3-Aminopyrazolo[4,3-c]pyridine-4,6-dione as a precursor for novel pyrazolo[4,5,1-ij][1,6]naphthyridines and pyrido[4’,3’:3,4]pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1080/00397911.2018.1457162

The versatile, 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) was synthesized and allowed to react with aldehydes, aryldiazonium chlorides, chalcones and enaminones to afford regioselectively the novel pyrazolo[4,3-c]pyridine derivatives 4a-c, pyrazolo[4,5,

Full text of DOI:10.1080/00397911.2018.1457162

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
3-Aminopyrazolo[4,3-c]pyridine-4,6-
dione as a precursor for novel
pyrazolo[4,5,1-ij][1,6]naphthyridines and
pyrido[4’,3’:3,4]pyrazolo[1,5-a]pyrimidines
Nadia H. Metwally & Emad A. Deeb
To cite this article: Nadia H. Metwally & Emad A. Deeb (2018) 3-Aminopyrazolo[4,3-
c]pyridine-4,6-dione as a precursor for novel pyrazolo[4,5,1-ij][1,6]naphthyridines and
pyrido[4’,3’:3,4]pyrazolo[1,5-a]pyrimidines, Synthetic Communications, 48:13, 1614-1628, DOI:
10.1080/00397911.2018.1457162
To link to this article: https://doi.org/10.1080/00397911.2018.1457162
View supplementary material
Published online: 08 Jun 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1614–1628
https://doi.org/10.1080/00397911.2018.1457162
3-Aminopyrazolo[4,3-c]pyridine-4,6-dione as a precursor for
novel pyrazolo[4,5,1-ij][1,6]naphthyridines and pyrido
[4’,3’:3,4]pyrazolo[1,5-a]pyrimidines
Nadia H. Metwally and Emad A. Deeb
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 30 December 2017
The versatile, 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) was synthe-
sized and allowed to react with aldehydes, aryldiazonium chlorides,
chalcones and enaminones to afford regioselectively the novel pyrazolo
[4,3-c]pyridine derivatives 4a-c, pyrazolo[4,5,1-ij][1,6] naphthyridines
9a-d and pyrido[4’,3':3,4]pyrazlo[1,5-a]pyrimidines 19a-i. The structure
of all the newly synthesized compounds was assigned from elemental
analysis and spectral data. Also, the mechanistic aspects for the
formation of the newly synthesized compounds is discussed.
KEYWORDS
Pyrazolo[4,5,1-ij][1,6]
naphthyridines; pyrazolo
[4,3-c]pyridines; pyrido
[40,30:3,4]-pyrazlo[1,5-a]
pyrimidines
GRAPHICAL ABSTRACT
Introduction
Fused heterocyclic compounds containing pyrazole moiety are considered as the most
versatile bioactive compounds in pharmaceutical and medicinal chemistry. Pyrazolo[3,
4-b]pyridines possess extensive spectrum of biological activities such as inhibitors of
xanthine oxidases,[1] trypanocidal activity,[2] treatment of Alzheimer’s diseases, drug addic-
tion and infertility.[3] Additionally, it have reported that they act as potent and selective
CONTACT Nadia H. Metwally
University, Giza, Egypt.
nhmmohamed@yahoo.com
Department of Chemistry, Faculty of Science, Cairo
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
1615
inhibitors of A1 adenosine receptors,[4] anti-inflammatory and antiplatelet agents.[5]
Moreover, pyrazolo[1,5-a]pyridines are found as part of the skeletal backbone of many
therapeutic drugs[6] and other biological activities.[7–11] Also, pyrazolo[4,3-c]pyridine
derivative represent one of the most important building block in organic synthesis due
to possess a wide range of biological activity which act as potent inhibitors of mycobacter-
ium tuberculosis pantothenate synthetase (PS), c-Met inhibitors,[12,13] γ-secretase, an intra-
membrane protease[14] and used also to treatment of neuropathic pain.[15] In continuation
of our interest in the synthesis of biologically, chemically valuable compounds,[16–25] and
on the bases of the above findings, promoted us to design a series of novel pyrazolo[4,
3-c]pyridine derivatives, pyrazolo[4,5,1-ij][1,6]naphthyridines and pyrido-[40,30:3,4]-
pyrazolo[1,5-a]pyrimidines starting from a key intermediate 3-aminopyrazolo[4,3-c]-
pyridinedione derivative 2.
Results and discussion
The starting material, 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) used in this study was
synthesized by acid hydrolysis of 3-cyanomethyl-4-cyano-5-amino-1H-pyrazole (1).
Condensation of compound 2 with aromatic aldehydes 3a–c in refluxing N,N-
dimethylformamide (DMF) containing a few drops of piperidene gave the respective
arylidene derivatives 4a–c (Scheme 1). The structure of 4a–c was assigned on the basis
1
of analytical and spectral data. The H NMR spectrum of compound 4b taken as an
example exhibited two singlet signals at δ ¼ 3.87 and 7.92 ppm assignable to the methoxy
and vinylidene protons, respectively, in addition to three singlet signals at δ ¼ 6. 29, 10.61
Scheme 1. Synthesis of 3-aminopyrazolo[4,3-c]pyridine derivatives 4a–c and 6a–e.

