Synthesis of some pyridothienopyrazolopyrimidopyrimidine and mercaptomethylpyrazolopyrimidine derivatives

Article abstract of DOI:10.1080/10426500802418479

Mercaptomethylpyrazolopyrimidine (2) was synthesized and reacted with ethyl chloroacetate to afford ethyl pyrazolpyrimidinylmethylmercapto acetate (3), which in turn was converted into the corresponding carbohydrazide 4. Carbohydrazide 4 reacts with a var

Full text of DOI:10.1080/10426500802418479

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Phosphorus, Sulfur, and Silicon
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Synthesis of Some
Pyridothienopyrazolopyrimidopyrim
and
Mercaptomethylpyrazolopyrimidine
Derivatives
A. M. Kamal El-Dean a , A. M. Elkhawaga a , Sh. M.
Radwan a & M. M. Ahmed a
a Chemistry Department, Faculty of Science, Assiut
University, Assiut, Egypt
Published online: 22 Jul 2009.
To cite this article: A. M. Kamal El-Dean , A. M. Elkhawaga , Sh. M. Radwan & M.
M. Ahmed (2009) Synthesis of Some Pyridothienopyrazolopyrimidopyrimidine and
Mercaptomethylpyrazolopyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and
the Related Elements, 184:8, 2034-2048, DOI: 10.1080/10426500802418479
To link to this article: http://dx.doi.org/10.1080/10426500802418479
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Phosphorus, Sulfur, and Silicon, 184:2034–2048, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802418479
Synthesis of Some
Pyridothienopyrazolopyrimidopyrimidine and
Mercaptomethylpyrazolopyrimidine Derivatives
A. M. Kamal El-Dean, A. M. Elkhawaga, Sh. M. Radwan,
and M. M. Ahmed
Chemistry Department, Faculty of Science, Assiut University,
Assiut, Egypt
Mercaptomethylpyrazolopyrimidine (2) was synthesized and reacted with ethyl
chloroacetate to afford ethyl pyrazolpyrimidinylmethylmercapto acetate (3), which
in turn was converted into the corresponding carbohydrazide 4. Carbohydrazide
4 reacts with a variety of reagents to give different pyrazolopyrimidines (5–12).
Chloromethyl-pyrazolopyrimidine (1) reacts with chloropyridine to give compound
13, which was subjected in a series of reactions to give new compounds 14–20.
Keywords Mercaptomethylpyrazolo-pyrimidine; pyrazolopyrimidine; reactions; syn-
thesis; thienopyrazolopyrimidopyrimidin
INTRODUCTION
Pyrazole derivatives are an important class of compounds that pos-
sess biological and pharmacological activities.1−8 They are used not
only as potential inhibitors of HIV,9 herbicides,10 bactericides,11 and
analgesic drugs,12 but they are also important and useful as starting
materials for the synthesis of other fused heterocyclic pyrazolo[3,4-
d]pyrimidine derivatives of considerable chemical and pharmaco-
logical importance such as purine analogs.13,14 Several substituted
pyrazolo[3,4-d]pyrimidine derivatives have xanthine oxidase inhibitor
activity.14,15
We have previously reported that the synthesis of novel
heterocyclic systems such as 3-(aryl or heteroaryl)azothieno[2,3-
b]pyridines from 4,6-dimethylpyrazolo[2,3-b]pyridine-3-sulfonamide,16
pyridopyrazolopyrimidine,17 and pyrazolopyrimidines.18,19 In contin-
uation of our studies, we report here the synthesis of some new
Received 1 May 2008; accepted 18 August 2008.
Address correspondence to A. M. Kamal El-Dean, Chemistry Department, Faculty of
Science, Assiut University, Assiut 71516, Egypt. E-mail: a.eldean@aun.edu.eg
2034

