,8H)-dione (4t). ir (KBr): 1715
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1
(C=O), 1670 (C=O) cm-1; H nmr: ꢀ 8.21 (d, 2H, J = 7.6 Hz,
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7.34-7.27 (m, 3H, ArH), 3.67 (s, 3H, NCH3), 3.14 (s, 3H,
NCH3), 1.72 (s, 3H, CH3). 13C nmr: ꢀ 160.5, 151.6, 151.2, 151.0,
149.3, 145.5, 138.6, 136.3, 128.8, 128.0, 127.8, 126.6, 125.7,
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4-(2,4-Dichlorophenyl)-3,6,8-trimethyl-1-phenyl-1H-pyraz-
olo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (4u).
1
ir (KBr): 1710 (C=O), 1663 (C=O) cm-1; H nmr: ꢀ 8.25 (d, 2H,
J = 8.0 Hz, ArH), 7.85-7.84 (m, 1H, ArH), 7.61 (t, 3H, J = 8.0
Hz, ArH), 7.43-7.38 (m, 2H, ArH), 3.72 (s, 3H, NCH3), 3.21 (s,
3H, NCH3), 1.89 (s, 3H, CH3). 13C nmr: ꢀ 160.1, 151.4, 150.9,
149.5, 146.3, 144.7, 138.5, 134.7, 133.9, 132.1, 130.6, 128.6,
127.4, 126.4, 120.5, 114.7, 112.6, 104.5, 30.5, 28.2, 13.5. Anal.

1310
F. Shi, D. Zhou, S. Tu, C. Li, L. Cao, Q. Shao
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