1616
N. H. METWALLY AND E. A. DEEB
and 12.29 ppm due to NH2 and two NH protons, respectively. Its 13C NMR appeared the
characteristic signals at 55.85 (OCH3), 146.14 (CH), 161.75 (CO) and 167.59 (CO) ppm.
Elemental analyses with spectral data are in agreement with the suggested structure 4.
Also, compound 2 coupled with aryldiazonium chlorides 5a–e in N,N-dimethylforma-
mide containing sodium acetate under stirring at 0–5 °C to produce the arylhydrazo
derivatives 6a–e (Scheme 1). The spectral data of the isolated products was in complete
agreement with structure 6. Thus IR spectrum of compound 6b showed the absorption
bands at νmax 3419, 3338, 3211, 3195 and 1691 cm−1 due to the NH2, three NH and CO
1
functions, respectively. Its H NMR revealed four singlet signals exchangeable D2O at
δ ¼ 6.57, 10.63, 12.10 and 12.58 ppm attributable to NH2 and three NH protons. Also, mass
spectrum showed a corrected molecular ion peak at m/z ¼ 284 (Mþ, 88.3%) beside some
other abundant fragments, that established the molecular formula C13H12N6O2. Elemental
analysis with mass spectrum are in agreement with the proposed structure 6.
It is interesting in this connection that the condensation of 2 with α,β-unsatutated
carbonyl compounds 7a–d in refluxing N,N-dimethylformamide in the presence of a few
drops of piperedine as a catalyst does not afforded the pyrazolo[1,5-a]pyrimidine deriva-
tives, as could have been expected in analogy to the formation of 8. Actually, the products
of this reaction were identified on the basis of their spectral data as 2-amino-6-phenyl-8-
aryl-3H-pyrazolo[4,5-1-ij][1,6]naphthryidine-3,5(4H)-3,5-diones 9a–d (Scheme 2). The IR
Scheme 2. 6-Phenyl-8-aryl-3H-pyrazolo[4,5,1-ij][1,6]naphthyridinediones 9a–d.

SYNTHETIC COMMUNICATIONS®
1617
spectrum of compound 9d taken as an typical example of the prepared series showed the
absorption bands at νmax 3413, 3117 and 1681 cm−1 corresponding to NH2, NH and CO,
1
respectively. The H NMR spectrum of 9d supported its structure, as it revealed a singlet
signal at δ ¼ 6.26 ppm assigned to methylene protons and two singlet signals exchangeable
with D2O at δ ¼ 6.64 and 10.93 ppm characteristic to NH2 and NH protons, beside the
other expected signals for aromatic protons. Its 13C NMR exhibited a characteristic signals
at 101.75 (CH2), 124.15 (CH=C), 147.64 (C-NH2), 160.27 (CO) and 162.77 (CO). Also,
mass spectrum of 9d showed the molecular ion peak at m/z 398 (Mþ, 2.8%) which was
consistent with the molecular formula C22H14N4O2. Elemental analyses with mass spec-
trum are agreement with the proposed structure 9. The above collective data with the
elemental analysis are in agreement with the suggested structure 9. The formation of 9
from the reaction of 2 with 7 is believed to proceed via a Michael addition reaction to give
non-isolable adducts, which in turn undergo cyclodehydration to give the non-isolable
dihydropyrazolonaphthyridine followed by spontaneous oxidation to 9.
On the other hand, the reaction of arylhydrazo derivatives 6a-d with α,β-unsaturated
carbonyl compounds 7a–d under the same reaction conditions afforded the isolated pro-
ducts 10a–p (Scheme 3). The spectral and microanalytical data of compounds 10a–p were
consistent with their structures. For example, the IR spectrum of compound 10c displayed
absorption bands at νmax 3378, 3148 and 1689 cm−1 corresponding to NH and CO
1
functions. Its H NMR spectrum exhibited two singlet signals exchangeable with D2O at
δ ¼ 11.13 and 12.42 ppm due to NH protons. Also, mass spectrum of 10c showed a cor-
rected molecular ion peaks at m/z ¼ 492 (Mþ, 30.2%) and m/z ¼ 494 (Mþ þ 2, 11.7%)
which consistent the formula C27H17ClN6O2. Elemental analysis with mass spectrum are
in agreement with the structure 10c.
The behavior of the enaminones towards some N-nucleophiles to attain fused ring
systems such as pyrazolo[1,5-a]pyrimidines of potential pharmaceutical interest, has been
Scheme 3. Synthesis of 7-arylhydrazopyrido[40,30:3,4]pyrazolo[1,5-a]pyrimidine-8,10(7H,9H)-dione
derivatives 10a–p.

1618
N. H. METWALLY AND E. A. DEEB
investigated.[26–28] Thus the key intermediate 2 reacted with enaminones 11a–e in refluxing
N,N-dimethylformamide containing piperidene to produce one single product in each case
13a–e (Scheme 4). The structure of the adducts 13a–e was determined by elemental analy-
sis and spectral data. The IR spectrum of compound 13c was characterized by the presence
of absorption bands at νmax 3,466, 3,208, and 1,701 cm−1 due to the NH2, NH and CO
1
groups, respectively. Also, its H NMR spectrum revealed the presence of a singlet signal
at δ ¼ 2.42 due to methyl protons with another two singlet signals exchangeable with
D2O in the region 6.66 and 10.89 ppm assigned to NH2 and NH protons. Also, mass spec-
trum showed a molecular ion peak at m/z ¼ 292 (Mþ, 28.7%), which confirmed the mol-
ecular formula C16H12N4O2. The formation of cycloadducts 13a-e indicates that the
reaction mechanism proceeds through a Michael type addition of NH in pyrazole ring
to the activated double in enaminoes 11 to form the non-isolable intermediate which read-
ily undergo cyclization by loss of dimethylamine and water molecules via active methylene
in pyridine ring to furnish the 2-amino-6-aryl-3H-pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5
(4H)diones rather than the expected pyrazolo[1,5-a]pyrimidines as a sole products from
the reaction of aminopyrazoles with enaminones. Also, the structure of the isolated pro-
ducts 13a–e can be confirmed chemically by acetylation reaction. Thus the treatment of
compounds 13a,b with acetic anhydride furnished the acetyl derivatives 14a,b. The structure
of the acetyl derivatives was assigned from their elemental analyses and spectral data (Scheme
5 and exp.). Moreover, treatment of compound 13a with dimethylformamide-dimethylacetal
(DMF-DMA) in dry dioxane produced the enamine derivative 15 (Scheme 5).
Scheme 4. Synthesis of 2-amino-6-aryl-3H-pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5(4H)-diones 13a–e.