Synthesis of Some Pyrazolopyrimidine Derivatives
2035
polynuclear heterocyclic compounds containing pyrazolopyrimidines
fused with thienopyridine.
RESULTS AND DISCUSSION
6-Chloromethyl-1-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-one (1) was
synthesized and used for the synthesis of 6-mercaptomethyl-
1-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-one (2). When mercap-
tomethylpyrazolopyrimidine compound 2 was allowed to react with
ethyl chloroacetate, ethyl (1-phenyl-4-oxopyrazolo[3,4-d]-pyrimidin-
6-yl)-mercaptoacetate was formed (3). Hydrazinolysis of 3 using
hydrazine hydrate in ethanol afforded the corresponding mercapto-(1-
phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-yl)acetic hydrazide (4), which
upon reaction with a variety of reagents gave a series of products
discussed here (5–12), based on the conditions and reagent used.
When the hydrazoninolysis was carried out under neat conditions,
the ethyl mercaptoacetate group was eliminated to form 6-methyl-1-
phenylpyrazolo[3,4-d]pyrimidin-4[5H]-one (5).20 The structure of the
resulting compound 5 was confirmed using spectral analyses, where
its mass spectrum showed a peak at m/z = 226 as a molecular ion peak
and as a base peak. Its 13C NMR spectra showed signals at 20 for Me
group, at 158 for C2 of pyrimidine, and at 160 for the CO group.
When, carbohydrazide derivative 4 was reacted with phenyl
isothiocyanate in refluxing ethanol, N-(mercapto-(1-phenyl-4-
oxopyrazolo[3,4-d]pyrimidin-6-yl)-acetyl-Nꢀ-phenyl thiosemicarbazide
(6) was produced. When thiosemicarbazide derivative 6 was heated in
sodium hydroxide solution,21 it underwent a ring closure accompanied
by the elimination of water to afford (4-oxo-1-phenylpyrazolo-[3,4-
d]pyrimidin-6-yl)-2,3-dihydro3-thioxo-4-phenyl-[1,2,4]triazol-5-yl)-di-
methylthioether 7. When the same above reaction was applied on
the thiosemicarbazide derivative 6 using ortho phosphoric acid22
instead of sodium hydroxide at 70–80◦C on a steam bath, ring
closure occurred accompanied by the elimination of water to give (4-
oxo-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)-2–4-phenylamino[1,3,4]-
thiadiazol-5-yl)-dimethylthioether (8) (Scheme 1).
Alternatively, when compound 4 was allowed to react with acetyl ace-
tone in refluxing ethanol, 1-(1-phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-
yl)-mercaptoacetyl)-3,5-dimethyl-pyrazole (9) was synthesized. When
carbohydrazide 4 was heated under reflux on a steam bath with carbon
disulfide in pyridine, (4-oxo-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)-2-
mercapto[1,3,4]-oxadiazol-5-yl)-dimethylthioether (10) was obtained.
Upon treatment of carbohydrazide 4 with sodium nitrite at a low

2036
A. M. K. El-Dean et al.
SCHEME 1
temperature in an acetic acid/HCl mixture, the corresponding 1-phenyl-
4-oxopyrazolo[3,4-d]pyrimidin-6-methyl-mercaptoacetic azide (11) was
obtained. Carboazide derivative 11 underwent a Curtis rearrangement
when boiled in ethanol, yielding the corresponding ethyl N-(1-Phenyl-4-
oxopyrazolo[3,4-d]pyrimidin-6-methylmercaptomethyl carbamate (12)
(Scheme 2).
Chloromethylpyrazoloprimidine (1) was reacted with 4,6-dimethyl-
2-mercaptopyridin-3-carbonitrile in refluxed ethanol and in the
presence of sodium acetate to afford 1-phenyl-6-(3-cyano-4,6-
dimethylpyridin-2-ylmercaptomethyl)pyrazolo-[3,4-d]pyrimidin-4[5H]-
one (13). Compound 13 was cyclized in refluxing ethanol in the pres-
ence of K2CO3 to give 1-phenyl-6-(3-amino-4,6-dimethyl-thieno[2,3-
b]pyridin-2-yl)-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one
(14)
(Scheme 3). The structures and formation of 13 and 14 were es-
tablished by their spectral analyses, whereas the IR spectrum of
1
compound 13 showed absorption bands at 2220 cm−1 for CN. The H

Synthesis of Some Pyrazolopyrimidine Derivatives
2037
SCHEME 2
SCHEME 3

2038
A. M. K. El-Dean et al.
NMR spectrum of compound 13 exhibited two singlets at 2.5 and 2.6
corresponding to 2CH3 and another broad singlet at 4.4 corresponding
to the CH2. IR spectra of compound 14 revealed the disappearance
of the band corresponding to the CN group in the starting material
and appearance of absorption band at 3480, 3400 cm−1 corresponding
1
to the NH2group. The H NMR spectra of compound 14 showed the
disappearance of the signal characteristic of CH2 in the starting
material. The mass spectrum of compound 14 showed a molecular ion
peak at 288, which is in agreement with the expected structure.
Compound 14 was used to synthesize fused polycyclic heterocyclic. It
was condensed with triethyl orthoformate in the presence of acetic acid
as catalyst to afford 1-phenyl-8,10-dimethylpyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-
e]pyrazolo[3ꢀ,4ꢀ:4,5]pyrimido[1,2-c]pyrimidin-4-one (15). The expected
structure was established on the basis of elemental and spectral data.
IR spectrum of 15 revealed the disappearance of bands characteristic
of NH2 and NH groups in the starting material. The mass spectrum of
compound 15 showed a peak at m/z = 298 as a molecular ion peak.
When compound 14 was refluxed with acetic anhydride, acyla-
tion of the amino group occurred, followed by spontaneous dehy-
dration to give 1-phenyl-6,8,10-trimethyl-pyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-
e]pyrazolo[3ꢀ,4ꢀ:-4,5]-pyrimido[1,2-c]pyrimidin-4-one (16). Formation of
16 was confirmed using spectral data. Its IR spectra revealed the dis-
appearance of bands corresponding to the NH and NH2 group in the
1
starting material. Its H NMR spectra revealed three singlets at 2.5,
2.9, and 3.2 for 3Me group, and its mass spectrum showed a molecular
ion peak at 412 as a molecular ion beak and as base peak.
When compound 14 was allowed to react with aromatic aldehydes
in the presence of piperidine as a catalyst, 1-phenyl-6-aryl-8,10-
dmethylpyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-e]-pyrazolo[3ꢀ,4ꢀ:4,5]pyrimido[1,2-
c]pyrimidin-4-one (17a–c) were obtained in good yield. Formation
of 17a–c was established using spectral data. IR spectra of 17a,b
revealed the disappearance of bands characteristic for an amino group
and showed absorption bands at 3320–3300 cm−1 for the NH group.
1H NMR (DMSO-d6) of compound 17b showed the disappearance of
a signal characteristic of the NH2 group, three singlet signals, and
revealed the appearance of new signal at 3.8 for OMe group. Mass
spectrum of compound 17a showed a peak at m/z = 474 as a molecular
ion peak after elimination of the hydrogen molecule and aromatization
of pyrimidine ring.
Chloroacylation of compound 14 using chloroacetyl chloride and
acylation of the amino group occurred to give the corresponding
chloroacetylamino derivative 18, which underwent elimination of

