Synthesis, Reactions, and Spectral Characterization of New Fused Pyrazolothienopyridine and Pyrazolopyrrolopyridine Systems

Article abstract of DOI:10.1002/jhet.2798

4-Oxo-1-phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile compound (4) was prepared by the reaction of 5-amino-3-methyl-1-phenyl pyrazole (1) with ethyl 2-cyano-3-ethoxyacrylate followed by cyclization using diphenyl ether. The pyrazolopyridinone c

Full text of DOI:10.1002/jhet.2798

Month 2017
Synthesis, Reactions, and Spectral Characterization of New Fused
Pyrazolothienopyridine and Pyrazolopyrrolopyridine Systems
*
A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem
Chemistry Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt
*
E-mail: remonch2003@yahoo.com, remon.asal2015@gmail.com
Received July 27, 2016
DOI 10.1002/jhet.2798
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
4-Oxo-1-phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile compound (4) was prepared by the
reaction of 5-amino-3-methyl-1-phenyl pyrazole (1) with ethyl 2-cyano-3-ethoxyacrylate followed by
cyclization using diphenyl ether. The pyrazolopyridinone compound
4 was converted to the
chloropyrazolopyridine 5 by the reaction with phosphorus oxychloride. Compound 5 was used as a starting
material to synthesize 3-amino-4-substituted pyrazolothienopyridine derivatives 10a–f and ethyl-3-
aminopyrazolopyrrolopyridine-2-carboxylate 21, which were used as a versatile precursors for synthesis
of poly-fused heterocyclic compounds.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
Pyrazolo[3,4-b]pyridine compounds are
interesting class of heterocyclic compounds and play an
important role in medicinal chemistry [1,2] because
they were used as an anxiolytic drug, which have
similar effects to benzodiazepine drugs, but is
also acts as a phosphodiesterase inhibitor selective for
the PDE4 isoform and ICI-190,622 effective anxiolytic
with significant advantages over benzodiazepines [8,9]
(Fig. 1).
a
very
The pyrazolopyridine compounds exhibit a broad
spectrum of biological activities such as antimalarial
[10], antiproliferative [11], and cardiovascular activities
[12–14] and are used as antiviral [15,16],
antileishmanial [17], and anti-inflammatory agents [18].
Our target in this work aims to synthesize fused
heterocyclic systems containing thienopyrazolopyridine
nucleus. Earlier, we reported the synthesis of pyrazolo
[3,4-b]pyridines and their sulfonamide derivatives as
antibacterial agents [19], but recently, we have
synthesized thieno[2,3-c]pyrazoles and we have tested
them as antimicrobial, anti-inflammatory [20] and
antioxidant against toxicity of 4-nonylphenol in Clarias
gariepinus [21]. Also, some selenolo[2,3-c]pyrazole
structurally distinct and so is classed as
a non-
benzodiazepine anxiolytic drug [3,4]. The best examples
of compounds from these categories are cartazolate,
which acts as a GABAA receptor-positive allosteric
modulator at the barbiturate binding site of the complex
and has anxiolytic effects in animals. Tracazolate,
which gave the same action as benzodiazepines, acts at
the same receptor but has distinct chemical
structures [5]. Etazolate is a selective inhibitor of type
4
phosphodiesterase (PDE4) [6] and acts as an
adenosine antagonist of the A1 and A2 subtypes [7]. It
© 2017 Wiley Periodicals, Inc.

A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem Vol 000
Figure 1. Non-benzodiazepine anxiolytic drugs containing pyrazolo[3,4-b]pyridine moiety.
compounds were synthesized and used as antimicrobial
and anti-inflammatory agents [22].
salt 6 was carried out by reflux with sodium hydroxide
solution (10%) to afford the corresponding sulfanyl
sodium salt 7, which upon acidification with conc. HCl
solution afforded the mercapto pyrazolopyridine
carbonitrile compound 8. The chemical structure of
compound 8 was elucidated by elemental and spectral
analyses. Mass spectrum fragmentation pattern showed a
base peak at 266 corresponding to the molecular ion peak
(Scheme 1).
The thiole group in 4-mercapto-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile compound (8) was
alkylated by the reaction with α-halogenated carbonyl
compounds in refluxing ethanol in the presence of
anhydrous sodium carbonate to afford the non-isolated
S-alkylated pyrazolopyridine intermediates 9a–f, which
underwent Thorpe–Ziegler cyclization in situ to the
3-amino-2-substituted-pyrazolothieno-pyridines (10a–f)
under the same reaction conditions. Formation of
compounds 10a–e was established on the basis of
spectral analyses. IR spectra revealed appearance of
absorption bands characteristic to NH2 group. Also the
1H NMR spectra showed appearance of singlet signals
characteristic for NH2 groups in compounds 10a–e
(Scheme 2).
RESULTS AND DISCUSSION
Condensation
of
5-amino-3-methyl-1-phenyl-1H-
pyrazole (1) with ethyl 2-cyano-3-ethoxyacrylate (2) in
refluxing ethanol afforded ethyl 2-cyano-3-(3-methyl-1-
phenyl-1H-pyrazol-5-ylamino)acrylate (3), which was
considered as
a starting intermediate for building
pyrazole[3,4-b]pyridine nucleus (4). The ethyl acrylate
ester compound 3 was cyclized upon boiling in diphenyl
ether through loss of ethanol molecule to give 3-methyl-
4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-
5-carbonitrile (4). The structure of compounds 3 and 4 was
established by their elemental and spectral analyses. IR
spectrum of compound 3 showed an absorption band at
3130cmꢀ1 characteristic for NH group; 2973 and
2930cmꢀ1 for ethyl group; and 2118 and 1670cmꢀ1 for
CN and CO groups, respectively. Upon cyclization of the
pyrazolyl ester compound 3 to the oxopyrazolo[3,4-b]
pyridine carbonitrile compound 4, the band characteristic
for NH group shifted to 3195cmꢀ1, the band characteristic
for CN group shifted to 2234cmꢀ1, and the band
characteristic for ethyl group disappeared. 1H NMR of
compound 3 in CDCl3 showed triplet and quartet signals
at δ 2.30 and 4.20ppm characteristic for CH3 and CH2
ester group. The latter triplet and quartet signals
disappeared by cyclization to compound 4.