SYNTHETIC COMMUNICATIONS®
1619
Scheme 5. Synthesis of pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5(4H)-dione derivatives 14a,b and 15.
The structure of the enamine derivative 15 was supported by its elemental analysis and spec-
tral data. Its IR spectrum displayed the absorptions bands for NH and CO functions at νmax
3,194 and 1,695 cm−1. Also, its 1H NMR spectrum revealed the two singlet signals at δ ¼ 3.02
and 3.12 ppm due to the two methyl protons and another a singlet signal at δ ¼ 9.12 ppm
assigned to an iminic proton, in addition to the other expected signals for aromatic protons.
The microanalytical with spectral data are in agreement with suggested structure 15. The
reaction of enamine derivative 15 with hydroxylamine hydrochloride furnished the isolated
product 17 (Scheme 6). The structure of 17 was confirmed on its elemental analysis and spec-
tral data. Its` IR spectrum exhibited the absorption bands at νmax 3,411, 3,270, and 1,694 cm
−1
1
assignable to OH, NH and CO groups. Its H NMR spectrum confirmed the proposed
structure which revealed the presence of two characteristic singlet signals exchangeable with
D2O at δ ¼ 10.61 and 11.24 ppm corresponding to NH and OH protons, respectively. In
addition to the other expected signals for aromatic, NH and olefinic protons. The elemental
Scheme 6. Synthesis of N0-(3,5-dioxo-6-phenyl-4,5-dihydro-3H-pyrazolo[4,5,1-ij][1,6]-naphthyridin-2yl)-
N-hydroxyformaimidamide 16.

1620
N. H. METWALLY AND E. A. DEEB
analyses together with spectral data are in agreement the proposed structure 17 rather than
the tetracyclic compound 16.
On the other hand, cyclocondensation of compounds 4a–c with enaminones 11a–c in
refluxing N,N-dimethylformamide containing a few drops of piperidene afforded the iso-
lated products 19a–i which confirmed from their elemental analyses and spectral data
(Scheme 7). The IR spectrum of compound 19c was characterized by the presence of
absorption bands at νmax 3245 and 1697 cm−1 assignable to both NH and CO groups. Also,
1
the H NMR spectrum of 19c confirmed the proposed structure revealed the presence of a
characteristic singlet signal at δ ¼ 11.0 ppm corresponding to NH proton and a doublet of
doublet signals due to the vinylic protons and another singlet signals at δ ¼ 8.11 and
8.28 ppm attributable to diene protons. Elemental analyses together with spectral data
are confirmed the suggested structure 19. The formation of compounds 19 denotes that
the reaction mechanism proceeds via an initial Michael addition of the exocyclic amino
group in the compound 4 to the α,β-unsaturated moiety in the enaminone 11 yielded
the corresponding acyclic non-isolable intermediates which undergo dehydrative cycliza-
tion and aromatization gave the final product 19 rather than the isomeric structure 18
(Scheme 7).
Compounds 4a–c reacted with acetylacetone in refluxing N,N-dimethylformamide in
the presence of a few drops of piperidene to yield the cycloadducts 21a–c which established
by elemental analyses and spectral data (Scheme 8). The IR spectrum of compound 21b
was exhibited the presence of absorption bands at νmax 3474, 3279, 1720 and 1680 cm−1
1
assignable to NH2, NH and CO groups. The H NMR spectrum of compound 21b con-
firmed the suggested structures which revealed the presence of a characteristic two singlet
Scheme 7. Synthesis of pyrido[40,30:3,4]pyrazolo[1,5-a]pyrimidenes 19a–i.

SYNTHETIC COMMUNICATIONS®
1621
Scheme 8. Synthesis of 2-acetyl-3H-pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5(4H)-diones 21a–c.
Scheme 9. Synthesis of the designed pyrido[40,30:3,4]pyrazolo[1,5-a]pyrimidines 22a–i.