Synthesis of Some Pyrazolopyrimidine Derivatives
2039
water when refluxed with acetic anhydride to afford 1-phenyl
-6-chloromethyl-8,10-trimethyl-pyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-e]pyrazolo
[3ꢀ,4ꢀ:4,5]pyrimido-[1,2-c]pyrimidin-4-one (19). The IR spectrum of
18 showed absorption bands at 3450, 3200 cm−1 for two NH and at
1695 cm−1 for CO. 1H NMR spectrum (CDCl3) of compound 18 is
in agreement with the expected structure. It showed signals at 2.9,
3.2 ppm for 2CH3 and CH2. IR spectrum of compound 19 showed
1
absorption bands at 1720 cm−1 for CO. H NMR spectra (CF3CO2D)
of compound 19 showed signals at δ 3.1(s, 3H, CH3), 3.5(s, 3H,
CH3), 5.6(s, 2H, CH2), and 7.6–8.9 (aromatic protons). The mass
spectrum of compound 19 exhibited a peak at m/z = 446 and M+1
(447), and after elimination of chlorine atom at 412, and base beak
at 398 for the structure 15 after elimination of CH2Cl. Heating
of chloromethylpyridothienopyrimidopyrimidine (19) with morpho-
line in ethanol produced 8,10-dimethyl-6-(N-methylmorphonyl)-1-
phenylpyrido[2ꢀ,3ꢀ:2,3]-thieno[4,5-e]pyraolo-[3ꢀ,4ꢀ:4,5]pyrimido[1,2-c]
pyrimidin-4-one (20) (Scheme 4). The structure of compound 20
SCHEME 4

2040
A. M. K. El-Dean et al.
was confirmed using spectral analysis. 1H NMR spectra (CDCl3) of
compound 20 showed beside the aromatic protons signals at 2.2 (s,
CH2), 2.8–3.8 (m, 8H, 4CH2). The mass spectrum showed a molecular
ion peak at m/z = 499 corresponding to the expected structure and
gave the base peak corresponding to the molecular weight of the
expected structure after elimination of morpholinyl group.
EXPERIMENTAL
Melting points were determined on a Gallen-Kamp melting point appa-
ratus and are uncorrected. IR spectra were recorded on a Pye-Unicam
SP 3100 spectrophotometer using KBr wafer technique. 1H NMR spec-
tra were recorded on a Varian EM-390 90 MHz spectrometer and in a
suitable deuterated solvent using TMS as internal standard (chemical
shifts in ppm). Mass spectra were measured on a Jeol-JMS 600 spec-
trometer. Elemental analyses were determined on Elementar Analyse
system GmbH-VarioEL V.3 microanalyzer in the central lab of Assiut
University.
6-Mercaptomethyl-1-phenylpyrazolo[3,4-d]pyrimidin-
4(5H)-one (2)
A mixture of (1) (1.5 g, 5.75 mmol) and thiourea (1.3 g, 0.01 mol) in
ethanol (25 mL) was refluxed for 5 h. The solid yellow product, which
was obtained while hot, was filtered in dissolved sodium hydroxide (20
mL, 5%), then acidified with (0.01 N) HCl until acidic. The solid product
was collected by filtration, dried under vacuum, and recrystallized from
dioxan as yellow crystals in 50% yield, mp 250–252◦C.
Anal. Calcd. for C12H10N4OS (258.30): C; 55.80; H, 3.90; N; 21.69;
H; 3.87, S; 12.41%. Found: C; 55.55; H, 3.70; N; 21.62; S; 12.21%. IR:
1
ν = 3250 cm−1 (NH), 1690 cm−1 (CO), 1590 cm−1 for C = N. H NMR
(DMSO-d6):δ 4.8 (s, 2H, CH2), 7.3–8.2 (m, 6H, 5Ar-H and CH pyrazole),
9.5 (s, 2H, NH, SH).
Ethyl (1-Phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-yl)-
mercaptoacetate (3)
A mixture of 2 (1 g, 3.87 mmol), ethyl chloroacetate (0.47 mL, 3.87
mmol), and sod. acetate (0.7 g, 8.5 mmol) was refluxed in ethanol (20
mL) for 3 h then allowed cool. The solid product was filtered off and
recrystallized from ethanol as yellowish crystals in 69% yield, mp 178–
180◦C.