Condensation
of
3-amino-8-methyl-6-phenyl-6H-
pyrazolo[3,4-b]thieno[2,3-d]pyridine-2-carbaldehyde
Scheme 1. Synthesis of 4-mercapto-3-methyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-5-carbonitrile (8).
The
4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]
pyridine-5-carbonitrile compound (5) was prepared in
quantitative yield according to literature procedure
[23,24] by refluxing the pyrazolopyridine carbonitrile
compound 4 with phosphorus oxychloride. The structure
of chloropyridine 5 was established by its elemental and
spectral analyses. IR spectrum revealed disappearance of
absorption bands characteristic for NH and CO groups
1
presented in the starting material 4. H NMR in CDCl3
showed singlet signal at δ 8.67 ppm for CH pyridine.
Compound 5 was converted to 4-mercapto-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (8) by
refluxing compound 5 with thiourea to afford the
thiouronium salt 6. Basic hydrolysis of the thiouronium
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Synthesis of New Pyrazolothienopyridine and Pyrazolopyrrolopyridine
Compounds
Scheme 2. Synthesis of 3-amino-2-substituted-8-methyl-6-phenyl-6H-
pyrazolo[3,4-b]thieno[2,3-d]pyridine (10a–f).
give the tetracyclic system 12. Formation of compound
12 was confirmed by elemental and spectral data. Mass
spectrum of compound 12 showed a peak at m/z= 356
corresponding to the molecular ion peak and the base
peak. On the other hand, reaction of amino
carboxyaldehyde compound 12 with acetyl acetone in
ethanolic potassium hydroxide solution afforded
1-(1,7-dimethyl-3-phenylpyrido[2′,3′:4,5]thieno[2,3-d]
pyrazolo[3,4-b]pyridin-8-yl)ethanone (13). The structure of
compound 13 was elucidated by elemental and spectral
analyses. IR spectrum revealed disappearance of
absorption bands characteristic for NH2 and CHO in the
starting compound 10e and appearance of absorption band
at 1670cmꢀ1 for (C¼O) of acetyl group. Mass spectrum
showed peak at 372 as a molecular ion peak in addition to
the base peak at 330 characteristic for molecular ion peak
minus 43, which means the molecule losses of COCH3
group (Scheme 3).
compound (10e) with N-methyl piperidone as
a
heterocyclic ketone in ethanol at room temperature in
the presence of potassium hydroxide solution afforded
the newly fused polyheterocyclic system, namely,
1,9-dimethyl-3-phenyl-7,8,9,10-tetrahydro-3H-pyrazolo
[4″,3″:5′,6′]pyrido[3′,4′:4,5]thieno[3,2-b][1,6]
naphthyridine (11).
When the amino pyrazolopyridine carbaldehyde
compound 10e was allowed to react with malononitrile in
refluxing ethanol in the presence of piperidine as a basic
Condensation of the amino pyrazolothienopyridine
carbonitrile compound 10f with triethyl orthoformate in
the presence of acetic anhydride afforded the ethyl
fomimidate compound 14. The imidate compound 14 was
cyclized by the reaction with hydrazine hydrate through
loss of ethanol molecule followed by cycloaddition
reaction of NH group on CN group to afford the
catalyst,
the
amino
pyridothienopyrazolopyridine
carbonitrile compound 12 was obtained. The reaction
proceeded via condensation of aldehydic group with
active methylene in malononitrile followed by
cycloaddition reaction of amino group on nitrile group to
corresponding
8-amino-9-iminopyrazolopyridothieno-
pyrimidine compound 15. The structure of compound 15
was established by mp, thin-layer chromatography, IR,
and mass spectra. Its IR spectrum showed absorption
Scheme 3. Reaction of amino carboxyaldehyde 10e compound with active methylene compounds.
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A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem Vol 000
bands at 3420, 3270, and 3246cmꢀ1 characteristic for NH2
and NH groups. Mass spectrum showed peak at 347 as a
molecular ion peak and peak at 317 as a base peak.
characteristic for NH and C¼S groups, respectively. Mass
spectrum showed peak at m/z 380 characteristic for the
molecular ion peak in addition to peak at m/z 300 as a base
peak (Scheme 4).
The amino imino compound 15 was used as a
versatile precursor for synthesis of other heterocyclic
compounds 16–18. Thus, reaction with carbon
disulfide in pyridine on a steam bath afforded the
triazolopyrazolopyridothienopyrimidine thione compound
16, which was alkylated with ethyl chloroacetate in
ethanol and fused sodium acetate to give the ethyl sulfanyl
acetate derivative 17. Also, reaction of the amino imino
compound 15 with acetic anhydride afforded the dimethyl
pyrazolopyridothieno-triazolopyrimidine compound 18.
The reaction proceeded with acetylation of amino group
followed by tautomerism and cyclization by loss of water
molecule to give the methyl pyrazolyl derivative 18. The
structure of compound 17 was established by elemental
and spectral data. IR spectrum showed absorption bands at
1735 cmꢀ1 for CO ester group. 1H NMR spectrum in
deuterated dimethyl sulfoxide (DMSO-d6) showed triplet
and quartet signals at δ 1.40 and 4.30ppm for the ethyl
ester group and singlet signal at δ 3.90ppm for SCH2
group. On the other hand, reaction of amino
pyrazolothienopyridine carbonitrile compound 10f with
carbon disulfide in pyridine on a steam bath yielded the
pyrazolopyridothienopyrimidine dithione compound 19 as
tetracyclic system. IR spectrum of the dithione compound
19 showed absorption bands at 3421 and 1174 cmꢀ1
The mechanism for formation of pyrimidine dithione
compound 19 was suggested to proceed through the
addition of carbon disulfide on the amino group to give
dithiocarbamic acid intermediate a followed by the
addition of mercapto group on the cyano group to give
the imino thiazine thione ring b. The latter intermediate b
underwent Dimroth rearrangement between the imino
group and sulfur atom in the thiazine ring, which yielded
finally the pyrimidine dithione compound 19 as shown in
Scheme 5.
