Synthesis of some new 6,8-disubstituted 7,8-dihydropyrimido[2,3:4,3] pyrazolo[1,5-a]pyrimidines and 6,7,8-trisubstituted pyrimido[2,3:4,3]pyrazolo[1, 5-a]pyrimidine derivatives

Article abstract of DOI:10.1002/jccs.200300043

Cyclization of 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 4 with excess of 85% hydrazine hydrate afforded the 3-amino-4-methyl-6- phenylpyrazolo[3,4-d]pyrimidine 5, which can react with appropriate Mannich base derivatives 13a-c and chalcones 27a,b to yield the corresponding 6,8-disubstituted 7,8-dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines 15a-c and 30a,b, respectively. On the other hand, the 6,7,8-trisubstituted pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine derivatives 8a-g, 20a-e, 36 and 38 were obtained by treatment of compound 5 with appropriate 1,3-diketones 6a-g, 3-dimethylamino-1-(substituted)prop-2-enones 18a-e, 3-aminocrotononitrile 3, and ethoxymethylenemalononitrile 37 under acidic condition, respectively.

Full text of DOI:10.1002/jccs.200300043

Journal of the Chinese Chemical Society, 2003, 50, 283-296
283
Synthesis of Some New 6,8-Disubstituted
7,8-Dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines and
6,7,8-Trisubstituted Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine Derivatives
Yuh-Wen Ho* (
Department of Textile Engineering, Nanya Institute of Technology, Chung-Li, Taiwan 32034, R.O.C.
) and Chia-Tseng Yao (
)
Cyclization of 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 4 with excess of 85% hy-
drazine hydrate afforded the 3-amino-4-methyl-6-phenylpyrazolo[3,4-d]pyrimidine 5, which can react with
appropriate Mannich base derivatives 13a-c and chalcones 27a,b to yield the corresponding 6,8-disubstituted
7,8-dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines 15a-c and 30a,b, respectively. On the other hand,
the 6,7,8-trisubstituted pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine derivatives 8a-g, 20a-e, 36 and 38 were
obtained by treatment of compound 5 with appropriate 1,3-diketones 6a-g, 3-dimethylamino-1-(substi-
tuted)prop-2-enones 18a-e, 3-aminocrotononitrile 3, and ethoxymethylenemalononitrile 37 under acidic con-
dition, respectively.
Keywords: 5-Cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine; 3-Amino-6-phenylpyrazolo-
[3,4-d]pyrimidine; 6,8-Disubstituted 7,8-dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimi-
dines; 6,7,8-Trisubstituted pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines.
INTRODUCTION
Some pyrazole derivatives possess biological and phar-
been reported. In a preceding paper23 we have described the
synthesis of 3-(2-amino-5,7-disubstituted-pyrazolo[1,5-a]-
pyrimidine-3-yl)azo-thieno[2,3-b]pyridines from 3-amino-
2-cyano-thieno[2,3-b]pyridine. In continuation of our stud-
ies, we report here the synthesis of some new 6,8-disub-
stituted 7,8-dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyr-
imidines and 6,7,8-trisubstituted pyrimido[2,3:4,3]pyra-
zolo[1,5-a]pyrimidines by making use of 5-cyano-1,6-dihy-
dro-4-methyl-2-phenyl-6-thioxopyrimidine 4 as the starting
material.
macological activites1-8 and also find application in dyes.9-10
The interesting biological activities reported for pyrazolo-
[1,5-a]pyrimidines have stimulated chemists to develop the
chemistry of this class of compounds.11-14 Robins and co-
workers reported that certain 3-substituted pyrazolo[1,5-
a]pyrimidines inhibit the metabolism schistosomiasis in
snails.15-16 Preliminary tests of some 2-aminopyrazolo[1,5-
a]pyrimidines showed strong antischistosomiasis.17-18 In
view of these it was considered of interest to synthesize some
new pyrazolo[1,5-a]pyrimidine derivatives. The most com-
mon methods for the preparation of pyrazolo[1,5-a]pyrimi-
dine derivatives are cyclocondensations of 5-aminopyrazoles
with b-bifunctional reagents.19-20 Hussein21 et al. have re-
cently described the synthesis of 6-amino-7-substituted pyr-
azolo[1,5-a]pyrimidines from arylidenemalononitrile with
5-amino-4-cyano-3-phenylpyrazole. The 7-(4-chlorophen-
yl)-2-substituted-1H-pyrazolo[1,5-a]pyrimidines22 also have
been prepared from 5-amino-3-phenyl-1H-pyrazole with 3-
(4-chlorophenyl)-2-(N,N-dimethylamino)-methylene-3-
oxopropanenitrile. Although a number of papers have been
published concerning the synthesis of pyrazolo[1,5-a]pyrimi-
dine derivatives, those containing a triheterocyclic system of
pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines have not yet
RESULTS AND DISCUSSION
The required compound 5-cyano-1,6-dihydro-4-meth-
yl-2-phenyl-6-thioxopyrimidine 4 was prepared by treating
benzoylisothiocyanate with 3-aminocrotononitrile 3 in re-
fluxing dioxane.24 The reaction of thioxopyrimidine 4 with
excess of 85% hydrazine hydrate in refluxing ethanol for 24 h
gave the corresponding 3-amino-4-methyl-6-phenylpyra-
zolo[3,4-d]pyrimidine 5 (Scheme I). The structure of 5 was
established by examining spectral data and elemental analy-
sis. The IR spectrum of compound 5 indicated the absence of
the CºN and C=S absorption bands, and contains the charac-
teristic absorption bands at 3424, 3307 cm-1 for the NH2
group and at 3213 cm-1 for the NH group. The 1H NMR spec-

284 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
Scheme I
CH3
C=C
H
dioxane
COCl + NH4SCN
CONCS
+
CN
NH2
2
1
3
dioxane
reflux
CH3
CH3
CN
S
NH2
N
N
.
NH2NH2 H2O
N
H
N
ethanol reflux
N
N
H
4
5
CH3
N
CH3
N
R
1
X
N
R1
X
N
C
CH COOH
3
N
N
5 + R1COCHCOR
CX
2
N
reflux
-H O
2
N
H
N
N
C
6a-g
HO
R
2
R2
8a-g
7
a
b
c
d
e
f
g
6,8
R1
CH3 CH3 CF3 CH3 CF3 CF3 CF3
CH3 CH3 CF3
R2
O
S
H
Cl
H
X
H
H
H
H
CH
3
N
CH
3
CH COOH/HCl
3
N
+
CH3COCH2CH(OCH3)2
5
N
H
reflux
N
N
9
-H O
2
OCH
3
-CH OH
3
-CH OH
3
(CH3O)2CHCH2CH(OCH3)2
11
CH3
N
CH3
C H OH/HCl
N
8
2
5
N
8
6
7
CH3
N
N
reflux
7
N
N
N
-4 CH OH
3
N
N
12
10
trum (DMSO-d6) showed a broad singlet at d 5.62 (2H, br) as-
signed to the NH2 protons, a broad singlet at d 12.44 (H, br)
assigned to the NH proton and a multiplet at d 8.43-7.48 (5H,
m) assigned to the phenyl protons. The reaction of 5 with ap-
propriate 1,3-diketones 6a-g in refluxing glacial acetic acid
yielded the corresponding 4-methyl-6,7,8-trisubstituted-2-
phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines 8a-g
(Scheme I). The reaction probably involves the condensation
of the 3-NH2 of the pyrazolo[3,4-d]pyrimidine ring with the
carbonyl group, followed by dehydration, and subsequent
cyclization with loss of water.25-27 The IR spectra of com-
pounds 8a-g indicated the absence of the NH2 and NH
groups. The 1H NMR spectra (CDCl3) of compounds 8a and
8c-g revealed a singlet at d 8.71-6.91 (1H, s), which were
readily assigned to the hydrogen attached at C7 of the pyr-
imido[2,3:4,3]pyrazolo[1,5-a]pyrimidine ring, respectively.
Under similar reaction conditions, condensation of
compound 5 with 4,4-dimethoxy-2-butanone 9 in refluxing
glacial acetic acid/hydrochloride afforded 4,6-dimethyl-2-
phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine 10. We
propose that the first step of the mechanism involves the con-
densation of the 3-NH2 of the pyrazolo[3,4-d]pyrimidine ring
with the carbonyl group, followed by dehydration, and subse-
quent nucleophilic cyclization with the loss of methanol28