Synthesis of Some Pyrazolopyrimidine Derivatives
2041
Anal. Calcd. for C16H16N4O3S(344.39): C, 55.80; H, 4.68; N, 16.27;
S, 9.31%. Found: C, 55.55; H, 4.45; N, 16.15; S, 9.19%. IR: ν = 3450
1
cm−1 for NH, 1720, 1690 cm−1 for CO and at 1590 cm−1 for C N. H
NMR(DMSO-d6): δ = 1.1 (s, 3H, CH3), 3.8(q, 2H, CH2), 3.6(s, 4H, 2CH2)
and at 7.3–8.2 (m, 6H, 5Ar-H, CH pyrazole) and at 10.5 (s, 1H, NH).
1-Phenyl-4-oxopyrazolo[3,4-d]pyrimidin-
6-methylmercaptoacetic Hydrazide (4)
A mixture of compound 3 (0.9 g, 2.6 mmol) and hydrazine hydrate
(99%, 0.5 mL, 10 mmol) was refluxed in ethanol (20 mL) for 3 h. The
solid product obtained upon heating was collected, washed well with
ethanol, and dried as white crystals in 34% yield, mp 238–240◦C. Anal.
Calcd. for (C14H14N6O2S (330.37): C, 50.90; H; 4.27; N, 25.44; S, 9.71%.
Found: C, 50.70; H; 4.12; N, 25.19; S, 9.47%. IR: ν = 3350, 3300, 3100
cm−1 (NHNH2), 1680 cm−1 for CO, 1590 Cm−1 (C N). 1H NMR (DMSO-
d6):δ = 3.2(s, 2H, CH2), 3.5(s, 2H, NH2), 3.8(s, 2H, CH2), 7.4–8.3(m, 7H,
5Ar-H, CH pyrazole and NH), 9.5 (s, 1H, NH).
6-Methyl-1-phenylpyrazolo[3,4-d]pyrimidin-4(5H)-one (5)
A mixture of compound 3 (5 mL, 0.10 mol) hydrazine hydrate was re-
fluxed for 3 h under neat condition. The white precipitate that obtained
upon heating was collected, mp > 300◦C, yield (34%). Anal. Calcd. for
C12H10N4O (226.24): C, 63.71; H, 4.46; N, 24.76%. Found: C; 63.92, H,
4.21; N, 24.73%. IR: ν = 3250 cm−1 for NH,1650 cm−1 (CO), 1570 cm−1
(C N). Mass spectrum m/z = (226, 100%), 211, 19% for (M+-CH3).
N-(1-phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-
methylmercaptoacetyl)-Nꢀ-phenyl Thiosemicarbazide (6)
A
mixture of 1-phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-methyl-
mercaptoacetic hydrazide (4) (0.5 g, 1.5 mmol) and phenyl isothio-
cyanate (0.24 mL, 2 mmol) in ethanol (20 mL) was refluxed for 1 h. The
solid product obtained upon heating was collected as white crystals in
84% yield, mp 208–210◦C. Anal. Calcd. for (C20H19N7O2S2,465.56): C,
54.18; H; 4.11; N, 21.06; S, 13.77%. Found: C, 53.98; H; 4.10; N, 21.77;
S, 14.00%. IR: ν = 3350, 3330, 3150 cm−1 (NH groups), 1690 for CO,
1600 (C N). 1H NMR (DMSO-d6):δ = 3.1, 3.8 (s, 4H, 2CH2), at 7.4–8.2
(m, 10H, Ar-H and CH pyrazole).