The chlorine atom in chloropyrazolopyridine
carbonitrile compound
5
underwent nucleophilic
substitution reaction with ethyl glycinate in
dimethylformamide and in the presence of potassium
carbonate to afford ethyl pyrazolopyridinyl aminoacetate
compound 20, which underwent Thorpe–Ziegler
cyclization upon heating with sodium ethoxide solution
to afford ethyl-3-amino-1,6-dihydro-6H-phenylpyrazolo
[3,4-b]pyrrolo[2,3-d]pyridine-2-carboxylate (21). Also,
the ethyl aminoacetate compound 20 was cyclized to
ethyl-3-amino-1-methyl-6H-phenylpyrazolo[3,4-b]pyrrolo
[2,3-d]pyridine-2-carboxylate (22) upon heating in acetone
in the presence of methyl iodide and anhydrous potassium
carbonate.
Scheme 4. Synthesis and reactions of 8-amino-9-imino-1-methyl-3-phenyl-3,9-dihydro-8H-pyrazolo[4″,3″:5′,6′]pyrido[3′,4′:4,5]thieno[3,2-d]pyrimidine (15).
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Synthesis of New Pyrazolothienopyridine and Pyrazolopyrrolopyridine
Compounds
Scheme 5. The suggested mechanism for formation pyrazolopyridothienopyrimidine dithione.
Scheme 6. Synthesis and reactions of ethyl pyrazolopyrrolopyridine carboxylate compounds 21 and 22.
Both compounds 21 and 22 reacted with formamide to
give the tetracyclic pyrazolopyridopyrrolopyrimidine
compounds (23a, b). The structure of compound 23a was
3279, and 3152 cmꢀ1 for NH and NH2 groups. Mass
spectrum of compound 24 showed a peak at m/z= 264
corresponding to its molecular ion peak and as a base
peak (Scheme 6).
1
confirmed by its IR, H NMR, and 13C NMR analyses.
IR spectrum showed two absorption bands at 3446 and
3350 cmꢀ1 characteristic for 2NH groups and at
1
1654 cmꢀ1 for CO amidic group. H NMR spectrum in
CONCLUSION
DMSO-d6 showed two singlet signals at δ 8.13 and
9.16ppm characteristic for CH and NH groups,
respectively. 13C NMR showed signal at δ 163.38 ppm
characteristic for CO pyrimidine.
The chloro pyrazolo[3,4-b]pyridine carbonitrile
compound 5 reacted with hydrazine hydrate in refluxed
The aim of this work was to synthesize new 3-amino-2-
substituted-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno
[2,3-d]pyridine derivatives (10a–f), which were used as a
versatile precursor for synthesis of new heterocyclic rings
fused to pyrazolothienopyridine system, namely:
pyridine, naphthyridine, pyrimidine, and triazolopymidine.
ethanol
dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-3-yl amine (24).
The reaction proceeded through nucleophilic
to
give
8-methyl-6-phenyl-1,6-
displacement of chlorine with hydrazino group followed
by cycloaddition reaction of amino group to cyano group
to give compound 24. Formation of compound 24 was
established by the elemental and spectral analyses. IR
spectrum revealed disappearance of absorption bands at
2234 cmꢀ1 characteristic for (CN), which presented in
compound 5 and appearance of absorption bands at 3432,
EXPERIMENTAL
All melting points are corrected and measured on a
Gallenkamp apparatus (LABEQUIP LTD., Ontario,
Canada). The IR spectra were recorded using on a
Shimadzu 470 IR-spectrophotometer (LABEQUIP LTD.,
1
Ontario, Canada) using KBr wafer technique. H NMR
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A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem Vol 000
and 13C NMR spectra were measured on 400 MHz Jeol and
400MHz Bruker spectrometers in deuterated chloroform
(CDCl3) or DMSO-d6 with trimethylsilyl as internal
standard and chemical shifts are expressed as ppm. Mass
spectrometric analysis was recorded on a Jeol JMS-600
mass spectrometer. Elemental analyses were determined on
an Elemental Analyses System GmbH VARIOEL V2,3
CHNS Mode in the central lab of Assiut University, and all
results were found to be in an acceptable range (ꢁ0.25).
Compounds 1 and 3 were prepared according to literature
procedure [23,24] with mp 114–117 and 180°C, respectively.
H, 3.38%; Cl, 13.19%; N, 20.85%. Found: C, 62.41%;
H, 3.22%; Cl, 13.01%; N, 20.45%.
4-Mercapto-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (8).
A mixture of chloro compound 5 (4 g,
0.01mol) and thiourea (1.1 g, 0.01 mol) in dry ethanol
(20mL) was heated under reflux for 2 h. The obtained solid
product of thiouronium salt was filtered off, dissolved in
sodium hydroxide solution (10%, 50 mL), and refluxed for
30 min. The sodium salt solution was allowed to cool and
then was acidified with dilute HCl to just neutral; solid
mercapto compound was filtered off, washed with water, and
recrystallized from ethanol to afford orange crystals of 8 in
75% yield; mp: 243–245°C; ir: NH 3446cmꢀ1, CN
2225cmꢀ1; 1H nmr: δ (CDCl3) 2.69 (s, 3H, CH3), 7.36–7.71
(m, 5H, Ar-H), 8.40 (s, 1H, CH pyridine), and 8.74 ppm (s,
1H, NH); ms: m/z= 266.12 (M+) and base peak. Anal. Calcd
for C14H10N4S (266.32): C, 63.14%; H, 3.78%; N, 21.04%;
S, 12.04%. Found: C, 63.04%; H, 3.45%; N, 21.01%; S,
Ethyl
2-cyano-3-((3-methyl-1-phenyl-1H-pyrazol-5-yl)
amino)acrylate (3).