1622
N. H. METWALLY AND E. A. DEEB
signals at δ ¼ 1.85, 2.61 and 3.82 ppm corresponding to the two methyl and methoxy pro-
tons, respectively with another two singlet signals exchangeable with D2O at δ ¼ 6.80 and
10.71 assigned to NH2 and NH, respectively. The elemental analyses together with spectral
data are in agreement the suggested structure 21. The formation of 21 from the reaction of
4 with acetylacetone is proceeds via a Michael addition reaction to give non-isolable inter-
mediates, which in turn undergo dehydrative cyclization to give the non-isolable pyrazolo
[4,5,1-ij][1,6]-naphthyridine-3,5(4H)-diones followed by spontaneous oxidation to
afford 21.
Additionally, the reaction of arylhydrazo derivatives 6a–c with enaminones 11a–c in
refluxing N,N-dimethylformamide containing piperidene as catalyst yielded the cyclo-
adducts 22a–i (Scheme 9). The structure of the isolated products was determined from
their elemental analyses and spectral data (Scheme 9 and exp.).
Conclusion
In conclusion, we have described an efficient synthesis of some novel pyrazolo[4,3-c]-
pyridine-4,6-dione derives and their fused derivatives such as pyrazolo[4,5,1-ij][1,6]
naphthyridine-3,5(4H)-dione derivatives via the reaction of readily accessible starting
material, 3-aminopyrazolo[4,3-c]pyridine-4,6-dione with some chemical reagents.
Experimental
Melting points were determined on an Electrothermal Gallenkamp apparatus and are
uncorrected. The IR spectra were recorded in KBr pellets using a Pye Unicam SP-1000
1
spectrophotometer. H-NMR spectra (300 MHz) and 13C-NMR spectra (75 MHz) were
obtained on a Varian EM-300 MHz spectrometer using DMSO-d6 as solvent with TMS
as internal standard and the results are expected as δ value. Mass spectra were taken on
a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Elemental analyses were
carried out by the Microanalytical Center of Cairo University, Giza, Egypt. Compounds
1 and 2 were prepared according to literature.[29,30]
Synthesis of 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (2)
A mixture of 3-cyanomethyl-4-cyano-5-aminopyrazole 1 (0.01 mol) and 5 ml of concen-
trated hydrochloric acid was refluxed for 15 minutes. The solid so formed was filtered
off and washed with water and recrystallized from N,N-dimethylformamide to afford white
crystals, yield 70%, m.p > 360 °C [Lit., > 360 °C],[30] νmax/cm−1 (KBr) 3402 (NH2), 3336
1
(NH), 3173 (NH), 1686 (CO); H NMR (DMSO) δ ¼ 3.68 (s, 2H, CH2), 5.96 (s, 2H,
NH2), 10.38 (s, 1H, NH), 11.81 (s, 1H, NH); m/z 166 ¼ (Mþ, 40%), 143 (4.9%), 131
(7.0%), 123 (42.2%), 113 (28.3%), 101 (18.6%), 87 (22.8%), 73 (8.4%), 59 (100%); Anal.
Calcd for C6H6N4O2: C, 43.38; H, 3.64; N, 33.72. Found: C, 43.52; H, 3.47; N, 33.49%.
General procedure of synthesis of compounds 4a–c
A solution of compound 2 (0.01 mol) in N,N-dimethylformamide (10 ml) containing a few
drops of piperidine was added to the appropriate aldehyde 3a–c (0.01 mol). The mixture
was heated under reflux for 5 h. The solid product that precipitated by cooling was filtered
off and recrystallized from N,N-dimethylformamide to give the respective products 4a–c.

SYNTHETIC COMMUNICATIONS®
1623
3-Amino-7-benzylidene-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,
6(5H)-dione (4a)
Yellow crystals, yield 66%, m.p. 240 °C, νmax/cm−1 (KBr) 3402 (NH2), 3200 (NH), 1692
1
(CO); H NMR (DMSO) δ ¼ 6.04 (s, 2H, NH2), 6.95–7.49 (m, 5H, Ar), 8.03 (s, 1H,
CH), 10.43 (s, 1H, NH), 12.09 (s, 1H, NH); m/z 254 ¼ (Mþ, 100%), 238 (22.9%), 210
(22.9%), 166 (24.2%), 127 (29.3%), 91 (64.0%), 77 (48.1%), 66 (20.8%), 51 (16.0%); Anal.
Calcd for C13H10N4O2: C, 61.41; H, 3.96; N, 22.04. Found: C, 61.59; H, 3.82; N, 22.31%.
General procedure of synthesis of compounds 6a–e
A solution of compound 2 (0.01 mol) and sodium acetate (0.01 mol) in N,N-
dimethylformamide (10 ml) was cooled in an ice bath at (0–5 °C) while being stirred. To
the resulting cold solution was added portionwise a cold solution of the appropriate
diazonium salt 5a–e prepared as usual by diazotizing the corresponding aromatic amine
(0.01 mol) in concentrated hydrochloric acid (3 ml) with sodium nitrite (0.01 mol) in water
(3 ml). After all the diazonium salt solution was added, the mixture was stirred for further
one hour. while cooling in an ice-bath. The solid that precipitated was filtered off,
washed with water, dried and finally crystallized from N,N-dimethylformamide to give
products 6a–e.
3-Amino-7-(2-(p-tolyl)hydrazono)-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6
(5H)-dione (6b)
Orange crystals, yield 74%, m.p. 315 °C, νmax/cm−1 (KBr) 3419 (NH2), 3338, 3211, 3195
1
(3NH), 1691 (CO); H NMR (DMSO) δ ¼ 2.28 (s, 3H, CH3), 6.57 (s, 2H, NH2), 7.18
(d, 2H, J ¼ 8.7 Hz, CH), 7.22 (d, 2H, J ¼ 9 Hz, CH), 10.63 (s, 1H, NH), 12.10 (s, 1H,
NH), 12.58 (s, 1H, NH); m/z 284 ¼ (Mþ, 88.3%), 239 (9.0%), 213 (1.7%), 166 (5.6%),
135 (31.5%), 106 (92.0%), 91 (100%), 77 (69.6%), 65 (59.1%), 52 (42.6%); Anal. Calcd
for C13H12N6O2: C, 54.93; H, 4.25; N, 29.56. Found: C, 54.81; H, 4.43; N, 29.79%.
General procedure of synthesis of compounds 9a–d
A mixture of compound 2 (0.01 mol) and α,β-unsaturated ketones 7a–d (0.01 mol) in N,
N-dimethylformamide (10 ml) containing a few drops of piperidine was heated under
reflux for 6 hours and the reaction mixture was followed by TLC. The solid so formed
was filtered off and recrystallized from N,N-dimethylformamide to give the respective
products 9a–d.
2-Amino-8-(benzo[d][1,3]dioxol-5-yl)-6-phenyl-3H-pyrazolo[4,5,1-ij][1,6]
naphthyridine-3,5(4H)-dione (9d)
Brown crystals, yield 81%, m.p 285 °C, νmax/cm−1 (KBr) 3413 (NH2), 3117 (NH), 1681
1
(CO); H NMR (DMSO) δ ¼ 6.26 (s, 2H, CH2), 6.64 (s, 2H, NH2), 7.18 (s, 1H, Ar), 7.27
(d, 2H, J ¼ 8.4 Hz, Ar), 7.57–7.69 (m, 3H, Ar), 7.84–8.41 (m, 3H, Ar), 10.93 (s, 1H,
NH). 13C NMR (DMSO) δ ¼ 89.32, 101.75, 108.05, 110.10, 110.89, 117.75, 124.15,
128.97, 130.09, 130.77, 131.27, 131.61, 142.29, 145.04, 146.05, 147.64, 149.87, 160.27,
162.77; m/z 398 ¼ (Mþ, 2.8%), 386 (1.7%), 363 (0.4%), 343 (0.1%), 326 (0.1%), 317
(0.5%), 305 (1.4%), 281 (0.2%), 268 (0.8%), 247 (1.8%), 229 (0.9%), 213 (0.9%), 201

1624
N. H. METWALLY AND E. A. DEEB
(1.6%), 189 (2.7%), 175 (2.0%), 159 (2.3%), 148 (4.4%), 131 (3.3%), 117 (17.0%), 105
(100%); Anal. Calcd for C22H14N4O4: C, 66.33; H, 3.54; N, 14.06. Found: C, 66.53; H,
3.65; N, 14.28%.
General procedure of synthesis of compounds 10a–p
A mixture of compounds 6a–d (0.01 mol) and α,β-unsaturated ketones 7a–d (0.01 mol) in
N,N-dimethylformamide (10 ml) containing a few drops of piperidine was heated under
reflux for 6 hours and the reaction mixture was followed by TLC. The solid so formed
was filtered off and recrystallized from N,N-dimethylformamide to give the respective
products 10a–p.
7-(2-(4-Chlorophenyl)hydrazono)-2,4-diphenylpyrido[4’,3':3,4]pyrazolo[1,5-a]
pyrimidine-8,10(7h,9h)-dione (10c)
Brown crystals, yield 72%, m.p. 335 °C, νmax/cm−1 (KBr) 3378 (NH), 3148 (NH), 1689
1
(CO); H NMR (DMSO) δ ¼ 7.18 (d, 2H, J ¼ 8.4 Hz, Ar), 7.41 (d, 2H, J ¼ 8.7 Hz, Ar),
7.59–7.85 (m, 6H, Ar), 8.13 (s, 1H, CH), 8.27–8.45 (m, 4H, Ar), 11.13 (s, 1H, NH),
12.42 (s, 1H, NH); m/z 492 ¼ (Mþ, 30.2%), 494 (Mþ þ 2, 11.7%), 452 (1.8%), 423
(1.3%), 396 (2.0%), 367 (3.6%), 346 (17.6%), 323 (24.6%), 304 (28.7%), 282 (17.0%), 231
(16.5%), 204 (21.5%), 165 (22.8%), 129 (55.3%), 111 (97.9%), 99 (48.5%), 77 (100%); Anal.
Calcd for C27H17ClN6O2: C, 65.79; H, 3.48; Cl, 7.19; N, 17.05. Found: C, 65.62; H, 3.32; Cl,
7.41; N, 17.28%.
General procedure of synthesis of compounds 13a–e
A mixture of compound 2 (0.01 mol) and enaminones 11a–e (0.01 mol) in
N,N-dimethylformamide (20 ml) containing a few drops of piperidine was heated under
reflux for 5 h. The solid so formed was filtered off and recrystallized from
N,N-dimethylformamide.
2-Amino-6-(4-methoxyphenyl)-3h-pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5(4H)-
dione (13d)
Brown crystals, yield 70%, m.p 320 °C, νmax/cm−1 (KBr) 3441 (NH2), 3198 (NH), 1691
1
(CO); H NMR (DMSO) δ ¼ 3.85 (s, 3H, OCH3), 6.65 (s, 2H, NH2), 7.09 (d, 2H, J ¼ 9 Hz,
Ar), 7.28 (d, 1H, J ¼ 7.8 Hz, CH), 7.99 (d, 1H, J ¼ 7.8 Hz, CH), 8.10 (d, 2H, J ¼ 8.7 Hz, Ar),
10.86 (s, 1H, NH); 13C NMR (DMSO) δ ¼ 55.42, 88.02, 113.02, 113.49, 113.90, 122.99,
128.27, 131.16, 142.68, 144.17, 158.05, 159.81, 161.17, 163.03; m/z 308 ¼ (Mþ, 100%),
289 (7.7%), 265 (4.6%), 237 (5.8%), 210 (9.2%), 194 (5.4%), 178 (2.0%), 166 (3.5%), 139
(4.8%), 117 (2.4%), 104 (3.6%), 89 (6.6%), 76 (10.0%), 63 (4.5%), 51 (2.1%); Anal. Calcd
for C16H12N4O3: C, 62.33; H, 3.92; N, 18.17. Found: C, 62.47; H, 3.75; N, 18.43%.
General procedure of synthesis of compounds 14a–c
A mixture of compounds 13a,d (0.01 mol) and acetic anhydride (5 ml) was refluxed
for two hours. The solid so formed was filtered off and recrystallized from
N,N-dimethylformamide.