2042
A. M. K. El-Dean et al.
(4-Oxo-1-phenylpyrazolo-[3,4-d]pyrimidin-6-yl)-2,3-dihydro3-
thioxo-4-phenyl-[1,2,4]triazol-5-yl)-dimethylthioether (7)
A sample of thiosemicarbazide derivative (6) (0.3 g, 0.9 mmol) in sodium
hydroxide solution (0.4 g, 0.01 mol in 5 mL H2O) was heated at 80◦C for
6 h, then allowed to cool and was acidified using acetic acid. The solid
product was collected and recrystallized from ethanol as white crystals
in 47% yield, mp > 300◦C. Anal. Calcd. for C21H17N7OS2 (447.53): C,
56.36; H, 3.83; N, 21.91; S, 14.33%. Found: C, 56.15; H, 3.57; N, 21.75;
S, 14.12%. IR: ν = 3400 cm−1 for NH, 1680 cm−1 (CO), 1580 cm−1
1
(C = N). H NMR (DMSO-d6):δ = 3.7(s, 2H, CH2), 3.8 (s, 2H, CH2),
7.4–8.2 (m, 10H, Ar-H), 8.9 (s, 1H, CH pyrazole), 9.8, 11.0 (2s, 2H,
2NH).
(4-Oxo-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)-2-
phenylamino[1,3,4]thiadiazol-5-yl)-dimethylthioether (8)
A sample of 6 (0.3 g, 0.9 mmol) in orthophosphoric acid (10 mL) was
heated at 80◦C for 6 h, then allowed to cool, and was neutralized with
ammonium hydroxide solution. The solid product thus formed was col-
lected and recrystallized from ethanol to give 8 as yellow crystals in
38% yield, mp 240–242◦C. Anal. Calcd. for (C22H17N7OS,44753): C,
56.36; H; 3.83; N; 21.91; S, 14.33%. Found: C, 56.23; H; 4.07, N, 22.17;
S, 14.26%. IR: ν = 3350, 3150 cm−1 for NH, 1680 cm−1 (CO), 1580 cm−1
1
(C = N). H NMR (DMSO-d6):δ = 3.9 (s, 2H, CH2), 4.1 (s, 2H, CH2),
7.0–8.0 (m, 10H, Ar-H), 8.9 (s, 1H, CH pyrazole), 9.8, 10.5 (2s, 2H,
2NH).
1-(1-Phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-yl)-
mercaptoacetyl-3,5-dimethyl-pyrazole (9)
A mixture of 4 (0.25 g, 0.75 mmol) and acetyl acetone (6 mL, 0.05 mol)
in ethanol (15 mL) was refluxed for 6 h. The reaction mixture was al-
lowed to cool, and the solid product was collected and recrystallized
from ethanol to give 9 as yellow crystals in 41% yield, mp > 300◦C.
Anal. Calcd for C19H18N6O2S (394.46): C, 57.85; H, 4.60; N, 21.31;
S, 8.13%. Found: C, 57.50; H, 4.35; N, 21.10; S, 7.98%. IR: ν = 3400
cm−1 (NH) 1720, 1690 cm−1 (CO), 1590 cm−1 (C N). 1H NMR (DMSO-
d6):δ = 2.1 (s, 3H, CH3), 2.5(s, 3H, CH3), 3.9, 4.1(2s, 4H, 3CH2), at 6.0(s,
1H, CH), 7.0–8.0(m, 5H, 5Ar-H), 8.9(s, 1H, CH pyrazole), 9.2 (s, 1H,
NH).

Synthesis of Some Pyrazolopyrimidine Derivatives
2043
(4-Oxo-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)-2-
mercapto-[1,3,4]oxadiazol-5-yl)-dimethylthioether (10)
A mixture of 4 (0.25 g, 0.75 mmol) and carbon disulfide (1 mL) in
pyridine (10 mL) was refluxed on a water bath for 15 h then allowed
to cool. The solid product was collected and recrystallized from ethanol
to give 10 as yellow crystals in 21% yield, mp 280◦C. Anal. Calcd for
C15H12N6O2S2 (372.43): C, 48.38; H, 3.25; N, 22.57; S, 17.22%. Found:
C, 48.21; H, 3.05; N, 22.45; S, 17.01%. IR: ν = 3450 cm−1 (NH), 1680
cm−1 (CO), 1590 cm−1 (C N). 1H NMR (DMSO-d6): δ = 3.5 (s, 1H, SH),
3.8 (s, 2H, CH2), at 4.2 (s, 2H, CH2), at 7.4–8.3 (m, 5H, Ar-H), 8.9 (s,
1H, CH pyrazole) and 9.8 (s, 1H, NH).
1-Phenyl-4-oxopyrazolo[3,4-d]pyrimidin-6-
methylmercaptoacetic azide (11)
To an ice cooled solution of carbohydrazide 4 (0.25 g, 0.75 mmol) in an
acetic acid (5 mL)/HCl (1 mL) mixture, sodium nitrite solution (0.14
g, 20 mmol in 3mL H2O) was added dropwise with stirring. After the
addition was finished, the stirring was continued for an additional 2
h at room temperature. The solid product was collected, washed with
water several times, and collected as pale green crystals in 44% yield,
mp 120–122◦C decomposed. Anal. Calcd. For C14H11N7O2S (341.35): C,
49.26; H; 3.25; N, 28.72; S, 9.39%. Found: C, 49.01; H; 3.05 N, 28.45; S,
8.98%. IR: ν =3100 (NH), 2100 cm−1 (N3), 1715, 1690, cm−1 (2CO). 1H
NMR (CDCl3): δ = 3.8 (s, 2H, CH2), at 4.1 (s, 2H, CH2), at 7.4–8.3 (m,
5H, Ar-H), 9.0 (s, 1H, CH pyrazole) and 10.5 (s, 1H, NH).
Ethyl-N-(1-phenyl-4-oxopyrazolo[3,4-d]pyrimidin-
6-methylmercaptomethyl Carbamate (12)
A sample of compound (11) (0.25 g, 0.73 mmol) in absolute ethanol (10
mL) was refluxed for 3 h, then was allowed to cool and was poured into
cold water. The solid product was collected, dried, and recrystallized
from pet. ether (60–80◦C) to give 12 as white crystals in 50% yield, mp
198–200◦C. Anal. Calcd. for C16H17N5O3S (359.40): C, 53.48; H, 4.77;
N, 19.49; S, 8.91%. Found: C, 53.23; H, 4.56; N, 39.10; S, 8.75%. IR: ν =
1
3350 cm−1 (NH), 1720, 1680 cm−1 (CO), 1590 cm−1 (C N). H NMR
(DMSO-d6):δ = 1.2 (t, 3H, CH3), 3.2 (s, 2H, CH2), 4 (q, 2H, OCH2), at
4.3 (s, 2H, CH2), 7.3–8.2(m, 5H, Ar-H), 9.0(s, 1H, CH pyrazole) and 9.3,
11.0 (2s, 2H, 2NH).