A mixture of ethyl 2-cyano-3-
ethoxyacrylate (2) (10.4 g, 0.06mol) and 5-amino-3-
methyl-1-phenyl pyrazole (1) (10.6 g, 0.06 mol) in
absolute ethanol (100 mL) was refluxed for 1 h and then
cooled. The solid product that formed upon cooling was
filtered off and recrystallized from ethanol to give 3 as
white crystals in 78% yield; mp: 198–200°C; ir: NH
12.03%.
1
3183, CH aliphatic 2973, CN 2218, C¼O 1670 cmꢀ1; H
Reaction of (8) with different halo compounds such as α-halo
ketones, α-halo ester, α-halo amide, α-halo anilides, and α-halo
nitrites: formation of 10a–f. General procedure. A mixture
nmr: δ (CDCl3) 1.28 (t, 3H, CH3 ester), 2.32 (s, 3H,
CH3), 4.20 (q, 2H, CH2 ester), 7.39–756 (m, 5H, ArH),
7.61 (d, 1, H, –CH¼C), and 10.83 ppm (s, 1H, NH); ms
m/z 296 (M+) as molecular ion peak and at m/z =250 as
base peak. Anal. Calcd for C16H16N4O2 (296.33): C,
64.85%; H, 5.44%; N, 18.91%. Found: C, 64.51%; H,
5.22%; N, 18.73%.
of compound
8
(0.01mol), α-halogenated carbonyl
compounds (0.01 mol), and anhydrous potassium carbonate
(2g, 0.015 mol) in ethanol (20mL) was refluxed for 1 h,
and then the mixture was allowed to cool. The solid
product was collected, washed with water several times,
dried, and recrystallized from the proper solvent.
3-Methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]
pyridine-5-carbonitrile (4). The acrylate 3 (3 g, 0.01mol)
2-Acetyl-3-amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]
thieno[2,3-d]pyridine (10a).
Produced according to the
was added to boiling biphenyl ether (20 mL) and heated
under reflux for 30 min until the crystals were
precipitated and then allowed to cool. The solid product
was collected, washed with petroleum ether, and
recrystallized from ethanol to give 4 as orange crystals in
60% yield; mp: 297–298°C; ir: NH 3195, CH aromatic
aforementioned general procedure as yellow crystals from
ethanol in 71% yield; mp: 320–321°C; ir: NH2 3431,
1
3328cmꢀ1; H nmr: (CDCl3) δ 2.10, 2.63 (2s, 6H, 2CH3),
7.27 (s, 2H, NH2), 7.19–7.49 (m, 5H, Ar-H), 8.12 (s, 1H,
CH pyridine), and 8.79ppm (s, 2H, NH2); 13C nmr: δ 13.91
(C9: CH3 pyrazole), 29.17 (C11: CH3 acetyl), 105.27
(C3a), 110.75 (C8b), 121.28, 123.34, 126.24 (C13–C17:
5CH aromatic carbons), 129.32 (C8a), 139.43 (C2), 141.50
(C12: C–N of aromatic), 142.15 (C8), 146.21 (C4), 149.39
1
3059, CN 2234, CO 1670 cmꢀ1; H nmr: δ (CDCl3) 2.49
(s, 3H, CH3), 7.36–7.71 (m, 5H, Ar-H), 8.35 (s, 1H, CH
pyridine), and 10.72 ppm (s, 1H, NH). Anal. Calcd for
C14H10N4O (250.26): C, 67.19%; H, 4.03%; N, 22.39%.
Found: C, 67.02%; H, 4.01%; N, 22.15%.
(C5a), 150.96 (C3), 190.47 (C10: CO); ms m/z=322 (M+)
and base peak. Anal. Calcd for C17H14N4OS (322.39): C,
63.34%; H, 4.38%; N, 17.38%; S, 9.94%. Found: C,
63.12%; H, 4.34%; N, 17.50%, S, 9.80%.
4-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-
carbonitrile (5).
A mixture of 4 (3.5 g, 0.01mol) in
phosphorous oxychloride (20 mL) was refluxed for 4h,
allowed to cool, poured into ice–water mixture, and then
neutralized with Na2CO3. The solid product was
collected by filtration and recrystallized from pure
ethanol to afford 5 as yellow crystals in 91% yield; mp:
Ethyl-3-amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno
[2,3-d]pyridine-2-carboxylate (10b). Produced according to
the previous general procedure as brown crystals from
acetic acid in 72% yield; mp: 238–240°C; ir: NH2 3436,
3328, CH aliphatic 2976, CO 1670 cmꢀ1 1H nmr: δ
;
1
164–165°C; ir: CN 2234 cmꢀ1; H nmr: δ (CDCl3) 2.83
(CDCl3) 1.45 (t, 3H, CH3 ester), 2.8 (s, 3H, CH3
pyrazole), 4.42 (q, 2H, CH2 ester), 7.28 (s, 2H, NH2),
7.3–7.55 (m, 5H, Ar H), and 8.20 ppm (s, 1H, CH
pyridine); 13C nmr: 13.92 (C9: CH3 pyrazole), 14.87
(C13: CH3 ester), 60.20 (C12: CH2 ester), 121.24,
123.50, 126.16 (C15–C19: 5 aromatic carbons), 129.30
(C3a), 139.30 (C8a), 141.66 (C3), 142.10 (C14: –C–N of
(s, 3H, CH3), 7.2–7.54 (m, 5H, Ar-H), and 8.64ppm (s,
1H, CH pyridine); 13C nmr: δ 9.88 (C8: CH3 pyrazole),
109.89 (C3a), 110.07 (C5), 116.63 (C9: CN), 124.44,
122.31, 116.68 (C11–C15 aromatic), 133.34 (C10:
aromatic), 137.76 (C4), 138.99 (C3), 146.15 (C6), 146.79
(C7a). Anal. Calcd for C14H9ClN4 (268.70): C, 62.58%;
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Compounds
aromatic), 145.55 (C8), 149.23 (C4), 150.75 (C5a), 164.40
(C10: CO ester); ms m/z= 351 (M+) and base peak. Anal.