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 285
(Scheme I). The 1H NMR spectrum (DMSO-d6) of compound
10 revealed two doublets at d 7.14 (1H, d) and 8.80 (1H, d) as-
signed to the 7-H and 8-H of pyrimido[2,3:4,3]pyrazolo[1,5-
a]pyrimidine ring, respectively. In addition, 4-dimethyl-2-
phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine 12 was
also obtained from the reaction of compound 5 with malon-
aldehydebis(dimethylacetal) 11 under acidic condition. The
1H NMR spectrum (DMSO-d6) of compound 12 displayed
signals at d 7.55-7.52 (1H, m), 8.87 (1H, d) and 9.27 (1H, d),
which were readily assigned to the hydrogen attached at C7,
C8 and C6 of the pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine
ring, respectively.
dines 15a-c (Scheme II). Compounds 15a-c were assumed to
be formed via condensation of the 3-NH2 of the pyrazolo-
[3,4-d]pyrimidine ring with the carbonyl group, followed by
dehydration, and subsequent nucleophilic cyclization with
loss of N,N-dimethylamine hydrochloride.28-30 The structures
of compounds 15a-c were established on the basis of their el-
1
emental analysis and spectral data. The H NMR spectra
(DMSO-d6 or CDCl3) revealed triplets at d 3.53 (2H, t) and d
4.63 (2H, t) for compound 15a, at d 3.31 (2H, t) and d 4.57
(2H, t) for compound 15b and at d 3.36 (2H, t) and d 4.55 (2H,
t) for compound 15c. These triplets were assigned to the
methylene protons at the 7- and 8-position of the pyrimido-
[2,3:4,3]pyrazolo[1,5-a]pyrimidine ring, respectively. Com-
pound 15b showed signals at d 6.61 (1H, m), 7.23 (1H, d) and
7.65 (1H, d), which were assigned to the protons of furyl moi-
ety. Compound 15c also showed signals at d 7.10 (1H, m) and
On the other hand, when compound 5 and Mannich
bases 13a-c were heated at 200 °C in the absence of solvent
they produced the corresponding 6-substituted-4-methyl-2-
phenyl-7,8-dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimi-
Scheme II
CH3
N
R
N
H
C
condensation
-H O
N
.
CH2
CH2
5 + RCOCH2CH2N(CH3)2 HCl
N
2
N
13a-c
.
N(CH3)2 HCl
14
nucleophilic
cyclization
.
-HN(CH ) HCl
3 2
a
b
c
13,15
R
O
S
CH3
N
N
R
N
7
N
N
8
15a-c
(CH3O)2CHN(CH3)2
+
RCOCH3
16a-f
H
N
CH3
N
17
CH
CH
N
CH COOH
3
N
xylene reflux
H
N
reflux
O
C
19a-f
R
5
RCOCH=CHN(CH3)2
19a
18a-f
reflux
CH3
CH COOH/HCl
3
18a-e
CH COOH/HCl
3
N
6
reflux
N
N
7
N
N
R
20a-e
a
b
c
d
e
f
a
b
c
d
e
16,18,19
R
20
R
N
N
O
S
N
N
O
S

286 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
7.61 (2H, m) assigned to the protons of thienyl moiety.
Furthermore, the reactions of compound 5 with enami-
nones 18a-f were also investigated. Thus, it has been found
that compound 5 with 3-dimethylamino-1-phenylprop-2-
enone 18a in refluxing glacial acetic acid gave a pale yellow
product of molecular formula C21H17N5O (31% yield, mp 277
°C). Spectroscopic analyses revealed that 3-(1-phenylprop-
2-enone-3-yl)amino-4-methyl-6-phenylpyrazolo[3,4-d]pyr-
imidine 19a was obtained (Scheme II). The IR spectrum of
the reaction product showed the characteristic absorption
band at 3125 cm-1 for the NH group and at 1630 cm-1 for the
carbonyl group (C=O). The 1H NMR spectrum (DMSO-d6) of
the reaction product, which showed two doublets at d 6.38
(1H, d) and 7.88 (1H, d) assigned to the -CH=CH- of 1-phen-
ylprop-2-enone moiety, and two signals at d 12.58 (1H, s) and
13.51 (1H, br) assigned to the NH proton, was also confirmed
by the mass spectrum m/z 355 (M+) (Table 4). Under similar
reaction condition, treatment of compound 5 with enami-
nones 18b-f afforded the corresponding 3-(1-substituted-
prop-2-enone-3-yl)amino-pyrazolo[3,4-d]pyrimidines
19b-f, respectively (Scheme II).
Next, reaction of compound 5 with 2-cyano-3-dimeth-
ylamino-1-phenylprop-2-enone 21 in refluxing ethanol in the
presence of catalytic amounts of piperidine afforded the
7-cyano-4-methyl-2,8-diphenylpyrimido[2,3:4,3]pyrazolo-
[1,5-a]pyrimidine 22 (Scheme III). The structure of com-
pound 22 was confirmed on the basis of its elemental analy-
sis, spectral data, and an independent synthesis by reacting an
equimolar amount of 3-N,N-dimethylaminomethyleneamino-
4-methyl-6-phenylpyrazolo[3,4-d]pyrimidine 23 with ben-
zoylacetonitrile 24 in glacial acetic acid under reflux. The IR
spectrum of compound 22 showed the characteristic absorp-
tion band at 2220 cm-1 for the CºN group. In addition, the
1
structure was supported by the H NMR spectrum (DMSO-
d6), which showed the expected proton signal at d 9.11 (1H, s)
assigned to the 6-H of pyrimido[2,3:4,3]pyrazolo[1,5-a]pyr-
imidine ring and a multiplet at d 7.91-7.30 (10H, m) assigned
to the phenyl protons.
Moreover, attempted preparation of compound 20a via
condensation of compound 5 with cinnamaldehyde 25 failed.
Only 4-methyl-2-phenyl-3-(cinnamylideneamino)-pyrazolo-
[3,4-d]pyrimidine 26 was obtained (Scheme III). The IR
spectrum of compound 26 showed the characteristic absorp-
tion band at 3124 cm-1 for the NH group. The 1H NMR spec-
trum (DMSO-d6) of compound 26 showed signals at d 8.92
(1H, d) and 9.67 (1H, d), which were assigned to the proton
Ha and Hc of cinnamylidene moiety, respectively, and a multi-
plet at d 8.48-7.30 (11H, m) assigned to the phenyl-H and Hb
of the cinnamylidene moiety. The spectrum also revealed a
broad singlet at 11.5 (1H, br) assigned to the NH proton. At-
tempted cyclization of 26 into compound 20a also failed.
Furthermore, the reaction of compound 5 with chalcones
27a,b in refluxing glacial acetic acid gave the corresponding
6-substituted 2,8-diphenyl-4-methyl-7,8-dihydropyrimido-
[2,3:4,3]pyrazolo[1,5-a]pyrimidines 30a,b rather than the
compound 28 (Scheme III). The formation of 30a,b can be
explained by the reaction pathway depicted in Scheme III.
The mechanism involves 1,2-nucleophilic addition of 3-
amino of pyrazolo[3,4-d]pyrimidine ring to the carbonyl
group, followed by dehydration and subsequent nucleophilic
On the other hand, the compound 5 could be cyclized
with enaminones 18a-e under different conditions to form cy-
clic compounds. Thus, the reaction of compound 5 with en-
aminone 18a in refluxing glacial acetic acid/hydrochloride
(1:1) afforded the 2,8-diphenyl-pyrimido[2,3:4,3]pyrazolo-
[1,5-a]pyrimidine 20a. The mass spectrum showed a peak at
m/z 337 (M+, 100). The formation of compound 20a would in-
volve an initial nucleophilic substitution of the exocyclic
amino group in compound 5 to the activated double bond in
enaminone 18a to form the compound 19a, which then under-
goes cyclization and aromatization via loss of water afford-
ing the final product 20a. Elnagdi et al.31-32 have also reported
an analogous reaction in their papers. The structure of com-
pound 20a was further confirmed from an independent syn-
thesis of compound 20a by the reacting of compound 19a in
glacial acetic acid/hydrochloride (1:1) under reflux to afford
a product identical in all respects (mp., mixed mp., TLC and
spectra) (Scheme II). Also, compound 5 reacted with enami-
nones 18b-e to yield products 20b-e under the same reaction
condition. The IR spectra of compounds 20a-e showed ab-
sence of the NH and C=O absorption bands, indicating the
formation of cyclic compounds. In addition, the structures of
1
cyclization.28 The H NMR spectrum (DMSO-d6) of com-
pounds 30a,b revealed a doublet at d 6.92 (2H, d) and 7.10
(2H, d) assigned to the methylene protons at the 7-position of
the pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidine ring, re-
spectively.
1
compounds 20a-e were supported by the H NMR spectra
(DMSO-d6 or CF3COOD), which revealed two downfield
doublets at d 8.25-7.91 (1H, d) and d 9.11-8.98 (1H, d) as-
signed to the 7-H and 6-H of the pyrimido[2,3:4,3]pyra-
zolo[1,5-a]pyrimidine ring, respectively.
On the other hand, heating of compound 5 with excess
of ethyl cyanoacetate 31 at 150 °C afforded the 8-amino-2-
phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidin-6(5H)-
one 32 (Scheme IV). However, treatment of compound 5 with