2044
A. M. K. El-Dean et al.
1-Phenyl-6-(3-cyano-4,6-dimethylpyridin-2-ylmercapto-
methyl)pyrazolo[3,4-d]pyrimidin-4[5H]-one (13)
A mixture of 2-chloromethyl-7-phenylpyrazolo[3,4-d]pyrimidin-4(3H)-
one (1) (1.3 g, 4.7 mmol), 3-cyano-4,6-dimethylpyridine-2(1H)-thione
(0.77 g, 4.7 mmol), and sodium acetate (0.82 g, 10 mmol) in ethanol (20
mL) was refluxed for 3 h. The solid product obtained upon heating was
collected and recrystallized from ethanol as pale green crystals in 55%
yield, mp 260–262◦C. Anal. Calcd. for C20H16N6OS (388.45): C, 61.84;
H, 4.15; N, 21.63; S, 8.25%. Found: C, 61.60; H, 4.01; N, 21.43; S, 8.05%.
IR: ν = 3250 cm−1 (NH), 2200 cm−1 (CN), 2950 cm−1 (CH aliphatic),
1
1725 cm−1 (CO). H NMR (DMSO-d6): δ = 2.5, 2.65 (2s, 6H, 2CH3),
4.7 (s, 2H, CH2), 6.9 (s, 1H, CH pyridine), 7.2–8.2 (m, 5H, Ar-H), 9.0 (s,
1H, CH pyrazole), 9.5(s, 1H, NH).
1-Phenyl-6-(3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)-1,
5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (14)
A sample of 1-phenyl-6-(3-cyano-4,6-dimethylpyridin-2-ylmercaptome-
thyl)-pyrazolo-[3,4-d]pyrimidin-4[5H]-one (0.47 g, 1.2 mmol) and potas-
sium carbonate (0.39 g, 2.8 mmol) in ethanol (20 mL) was refluxed for 3
h. The solid product thus obtained upon heating was filtered off, washed
with water several times, and recrystallized from dioxan to give 14
as greenish yellow crystals, mp >300◦C, yield (80%). Anal. Calcd. for
C20H16N6OS (388.45): C, 61.84; H, 4.15; N, 21.63; S, 8.25%. Found: C,
62.04; H, 4.01; N, 21.45; S, 8.02%. IR: ν = 3400–3480 cm−1 (NH, NH2),
1690 cm−1 (CO). 1H NMR (DMSO-d6): δ = 2.7, 2.8(2s, 6H, 2CH3), 5.9 (s,
2H, NH2), 6.9 (s, 1H, CH-pyridine), 7.2–8.3 (m, 5H, Ar-H), 8.9 (s, 1H,
CH pyrazole) and 9.7 (s, 1H, NH).
1-Phenyl-8,10-dimethyl-pyrido[2ꢀ,3ꢀ:2,3]thieno[4,
5-e]pyrazolo[3ꢀ,4ꢀ:4,5]pyrimido-[1,2-c]pyrimidin-4-one (15)
A sample of compound (14) (0.3 g, 0.77 mmol), triethyl orthoformate (1
mL), and few drops of acetic acid were refluxed for 2 h. The solid product
obtained upon heating was collected and recrystallized from acetic acid
to give 15 as green crystals in 66% yield, mp >300◦C. Anal. Calcd. for
C21H14N6OS (398.45): C, 63.30; H, 3.54; N, 21.09; S, 8.05%. Found: C,
63.10; H, 3.30; N, 20.98; S, 7.95%. IR: ν = 3030 cm−1 (CH aromatic),
1
1720 cm−1(CO), 1600 cm−1(C = N). H NMR (CF3CO2D): 2.8, 3.1 (2s,
6H, 2CH3), 7.1 (s, 1H, CH-pyridine), 7.2–8.2 (m, 6H, aromatic and