Calcd for C18H16N4O2S (352.41): C, 61.35%; H, 4.58%;
N, 15.90%; S, 9.10%. Found: C, 61.25%; H, 4.40%; N,
15.78%; S, 9.08%.
3-Amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2,3-d]
pyridine-2-carboxamide (10c). Produced according to the
13.84 (C9: CH3 pyrazole), 110.66 (C10, CN), 116.11,
121.37, 122.04 (C12–C16: 5C aromatic), 126.59 (C2),
129.59 (C11), 139.25 (C3a), 141.62 (C4), 142.13 (C8b),
145.27 (C8a), 149.12 (C5a) 153.34 (C3: C–NH2). Anal.
Calcd for C16H11N5S (305.36): C, 62.93%; H, 3.63%; N,
22.94%; S, 10.50%. Found: C, 62.90%; H, 3.58%; N,
22.88%; S, 10.34%.
previous general procedure as yellow crystals from
1,9-Dimethyl-3-phenyl-7,8,9,10-tetrahydro-3H-pyrazolo
[4″,3″:5′,6′]pyrido[3′,4′:4,5] thieno[3,2-b][1, 6]naphthyridine
(11). A mixture of 10e (1.54g, 0.001mol) and N-methyl-
ethanol in 85% yield; mp: 250–251°C; ir: 2NH2 3443,
1
3333, 3185, CO 1675 cmꢀ1; H nmr: (DMSO-d6) δ 2.67
(s, 3H, CH3), 7.27 (s, 2H, NH2), 7.36–7.71 (m, 5H, Ar-
H), 8.21 (s, 1H, CH pyridine), and 9.20 ppm (s, 2H,
NH2); 13C nmr: δ 13.5 (C9: CH3), 97.01 (C8a), 110.42
(C3a), 120.83, 123.91, 125.97, 129.15 (C12–C16: 5C
aromatic), 139.03 (C11: C–N aromatic), 139.15 (C8b: C4
in pyridine), 141.53 (C2), 144.82 (C8), 144.82 (C4),
148.31 (C3), 148.59 (C5a), 166.49 (C10: CO amide); ms
m/z= 322.78 as base beak and molecular ion peak. Anal.
Calcd for C16H13N5OS (323.37): C, 59.43%; H, 4.05%;
N, 21.66%; S, 9.91%. Found: C, 59.41%; H, 4.01%; N,
4-piperidone (0.56 mL, 0.005mol) in ethanolic KOH
(20mL, 10%) was stirred at room temperature for 1h. The
solid product that separated from the hot mixture was
filtered off and recrystallized from the acetic acid into
yellow crystals of compound 11 in 67% yield; mp: 235–
237°C; ir: CH aromatic 3075, CH aliphatic 2938, 2838,
1
C¼N 1592cmꢀ1; H nmr (CDCl3) δ 2.59, 2.85 (2s, 6H,
2CH3), 2.97–2.98 (t, 2H, CH2), 3.83 (t, 2H, CH2), 3.35 (s,
2H, CH2), 7.28–7.59 (m, 5H, Ar-H), and 8.26, 8.29 ppm
(2s, 2H, 2CH pyridine). 13C nmr δ (CDCl3):13.89 (C13:
CH3 pyrazole), 32.52 (C10: CH2 piperidine), 45.79 (C14,
CH3–N piperidine), 52.97 (C9: CH2 piperidine), 57.56 (C7:
CH2 piperidine), 121.65–124.97 (C15–C20, 6C aromatic),
126.16 (C10a), 128.27 (C12a), 129.14 (C6a), 139.41 (C1),
141.78 (C5b), 144.45 (C6a), 149.77 (C3a). Anal. Calcd for
C22H19N5S (385.49): C, 68.55%; H, 4.97%; N, 18.17%; S,
8.32%. Found: C, 68.23%; H, 4.80%; N, 18.09%; S, 8.28%.
21.53%; S, 9.88%.
3-Amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2,3-d]
pyridine-2-N-(4-chloro phenyl)carboxamide (10d).
Produced
according to the previous general procedure as pale brown
crystals from acetic acid in 67% yield; mp: 290–292°C; ir:
1
NH2 3440, 3330 cmꢀ1; H nmr (DMSO-d6) 2.71 (s, 3H,
CH3), 7.37 (s, 2H, NH2), 7.31–7.36, 7.49–7.58 (2m, 5H,
Ar-H), 7.76, 8.23 (2d, 4H, CH-Ar), 8.23 (s, 1H, CH
pyridine), 9.26 (s, 1H, NH). 13C nmr: 13.99 (C9: CH3
pyrazole), 89.44 (C8a), 110.73 (C4), 121.26, 121.30,
122.82, 123.96 (C19–C23: 5C aromatic), 128.72, 129.57,
139.44, 139.94 (C13, C14, C16, C17, p-Cl-phenyl), 142.00
(C15: C–Cl), 143.74 (C18, C–N phenyl), 145.35 (C15, C–
N p-Cl phenyl), 149.14 (C8b), 150.25 (C2), 152.81 (C8),
150.25 (C4), 155.62 (C3), 163.92 (C5a), 163.58 (C10, CO).