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 287
Scheme III
CH3
CN
N
ethanol/piperidine
reflux
COC=CHN(CH3)2
5
+
N
N
21
CN
N
N
22
(CH3O)2CHN(CH3)2
xylene
reflux
17
CH3
N
CH COOH
reflux
3
CNCH2CO
N=CHN(CH3)2
H
24
N
N
N
23
CH3
N
N=CH -CH =CH
c
b
a
N
N
H
N
ethanol
(C H ) N
26
2
5 3
+
CH=CHCHO
5
reflux
25
20a
RCOCH=CH
27a,b
CH
N
H
N
3
CH
3
R
OH
H
N
C
N
CH COOH
3
reflux
H
C
N
C
N
-H O
R
C
2
N
N
N
N
H
CH
1,2-nucleophilic
addition
CH
H
29
nucleophilic
cyclization
CH3
a
b
N
27,30
R
CH3
N
N
R
N
N
N
N
N
O
N
R
N
28
30a,b
malonic acid diethyl ester 33 under the same reaction condi-
tions, gave the major product ethyl 2-[(4-methyl-6-phenyl-
pyrazolo[3,4-d]pyrimidinyl-3-yl)amido]ethanoate 35, in-
stead of the expected compound 34, as evidenced by analyti-
cal and spectral data. The structure of compound 35 was as-
signed by its IR specturm [n 3224 cm-1 (NH) and 1740 (CO)
cm-1] and mass spectrum (m/z 339), confirmed by the satis-
factory elemental analysis. In particular, the 1H NMR spec-
trum (CF3COOD) revealed a methylene (d 3.42 (2H, s)) and
ethoxycarbonyl (d 1.50 (3H, t) and 4.53 (2H, q)) groups.
Moreover, when compound 5 was treated with 3-amino-
crotononitrile 3 and ethoxymethylenemalononitrile 37 in gla-
cial acetic acid/ethanol to give the corresponding 6- and
7-substituted 8-amino-2-phenylpyrimido[2,3:4,3]pyrazolo-
[1,5-a]pyrimidine 36 and 38, respectively. Nevertheless,
when compound 5 was reacting with appropriate alkyleth-
oxymethylenes 39a-c under the same reaction conditions, the
compounds 41a-c were smoothly obtained, rather than the
expected compounds 40a-c (Scheme IV). Evidence for the
structure of compounds 41a-c included the IR spectrum,
which revealed a strong absorption band at 3226-3217 cm-1
for the NH group and contains the characteristic absorption
1
band at 1700-1654 cm-1 for the C=O group. The H NMR
spectrum (DMSO-d6) of compounds 41a,b revealed a triplet
at d 1.31, 1.28 (3H, t) and a quartet at d 4.30, 4.27 (2H, q) as-
signed to the ethyl group (CH2CH3), and a broad singlet at
13.43, 13.95 assigned for the NH group, respectively. Also,
1
the H NMR spectrum (DMSO-d6) of compounds 41c re-
vealed two triplets at d 1.31-1.23 (6H, m) and two quartets at
d 4.14 (2H, q) and 4.25 (2H, q) assigned to the two ethyl

288 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
Scheme IV
H
N
CH
N
3
O
N
N
N
NH
2
32
150o
CNCH COOC H
2
2
5
31
CH
3
H
H
CN
CH
N
CH
N
3
3
C=C
C=C
N
N
CH
3
N
NH
2
CN
N
C H O
CN
2
5
37
3
N
N
CN
N
N
5
CrOeOfHlu/exthanol
2
CH
3
CH COOH/ethanol
3
NH
NH
2
38
36
reflux
R
R
1
C=C
CH (COOC H )
2
2
5 2
H
N
CH
N
3
150o
C H O
2
5
COOC H
2 5
33
O
CH COOH
3
/ethanol
39a-c
N
H
N
CH
N
N
3
reflux
N
R
N
O
34
N
R
1
N
H
CH3
N
O
O
2
H
N
N
H
CH3
N
C
N
40a-c
R
N
C
C
N
CH
N
N
H
R
O
C
1
N
35
OC H
O
C
2
5
OC H
2
5
41a-c
a
b
c
39,41
R
H
CH
3
H
CN CN COOC H
R
1
2
5
groups, also confirmed by the mass spectrum m/z 395 (M+).
In conclusion, 3-amino-4-methyl-6-phenylpyrazolo-
[3,4-d]pyrimidine 5 has been shown to be a useful building
block for the synthesis of some new 6,8-disubstituted 7,8-
dihydropyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines 15a-c
and 30a,b. The 6,7,8-trisubstituted pyrimido[2,3:4,3]pyr-
azolo[1,5-a]pyrimidine derivatives 8a-g, 20a-e, 36 and 38
were also prepared from compound 5.
spectra were obtained at 70 eV by using a Finnigan Mat
TSQ-46C spectrometer. Microanalyses for C, H, and N were
performed on a Perkin-Elmer 240 elemental analyzer. N,N-
Dimethyl-2-substitutedethylamine hydrochloride 13a,b,28
3-dimethylamino-1-(substituted)prop-2-enones 18a-c33 and
chalcones 28a,b28 were prepared according to the literature.
5-Cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimi-
dine (4)
To a suspension of ammonium thiocyanate (7.60 g, 0.1
mol) in dry dioxane (100 mL), benzoyl chloride (14 g, 0.1
mol) was added. The reaction mixture was refluxed for 5
mim., then treated with 3-aminocrotononitrile (8.20 g, 0.1
mol). The reaction mixture was refluxed for 2 h and poured
into ice water. The solid product was collected by filtration,
washed with water and recrystallized from ethanol to give 17
g of yellow needle crystals (74% yield), mp 212 °C; IR: n
EXPERIMENTAL SECTION
All melting points were determined in a capillary tube
and are uncorrected. The IR spectra were recorded on potas-
sium bromide pellets on a JASCO FTIR-3 spectrometer. The
1H NMR spectra were obtained on a Bruker AM-300WB
FT-NMR spectrometer and chemical shifts are expressed in d
ppm using TMS as an internal standard. Electron impact mass
1
2225 (CN), 1200 (C=S) cm-1; H NMR (DMSO-d6): d 2.50