Synthesis of Some Pyrazolopyrimidine Derivatives
2045
CH-pyrimidine) and at 8.7 (s, 1H, pyrazole). Mass spectrum: m/z =
(398, 38%) for M+, (397,100%) for (M+-1).
1-Phenyl-6,8,10-trimethylpyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-e]pyrazolo-
[3ꢀ,4ꢀ:4,5]pyrimido-[1,2-c]pyrimidin-4-one (16)
A sample of 14 (0.3 g, 0.77 mmol) in acetic anhydride (5 mL) was
refluxed for 4 h. The solid product obtained upon heating was collected
and recrystallized from dioxan to give 16 as green crystals in 48% yield,
mp 290–292◦C. Anal. Calcd. for C22H16N6OS(412.48): C, 64.06; H, 3.91;
N, 20.37; S, 7.77%. Found: C, 63.95; H, 3.69; N, 20.16; S, 7.53%. IR: ν =
1
2900 cm−1(CH aliphatic), 1720 cm−1(CO), 1600 cm−1(C N). HNMR
(CF3CO2D): δ = 2.7, 2.9, 3.2 (3s, 9H, 3CH3), 7.2 (s, 1H, CH-pyridine),
7.2–8.2 (m, 5H, CH-aromatic), 8.9 (s, 1H, CH-pyrazole). Mass spectrum
m/z = 412(M+, 100%).
1-Phenyl-6-aryl-8,10-dmethylpyrido[2ꢀ,3ꢀ:2,3]thieno[4,
5-e]pyrazolo-[3ꢀ,4ꢀ:4,5]pyrimido[1,2-c]pyrimidin-4-one (17a–c)
General Procedure
To a mixture of 14 (0.3 g, 0.77 mmol), benzaldehyde(3 mL, 29.7
mmol) and a few drops of piperidine were fused gently for 20 min,
then ethanol (20 mL) was added and then refluxed for additional 2 h.
The solid precipitate obtained on hot was collected and recrystalized as
yellow crystals, mp >300◦C, yield (58%). Anal. Calcd. for C27H20N6OS
(476.56): C, 68.05; H, 4.23; N, 17.63;S, 6.73%. Found: C, 68.10; H, 4.45;
N, 17.40; S, 6.56%. IR: ν = 3300 cm−1 for NH, 1670 cm−1 (CO), 1580
cm−1 (C N)). 1H NMR (CF3CO2D):δ = 3.0, 3.3 (2s, 6H, 2CH3), 7.1 (s, 1H,
CH-pyridimidin), 7.2 (s, 1H, CH-pyridine), 7.3–8.1 (m, 10H, aromatic
protons), 9.0 (s, 1H, CH pyrazole).
1-Phenyl-6-p-methoxyphenyl-8,10-dmethyl-pyrido[2ꢀ,3ꢀ:-2,3]-
thieno[4,5-e]-pyrazolo[3ꢀ,4ꢀ:4,5]pyrimido[1,2-c]pyrimidin-4-one
(17b)
Prepared as in the previous method from 14 (0.2 g, 0.51 mmol) and
anisaldehyde (0.3 mL, 2.4 mmol), as yellow crystals in 48% yield, mp
< 300◦C. Anal. Calcd. for C28H22N6O2S (506.59): C, 66.39; H, 4.38; N,
16.59; S, 6.33%. Found: C, 66.30; H, 4.17; N, 16.46; S, 6.09%. IR: ν =
3320 cm−1 for NH, 1670 cm−1 (CO), 1580 cm−1 (C N). 1H NMR (DMSO-
d6):δ = 2.7 (s, 3H, CH3), 2.8 (s, 3H, CH3), 3.8 (s, 3H, OCH3), 6.8 (a, 1H,
CH-pyrimidine), 6.9 (s, 1H, CH-pyridine), 7.1–8.3 (m, 9H, Ar-H), 8.5 (s,
1H, CH pyrazole) and 9.5 (s, 1H, NH).