Anal. Calcd for C22H16ClN5OS (433.91): C, 60.90%; H,
3.72%; Cl, 8.17%; N, 16.14%; S, 7.39%. Found: C,
7-Amino-1-methyl-3-phenylpyrido[4,5]thieno[2,3-d]pyrazolo
[3,4-b]pyridine-8-carbonitrile (12). A mixture of 10e (1.54g,
5 mmol), malononitrile (0.33g, 1mmol), and a few drops of
piperidine in ethanol (20 mL) was refluxed for 2h. The
solid product that separated from the hot mixture was
filtered off, washed with ethanol, and recrystallized from
dioxane into orange crystals of 12 in 60% yield; mp:
>300°C; ir: NH2 3387, 3346, CN 2219cmꢀ1 1H nmr:
;
(DMSO-d6) δ 2.60 (s, 3H, CH3), 7.16 (s, 2H, NH2), 7.36–
7.57 (m, 5H, Ar-H), and 8.14, 8.45ppm (2s, 2H, 2CH
pyridine); ms: m/z=356 as a molecular ion peak and base
peak. Anal. Calcd for C19H12N6S (356.41): C, 64.03%; H,
3.39%; N, 23.58%; S, 9.00%. Found: C, 64.00%; H,
3.28%; N, 23.51%; S, 8.93%.
60.88%; H, 3.66%; Cl, 8.14%; N, 16.03%; S, 7.34%.
3-Amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2,3-d]
pyridine-2-carbaldehyde (10e).
Produced according
previous general procedure as pale yellow from ethanol
in 58% yield; mp: 250–252°C; ir: NH2 3299, 3189, CO
1
1-(1,7-Dimethyl-3-phenylpyrido[4,5]thieno[2,3-d]pyrazolo
1617; H nmr: (DMSO-d6) δ 2.63 (s, 3H, CH3), 7.27 (s,
[3,4-b]pyridin-8-yl)ethan-1-one (13).
A mixture of 10e
2H, NH2), 7.38–7.72 (m, 5H, Ar-H), 8.09 (s, 1H, CH
pyridine), 8.39 (s, 2H, NH2), and 8.99 ppm (s, 1H, CHO).
Anal. Calcd for C16H12N4OS (308.36): C, 62.32%; H,
3.92%; N, 18.17%; S, 10.40%. Found: C, 62.21%; H,
3.90%; N, 18.13%; S, 10.22%.
3-Amino-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2,3-d]
(1.54 g, 1mmol) and acetylacetone (0.5 mL, 5 mmol) in
ethanolic KOH (20 mL, 10%) was stirred for 2 h. The
solid product that separated from the hot mixture was
filtered off and recrystallized from dioxane to afford
orange crystals of 13 in 46% yield; mp: 230–232°C; ir:
CH aromatic; CH aliphatic 3040, 2923, α,β-unsat CO
1670, C¼N 1628cmꢀ1; ms: (m/z) 372 (M+), 330 (M+–
CH3CO) as the base peak. Anal. Calcd for C21H16N4OS
(372.45): C, 67.72%; H, 4.33%; N, 15.04%; O, 4.30%; S,
8.61. Found: C, 67.66%; H, 4.23%; N, 15.00%; O,
4.18%; S, 8.43%.
pyridine-2-carbonitrile (10f).
Produced according to the
previous general procedure as pale yellow from ethanol
in 75% yield; mp: 289–290°C; ir: NH2 3432, 3338, CN
1
2197 cmꢀ1; H nmr (DMSO-d6): δ= 2.63 (s, 3H, CH3),
7.27 (s, 2H, NH2), 7.33–7.57 (m, 5H, Ar-H), 8.19 (s, 1H,
CH pyridine), 9.2 (s, 2H, NH2); 13C nmr (DMSO-d6) δ:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem Vol 000
Ethyl
N-(2-cyano-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]
Calcd for C22H17N7O2S2 (475.54): C, 55.57%; H, 3.60%;
N, 20.62%; S, 13.48%. Found: C, 55.48%; H, 3.52%; N,
20.54%; S, 13.32%.
thieno[2,3-d]pyridin-3-yl) formimidate (14). A mixture of
aminocarbonitrile compound 10f (3 g, 0.01 mol) and
triethyl orthoformate (10 mL) in acetic anhydride (10 mL)
was refluxed for 2 h and then cooled. The solid product
was filtered off and recrystallized from ethanol into buff
crystals of 14 in 57% yield; mp: 210–211°C. ir: CH
2,11-Dimethyl-9-phenyl-9H-pyrazolo[4″,3″:5′,6′]pyrido[3′,
4′:4,5]thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (18).
Compound 15 (0.2 g, 0.5mmol) and acetic anhydride
(3mL) were gently refluxed for 3h. The solid product
obtained after cooling was filtered off and recrystallized
from acetic acid to give white crystals of 18 in 40% yield;
mp: >300°C; ir: CH aromatic 3061, CH aliphatic 2994,
C¼N 1625cmꢀ1; ms: m/z 371 as a molecular ion peak and
base peak. Anal. Calcd for C19H13N7S (371.42): C,
61.44%; H, 3.53%; N, 26.40%; S, 8.63%. Found: C,
61.35%; H, 3.48%; N, 26.32%; S, 8.53%.
aliphatic CN 2988, 2206cmꢀ1; H nmr: (CDCl3) δ 1.23
1
(t, 3H, CH3 ester), 2.69 (s, 3H, CH3 pyrazole), 4.16 (q,
2H, CH2 ester), 7.26–7.29, 7.45–7.48 (2m, 5H, Ar-H),
8.11 (s, 1H, CH pyridine), 8.7 (s, 1H, N–CH–O); ms: m/
z =361 as a molecular ion peak and base peak. Anal.
Calcd for C19H15N5OS (361.42): C, 63.14%; H, 4.18%;
N, 19.38%; S, 8.87%. Found: C, 63.11%; H, 4.09%; N,
19.26%; S, 8.76%.
1-Methyl-3-phenyl-3H-pyrazolo[4″,3″:5′,6′]pyrido[3′,4′:4,
5]thieno[3,2-d]-pyrimidine-7,9(6H,8H)-dithione (19).