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 289
(3H, s, CH3), 2.90 (1H, s, NH), 8.11-8.08, 7.66-7.51 (5H, m,
phenyl-H); MS: 227 (M+).
pounds 8a-g are recorded in Tables 1, 2.
Anal. Calcd. for C12H9N3S: C, 63.43; H, 3.96; N, 18.50.
Found: C, 63.40; H, 4.00; N, 18.60%.
4-Methyl-2-phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyr-
imidine (10)
This compound was synthesized from compound 5
(0.50 g, 2.2 mmol) and 4,4-dimethoxy-2-butanone 9 (0.68 g,
2.2 mmol) in a manner similar to that described for the prepa-
ration of 8a. It was recrystallized from ethanol to give 0.46 g
of pink needles (76% yield), mp 275 °C; 1H NMR (DMSO-
d6): d 2.93 (3H, s, CH3), 3.12 (3H, s, CH3), 7.14 (1H, d, J = 1.0
Hz, 7-H), 8.65-8.60 (5H, m, phenyl-H), 8.80 (1H, d, J = 1.0
Hz, 8-H); MS: 275 (M+, 100), 260 (60), 233 (6), 207 (1), 172
(6), 157 (5), 137 (12), 103 (12), 79 (4), 77 (18), 51 (6).
Anal. Calcd. for C16H13N5: C, 69.82; H, 4.73; N, 25.45.
Found: C, 69.85; H, 4.70; N, 25.46%.
3-Amino-4-methyl-6-phenylpyrazolo[3,4-d]pyrimidine (5)
A mixture of thioxopyrimidine 4 (2.27 g, 0.01 mol) and
hydrazine hydrate (4 mL, 85% solution 0.04 mol) was re-
fluxed in absolute ethanol (10 mL) for 24 h. After cooling, the
resulting solid product was collected by filtration, washed
with water, and the crude product recrystallized from ethanol
to give 1.5 g of pale yellow needles (67% yield), mp 194 °C;
IR: n 3424, 3307 (NH2), 3213 (NH) cm-1; 1H NMR (DMSO-
d6): d 2.78 (3H, s, CH3), 5.62 (2H, br, NH2), 8.43-7.48 (5H, m,
phenyl-H), 12.44 (1H, br, NH); MS: 225 (M+, 100), 210 (25),
196 (8), 170 (8), 154 (2), 128 (1), 122 (23), 104 (21), 93 (9),
77 (19), 52 (5).
4-Methyl-2-phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyr-
imidine (12)
Anal. Calcd. for C12H11N5: C, 64.00; H, 4.92; N, 31.09.
Found: C, 64.00; H, 4.90; N, 31.09%.
To a mixture of compound 5 (0.50 g, 2.2 mmol) and
malonaldehydebis(dimethylacetal) 11 (0.37 g, 2.2 mmol) in
ethanol (5 mL), a few drops of hydrochloride was added. The
reaction mixture was refluxed for 10 h. A crystalline solid
was obtained on cooling. It was recrystallized from etha-
nol/acetic acid to give 0.31 g of pale yellow needles (53%
yield), mp 261 °C; 1H NMR (DMSO-d6): d 3.12 (3H, s, CH3),
7.55-7.52 (1H, m, 7-H), 8.52, 7.44-7.43 (5H, m, phenyl-H),
8.87 (1H, d, J = 1.0, Hz, 8-H), 9.27 (1H, d, J = 1.0, Hz, 6-H);
General procedure of 4-methyl-6,7,8-trisubstituted-2-
phenylpyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines (8a-g)
A mixture of compound 5 (0.50 g, 2.2 mmol) and ap-
propriate 1,3-diketones 6a-g (2.3 mmol) was refluxed in gla-
cial acetic acid (5 mL) for 10 h. A crystalline solid was ob-
tained on cooling. It was recrystallized from an appropriate
solvent. The physical constants and spectral data of com-
Table 1. Physical and Analytical Data of Compounds 8a-g
Yield
%
Element Analysis (%)
Mp
°C
Molecular
Formula
Compound
R1
R2
X
Calcd/Found
H N
(recrystallization solvent)
C
8a
8b
8c
8d
8e
8f
CH3
CH3
CF3
CH3
CH3
CF3
H
Cl
H
H
H
H
H
69
272
280
245
308
177
319
229
C17H15N5
C17H14ClN5
C17H9F6N5
C22H19N5
70.59 5.20 24.22
70.46 5.55 24.22
glacial acetic acid
83
63.06 4.33 21.64
63.16 4.58 21.32
ethanol/chloroform
56
acetone
51.38 2.27 17.63
51.32 2.31 17.40
CH3 phenyl
CF3 furyl
85
75.21 5.41 19.94
75.12 5.36 19.99
DMF/H2O
51
C20H12F3N5O
C22H14F3N5
C20H12F3N5S
69.53 3.31 18.27
69.52 3.32 18.30
DMF/ethanol
CF3 phenyl
CF3 thienyl
45
65.18 3.45 17.28
65.18 3.52 17.22
DMF/H2O
8g
32
58.39 2.91 17.03
58.41 2.89 17.11
DMF/ethanol

290 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
Table 2. Spectral Data of Compounds 8a-g
1H NMR
(CDCl3)
d (ppm)
MS
Compound
(M+)
8a
8b
8c
8d
8e
289
2.61 (3H, s, CH3), 2.85 (3H, s, CH3), 3.07 (3H, s, CH3), 6.91
(1H, s, 7-H), 8.65-8.63, 7.44-7.42 (5H, m, phenyl-H).
323.5 2.73 (3H, s, CH3), 3.05 (3H, s, CH3), 3.08 (3H, s, CH3), 8.63,
7.47 (5H, m, phenyl-H).
397
351
395
3.24 (3H, s, CH3), 8.69-8.68, 7.49 (5H, m, phenyl-H), 7.96 (1H,
s, 7-H).
2.77 (6H, s, 4,6-CH3), 7.78 (1H, s, 7-H), 8.18-8.03, 7.56-7.51
(10H, m, phenyl-H).a
2.77 (3H, s, CH3), 6.74 (1H, m, 4-H of furyl-H), 8.35-8.33, 7.52-
7.49 (5H, m, phenyl-H), 7.81 (1H, d, J = 1.0 Hz, 3-H of furyl-
H), 8.01 (1H, d, J = 1.0 Hz, 5-H of furyl-H), 8.39 (1H, s, 7-H).
8f
405
441
2.08 (3H, s, CH3), 8.10-7.81, 7.58-7.29 (10H, m, phenyl-H),
8.28 (1H, s, 7-H).
8g
2.78 (3H, s, CH3), 7.20-7.18 (1H, m, 4-H of thienyl-H), 8.21-
8.19, 8.00-7.96 (5H, m, phenyl-H), 7.43 (1H, d, J = 1.5 Hz, 3-H
of thienyl-H), 7.44 (1H, d, J = 1.5 Hz, 5-H of thienyl-H), 8.71
(1H, s, 7-H).
a 1H NMR in CF3COOD
MS: 261 (M+, 100), 246 (52), 219 (8), 193 (1), 158 (2), 143
(10), 130 (15), 116 (10), 103 (12), 91 (7), 77 (18), 51 (9).
Anal. Calcd. for C15H11N5: C, 68.97; H, 4.21; N, 26.82.
Found: C, 68.95; H, 4.20; N, 26.66%.
Hz, 8-H), 8.48-7.96, 7.66-7.49 (10H, m, phenyl-H); MS: 339
(M+, 100), 324 (45), 296 (5), 235 (4), 210 (6), 169 (8), 153
(5), 115 (13), 103 (25), 77 (18), 51 (3).
Anal. Calcd. for C21H17N5: C, 74.33; H, 5.01; N, 20.65.
Found: C, 74.21; H, 4.96; N, 20.66%.
N,N-Dimethyl-2-thenoylethylamine Hydrochloride (13c)
This compound was synthesized according to a litera-
ture report.28 It was recrystallized from 95% ethanol to give
3.82 g of colorless needles (58% yield), mp 184 °C; IR: n
6-Furyl-4-methyl-2-phenyl-7,8-dihydropyrimido[2,3:4,3]-
pyrazolo[1,5-a]pyrimidine (15b)
This compound was synthesized from compound 5
(0.30 g, 1.3 mmol) and N,N-dimethyl-2-furoylethylamine
hydrochloride 13b (0.28 g, 1.36 mmol) in a manner similar to
that described for the preparation of 15a. It was recrystallized
from THF/DMF to give 0.23 g of yellow needles (53% yield),
mp 270 °C; 1H NMR (CDCl3): d 2.97 (3H, s, CH3), 3.31 (2H,
t, J = 2.0 Hz, 7-H), 4.57 (2H, t, J = 2.0 Hz, 8-H), 6.61 (1H, m,
4-H of furyl), 7.23 (1H, d, J = 1.0 Hz, 3-H of furyl), 7.65 (1H,
d, J = 1.0 Hz, 5-H of furyl), 8.56-8.54, 7.44-7.42 (5H, m,
phenyl-H); MS: 329 (M+, 100) 314 (38), 300 (5), 236 (3), 209
(2), 183 (3), 153 (8), 104 (6), 93 (11), 77 (22), 65 (9).
Anal. Calcd. for C19H15N5O: C, 69.30; H, 4.56; N,
21.27. Found: C, 69.55; H, 4.50; N, 21.66%.
1
1652 (C=O) cm-1; H NMR (DMSO-d6): d 2.78 (6H, s,
N(CH3)2), 3.57-3.37 (4H, m, CH2CH2), 7.29 (1H, dd, J = 1.0,
1.0 Hz, 4-H of thienyl), 8.08 (2H, m, 3-H, 5-H of thienyl);
MS: 219.5 (M+).
Anal. Calcd. for C9H14NClOS: C, 49.20; H, 6.37; N,
31.09. Found: C, 49.40; H, 6.80; N, 31.22%.
2,6-Diphenyl-4-methyl-7,8-dihydropyrimido[2,3:4,3]pyra-
zolo[1,5-a]pyrimidine (15a)
A mixture of compound 5 (0.30 g, 1.3 mmol) and N,N-
dimethyl-2-benzoylethylamine hydrochloride 13a (0.29 g,
1.36 mmol) was heated at 200 °C for ten minutes. The reac-
tion mixture was left to cool then triturated with ethanol. The
solid product, so formed, was collected by filtration and
recrystallized from dioxane/DMF to give 0.27 g of yellow
needles (60% yield), mp 310 °C; 1H NMR (DMSO-d6): d 2.97
(3H, s, CH3), 3.53 (2H, t, J = 3.0 Hz, 7-H), 4.63 (2H, t, J = 3.0
4-Methyl-2-phenyl-6-thienyl-7,8-dihydropyrimido[2,3:4,3]-
pyrazolo[1,5-a]pyrimidine (15c)
This compound was synthesized from compound 5
(0.30 g, 1.3 mmol) and N,N-dimethyl-2-thenoylethylamine

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 291
hydrochloride 13c (0.30 g, 1.36 mmol) in a manner similar to
that described for the preparation of 15a. It was recrystallized
from THF/DMF to give 0.27 g of yellow needles (59% yield),
mp 292 °C; 1H NMR (DMSO-d6): d 2.91 (3H, s, CH3), 3.36
(2H, t, J = 2.0 Hz, 7-H), 4.55 (2H, t, J = 2.0 Hz, 8-H), 7.10
(1H, m, 4-H of thienyl), 7.61 (2H, m, 3-H ,5-H of thienyl),
8.48-8.46, 7.38-7.36 (5H, m, phenyl-H); MS: 345 (M+, 100),
330 (31), 302 (2), 236 (3), 199 (2), 172 (14), 109 (40), 77
(22), 65 (7), 51 (5).
N(CH3)2), 5.56 (1H, d, J = 3.0 Hz, 2-H), 7.59 (2H, d, J = 1.0
Hz, 3-H, 5-H of pyridyl), 7.75 (1H, d, J = 3.0 Hz, 3-H), 8.59
(2H, d, J = 1.0 Hz, 2-H, 6-H of pyridyl); MS: 176 (M+).
Anal. Calcd. for C10H12N2O: C, 68.18; H, 6.81; N,
15.90. Found: C, 68.23; H, 6.80; N, 16.01%.
3-Dimethylamino-1-(4-biphenyl)prop-2-enone (18e)
This compound was synthesized from 4-acetylbiphenyl
16e (1.96 g, 0.01 mol) and dimethylformamide dimethyl-
acetal (1.20 g, 0.01 mol) in a manner similar to that described
for the preparation of 18d. It was recrystallized from ethanol
to give 1.53 g (61% yield) of 18e, mp 101 °C; IR: n 1680
(C=O) cm-1; 1H NMR (CDCl3): d 2.62 (6H, s, N(CH3)2), 5.75
(1H, d, J = 3.0 Hz, 2-H), 7.82 (1H, d, J = 4.0 Hz, 3-H),
8.02-7.95, 7.68-7.60, 7.47-7.33 (9H, m, biphenyl-H); MS:
251 (M+).
Anal. Calcd. for C19H15N5S: C, 66.08; H, 4.34; N,
20.29. Found: C, 66.15; H, 4.30; N, 20.26%.
3-Dimethylamino-1-(4-pyridyl)prop-2-enone (18d)
To a solution of 4-acetylpyridine 16d (1.21 g, 0.01 mol)
in dry xylene (10 mL), dimethylformamide dimethylacetal
(1.20 g, 0.01 mol) was added. The reaction was heated under
reflux for 6 h. The solvent was removed by evaporation under
reduced pressure and the remainder was left to cool. The solid
product so formed was collected by filtration, washed with
petroleum ether (bp 40-60 °C), and the crude product recrys-
tallized from ethanol to give 1.53 g (87% yield) of 18d, mp 89
°C; IR: n 1640 (C=O) cm-1; 1H NMR (CDCl3): d 2.84 (6H, s,
Anal. Calcd. for C17H17NO: C, 81.27; H, 6.77; N, 5.57.
Found: C, 81.23; H, 6.80; N, 5.51%.
3-Dimethylamino-1-(2-pyrazinyl)prop-2-enone (18f)
This compound was synthesized from 2-acetylpyrazine
16f (1.22 g, 0.01 mol) and dimethylformamide dimethyl-
Table 3. Physical and Analytical Data of Compounds 19a-f and 20a-e
Element Analysis (%)
Calcd/Found
Yield
%
Mp
°C
Molecular
Formula
Compound
R1
C
H
N
19a
19b
19c
19d
19e
19f
phenyl
furyl
31
37
52
51
37
35
82
95
98
82
60
277
269
229
261
297
253
257
271
281
270
350
C21H17N5O
C19H15N5O2
C19H15N5OS
C20H16N6O
C27H21N5O
C19H15N7O
C21H15N5
70.98 4.79 19.72
70.98 4.71 19.81
66.09 4.35 20.29
66.08 4.32 20.36
63.16 4.16 19.39
63.46 4.26 19.65
67.41 4.49 23.60
67.51 4.44 23.59
75.17 4.87 16.24
75.14 4.92 16.33
63.87 4.20 27.45
63.46 4.19 27.55
74.77 4.45 20.77
74.46 4.55 20.33
69.72 3.97 21.40
69.79 3.58 21.32
66.47 3.79 20.40
66.32 3.80 20.40
71.00 4.14 24.85
71.12 4.16 24.99
78.45 4.60 16.95
78.52 4.78 16.95
thienyl
pyridyl
biphenyl
Pyrazinyl
phenyl
furyl
20a
20b
20c
20d
20e
C19H13N5O
C19H13N5S
C20H14N6
thienyl
pyridyl
biphenyl
C27H19N5