SYNTHETIC COMMUNICATIONS®
1625
N-(3,5-dioxo-6-phenyl-4,5-dihydro-3h-pyrazolo[4,5,1-ij][1,6]naphthyridin-2-yl)
acetamide (14a)
Brown crystals, yield 60%, m.p 200 °C, νmax/cm−1 (KBr) 3217 (NH), 3165 (NH), 1716 (CO),
1
1689 (CO); H NMR (DMSO) δ ¼ 2.20 (s, 3H, CH3), 7.40–7.50 (m, 3H, Ar), 7.61-8.01 (m,
3H, Ar), 10.30 (s, 1H, NH), 13.60 (s, 1H, NH); m/z 320 ¼ (Mþ, 22.0%), 305 (8.1%), 278
(100%), 259 (10.2%), 235 (12.0%), 208 (32.2%), 193 (20.5%), 180 (17.6%), 178 (16.5%),
152 (15.4%), 122 (14.3%), 105 (58.7%), 102 (21.1), 77 (72.5%), 45 (20.1%), 40 (7.5%); Anal.
Calcd for C17H12N4O3: C, 63.75; H, 3.78; N, 17.49. Found: C, 63.63; H, 3.62; N, 17.72%.
Synthesis of N,N-dimethyl-N’-(4-oxo-5-phenyl-2a,2a1,4,5-tetrahydro-3H-pyrazolo
[4,5,1-ij]-[1,7]naphthyridin-2-yl)formimidamide (15)
A mixture of compound 13a (0.01 mol) and dimethylformamide dimethylacetal (0.01 mol)
in dry dioxane (20 ml) was heated under reflux for 5 hours. The solid so formed was
filtered off and recrystallized from N,N-dimethylformamide to give brown crystals, yield
1
70%, m.p 350 °C, νmax/cm−1 (KBr) 3194 (NH), 1695 (CO); H NMR (DMSO) δ ¼ 3.02
(s, 3H, CH3), 3.12 (s, 3H, CH3), 7.40 (d, 1H, J ¼ 7.5 Hz, Ar), 7.59–7.62 (m, 3H, Ar),
8.07-8.12 (m, 3H, Ar), 9.12 (s, 1H, CH), 10.99 (s, 1H, NH); Anal. Calcd for
C18H15N5O2: C, 64.86; H, 4.54; N, 21.01. Found: C, 64.69; H, 4.41; N, 21.23%.
Synthesis of N’-(3,5-dioxo-6-phenyl-4,5-dihydro-3H-pyrazolo[4,5,1-ij][1,6]
naphthyridin-2-yl)-N-hydroxyformimidamide (17)
A mixture of compound 15 (0.01 mol), hydroxylamine hydrochloride (0.01 mol) and
anhydrous sodium acetate (0.01 mol) in N,N-dimethylformamide (20 ml) was heated under
reflux for 7 hours. The solid so formed was filtered off and recrystallized from
N,N-dimethylformamide.
Brown crystals, yield 70%, m.p > 350 °C, νmax/cm−1 (KBr) 3411 (OH), 3270 (NH), 1694
1
(CO); H NMR (DMSO) δ ¼ 7.53 (d, 1H, J ¼ 7.5 Hz, Ar), 7.62-7.65 (m, 5H, Ar and CH),
8.09–8.22 (m, 4H, Ar and NH), 10.61 (s, 1H, NH), 11.24 (s, 1H, OH); Anal. Calcd for
C16H11N5O3: C, 59.81; H, 3.45; N, 21.80. Found: C, 59.64; H, 3.26; N, 21.56%.
General procedure of synthesis of compounds 19a–i
A mixture of compounds 4a–c (0.01 mol) and enaminones 11a–c (0.01 mol) in
N,N-dimethylformamide (20 ml) containing a few drops of piperidine was heated under
reflux for 6 hours. The solid so formed was filtered off and recrystallized from
N,N-dimethylformamide.
7-Benzylidene-4-phenylpyrido[4’,3':3,4]pyrazolo[1,5-a]pyrimidine-8,10(7H,9H)-
dione (19a)
1
Yellow crystals, yield 54%, m.p 281 °C, νmax/cm−1 (KBr) 3189 (NH), 1693 (CO); H NMR
(DMSO) δ ¼ 6.96-7.05 (m, 4H, Ar), 7.40–7.60 (m, 6H, Ar), 7.79 (s, 1H, CH), 8.03 (d, 1H,
J ¼ 7.5 Hz, CH), 8.18 (d, 1H, J ¼ 8.4 Hz, CH), 11.21 (s, 1H, NH); Anal. Calcd for
C22H14N4O2: C, 72.12; H, 3.85; N, 15.29. Found: C, 72.26; H, 3.74; N, 15.55%.

1626
N. H. METWALLY AND E. A. DEEB
General procedure of synthesis of compounds 21a–c
A mixture of compounds 4a–c (0.01 mol) and acetylacetone (0.01 mol) in N,N-dimethyl-
formamide (20 ml) containing a few drops of piperidine was heated under reflux for 5
hours. The solid so formed was filtered off and recrystallized from N,N-
dimethylformamide.
7-Acetyl-2-amino-8-methyl-6-phenyl-3h-pyrazolo[4,5,1-ij][1,6]naphthyridine-3,5
(4H)-dione (21a)
Yellow crystals, yield 61%, m.p. 334 °C, νmax/cm−1 (KBr) 3417 (NH), 3284 (NH2), 1722
1
(CO), 1689 (CO); H NMR (DMSO) δ ¼ 1.84 (s, 3H, CH3), 2.62 (s, 3H, CH3), 6.86
(s, 2H, NH2), 7.25-7.43 (m, 5H, Ar), 10.69 (s, 1H, NH); Anal. Calcd for C18H14N4O3: C,
64.67; H, 4.22; N, 16.76. Found: C, 64.59; H, 4.34; N, 16.51%.
General procedure of synthesis of compounds 22a–i
A mixture of arylhydrazo derivatives 6a–c (0.01 mol) and enaminones 11a–c (0.01 mol) in
N,N-dimethylformamide (20 ml) containing a few drops of piperidine was heated
under reflux for 6 hours. The solid so formed was filtered off and recrystallized from
N,N-dimethylformamide
4-Phenyl-7-(2-phenylhydrazono)pyrido[4’,3':3,4]pyrazolo[1,5-a]pyrimidine-8,10
(7H,9H)-dione (22a)
1
Yellow crystals, yield 61%, m.p. 291 °C, νmax/cm−1 (KBr) 3309 (NH), 1699 (CO); H NMR
(DMSO) δ ¼ 6.87–6.97 (m, 5H, Ar), 7.22-7.51 (m, 5H, Ar), 7.65 (d, 1H, J ¼ 8.1 Hz, CH),
7.76 (d, 1H, J ¼ 8.4 Hz, CH), 11.0 (s, 1H, NH), 12.20 (s, 1H, NH); Anal. Calcd for
C21H14N6O2: C, 65.96; H, 3.69; N, 21.98. Found: C, 65.84; H, 3.50; N, 21.74%.
References
[1] Chu, I.; Lynch, B. M. Synthesis and Biological Evaluation of Xanthine Oxidase Inhibitors.
Pyrazolo[3,4-d]Pyrimidines and Pyrazolo[3,4-b]Pyridines. J. Med. Chem. 1975, 18, 161–165.
DOI: 10.1021/jm00236a010.
[2] Salvador, R. R. S.; Bello, M. L.; Barreto, I. R. L.; Vera, M. A. F.; Muti, E. M. F.; De-Albuquerque,
S.; Dias, L. R. S. New Carbohydrazide Derivatives of 1H-Pyrazolo[3,4-b]-Pyridine and
Trypanocidal Activity. An. Acad. Bras. Cienc. 2016, 88, 2341–2348.
[3] Owens, M. J.; Nemeroff, C. B. Corticotrepin-Releasing Factor Antagonists in Affective
Disorder. Exp. Opin. Invest. Drugs 1999, 8, 1849–1856.
[4] Manetti, F.; Schenone, S.; Bondavalli, F.; Brullo, C.; Bruno, O.; Ranise, A.; Mosti, L.; Menozzi,
G.; Fossa, P.; Trincavelli, M. L.; Synthesis and 3D QSAR of New Pyrazolo[3,4-b]Pyridines:
Potent and Selective Inhibitors of A1 Adenosine Receptors. J. Med. Chem. 2005, 48,
7172–7185. DOI: 10.1021/jm050407k.
[5] Sharma, P. K.; Singh, K.; Kumar, S.; Kumar, P.; Dhawan, S. N.; Lal, S.; Ulbrich, H.; Dannhardt,
G. Synthesis and Anti-Inflammatory Evaluation of Some Pyrazolo[3,4-b]Pyridines. Med. Chem.
Res. 2010, 19, 107–114. DOI: 10.1007/s00044-010-9312-7.
[6] Carey, J. S.; Laffan, D.; Thompson, C.; Williams, M. T. Analysis of the Reactions used for the
Preparation of Drug Candidate Molecules. Org. Biomol. Chem. 2006, 4, 2337. DOI: 10.1002/
chin.200642267.

SYNTHETIC COMMUNICATIONS®
1627
[7] Mohamed, A. E.; Hale, F. R.; Doha, M. B.; Ibrahim, Y. E. Microwave-Assisted Synthesis of
Some New Pyrazolopyridines and Their Antioxidant, Antitumor and Antimicrobial Activities.
Eur. J. Med. Chem. 2013, 66, 415–422. DOI: 10.1016/j.ejmech.2013.04.043.
[8] Farag, M. A. A. Synthesis and Antimicrobial Evaluation of some Novel Bis-α,β-Unsaturated
Ketones, Nicotinonitrile, 1,2-Dihydropyridine-3-Carbonitrile, Fused Thieno[2,3-b]Pyridine
and Pyrazolo[3,4-b]Pyridine Derivatives. Int. J. Mol. Sci. 2013, 14, 2967–2979. DOI: 10.3390/
ijms14022967.
[9] Wenglowsky, S.; Rent, L.; Ahrendt, K. A.; Laird, E. R.; Aliagast, I.; Alicket, B.; Buckmelter, A. J.;
Choo, E. F.; Dinkel, V.; Feng, B.; Pyrazolopyridine Inhibitors of β-RafV600E. Part 1: The
Development of Selective, Orally Bioavailable, and Efficacious Inhibitor. ACS Med. Chem. Lett.
2011, 2, 342–347.
[10] Qin, J.; Zhou, W.; Huang, X.; Dhondi, P.; Palani, A.; Aslanian, R.; Zhu, Z.; Greenlee, W.; Cohen,
M. W.; Jones, N.; Discovery of a Potent Pyrazolopyridine Series of γ-Secretase Modulators. ACS
Med. Chem. Lett. 2011, 2, 471–476. DOI: 10.1021/ml2000438.
[11] Tucker, T. J.; Sisko, J. T.; Tynebor, R. M.; Williams, T. M.; Felock, P. J.; Flynn, J. A.; Lai, M. T.;
Liang, Y.; McGaughey, G.; Liu, M.; Discovery of 3-{5-[(6-Amino-1H-Pyrazolo[3,4-b]Pyridine-
3-yl)Methoxy]-2-Chlorophenoxy}-5-Chlorobenzo-nitrile (MK-4965):
A
Potent, Orally
Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency
Against Key Mutant Viruses. J. Med. Chem. 2008, 51, 6503–6511. DOI: 10.1021/jm800856c.
[12] Ganesh, S.; Devi, P. B.; Radhika, N.; Yogeeswari, P.; Sriram, D. Development of 3-Phenyl-
4,5,6,7-Tetrahydro-1H-Pyrazolo[4,3-c]Pyridine Derivatives as Novel Mycobacterium
Tuberculosis Pantothenate Synthestase Inhibitors. Eur. J. Med. Chem. 2013, 69, 356–364.
[13] Zhang, L.; Zhang, B.; Zhao, J.; Zhi, Y.; Wang, L.; Lu*, T.; Chen, Y. Structure-Based Design,
Synthesis, and Evaluation of 4,5,6,7- Tetrahydro-1H-Pyrazolo[4,3-c]Pyridine Derivatives as
Novel cMet Inhibitors. Eur. J. Med. Chem. 2017, 138, 942–951.
[14] Ye, X. M.; Konradi, A. W.; Smith, J.; Xu, Y.-Z.; Dressen, D.; Garofalo, A. W.; Marugg, J.; Sham,
H. L.; Troung, A. P. T.; Jagodzinski, J. et al. Discovery of a Novel Sulfonamide-
Pyrazolopiperidine Series as Potent and Efficacious γ-Secretase Inhibitors. Bioorg. Med. Chem.
Lett. 2010, 20, 2195–2199.
[15] Yogeeswari, P.; Sharma, M.; Samala, G.; Gangadhar, M.; Karthick, S.; Mallipeddi, S.; Semwal,
A.; Sriram, D. Discovery of Novel Tetrahydro-Pyrazolo [4,3-c] Pyridines for the Treatment
of Neuropathic Pain: Synthesis and Neuropharmacology. Eur. J. Med. Chem. 2013, 66,
211–220. DOI: 10.1016/j.ejmech.2013.05.022.
[16] Elgemeie, G. E. H.; Mansour O. A.; Metwally, N. H. Synthesis and Anti-HIV Activity of
Different Noval Nonclassical Nucleosides. Nucleosides Nucleotides 1999, 18, 113–123. DOI:
10.1080/07328319908045598.
[17] Elgemeie, G. E. H.; Metwally, N. H. Synthesis of Structurally Related Purines: Benzimidazo[1,2-
a]Pyridines, Benzimidazo-[1,2-c]Pyrimidines, and Pyrazolo[1,5-a]Pyrimidines. Monatsh Chem.
2000, 131, 779–785. DOI: 10.1007/s007060050025.
[18] Abdelrazek, F. M.; Metwally, N. H. Some Reactions with ω-Bromoacetophenone: A Novel
Synthesis of Some Polysubstituted Pyridine, Pyrimidine, Pyrazolo[1,2-a]-Pyrimidine
Derivatives. Afinidad 2003, 60, 554–557.
[19] Metwally, N. H.; Abdelrazek, F. M. Reaction of Anthranilo Nitrile with Some Active Methylene
Reagents, Synthesis of Some New Quinoline & Quinazoline Derivatives. Synth. Comm. 2005,
35, 2481–2487. DOI: 10.1080/00397910500192068.
[20] Abdelrazek, F. M.; Metwally, N. H. Synthesis of Some New N-Substituted Pyrroles, Pyrrolo[1,
2-a]Quinazoline, and diaza-as-in Dacene Derivatives. Synth. Comm. 2006, 36, 83–89. DOI:
10.1002/chin.200623031.
[21] Abdelrazek, F. M.; Metwally, N. H. Novel Synthesis of N-Arylpyrrole, Pyrrolo[1,2-a]-
Quinazoline, and Pyrrolo[3,4-d]Pyridazine Derivatives. Synth. Comm. 2009, 39, 4088–4099.
[22] Metwally, N. H.; Abdallah, M. A.; Mosselhi, M. A.; El-Desoky, E. A. Synthesis and
Antimicrobial Activity of Some New N-Glycosides of 2-Thioxo-4-Thiazolidinone Derivatives.
Carbohydrate Res. 2010, 345, 1135–1141. DOI: 10.1016/j.carres.2010.04.011.