A
8-Amino-9-imino-1-methyl-3-phenyl-3,9-dihydro-8H-
pyrazolo[4″,3″:5′,6′]pyrido[3′,4′:4,5]thieno[3,2-d]pyrimidine
mixture of amino carbonitrile compound 10f (2 g,
5 mmol) and carbon disulfide (1.5 mL) in pyridine
(5 mL) was refluxed on steam bath for 4 h. The solid
precipitate that formed upon heating was recrystallized
from ethanol to afford orange crystals in 45% yield;
mp: >300°C; ir: NH 3421, C¼N 1589, C¼S
1174 cmꢀ1; ms: m/z 380 as a molecular ion peak and at
m/z = 300 as base peak. Anal. Calcd for C17H11N5S3
(381.49): C, 53.52%; H, 2.91%; N, 18.36%; S, 25.21.
Found: C, 53.49%; H, 2.85%; N, 18.31%; S, 25.18%.
(15).
A solution of 14 (4 g, 0.01 mol) in cold dioxane
(10mL) was stirred at room temperature, then hydrazine
hydrate (98%, 2 mL) was added to the solution with stirring
for 1h. The solid product that formed was collected and
recrystallized from ethanol-dioxane as white crystals of 15
in 68% yield; mp: 265–266°C; ir: 3420, 3270, 3246 cmꢀ1
(NH2, NH), 1635 cmꢀ1 (C¼N). ms: m/z 347 as a molecular
ion peak and base peak at m/z=317. Anal. Calcd for
C17H13N7S (347.40): C, 58.78%; H, 3.77%; N, 28.22%; S,
9.23%. Found: C, 58.48%; H, 3.63%; N, 28.19%; S, 9.19%.
Ethyl(5-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyrid
in-4-yl)glycinate (20). A mixture of chloropyrazolo[3,4-
b]pyridine carbonitrile compound 5 (3 g, 0.01 mol), ethyl
11-Methyl-9-phenyl-3H-pyrazolo[4″,3″:5′,6′]pyrido[3′,4′:
4,5]thieno[2,3-e][1, 2, 4]-triazolo[1,5-c]pyrimidine-2(9H)-
thione (16).
A mixture of compound 15 (0.4 g,
glycinate hydrochloride (3 g, 0.02 mol), and anhydrous
1 mmol) and carbon disulfide (1.5 mL) in pyridine
(5 mL) was refluxed on a steam bath for 4 h. The solid
precipitate that formed upon heating was recrystallized
from ethanol to afford orange crystals of 16 in 45%
yield; ir: NH 3430 and C¼N 1590cmꢀ1; mp: 298–300°C;
1H nmr: (DMSO-d6) δ 2.51 (s, 3H, CH3 pyrazole),
7.38–7.41, 7.57–7.62 (m, 5H, Ar-H), 8.58 (s, 1H, CH
pyridine), and 8.10ppm (s, 1H, NH). Anal. Calcd for
C18H11N7S2 (389.45): C, 55.51%; H, 2.85%; N,
25.18%; S, 16.46%. Found: C, 55.42%; H, 2.76%; N,
25.09%; S, 16.35%.
potassium
carbonate
(3.4 g,
2.5 mmol)
in
dimethylformamide (35 mL) was heated on steam bath
at 70–80°C for 8 h. After cooling, the reaction mixture
was poured into ice–water mixture slowly with stirring.
The solid product was filtered off and recrystallized
from ethanol to give white crystals of 20 in 83% yield;
mp: 199–200°C; ir NH 3398, CH aliphatic 2988, CN
2216 and CO 1731 cmꢀ1; H nmr: (CDCl3) δ 1.39 (t,
1
3H, CH3), 2.85 (s, 3H, CH3), 4.38 (q, 2H, CH2), 4.65
(d, 2H, CH2), 7.31–7.41, 7.49–7.57 (m, 5H, Ar-H),
8.13 (s, 1H, CH pyrimidine), and 8.41 ppm (s, 1H,
NH). Anal. Calcd for C18H17N5O2 (353.37): C,
64.47%; H, 5.11%; N, 20.88%. Found: C, 64.42%; H,
5.07%; N, 20.83%.
Ethyl
2-((11-methyl-9-phenyl-9H-pyrazolo[4″,3″:5′,6′]
pyrido[3′,4′:4,5]thieno[2,3-e][1,2,4]-triazolo[1,5-c]pyrimidin-
2-yl)thio)acetate (17). A mixture of the triazolothione 15
(0.2 g, 0.4mmol) and ethyl chloroacetate (0.06 mL,
0.4mmol) in ethanol (30 mL) in the presence of
anhydrous sodium acetate (2g) was refluxed for 2 h and
then cooled. The solid product was filtered off, washed
several times with water, and recrystallized from ethanol
into yellow crystals of 17; mp: >300°C, yield 65%; ir:
CH aromatic 3030, CH aliphatic 2920, 2850, CO ester
1735; H nmr: (DMSO-d6) δ 1.40 (t, 3H, CH3), 2.75 (s,
3H, CH3), 3.90 (s, 2H, SCH2), 4.30 (q, 2H, CH2), 7.25–
7.80 (m, 5H, ArH), and 10.80ppm (s, 1H, NH). Anal.
Ethyl-3-amino-8-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-
b]pyrrolo[2,3-d]pyridine-2-carboxylate (21).
To
a
solution of the ethyl glycinate derivative 20 (3.5 g,
0.01 mol) in absolute ethanol (20 mL), a few drops of
ethanolic sodium ethoxide were added. The mixture
was heated under reflux for 30 min. The solid product
was filtered off and recrystallized from ethanol as pale
brown crystals of compound 21 in 91% yield; mp:
1
263–265°C; ir: NH2, NH 3487, 3301, CO 1656 cmꢀ1
1H nmr: (DMSO-d6) δ 1.27 (t, 3H, CH3), 2.75 (s, 3H,
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New Pyrazolothienopyridine and Pyrazolopyrrolopyridine
Compounds
CH3), 4.33 (q, 2H, CH2), 7.41–7.68 (m, 5H, Ar-H), 8.17
(s, 1H, CH pyridine), 7.19 (s, 2H, NH2), and 10.62 ppm
(s, 1H, NH); ms: m/z 335 as molecular ion peak and
base peak. Anal. Calcd for C18H17N5O2 (335.37): C,
64.47%; H, 5.11%; N, 20.88%. Found: C, 64.45%; H,
5.07%; N, 20.80%.