2046
A. M. K. El-Dean et al.
1-Phenyl-6-p-chlorophenyl-8,10-dmethyl-pyrido[2ꢀ,3ꢀ:-2,3]-
thieno[4,5-e]pyrazolo-[3ꢀ,4ꢀ:4,5]-
pyrimido[1,2-c]pyrimi-din-4-one (17c)
As previously described, this compound was prepared from 14 (0.3 g,
0.77 mmol) and p-chlorbenzaldehyde (0.4 g, 2.8 mmol) in yield (40%),
mp >300◦C. Anal. Calcd. for C27H19ClN6OS (511.01): C, 63.46; H; 3.75;
Cl, 6.94; N, 16.45; S, 6.27%. Found: C, 63.23; H, 3.55; Cl, 6.77; N, 16.25;
S, 6.07%. IR: ν = 3300 cm−1 (NH), 1710cm−1 for (CO). 1H NMR (DMSO-
d6):δ = 2.7 (s, 3H, CH3), 2.9(s, 3H, CH3), 6.9 (s, 2H, CH-pyrimidine,
CH-pyridine), 7.3–8 (am, 9H, Ar-H), 8.9 (s, 1H, CH-pyrazole), 9.7 (s,
1H, NH).
1-Phenyl-6-(3-N-chloroacetylamino-4,6 di methylthieno
(2,3-b)pyridine-2-yl)pyrazole[3,4-d]pyrimidin-4(3H)-one (18)
A mixture of 14 (1 g, 2.5 mmol) and chloroacetylchlorid (1 mL, 0.01
mol) were refluxed at 80◦C for 2 h, and then was allowed to cool and
was neutralized using Na2CO3 (10%) solution. The solid product thus
formed was collected and recrystallized from EtOH/CHCl3 mixture to
give 18 as yellow crystals in 76% yield, mp > 300◦C. Anal. Calcd. For:
C22H17ClN6O2S (464.94): C, 56.83; H, 3.69; Cl, 7.63; N, 18.08; S, 6.90%.
Found: C; 56.68; H, 3.45; Cl, 7.43; N, 17.97; S, 6.65%. IR: ν = 3450, 3200
cm−1 (2NH), 2900 cm−1 (CH aliphatic), 1695, 1660 cm−1 (2CO), 1560
1
cm−1 (C N). H NMR (CDCl3):δ = 2.6–2.9 (2s, 6H, 2CH3), 3.8(s, 1H,
CH2), 6.9–7.7 (m, 6H, Ar-H and CH pyridine), 8.9 (s, 1H, CH pyazole),
9.2, 10.3 (2s, 2H, 2NH).
1-Phenyl-6-chloromethyl-8,10-trimethylpyrido-
[2ꢀ,3ꢀ:2,3]thieno[4,5-e]pyrazolo-[3ꢀ,4ꢀ:4,5]pyrimido-
[1,2-c]pyrimidin-4-one (19)
A sample of 18 (2.1 g, 5.4 mmol) in acetic anhydride (20 mL) was re-
fluxed for 20 min after cooling the reaction mixture. The solid prod-
uct obtained was collected and recrystallized from dioxan to give
19 as yellowish crystals, mp 178–180◦C, yield (69%). Anal. Calcd.
for C22H15N6OSCl (446.91): C, 59.13; H, 3.38; Cl, 7.93; N, 18.80; S,
7.17%. Found: C, 59.01; H, 3.15; Cl, 8.14; N, 18.60; S, 7.01%. IR:
ν = 2990 cm−1 (CH aliphatic), 1720 cm−1 (CO), 1610 cm−1 (C =
N). 1H-NMR (CF3CO2D): δ = 3.1(s, 3H, CH3), 3.5 (s, 3H, CH3), 5.6
(s, 2H, CH2), 7.1(s, 1H, CH pyridine), 7.6–8.9 (m, 6H, Ar-H, CH
pyrazole).

Synthesis of Some Pyrazolopyrimidine Derivatives
2047
8,10-Dimethyl-6-(N-methylmorphonyl)-1-phenylpyrido-
[2ꢀ,3ꢀ:2,3] thieno[4,5-e]-pyrazolo[3ꢀ,4ꢀ:4,5]pyrimido-
[1,2-c]pyrimidin-4-one (20)
A mixture of 19 (0.25 g, 0.55 mmol) and morpholine (0.5 mL, 5.6 mmol)
was fused for 15 min then refluxed in ethanol for 3 h. The reaction
mixture was allowed to cool, and the solid product that formed was col-
lected and recrystallized from ethanol to give 20 as pale green crystals
in 47% yield, mp > 300◦C. Anal. Calcd. for C26H23N7O2S (497.58): C,
62.76; H, 4.66; N, 19.70; S, 6.44%. Found: C, 62.57; H, 4.47; N, 19.45;
S, 6.20%. IR: ν = 2950 cm−1 (CH aliphatic), 1690 cm−1 (C O). 1H NMR
(CDCl3): δ = 2.5, 2.7(2s, 6H, 2CH3), 2.3, 3.3 (2m, 8H, 4CH2), 3.9 (s,
2H, CH2), 6.9 (s, 1H, CH pyridine), 7.3–7.8 (m, 5H, 5Ar), 8.9 (s, 1H,
CH pyrazole). Mass spectrum m/z = 497 (M+, 5%), 412 (M+-(CH2)4NO,
100%), (86, 48.5%) for (CH2)4NO+.
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