1628
N. H. METWALLY AND E. A. DEEB
[23] Metwally, N. H. 3-Aryl-2-Sulfanyl Propenoic Acids as Precursors for Some Novel (Z)-5-
Substituted-2-Trichloromethyl-4-Thiazlidinones. Arkivoc 2011, 2011, 254–265.
[24] Metwally, N. H. 2-Keto-3-Mercaptocinchroninic Acids as Precursors for Noval Thiazino[6,5-c]
Quinoline-1,5-Dione Derivatives. Synth. Comm. 2013, 43, 398–405. DOI: 10.1080/00397911.
2011.601838.
[25] Ragb, E. A.; Metwally, N. H.; Mohamed, M. S. Synthesis of Some Novel Pyrazolo[1,5-a]-
Quinazolines and Their Fused Derivatives. Synth. Comm. 2017, 47, 148–158. DOI: 10.1080/
00397911.2016.1257722.
[26] Qi, J.; Zhang, F.; Mi, Y.; Fu, Y.; Xu, W.; Zhang, D.; Wu, Y.; Du, X.; Jai, Q.; Wang, K.; Design,
Synthesis and Biological Activity of Pyrazolo[1,5-a]Pyrimidine-7(4H)-Ones as Novel Kv7/
KCNQ Potassium Channel Activators. Eur. J. Med. Chem. 2011, 46, 934–943.
[27] Almansa, C.; Fernando, A. F.; Cavalcanti, F. L.; Gomez, L. A.; Miralles, A.; Merlos, M.; Rafanell,
J. G.; Forn, J. Synthesis and SAR of a New Series of COX-2-Selective Inhibitors: Pyrazolo[1,5-a]
Pyrimidines. J. Med. Chem. 2001, 44, 350–361. DOI: 10.1021/jm0009383.
[28] Vrylskii, D. V.; Chuvashlev, A. S.; Arzamaslsev, A. P.; Slivkin, A. S. Synthesis of New Pyrazolo
[1,5-a]Pyrimidines. Pharm. Chem. J. 2009, 43, 294–296. DOI: 10.1007/s11094-009-0301-4.
[29] Carboni, R. A.; Coffman, D. D.; Howard, E. G. Cyanocarbon Chemistry. XI.1 Malononitrile
Dimer. J. Amer. Chem. Soc. 1958, 80, 2838–2840. DOI: 10.1021/ja01544a061.
[30] Sato, T. Reaction of Hydrazine Hydrate and Phenylhydrazine with Malononitrile. J. Org. Chem.
1959, 24, 963–966. DOI: 10.1021/jo01089a019.