292 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Table 4. Spectral Data of Compounds 19a-f and 20a-e
Ho and Yao
IR
1H NMR
(DMSO-d6)
d (ppm)
MS
Compound
(KBr)
(M+)
n (cm-1)
19a
355(77), 338(18), 278 (15),
250(100), 223(19), 210(10),
177(5), 153(8), 131(10),
105(61), 77(83), 51(13).
345(100), 327(19), 316(94),
299(51), 288(7), 262(7),
250(93), 225(28), 210(16),
196(7), 158(4), 131(4),
104(61), 77(38), 66(22),
51(12).
3125 (NH),
1630 (C=O)
2.99 (3H, s, CH3), 6.38 (1H, d, J = 2.0 Hz, =CH-), 7.88 (1H, d, J = 2.0
Hz, -CH=), 8.46-7.52 (10H, m, phenyl-H), 12.58 (1H, s, NH), 13.51 (1H,
br, NH).
19b
3120 (NH),
1629 (C=O)
2.94 (3H, s, CH3), 6.13 (1H, d, J = 2.0 Hz, =CH-), 6.70-6.69 (1H, m, 4-H
of furyl), 7.20 (1H, d, J = 1.0 Hz, -CH=), 7.38 (1H, d, J = 1.0 Hz, 3-H of
furyl), 8.00-7.93, 7.51-7.48 (6H, m, phenyl-H and 5-H of furyl), 12.30
(1H, s, NH), 13.48 (1H, br, NH).
19c
19d
361(78), 344(10), 328(18),
277(6), 250(100), 222(14),
210(7), 196(3), 153(5),
137(4), 111(61), 104(30),
77(18), 66(8), 51(4).
356(65), 337(22), 327(18),
278(39), 250(100), 237(42),
223(18), 210(10), 178(17),
153(8), 147(17), 118(8),
104(56), 77(47), 66(11),
51(26).
3122 (NH),
1627 (C=O)
2.94 (3H, s, CH3), 6.25 (1H, d, J = 2.0 Hz, =CH-), 7.23-7.21 (1H, m, 4-H
of thienyl), 7.74 (1H, d, J = 1.0 Hz, -CH=), 7.99-7.92, 7.52-7.51 (6H, m,
phenyl-H and 3-H of thienyl), 7.89 (1H, d, J = 1.0 Hz, 5-H of thienyl),
12.24 (1H, s, NH), 13.48 (1H, br, NH).
3125 (NH),
1663 (C=O)
2.98 (3H, s, CH3), 6.38 (1H, d, J = 2.0 Hz, =CH-), 7.71 (1H, d, J = 2.0
Hz, -CH=), 8.14-8.10, 7.87-7.52 (7H, m, phenyl-H and 3, 5-H of
pyridyl), 8.75 (2H, d, J = 1.0 Hz, 2, 6-H of pyridyl), 12.58 (1H, s, NH),
13.58 (1H, br, NH).
19e
19f
331(75), 412(32), 388 (2),
354(7), 278(9), 250 (188),
237(17), 225(22), 210(10),
181(60), 153(100), 127(9),
104(38), 77(30), 66(10),
51(6).
357(83), 339(42), 328 (5),
303(10), 285(18), 278(74),
250(100), 237 (78), 225(16),
210(18), 182(8), 153(9),
133(17), 120(20), 104(61),
79 (65), 66(15), 52(28).
3124 (NH),
1628 (C=O)
3.19 (3H, s, CH3), 8.13-7.20 (15H, m, phenyl-H, and =CH-), 7.84 (1H, d,
J = 1.0 Hz, -CH=).a
3128 (NH),
1636 (C=O)
3.02 (3H, s, CH3), 7.88 (1H, d, J = 1.0 Hz, =CH-), 8.64-8.43 (5H, m,
phenyl-H), 9.49 (1H, s, 5-H of pyrazinyl), 10.05 (1H, d, J = 1.0 Hz,
-CH=), 10.33 (1H, d, J = 1.0 Hz, 6-H of pyrazinyl), 10.51 (1H, d, J = 1.0
Hz, 3-H of pyrazinyl).a
20a
20b
337(100), 322(4), 295(1),
244(5), 231(15), 206(4),
180(2), 153(2),103(2),
77(1), 52(2).
337(100), 312(62), 299(13),
272(2), 231(2), 209(5),
194(7), 181(4), 163(6),
154(10), 129(3), 103(3),
77(11), 52(5).
3.15 (3H, s, CH3), 7.71-7.67, 7.56-7.53 (5H, m, phenyl-H), 8.57-
8.52, 8.27-8.22 (5H, m, phenyl-H), 7.91 (1H, d, J = 2.4 Hz, 7-H),
9.06 (1H, d, J = 2.4 Hz, 6-H).
3.12 (3H, s, CH3), 7.00-6.97 (1H, m, 4-H of furyl), 8.54-8.50, 7.59-
7.55 (5H, m, phenyl-H), 8.03 (1H, d, J = 2.5 Hz, 7-H), 8.25 (1H, d, J
= 1.0 Hz, 3-H of furyl), 8.36 (1H, d, J = 1.8 Hz, 5-H of furyl), 9.00
(1H, d, J = 2.6 Hz, 6-H).
20c
20d
20e
343(100), 328(20), 301(3),
275(1), 239(6), 198(7),
171(15), 146(6), 121(8),
109(8), 77(16), 52(4).
338(100), 323(9), 285(2),
245(1), 234(13), 207(9),
180(8), 166(5), 129(10),
104(20), 77(22), 52(11).
413(100), 384(1), 336(11),
282(4), 233(34), 204(9),
152(1).
3.12 (3H, s, CH3), 7.47-7.43 (1H, m, 4-H of thienyl), 8.58-8.53, 7.59-
7.55 (5H, m, phenyl-H), 8.25 (1H, d, J = 3.0 Hz, 7-H), 8.40 (1H, d, J
= 2.6 Hz, 3-H of thienyl), 8.69 (1H, d, J = 2.6 Hz, 5-H of thienyl),
8.98 (1H, d, J = 2.6 Hz, 6-H).
3.14 (3H, s, CH3), 8.59-8.54, 7.56-7.53 (5H, m, phenyl-H), 8.03 (1H,
d, J = 2.8 Hz, 7-H), 8.26 (2H, d, J = 3.0 Hz, 3, 5-H of pyridyl), 8.95
(2H, d, J = 3.0 Hz, 2, 6-H of pyridyl), 9.11 (1H, d, J = 2.4 Hz, 6-H).
2.29 (3H, s, CH3), 8.28-8.24, 8.03-7.50 (14H, m, phenyl-H), 8.10
(1H, d, J = 2.5 Hz, 7-H), 9.11 (1H, d, J = 2.5 Hz, 6-H).a
a 1H NMR in CF3COOD

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 293
acetal (1.20 g, 0.01 mol) in a manner similar to that described
for the preparation of 18d. It was recrystallized from ethanol
to give 1.24 g (73% yield) of 18f, mp 138 °C; IR: n 1637
(C=O) cm-1; 1H NMR (CDCl3): d 2.95 (6H, s, N(CH3)2), 6.31
(1H, d, J = 3.0 Hz, 2-H), 7.88 (1H, d, J = 3.0 Hz, 3-H), 8.51
(1H, d, J = 1.0 Hz, 5-H of pyrazinyl), 8.59 (1H, d, J = 1.0 Hz,
6-H of pyrazinyl), 9.27 (1H, s, 3-H of pyrazinyl); MS: 177
(M+).
7-Cyano-4-methyl-2,8-diphenylpyrimido[2,3:4,3]pyrazolo-
[1,5-a]pyrimidine (22)
Method A
To a mixture of compound 5 (0.46 g, 2.0 mmol) and
compound 21 (0.40 g, 2.0 mmol) in ethanol (10 mL), a few
drops of piperidine was added. The reaction mixture was
refluxed for 6 h. The resulting solid product was collected by
filtration and recrystallized from DMF/ethanol to give 0.21 g
of yellow needles (29% yield), mp > 340 °C; IR: n 2220 (CN)
Anal. Calcd. for C9H11N3O: C, 61.01; H, 6.21; N, 23.72.
Found: C, 61.03; H, 6.21; N, 23.70%.
1
cm-1; H NMR (DMSO-d6): d 3.13 (3H, s, CH3), 7.91-7.30
(10H, m, phenyl-H), 9.11 (1H, s, 6-H); MS: 362 (M+).
Anal. Calcd. for C22H14N6: C, 72.92; H, 3.86; N, 23.20.
Found: C, 72.84; H, 3.94; N, 23.36%.
General procedure of 3-(1-substituted prop-2-enone-3-
yl)amino-4-methyl-6-phenylpyrazolo[3,4-d]pyrimidines
(19a-f)
Method B
To a solution of benzoylacetonitrile 24 (0.15 g, 1.0
mmol) in glacial acetic acid (5 mL), 3-N,N-dimethylamino-
methylene-4-methyl-6-phenylpyrazolo[3,4-d]pyrimidine 23
(0.28 g, 1.0 mmol) was added. The reaction mixture was
refluxed for 6 h, and then allowed to stand overnight. The re-
sulting solid product was collected by filtration and recrys-
tallized to give 0.16 g (45% yield).
A mixture of compound 5 (0.30 g, 1.33 mmol) and 3-
dimethylamino-1-(substituted)prop-2-enones 18a-f (1.33
mmol) in glacial acetic acid (10 mL) was refluxed with stir-
ring for 10 h. The reaction mixture was cooled. The resulting
solid product was collected by filtration and recrystallized
from DMF/ethanol. The physical constants and spectral data
of compounds 19a-f are recorded in Tables 3, 4.
3-N,N-Dimethylaminomethyleneamino-4-methyl-6-phenyl-
pyrazolo[3,4-d]pyrimidine (23)
General procedure of 4-methyl-8-substituted-2-phenyl-
pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines (20a-e)
A mixture of compound 5 (0.30 g, 1.33 mmol) and 3-
dimethylamino-1-(substituted)prop-2-enones 18a-e (1.33
mmol) in glacial acetic acid/hydrochloride (1:1 10 mL) was
refluxed with stirring for 10 h. The reaction mixture was
cooled. The resulting solid product was collected by filtration
and recrystallized from DMF/ethanol. The physical constants
and spectral data of compounds 20a-e are recorded in Tables
3, 4.
This compound was synthesized from compound 5
(2.25 g, 0.01 mol) and dimethylformamide dimethylacetal 17
(1.20 g, 0.01 mol) in a manner similar to that described for the
preparation of 18d. It was recrystallized from ethanol to give
2.30 g (82% yield) of 24, mp 235 °C; IR: n 3210 (NH) cm-1; 1H
NMR (DMSO-d6): d 2.84 (3H, s, CH3), 3.02 (6H, s, N(CH3)2),
8.44-8.43, 7.50-7.49 (5H, m, phenyl-H), 8.26 (1H, s, -N=CH),
12.86 (1H, s, NH); MS: 280 (M+, 100), 265 (12), 252 (15),
238 (38), 224 (23), 210 (15), 197 (5), 153 (5), 121 (3). 104
(25), 83 (3), 77 (15), 57 (8), 51 (4).
2-Cyano-3-dimethylamino-1-phenylprop-2-enone (21)
To a suspension of benzoylacetonitrile (1.80 g, 0.01
mol) in dry xylene (10 mL), dimethylformamide dimethyl-
acetal (1.20 g, 0.01 mol) was added. The reaction mixture
was refluxed for 6 h. The solvent was removed by evapora-
tion under reduced pressure and the remainder was left to
cool. The yellowish solid product so formed was collected by
filtration, washed with petroleum ether (bp 40-60 °C) and
dried. Recrystallization from ethanol afforded 1.92 g of yel-
low needles (96% yield), mp 96 °C; IR: n 2192 (CN), 1700
Anal. Calcd. for C15H16N6: C, 64.28; H, 5.71; N, 30.00.
Found: C, 64.23; H, 5.40; N, 30.25%.
4-Methyl-2-phenyl-3-(cinnamylideneamino)-pyrazolo[3,4-
d]pyrimidine (26)
To a mixture of compound 5 (0.30 g, 1.33 mmol) and
cinnamaldehyde 25 (0.18 g, 1.33 mmol) in ethanol (5 mL), a
few drops of triethylamine was added. The reaction mixture
was refluxed for 5 h. The resulting solid product was col-
lected by filtration and recrystallized from ethanol to give
0.24 g (53% yield) of 26, mp 239 °C; IR: n 3124 (NH) cm-1;
1H NMR (DMSO-d6): d 2.90 (3H, s, CH3), 8.48-8.38, 7.75-
7.30 (11H, m, CHb and phenyl-H), 8.92 (1H, d, J = 3.0 Hz,
CHa), 9.67 (1H, d, J = 2.0 Hz, CHc), 11.5 (1H, br, NH); MS:
1
(C=O) cm-1; H NMR (CDCl3): d 3.38 (6H, s, N(CH3)2),
7.42-7.29 (5H, m, phenyl), 7.84 (1H, s, olefinic CH); MS:
200 (M+).
Anal. Calcd. for C12H12N2O: C, 72.00; H, 6.00; N,
14.00. Found: C, 72.23; H, 6.10; N, 14.11%.

294 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
339(M+, 100), 297 (4), 262 (76), 235 (2), 225 (12), 210 (10),
192 (3), 169 (12), 140 (5), 115 (39), 77 (21), 66 (4).
Anal. Calcd. for C21H17N5: C, 74.33; H, 5.01; N, 20.64.
Found: C, 74.54; H, 5.20; N, 20.61%.
MS: 292 (M+).
Anal. Calcd. for C15H12N6O: C, 61.64; H, 4.11; N,
28.76. Found: C, 61.56; H, 4.11; N, 28.66%.
Ethyl 2-[(4-methyl-6-phenylpyrazolo[3,4-d]pyrimidinyl-
3-yl)amido]ethanoate (35)
4-Methyl-2,6,8-triphenyl-7,8-dihydropyrimido[2,3:4,3]-
pyrazolo[1,5-a]pyrimidine (30a)
This compound was synthesized from compound 5
(0.30 g, 1.33 mmol) and malonic acid diethyl ester 33 (1.4 g,
8.8 mmol) in a manner similar to that described for the prepa-
ration of 32. It was recrystallized from ethanol to give 0.28 g
(62% yield) of 35, mp 308 °C; IR: n 3224 (NH), 1740 (CO)
cm-1; 1H NMR (CF3COOD): d 1.50 (3H, t, J = 2.0 Hz, CH3),
2.33 (3H, s, CH3), 3.42 (2H, s, CH2), 4.53 (2H, q, J = 3.0 Hz,
CH2), 8.33-7.78 (5H, m, phenyl-H); MS: 339 (M+, 38), 294
(6), 252 (5), 225 (100), 210 (5), 170 (1), 104 (3).
To a solution of compound 5 (0.30 g, 1.33 mmol) in gla-
cial acetic acid (10 mL), chalcone 27a (0.28 g, 1.33 mmol)
was added. The reaction mixture was refluxed for 10 h. The
solvent was removed by evaporation under reduced pressure
and the remainder was left to cool. The solid product so
formed was collected by filtration, and washed with ether.
Recrystallization from DMF/ethanol gave 0.21 g (38% yield)
of 30a, mp 285 °C; 1H NMR (DMSO-d6): d 3.08 (3H, s, CH3),
6.92 (2H, d, J = 1.0 Hz, 7-H), 8.52-8.17, 7.71-7.25 (16H, m,
phenyl-H); MS: 415 (M+, 100), 402 (2), 338 (8), 314 (38),
282 (6), 236 (5), 206 (31), 153 (14), 115 (10), 104 (46), 77
(38), 51 (7).
Anal. Calcd. for C17H17N5O3: C, 60.17; H, 5.01; N,
20.64. Found: C, 60.25; H, 5.01; N, 20.56%.
8-Amino-4,6-dimethyl-2-phenylpyrimido[2,3:4,3]pyrazolo-
[1,5-a]pyrimidine (36)
Anal. Calcd. for C27H21N5: C, 78.07; H, 5.06; N, 16.86.
Found: C, 78.03; H, 5.10; N, 16.66%.
To a mixture of compound 5 (0.30 g, 1.33 mmol) and
3-aminocrotononitrile 3 (0.12 g, 1.35 mmol) in ethanol (5
mL), a few drops of glacial acetic acid was added. The reac-
tion mixture was refluxed for 6 h. The resulting solid product
was collected by filtration and recrystallized from DMF/etha-
nol to give 0.16 g (42% yield) of 36, mp 337 °C; IR: n 3412,
3308 (NH2) cm-1; 1H NMR (DMSO-d6): d 2.55 (3H, s, CH3),
2.98 (3H, s, CH3), 6.54 (1H, s, 7-H), 8.55-8.50, 7.55-7.50
(5H, m, phenyl-H), 8.20 (2H, br, NH2); MS: 290 (M+).
Anal. Calcd. for C16H14N6: C, 66.20; H, 4.82; N, 28.96.
Found: C, 66.25; H, 4.90; N, 29.01%.
6-Furyl-4-methyl-2,8-diphenyl-7,8-dihydropyrimido-
[2,3:4,3]pyrazolo[1,5-a]pyrimidine (30b)
This compound was synthesized from compound 5
(0.30 g, 1.33 mmol) and 1-phenyl-3-(2-furyl)-2-propen-1-
one 27b (0.26 g, 1.33 mmol) in a manner similar to that de-
scribed for the preparation of 30a. It was recrystallized from
DMF/THF to give 2.80 g (52% yield) of 30b, mp 279 °C; 1H
NMR (DMSO-d6): d 2.98 (3H, s, CH3), 6.78 (1H, m, 4-H of
furyl), 7.10 (2H, d, J = 2.0 Hz, 7-H), 8.08-8.06, 7.85-7.30
(11H, m, phenyl-H), 8.48 (2H, m, 3-H, 5-H of furyl); MS: 405
(M+, 100), 376 (15), 328 (28), 311 (15), 244 (4), 196 (9), 181
(22), 40), 93 (22), 77 (19), 65 (13), 51 (4).
8-Amino-7-cyano-4-methyl-2-phenylpyrimido[2,3:4,3]-
pyrazolo[1,5-a]pyrimidine (38)
Anal. Calcd. for C25H19N5O: C, 74.07; H, 4.69; N,
17.28. Found: C, 74.22; H, 4.40; N, 17.25%.
This compound was synthesized from compound 5
(0.30 g, 1.33 mmol) and ethoxymethylenemalononitrile 37
(0.23 g, 1.35 mmol) in a manner similar to that described for
the preparation of 36. It was recrystallized from DMF/etha-
nol to give 0.21 g (53% yield) of 38, mp > 350 °C; IR: n 3434,
3325 (NH2), 2220 (CN) cm-1; 1H NMR (CF3COOD): d 2.96
(3H, s, CH3), 8.54-8.40 (5H, m, phenyl-H), 8.56 (2H, br,
NH2), 9.78 (1H, s, 6-H); MS: 301 (M+).
8-Amino-4-methyl-2-phenylpyrimido[2,3:4,3]pyrazolo[1,5-
a]pyrimidin-6(5H)-one (32)
A mixture of compound 5 (0.30 g, 1.33 mmol) and ethyl
cyanoacetate 31 (1.0 g, 8.8 mmol) was heated at 150 °C with
stirring for 2 h. The reaction mixture was diluted with etha-
nol. The solid product so formed was collected by filtration
and washed with ether. Recrystallization from DMF/ethanol
to give 0.36 g (93% yield) of 32, mp > 350 °C; IR: n 3424,
3236 (NH2), 3124 (NH), 1678 (CO) cm-1; 1H NMR (DMSO-
d6): d 2.93 (3H, s, CH3), 4.05 (2H, br, NH2), 7.94 (1H, s, 7-H),
8.52-8.45, 7.54-7.48 (5H, m, phenyl-H), 13.84 (1H, br, NH);
Anal. Calcd. for C16H11N7: C, 63.78; H, 3.65; N, 32.55.
Found: C, 63.92; H, 3.31; N, 32.66%.
Ethyl (4-methyl-6-phenylpyrazolo[3,4-d]pyrimidinyl-3-
yl)aminomethylenecyanoacetate (41a)
To a mixture of compound 5 (0.30 g, 1.33 mmol) and

Pyrimido[2,3:4,3]pyrazolo[1,5-a]pyrimidines
J. Chin. Chem. Soc., Vol. 50, No. 2, 2003 295
Received June 24, 2002.
ethoxymethylenecyanoacetate 39a (0.23 g, 1.33 mmol) in
ethanol (5 mL), a few drops of glacial acetic acid was added.
The reaction mixture was refluxed for 7 h. The resulting solid
product was collected by filtration and recrystallized from
ethanol to give 0.35 g (75% yield) of 41a, mp 268 °C; IR: n
3217 (NH), 2226 (CN), 1683 (CO) cm-1; 1H NMR (DMSO-
d6): d 1.31 (3H, t, J = 8.3 Hz, CH3), 2.82 (3H, s, CH3), 4.30
(2H, q, J = 6.9 Hz, CH2), 8.47-8.40, 7.45-7.40 (5H, m,
phenyl-H), 8.30 (1H, s, -CH=C), 11.17 (1H, s, NH), 13.43
(1H, br, NH); MS: 348 (M+).
REFERENCES
1. Taylor, E. C.; Hartke, K. S. J. Am. Chem. Soc. 1959, 81,
2456.
2. Rutavichyus, A. I.; Valyulene, S. P.; Mozolis, V. V. J. Org.
Chem. USSR. 1987, 1083.
3. Singh, S. P.; Kumer, D. Heterocycles. 1990, 31, 855.
4. Langenscheid, K.; Luduing, G. German Patent 1975, 2508;
Chem. Abstr. 1976, 85, 78124; Chem. Abstr. 1976, 84,
44041e.
Anal. Calcd. for C18H16N6O2: C, 62.06; H, 4.60; N,
24.13. Found: C, 62.33; H, 4.52; N, 24.26%.
5. Anderson, E. L.; Lasey, J. E.; Greene, L. C.; Lafferty, J. L.;
Reiff, H. E. J. Med. Chem. 1964, 7, 259.
6. Mohant, S. K.; Sriahar, R.; Padmanavan, S. Y.; Mittra, A. A.
Indian J. Chem. 1977, 15B, 1146.
7. Sternbach, L. M. Prog. Drug. Res. 1978, 22, 229.
8. Jaiswal, N.; Jaiswal, R.; Barthwal, J.; Kishor, K. Indian J.
Chem. 1981, 20B, 252.
9. Henning, G. German Patent 1977, 261698.
10. Jain, R.; Shukla, A. J. Indian Chem. Soc. 1990, 67, 575.
11. Elnagdi, M. H.; Elmoghayar, M. R.; Elgemeie, G. E. H. Ad-
vances in Heterocyclic Chemistry 1987, 41, 319.
12. Youssif, S. Monatsh. Chem. 1997, 128, 493.
13. Kandeel, E. M.; Baghos, V. B.; Mohareb, I. S.; Elnagdi, M.
H. Arch. Pharm. (Weinhein). 1983, 316, 713.
14. Kandeel, Z. E.; Farag, A. M.; Negm, A. M.; Khalafalla, A.
K.; Rasslan, M. A. M.; Elnagdi, M. H. J. Chem. Res. (S),
1994, 416 (M), 2332.
Ethyl (4-methyl-6-phenylpyrazolo[3,4-d]pyrimidinyl-3-
yl)aminomethylmethylenecyanoacetate (41b)
This compound was synthesized from compound 5
(0.30 g, 1.33 mmol) and methylethoxymethylenecyanoace-
tate 39b (0.25 g, 1.33 mmol) in a manner similar to that de-
scribed for the preparation of 41a. It was recrystallized from
ethanol to give 0.29 g (60% yield) of 35, mp 271 °C; IR: n
3218 (NH), 2212 (CN), 1669 (CO) cm-1; 1H NMR (DMSO-
d6): d 1.28 (3H, t, J = 1.8 Hz, CH3), 2.47 (3H, s, CH3), 2.83
(3H, s, CH3), 4.27 (2H, q, J = 1.8 Hz, CH2), 8.46, 7.55-7.53
(5H, m, phenyl-H), 11.83 (1H, br, NH), 13.95 (1H, br, NH);
MS: 362 (M+).
Anal. Calcd. for C19H18N6O2: C, 62.98; H, 4.97; N,
23.20. Found: C, 62.70; H, 5.01; N, 23.26%.
15. Skipper, H. E.; Robins, R. K.; Thomson, J. R.; Ching, C. C.;
Brockman, R. W.; Schabel, F. M. Cancer Res. 1957, 17, 579.
16. Skipper, H. E.; Robins, R. K.; Thomson, J. R. Proc. Soc.
Exptl. Biol. Med. 1955, 89, 594.
17. Elnagdi, M. H.; Zayed, E. M.; Khalifa, M. E.; Ghozlan, S. A.
Monatsh. Chem. 1981, 112, 245.
18. Hafez, E. A. A.; Elmoghayar, M. R. H.; Ramiz, M. M. M.
Liebigs Ann. Chem. 1987, 65.
19. Checch, S.; Rid, M. Gazz. Chem. Ital. 1957, 87, 597.
20. Senga, K.; Novinson, T.; Wilson, H. R. J. Med. Chem. 1981,
24, 610.
Diethyl (4-methyl-6-phenylpyrazolo[3,4-d]pyrimidinyl-3-
yl)aminomethylenemalonate (41c)
This compound was synthesized from compound 5
(0.30 g, 1.33 mmol) and ethoxymethylenemalonic acid di-
ethyl ester 39c (0.29 g, 1.33 mmol) in a manner similar to that
described for the preparation of 41a. It was recrystallized
from ethanol to give 0.45 g (85% yield) of 41c, mp 258 °C;
IR: n 3226 (NH), 1700, 1654 (CO) cm-1; 1H NMR (DMSO-
d6): d 1.31-1.23 (6H, m, CH3), 2.84 (3H, s, CH3), 4.14 (2H, q,
J = 3.0 Hz, CH2), 4.25 (2H, q, J = 2.7 Hz, CH2), 8.76 (1H, s,
CH=C), 8.74-8.38, 7.41-7.38 (5H, m, phenyl-H), 11.33 (1H,
s, NH), 13.27 (1H, br, NH); MS: 395 (M+).
21. Hussein, A. M.; Abdel, H. I. S.; Elnagdi, M. H. J. Chin.
Chem. Soc. 2000, 47, 347.
22. Al-Afalaq, E. I. Synthetic Communications 2000, 30, 1985.
23. Ho, Y. W. J. Chin. Chem. Soc. 1999, 46, 955.
24. Elnagdi, M. H.; Abdelrazek, F. M.; Ibrahim, N. S.; Erian, A.
W. Tetrahedron 1989, 45, 3597.
Anal. Calcd. for C20H21N5O4: C, 60.75; H, 5.31; N,
17.72. Found: C, 60.70; H, 5.41; N, 17.66%.
25. Kreutzberger, A.; Leger, M. Arch. Pharm. (Weinhein). 1982,
315, 438.
ACKNOWLEDGEMENT
26. Novinson, T.; Okabe, T.; Robins, R. K.; Dea, P. J.
Heterocyclic Chem. 1975, 12, 1187.
27. Novinson, T.; Springer, R. H.; O’Brien, D. E.; Scholten, M.
We are grateful to the National Science Council of the
Republic of China for their financial support.

296 J. Chin. Chem. Soc., Vol. 50, No. 2, 2003
Ho and Yao
B.; Miller, J. P.; Robins, R. K. J. Med. Chem. 1982, 25, 420.
28. Ho, Y. W. J. Chin. Chem. Soc. 1999, 46, 91.
31. Al-Enezi, A.; Al-Saleh, B.; Elnagdi, M. H. J. Chem. Res. (S)
1997, 4.
29. Kabli, R. A.; Khalaf, A. A.; Zimaity, M. T.; Kaddah, A. M.;
Al-Rifaie, H. A. J. Indian Chem. Soc. 1991, 68, 47.
32. Al-Saleh, B.; Abdel-Khalik, M. M.; Al-Enzy, A.; Elnagdi,
M. H. J. Chem. Res. (S) 1999, 654.
30. Jacobs, T. L. Heterocyclic Compounds; Vol. 5, R. C.
Eldergield, John Wiley & Sons: New York, 1957; pp 47.
33. Tseng, S.; Epstein, J. W.; Brbander, H. J.; Francisco, G. J.
Heterocyclic Chem. 1987, 24, 837.