C18H14N6O (330.35): C, 65.44%; H, 4.27%; N, 25.44%.
Found: C, 65.40%; H, 4.23%; N, 25.41%.
3-Amino-8-methyl-6-phenyl-1,6-dihydrodipyrazolo[3,4-b:
3′,4′-d]pyridine (24). A mixture of chloro compound 5
(1.4 g, 5 mmol) and hydrazine hydrate (99%, 1 mL,
0.02 mol) in ethanol (40 mL) was refluxed for 3 h and
then left to cool. The precipitated solid was collected
and recrystallized from ethanol to give 24 as brown
crystals; mp: 268–270°C; yield 85%; ir: NH, NH
Ethyl-3-amino-1,8-dimethyl-6-phenyl-1,6-dihydropyrazolo
[3,4-b]pyrrolo[2,3-d]pyridine-2-carboxylate
(22).
A
mixture of the ethyl pyrazolopyridinyl glycinate
compound 20 (1.7 g, 5 mmol), methyl iodide (0.75 mL,
5 mmol), and anhydrous potassium carbonate (3 g,
0.022 mol) in acetone was refluxed with stirring for 24h;
after that, the mixture was allowed to cool. The solid
product was filtered off and recrystallized from ethanol to
give yellow crystals of compound 22 in 76% yield; mp:
238–240°C; ir: NH2 3446, CH aliphatic 3350, 2976, CO
1
3432, 3279, 3152, C¼N 1644 cmꢀ1; H nmr: (DMSO-
d6) δ 2.67 (s, 3H, CH3), 6.00 (s, 2H, NH2), 7.28–7.30,
7.49–7.53 (m, 5H, Ar-H), 8.25 (s, 1H, CH pyridine),
and 8.91 ppm (s, 1H, NH); ms: m/z = 246 as molecular
ion peak and base peak. Anal. Calcd for C14H12N6
(264.29): C, 63.62%; H, 4.58%; N, 31.80%. Found: C,
63.59%; H, 4.55%; N, 31.77%.
1
1654 cmꢀ1; H nmr: (CDCl3) δ 1.47 (t, 3H, CH3), 2.95
(s, 3H, CH3 pyrazole), 4.27 (s, 3H, CH3 pyrrole), 4.45 (q,
2H, CH2), 7.28 (s, 2H, NH2), 7.33–7.37, 7.52–7.56 (m,
5H, Ar-H), and 8.15 ppm (s, 1H, CH pyridine). Anal.
Calcd for C19H19N5O2 (349.39): C, 65.32%; H, 5.48%;
N, 20.04%. Found: C, 65.29%; H, 5.44%; N, 20.01%.
Acknowledgments. We thank Prof Dr Kamal I. Aly, Chairman of
Chemistry Department, for all the facilities provided to us and to
the staff members of Chemistry Department, Faculty of Science,
Assiut University, for their support during this work.
General
procedure
for
synthesis
of
pyrazolopyridopyrrolopyrimidine (23a, b). A suspension
of the amino ester compounds 21 or 22 (1 g) in
formamide(10mL) was refluxed for 3 h. The solid
product that separated from the hot mixture was filtered
off, washed several times with ethanol, and recrystallized
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from dioxaneto give the pyrimidine derivatives 23a and
23b.
1-Methyl-3-phenyl-3,10-dihydropyrazolo[4″,3″:5′,6′]pyrido[3′,4
′:4,5]pyrrolo[3,2-d]pyrimidin-9(8H)-one (23a).
Produced
according to the previous general procedure as gray crystals
in 75% yield; mp: >300°C; ir: 2NH 3446, 3350, CH
1
aliphatic 2976, CO 1654cmꢀ1; H nmr: (DMSO-d6) δ 2.86
(s, 3H, CH3), 7.31–7.35, 7.53–7.57 (2m, 5H, Ar-H), 8.13
(s, 1H, CH pyrimidine), 8.28 (s, 1H, NH pyrrole), and
9.16ppm (s, 1H, NH pyrimidine); 13C nmr: (DMSO-d6) δ
14.91 (C11: CH3 pyrazole), 121.45 (C15 phenyl), 122.30
(C13, C17 phenyl), 126.15 (C14, C16 phenyl), 129.45
(C12: C–N phenyl), 136.44 (C10b), 139.82 (C5b), 140.22
(C1), 141.74 (C5), 144.13 (C5a), 144.23 (C10a), 150.37
(C7), 154.40 (C3a), 163.38 (C9: C¼O pyrimidine). Anal.
Calcd for C17H12N6O (316.32): C, 64.55%; H, 3.82%; N,
26.57%. Found: C, 64.51%; H, 3.79%; N, 26.52%.
1,10-Dimethyl-3-phenyl-3H-pyrazolo[4″,3″:5′,6′]pyrido[3′,4′
[13] Boerrigter, G.; Costello-Boerrigter, L. C.; Cataliotti, A.;
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:4,5]pyrrolo[3,2-d] pyrimidin-9(8H)-one (23b).
Produced
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according previous general procedure as pale yellow
crystals in 68% yield; mp: >300°C; ir: NH pyrimidine
3340, CH aromatic 3050, CH aliphatic 2940, 2824, CO
amide 1667, C¼N 1608cmꢀ1
;
1H nmr: (DMSO-d6) δ
2.90 (s, 3H, CH3), 4.15 (s, 3H, CH3 pyrrole), 7.40–7.85
(m, 5H, Ar-H), 8.13 (s, 1H, CH pyrimidine), and
9.85ppm (s, 1H, NH pyrimidine). Anal. Calcd for
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Loureiro, N. I. V.; Azevedo, A. R.; Pinheiro, L. C. S.; Souza, T. M. L.;
Journal of Heterocyclic Chemistry
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A. A. Geies, M. I. Abdel Moneam, A. M. Kamal El-Dean, R. M. Zaki, and E. E. Abd El-Naeem Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet