Pyrazolo[3,4-b]pyridine in heterocyclic synthesis: Synthesis of new pyrazolo[3,4-b]pyridines, imidazo[1′,2′:1,5]pyrazolo[3,4-b] pyridines, and pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1139/V07-089

Pyrazolo[3,4-b]pyridine derivatives 7 and 9 were synthesized via the reaction of 3-amino-1H-pyrazolo-[3,4-b]pyridine derivative 2 with ω-bromoacetophenones. Reaction of 7 and 9 with Ac₂O afforded the imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridine derivative 8 and pyrazolo[3,4-b]pyridine derivative 10, respectively. Reaction of 2 with chloroacetonitrile followed by DMF-DMA gave imidazo[1′,2′:1,5] pyrazolo[3,4-b]pyridines 4 and 5, respectively. Acetylacetone and 1,1-dicyano-2,2-dimethylthioethene were reacted with 2 to afford the pyrido[2′,3′:3,4]pyrazolo-[1,5-a]-pyrimidines 11 and 14, respectively. Also, 2 reacted with DMF-DMA to yield the formamidine 15, which in turn, reacted with active methylene reagents, yielding the corresponding pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines 18 and 23a-23d.

Full text of DOI:10.1139/V07-089

592
Pyrazolo[3,4-b]pyridine in heterocyclic synthesis:
synthesis of new pyrazolo[3,4-b]pyridines,
imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridines, and
pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines
Mohamed A.M. Gad-Elkareem, Azza M. Abdel-Fattah, and Mohamed A.A. Elneairy
Abstract: Pyrazolo[3,4-b]pyridine derivatives 7 and 9 were synthesized via the reaction of 3-amino-1H-pyrazolo-[3,4-
b]pyridine derivative 2 with ω-bromoacetophenones. Reaction of 7 and 9 with Ac2O afforded the imidazo[1′,2′:1,5]py-
razolo[3,4-b]pyridine derivative 8 and pyrazolo[3,4-b]pyridine derivative 10, respectively. Reaction of 2 with
chloroacetonitrile followed by DMF–DMA gave imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridines 4 and 5, respectively. Acetyl-
acetone and 1,1-dicyano-2,2-dimethylthioethene were reacted with 2 to afford the pyrido[2′,3′:3,4]pyrazolo-[1,5-a]-py-
rimidines 11 and 14, respectively. Also, 2 reacted with DMF–DMA to yield the formamidine 15, which in turn, reacted
with active methylene reagents, yielding the corresponding pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines 18 and 23a–23d.
Key words: 1H-pyrazolo[3,4-b]pyridines, imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridines, pyrido[2′,3′:3,4]pyrazolo[1,5-a]py-
rimidines.
Résumé : On a réalisé la synthèse des dérivés pyrazolo[3,4-b]pyridines 7 et 9 par le biais d’une réaction de la 3-
amino-1H-pyrazolo-[3,4-b]pyridine 2 avec des ω-bromoacétophénones. Les réactions de composés 7 et 9 avec
l’anhydride acétique conduisent respectivement à la formation de la imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridine 8 et de la
pyrazolo[3,4-b]pyridine 10. La réaction du composé 2 avec le chloroacétonitrile, suivie d’un traitement avec du DMF et
du DMA conduit à la formation respectivement des imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridines 4 et 5. Les réactions de
l’acétylacétone et du 1,1-dicyano-2,2-diméthylthioéthène avec le composé 2 conduisent respectivement à la formation
des pyrido[2′,3′:3,4]pyrazolo-[1,5-a]pyrimidines, 11 et 14. Le produit 2 réagit aussi avec le mélange DMF–DMA pour
conduire à la formation d’une formamidine 15 qui réagit ensuite avec des réactifs portant des groupes méthylènes actifs
pour conduire à la formation des [2′,3′:3,4]pyrazolo[1,5-a]pyrimides, 18 et 23a–23d.
Mots-clés : 1H-pyrazolo[3,4-b]pyridines, imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridines, pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines.
[Traduit par la Rédaction] Gad-Elkareem et al. 599
Introduction
5, 15–19) directed towards the synthesis of substituted con-
densed pyrazoles, we report a new and convenient method
for the synthesis of such ring systems that are required in
medicinal chemistry, utilizing 3-amino-1H-pyrazolo-[3,4-
b]pyridine derivative 2.
1H-Pyrazolo[3,4-b]pyridines comprise a very interesting
class of compounds because of their significant and versatile
biological and pharmacological activities, such as antimalarial
(1), antiproliferative (2), antimicrobial (3–5), inhibition of
cyclin-dependent kinases (6), and cardiovascular (7–9), anti-
viral (10, 11), and antileishmanial (12) activities. Moreover,
pyridopyrazolopyrimidines revealed antiproliferative activity
(13) and are used as potent kinase inhibitors (14). In view of
these reports and as a continuation of our pervious work (4,
Results and discussion
Pyridine-2(1H)-thione derivative 1 reacted with hydrazine
hydrate to afford the corresponding 3-amino-1H-
pyrazolo[3,4-b]pyridine derivative 2 (20). The reactivity of
compound 2 towards halo-reagents is studied in this paper.
Thus, compound 2 reacted with chloroacetonitrile in potas-
sium hydroxide – dimethyl formamide (DMF) solution to af-
ford a reaction product 4, which exhibited NH2 (3454 and
3313 cm–1) absorption bands in its IR spectrum with the ab-
sence of any absorption band due to CϵN function. The
1H NMR spectrum of 4 revealed the singlet signal of two
protons at δ = 3.91 ppm, assignable for NH2, and a singlet
signal of two protons at δ = 5.2 ppm characterized for CH2.
Based on the data obtained, the reaction product was formu-
lated as 2-amino-3-hydroimidazo[1′,2′:1,5]pyrazolo[3,4-b]py-
ridine derivative 4. The formation of 4 was assumed to
Received 06 April 2007. Accepted 09 July 2007. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
16 August 2007.
M.A.M. Gad-Elkareem.1 Department of Chemistry, Faculty
of Science, Al-Azhar University (Assiut branch), Assiut
71524, Egypt.
A.M. Abdel-Fattah and M.A.A. Elneairy. Department of
Chemistry, Faculty of Science, Cairo University, Giza 12613,
Egypt.
1Corresponding author (e-mail: m65gad@yahoo.com).
Can. J. Chem. 85: 592–599 (2007)
doi:10.1139/V07-089
© 2007 NRC Canada

Gad-Elkareem et al.
Scheme 1.
593
Ar
N
Ar
NH2
EtO2C
CN
S
EtO2C
H3C
N2H4.H2O
ClCH2CN
N
N
2
N
H3C
H
H
1
BrCH2COR
6a, R = C6H4-CH3-p
b, R = C6H5
Ar
..
Ar
N
NH2
O
NH2
EtO2C
H3C
EtO2C
H3C
6a
N
N
N
N
N
N
6b
R
7, R = C6H4-CH3-p
3
Ar
NH2
Ac2O
Ar
AcOH
EtO2C
H3C
N
N
N
Ar
N
COCH3
O
EtO2C
H3C
EtO2C
H3C
N
N
N
R
N
N
N
R
9, R = C6H5
N
NH2
4
8, R = C6H4-CH3-p
Ac2O
AcOH
DMF-DMA
COCH3
Ar
Ar
EtO2C
H3C
NH
EtO2C
H3C
N
N
N
R
N
N
N
N
N
O
5
N(CH3)2
Ar = C6H4-OCH3-p
10, R = C6H5
1
proceed via initial N-2 alkylation (21) of the ring nitrogen in
compound 2 to give the non-isolable intermediate 3, which
underwent cyclization via addition of the amino group to the
nitrile function to afford the final product, compound 4.
Condensation of 4 with dimethylformamide–dimethylacetal
(DMF–DMA) in dry dioxane under reflux yielded the
formamidine derivative 5. The IR spectrum of compound 5
its H NMR spectrum revealed the absence of CH2 and NH2
protons, and instead, the signal of C(3)–H of the imidazole
moiety and COCH3 was detected at δ = 7.28 and 2.42 ppm,
respectively. Based on the data obtained, the reaction prod-
uct was formulated as ethyl-1-acetyl-9-(4-methoxyphenyl)-
7-methyl-2-(4-p-tolyl)-1H-imidazo-[1′,2′:1,5]pyrazolo[3,4-
b]pyridine-8-carboxylate (8). The formation of 8 was
assumed to proceed via the cyclization of 7 with the loss of
water molecule followed by acetylation of the imidazole
ring nitrogen (cf. Scheme 1 and Experimental Section).
1
revealed the absence of the NH2 group, and its H NMR
spectrum exhibited the absence of the signal due to the NH2
group (at δ = 3.91 ppm in compound 4) and the presence of
the signals of N(CH3)2 at δ = 2.74 and 2.84 ppm and the sig-
nal of N=CH at δ = 7.70 ppm (cf. Scheme 1 and Experimen-
tal Section).
On the other hand, compound 2 reacted with -bromo-
ω
acetophenone (6b) to give the N-1-alkyl product 9, which es-
tablished on the basis of the elemental analysis, spectral
data, and chemical evidence. Treatment of 9 with acetic
anhydride in glacial acetic acid under reflux afforded the
corresponding acetylation product ethyl-3-acetylamino-4-
(4-methoxyphenyl)-6-methyl-2-(2-oxo-2-phenylethyl)-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (10). The structure of
10 was established on the basis of the elemental and spectral
data, which showed the presence of NH, CH2, and three
C=O groups. The failure of all the attempts to cyclize 10 as
in case of 8 led to the conclusion that the alkylation first
took place at N-1 at compound 2 (cf. Scheme 1 and Experi-
mental Section).
Also, compound 2 reacted with p-methyl-ω-bromoaceto-
phenone (6a) under the same reaction conditions to give the
N-2-alkyl product 7. The IR spectrum of compound 7
showed the presence of the absorption bands of NH2 and
1
two carbonyl groups. Moreover, the H NMR spectrum of
compound 7 revealed the presence of NH2 and CH2 protons
(cf. Scheme 1 and Experimental Section).
Reaction of compound 7 with acetic anhydride in glacial
acetic acid under reflux afforded a reaction product 8 of the
molecular formula C28H26N4O4. IR spectrum of 8 showed
the disappearance of the absorption bands of NH2 group, and
© 2007 NRC Canada

594
Can. J. Chem. Vol. 85, 2007
Scheme 2.
Ar
N
EtO2C
H3C
N
CH3
(Ac)2CH2
N
N
CH3
11
H3CS
H3CS
Ar
N
Ar
..
NH2
CN
CN
EtO2C
H3C
N
NH2
CN
EtO2C
H3C
CN
CN
2
N
N
12
N
N
N
SCH3
SCH3
13
14
Ar
N
N=CHN(CH3)2
EtO2C
H3C
DMF-DMA
Ar = C6H4-OCH3-p
N
N
H
15
Condensation of compound 2 with acetyl acetone in gla-
cial acetic acid (22) under reflux afforded the corresponding
pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine derivative 11, its
structure was confirmed by elemental analysis and spectral
data, which showed the disappearance of NH and NH2 pro-
tons, indicating their participation in the condensation pro-
cess (cf. Scheme 2 and Experimental Section).
[2,3:4,3]pyrazolo[1,5-a]pyrimidines (27). Thus, treatment of
dimethylaminomethyleneaminopyrazolo[3,4-b]pyridine
derivative 15 with cyanothioacetamide (16a) in ethanol con-
taining catalytic amount of piperidine afforded a condensa-
tion product via dimethylamine elimination. Two structures
were considered for this reaction product: compounds 18
and 19. Elemental analysis of this reaction product indicated
the absence of sulfur; the IR spectrum showed the absorp-
The reactivity of compound 2 towards ketene dithioacetal
was also investigated; thus, 1,1-dicyano-2,2-dimethylthioethene
(12) (23) reacted with compound 2 in dimethylformamide
under reflux in the presence of potassium carbonate as a
catalyst to afford the corresponding pyrido[2′,3′:3,4]py-
razolo[1,5-a]pyrimidine derivative 14. The IR spectrum of
compound 14 showed the presence of NH2 (3444 and
1
tion band of CϵN (2223 cm–1) group, and its H NMR spec-
trum indicated the presence of only one NH2 group at δ =
9.27 ppm. Based on these data, structure 19 was excluded,
and structure 18 could be readily established for the main re-
action product (cf. Scheme 3 and Experimental Section).
The formation of compound 18 in this reaction product
can be assumed to proceed via the formation of the non-
isolable adduct 17, followed by intramolecular cyclization
involving the loss of one molecule of H2S (28) (turned lead
acetate paper into black during the reaction) and HN(CH3)2
to yield compound 18 (cf. Scheme 3).
A solid evidence for the structure of compound 18 came
from its authentic synthesis by the reaction of compound 15
with malononitrile (16b) under the same reaction conditions
to afford one and the same reaction product 18. Compound
18, prepared via this route, was found to be completely iden-
tical in all aspects (mp, mixed mp, and TLC) with com-
pound 18 prepared via the first route (cf. Scheme 3).
On the other hand, compound 15 reacted with
benzoylacetonitrile (20a) in ethanol containing catalytic
amount of piperidine under reflux to give 3-amino-
pyrazolo[3,4-b]pyridine derivative 2 (20) and 3-phenyl-2-
[(N,N-dimethylamino)methylene]-3-oxopropanenitrile (21a)
(25) instead of the addition product that would be expected
by analogy with the earlier reports (24–27). The formation
of compounds 2 and 21a in this reaction is assumed to pro-
ceed via N,N-dimethylaminomethylene exchange under the
1
3324 cm–1) and CϵN (2214 cm–1) groups. The H NMR
spectrum of compound 14 exhibited a signal at δ = 2.97 ppm
assignable to methylsulfanyl group. The formation of 14 was
preceded via initial alkylation (21) at N-2 to give the non-
isolable intermediate 13 and subsequent ring closure to yield
the final product 14 (cf. Scheme 2 and Experimental Sec-
tion).
Condensation of 2 with DMF–DMA in dry dioxane under
reflux afforded the ethyl 3-{[(N,N-dimethylamino)methy-
lene]amino}-4-(4-methoxyphenyl)-6-methyl-1H-pyrazolo-
[3,4-b]pyridine-5-carboxylate (15). Structure 15 was inferred
from its spectral data, elemental analysis, and chemical
transformations. 1H NMR spectrum of 15 confirmed the
presence of CH3 protons and disappearance of NH2 protons,
indicating that the condensation was carried out on the
amino group not the methyl group (cf. Scheme 2 and Exper-
imental Section).
The chemistry of the dimethylaminomethyleneamino-
pyrazole derivatives is now receiving considerable attention
as one of the major routes to synthesize the biologically ac-
tive pyrazolo[1,5-a]pyrimidines (24–26) and pyrimido-
© 2007 NRC Canada

Gad-Elkareem et al.
595
Scheme 3.
H
H
Ar
N
Ar
N
N(CH3)2
H
N
R
CN
EtO2C
H3C
EtO2C
H3C
N
-NH(CH3)2
Cycl.
CN
NH
N
NH
NH2
16a, R = CSNH2
EtOH/pip.
N
N
HS
NH2
S
17
19
-NH(CH3)2
- H2S
Ar
N
R
CN
EtO2C
H3C
N
N
15
16b, R = CN
EtOH/pip.
N
CN
NC
NH2
DMF-DMA
18
20a
O
NC
O
Ph
EtOH/pip.
2
+
Ph
Me2N
20a
21a
AcOH
AcOH
H
H
Ar
Ar
N
N(CH3)2
N
EtO2C
H3C
H
EtO2C
H3C
N
-NH(CH3)2
Cycl.
Ph
NH
N
Ph
NC
N
N
N
O
NH2
O
22a
23a
-H2O
-NH(CH3)2
Ar = C6H4-OCH3-p
Ar
EtO2C
H3C
N
N
N
N
CN
Ph
24a
applied reaction conditions leading to the regeneration of the
amino group (17, 29) and hence the formation of 2 (cf.
Scheme 3).
was found at m/z = 105 (100%), which was attributed to the
benzoyl radical (PhCO+). Based on the data obtained, the re-
action product was formulated as 4-amino-3-benzoyl-
pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine derivative 23a
rather than the possible alternative 3-cyano-4-phenyl-
pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine derivative 24a
(cf. Scheme 3 and Experimental Section).
The formation of compound 23a proceeds via first the for-
mation of the non-isolable adduct 22a followed by the
cyclization involving addition to the nitrile function group
with the loss of one molecule of dimethylamine to afford
compound 23a rather than the loss of water molecule that
gives compound 24a as we would expect by analogy with
the earlier reports (24–27) (cf. Scheme 3).
The reaction of 15 with 20a in glacial acetic acid under
reflux afforded an addition product with dimethylamine
elimination. Two structures seemed possible for this reaction
product: 23a and 24a. The IR spectrum of the reaction prod-
uct indicated the presence of absorption bands due to NH2
(3369 and 3235 cm–1) and COPh (1647 cm–1) groups and the
absence of any absorption band that might be attributed to
the CϵN group. The 1H NMR spectrum of the reaction prod-
uct exhibited the signal of NH2 protons at δ = 9.67 ppm
(D2O-exchangeable), and its 13C NMR spectrum revealed
the signal of C=O at δ = 195.78 ppm. Moreover, the mass
spectrum of this reaction product showed the molecular ion
peak M+ at m/z = 481 (63.9%), corresponding to the molecu-
lar formula C27H23N5O4; also, the base peak in the spectrum
An unequivocal support for the structure of 23a was
achieved via its synthesis through other route, i.e., condens-
ing 20a with DMF–DMA and subsequent condensation of
© 2007 NRC Canada

596
Can. J. Chem. Vol. 85, 2007
Scheme 4.
H
H
Ar
N
Ar
N
N(CH3)2
H
R
RCOCH2CN
(20b-20d)
N
EtO2C
H3C
EtO2C
H3C
N
N
-NH(CH3)2
-H2O
15
NH
AcOH
NC
N
N
CN
O
R
22b-22d
24b-24d
Cycl.
-NH(CH3)2
Ar
EtO2C
H3C
N
N
CN
Me2N
DMF-DMA
2
R
20b-20d
N
N
O
NH2
O
R
23b-23d
21b-21d
24b, R = C6H4-Cl-p
c, R = C6H4-CH3-p
d, R = OH
20-23b, R = C6H4-Cl-p
c, R = C6H4-CH3-p
d, R = OEt
Ar = C6H4-OCH3-p
the so-formed 3-phenyl-2-[(N,N-dimethylamino)methylene]-
3-oxopropanenitrile (21a) (25) with 2 in glacial acetic acid
to afford a product that is identical in all respects (mp,
mixed mp, and spectral data) to compound 23a (cf.
Scheme 3).
Similarly, compound 15 reacted with aroylacetonitriles
20b–20c and ethyl cyanoacetate (20d) in glacial acetic acid
under reflux to yield the corresponding 4-amino-3-aroyl-
pyrido[2′,3′:3,4]pyrazolo[1,5-a]-pyrimidine derivatives 23b
and 23c and 4-amino-3-ethoxycarbonylpyrido[2′,3′:3,4]py-
razolo[1,5-a]pyrimidine derivative 23d, respectively, instead
of the 3-cyano-4-arylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimi-
dine derivatives 24b and 24c and 3-cyano-4-hydroxy-
pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine derivative 24d (cf.
Scheme 4).
lowed by cyclocondensation reaction involving the nitrile
function instead of loss of water molecule as would be ex-
pected by analogy with the earlier reports (24–27).
Experimental
Melting points were measured with a Gallenkamp appara-
tus and are uncorrected. IR spectra (KBr discs) were re-
1
corded on BRUKER Vector 22 FT-IR spectrophotometer. H
and 13C NMR spectra were determined in DMSO-d6 and
CDCl3 at 300 MHz on Varian Mercury VX spectrometer us-
ing TMS as an internal standard. Chemical shifts are ex-
pressed as δ ppm and J as Hz units. Mass spectra were
recorded on GCMS-QP 1000 EX spectrometer at 70 eV. Ele-
mental analyses were carried out at the Microanalytical Cen-
ter of Cairo University. Compounds 1 (20), 2 (20), 12 (23),
and 21a–21d (25, 26) were prepared according to the litera-
ture procedures.
The reactions of 15 with 20b–20c in this study did not
take place as would have been expected by analogy with the
earlier reports (24–27).
Also, the structure of compounds 23b–23d was estab-
lished on the basis of the elemental analysis and spectral
data. A further support for the structure of 23b–23d was
achieved via its synthesis through other routes, i.e., via con-
densing 2 with 21b–21d (25, 26) in glacial acetic acid to af-
ford a product identical in all respects (mp, mixed mp, and
spectral data) to those corresponding to compounds 23b–
23d (cf. Scheme 4).
Reactions of compound 2 with halo-reagents
General procedure
A mixture of compound 2 (10 mmol) and each of
chloroacetonitrile and compounds 6a and 6b (10 mmol) was
stirred in DMF (30 mL) containing 10 mmoles of KOH at
room temperature for 2 h. The reaction mixtures were
poured on cold water and acidified with dilute HCl. The
solid products obtained were collected by filtration and crys-
tallized from ethanol to afford compounds 4, 7, and 9, re-
spectively.
Conclusion
The reaction of 3-amino-1H-pyrazolo[3,4-b]pyridine
derivative 2 with ω-bromoacetophenones gave either N-1 or
N-2 alkylation products, and the reaction of dimethylamino-
methyleneaminopyrazolo[3,4-b]-pyridine derivative 15 with
β-keto nitrile was found to be highly dependent on the reac-
tion mediums whether it is a basic medium (ethanol–
pipredine), which gave dimethylaminomethylene group ex-
change or acidic (acetic acid), which afforded addition fol-
Ethyl-2-amino-3-hydro-9-(4-methoxyphenyl)-7-methyl-
imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridine-8-carboxylate (4)
Yellow crystals (65%) from ethanol, mp 146 °C. IR υ
(cm–1): 3454, 3313 (NH2), 1718 (C=O), 1612 (C=N). H
1
NMR (CDCl3): δ 0.99 (t, J = 7.23 Hz, 3H, CH2CH3), 2.66
(s, 3H, CH3), 3.86 (s, 3H, OCH3), 3.91 (s, 2H, NH2), 4.07
© 2007 NRC Canada

Gad-Elkareem et al.
597
(q, J = 7.2 Hz, 2H, CH2CH3), 5.20 (s, 2H, CH2, C(3)–H),
6.99 (d, J = 8.8 Hz, 2H, Ar–H), 7.31 (d, J = 8.8 Hz, 2H, Ar–
H). 13C NMR (CDCl3): δ 13.79 (CH3CH2), 23.14 (7-CH3),
55.44 (OCH3), 61.59 (OCH2CH3), 77.21 (C-3), 114.19 (C-
9a), 118.85 (C-9b), 125.45 (C-8), 143.8 (C-9), 149.32 (C-
5a), 156.35 (C-7), 161.38 (C-2), 167.45 (C=O), 114.75,
127.63, 130.03, 160.62 (arom. C’s). Anal. calcd. for
C19H19N5O3 (365): C 62.46, H 5.20, N 19.17; found: C
62.15, H 5.49, N 18.85.
ucts thus formed were filtered off and crystallized from
ethanol to give compounds 8 and 10, respectively.
Ethyl-1-acetyl-9-(4-methoxyphenyl)-7-methyl-2-(4-p-tolyl)-
1H-imidazo[1′,2′:1,5]pyrazolo[3,4-b]pyridine-8-carboxylate (8)
Yellowish brown crystals (53%) from ethanol, mp 324–
326 °C. IR υ (cm–1): 1724 (ester C=O), 1676 (amide C=O).
1H NMR (CDCl3): δ 1.09 (t, J = 7.2 Hz, 3H, CH2CH3), 2.42
(s, 6H, CH3-tolyl and NCOCH3), 2.77 (s, 3H, CH3, C(7)),
3.97 (s, 3H, OCH3), 4.17 (q, J = 7.2 Hz, 2H, CH2CH3), 7.09
(d, J = 8.4 Hz, 2H, Ar–H), 7.28 (s, 1H, C(3)–H), 7.65–7.76
(m, 4H, Ar–H), 7.87 (d, J = 8.4 Hz, 2H, Ar–H). Anal. calcd.
for C28H26N4O4 (482): C 69.71, H 5.39, N 11.62; found: C
69.40, H 5.11, N 11.91%.
Ethyl-3-amino-4-(4-methoxyphenyl)-6-methyl-2-(2-oxo-2-
p-tolylethyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (7)
Yellow crystals (65%) from ethanol, mp 172 °C. IR υ
(cm–1): 3432, 3354 (NH2), 1724 (ester C=O), 1699 (Ar.
1
C=O), 1610 (C=N). H NMR (CDCl3): δ 1.02 (t, J = 7.0 Hz,
3H, CH2CH3), 2.43 (s, 3H, CH3-p-tolyl), 2.69 (s, 3H, CH3),
3.89 (s, 3H, OCH3), 4.05 (q, J = 7.0 Hz, 2H, CH2CH3), 5.16
(s, 2H, CH2, N–CH2CO), 6.69 (br, 2H, NH2), 7.03 (d, J =
8.1 Hz, 2H, Ar–H), 7.26–735 (m, 4H, Ar–H), 7.74 (d, J =
7.8 Hz, 2H, Ar–H). Anal. calcd. for C26H26N4O4 (458): C
68.12, H 5.67, N 12.22; found: C 67.83, H 5.98, N 12.00.
Ethyl-3-acetylamino-4-(4-methoxyphenyl)-6-methyl-2-(2-
oxo-2-phenyl-ethyl)-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (10)
Yellow crystals (60%) from ethanol, mp 224–226 °C. IR υ
(cm–1): 3183 (NH), 1723 (ester C=O), 1698 (Ar. C=O), 1664
1
(amide C=O). H NMR (DMSO-d6): δ 0.97 (t, J = 7.0 Hz,
3H, CH2CH3), 1.54 (s, 3H, COCH3), 2.55 (s, 3H, CH3), 3.82
(s, 3H, OCH3), 4.05 (q, J = 7.0 Hz, 2H, CH2CH3), 6.13 (s,
2H, CH2, N–CH2COPh), 7.0–726 (m, 4H, Ar–H), 7.59–7.75
(m, 3H, Ar–H), 8.12 (d, J = 7.25 Hz, 2H, Ar–H), 9.75 (s,
1H, NH). 13C NMR (DMSO-d6): δ 13.38 (CH3CH2), 22.89
(6-CH3), 32.56 (CH3CO), 53.09 (NCH2COPh), 55.17
(OCH3), 60.89 (OCH2CH3), 107.03 (C-3a), 123.66 (C-5),
138.29 (C-4), 142.79 (C-3), 154.81 (C-6 and C-8a), 159.49
(CO2Et), 192.91 (COCH3), 197.19 (COPh), 113.15, 126.06,
128.06, 128.84, 129.74, 132.06, 132.89, 159.49 (arom. C’s).
Anal. calcd. for C27H26N4O5 (486): C 66.66, H 5.34, N
11.52; found: C 66.92, H 5.20, N 11.22.
Ethyl-3-amino-4-(4-methoxyphenyl)-6-methyl-2-(2-oxo-2-
phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (9)
Yellow crystals (69%) from ethanol, mp 192–193 °C. IR υ
(cm–1): 3462, 3334 (NH2), 1719 (ester C=O), 1701
1
(PhC=O), 1613 (C=N). H NMR (CDCl3): δ 0.98 (t, J =
7.2 Hz, 3H, CH2CH3), 2.62 (s, 3H, CH3), 3.61 (br., 2H,
NH2), 3.85 (s, 3H, OCH3), 4.07 (q, J = 7.2 Hz, 2H,
CH2CH3), 5.75 (s, 2H, CH2, N–CH2COPh), 6.98 (d, J =
8.4 Hz, 2H, Ar–H), 7.34 (d, J = 8.4 Hz, 2H, Ar–H), 7.45–
7.60 (m, 3H, Ar–H, COPh), 8.01 (d, J = 7.2 Hz, 2H, Ar–H,
COPh). Anal. calcd. for C25H24N4O4 (444): C 67.56, H 5.40,
N 12.61; found: C 67.30, H 5.65, N 12.31.
Ethyl-10-(4-methoxyphenyl)-2,4,8-trimethylpyrido-
Ethyl-2-{[(N,N-dimetylamino)methylene]amino}-3-hydro-9-
(4-methoxy-phenyl)-7-methylimidazo[1′,2′:1,5]pyrazolo-
[3,4-b]pyridine-8-carboxylate (5)
[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-carboxylate (11)
A mixture of compound 2 (10 mmol) and acetylacetone
(10 mmol) in glacial acetic acid (30 mL) was heated under
reflux for 3 h then cooled. The solid product thus formed
was filtered off and crystallized from acetic acid to afford
compound 11 as yellow crystals (58%), mp 168 °C. IR υ
A mixture of compound 4 (10 mmol) and DMF–DMA
(12 mmol) in dry dioxane (30 mL) was heated under reflux
for 3 h. The solid product thus formed after cooling was col-
lected by filtration and crystallized from ethanol to yield
compound 5 as yellow crystals (63%), mp 122 °C. IR υ (cm–1):
1
(cm–1): 1721 (C=O), 1622 (C=N). H NMR (CDCl3): δ 1.07
(t, J = 7.02 Hz, 3H, CH2CH3), 2.61 (s, 3H, CH3), 2.83 (s,
3H, CH3), 2.94 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.16 (q,
J = 7.02 Hz, 2H, CH2CH3), 7.00 (d, J = 8.4 Hz, 2H, Ar–H),
7.15 (s, 1H, C(3)–H), 7.56 (d, J = 8.4 Hz, 2H, Ar–H). Anal.
calcd. for C22H22N4O3 (390): C 67.69, H 5.64, N 14.35;
found: C 67.42, H 5.33, N 14.10
1
1722 (C=O), 1627 (C=N). H NMR (CDCl3): δ 1.00 (t, J =
7.16 Hz, 3H, CH2CH3), 2.66 (s, 3H, CH3), 2.74 (s, 3H, CH3,
N(CH3)2), 2.84 (s, 3H, CH3, N(CH3)2), 3.83 (s, 3H, OCH3),
4.07 (q, J = 7.16 Hz, 2H, CH2CH3), 5.28 (s, 2H, CH2, C(3)–
H), 6.89 (d, J = 8.6 Hz, 2H, Ar–H), 7.35 (d, J = 8.6 Hz, 2H,
Ar–H), 7.70 (s, 1H, N=CH). 13C NMR (CDCl3): δ 13.61
(CH3CH2), 23.29 (7-CH3), 33.88, 34.04 (N(CH3)2), 39.84
(C-3), 55.23 (OCH3), 61.10 (OCH2CH3), 106.97 (C-9a),
114.47 (C-9b), 123.69 (C-8), 144.79 (C-9), 151.05 (C-5a),
154.23 (C-7), 156.17 (C-2 and C=NH), 169.06 (C=O),
112.64, 127.19, 131.06, 159.81 (arom. C’s). Anal. calcd. for
C22H24N6O3 (420): C 62.85, H 5.71, N 20.00; found: C
62.53, H 5.46, N 19.73.
Ethyl-2-amino-3-cyano-10-(4-methoxyphenyl)-8-methyl-4-
methylsulfanylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-
carboxylate (14)
A mixture of compound 2 (10 mmol) and compound 12
(10 mmol) in dimethylformamide (30 mL) containing 1.0 g
of anhyd. potassium carbonate was heated under reflux for
5 h. The reaction mixture was then cooled, poured onto ice-
cold water, and acidified with dilute HCl. The solid product
obtained was filtered off and crystallized from ethanol to
give compound 14 as brown crystals (55%), mp 201–202 °C.
IR υ (cm–1): 3445, 3335 (NH2), 2214 (CϵN), 1718 (C=O),
Reaction of compounds 7 and 9 with acetic anhydride
A solution of each of compounds 7 and 9 (10 mmol) in
glacial acetic acid (30 mL) was treated with acetic anhydride
(5 mL) and heated under reflux for 6 h. The reaction mixture
was then cooled and poured onto cold water. The solid prod-
1
1637 (C=N). H NMR (CDCl3): δ 1.05 (t, J = 7.2 Hz, 3H,
CH2CH3), 2.76 (s, 3H, CH3), 2.97 (s, 3H, SCH3), 3.87 (s,
© 2007 NRC Canada

598
Can. J. Chem. Vol. 85, 2007
3H, OCH3), 4.13 (q, J = 7.2 Hz, 2H, CH2CH3), 6.97–7.44
(m, 6H, Ar–H and NH2). Anal. calcd. for C22H20N6O3S
(448): C 58.92, H 4.46, N 18.75, S 7.14; found: C 58.64, H
4.18, N 18.99, S 6.88.
(CDCl3): δ 1.05 (t, J = 7.2 Hz, 3H, CH2CH3), 2.80 (s, 3H,
CH3), 3.85 (s, 3H, OCH3), 4.12 (q, J = 7.2 Hz, 2H,
CH2CH3), 7.25–7.57 (m, 9H, Ar–H), 8.62 (s, 1H, C(2)–H),
9.67 (br, 2H, NH2, lost after D2O-exchange). 13C NMR
(CDCl3): δ 13.80 (CH3CH2), 24.73 (8-CH3), 55.20 (OCH3),
61.41 (OCH2CH3), 102.55 (C-10a), 102.87 (C-3), 123.95
(C-9), 138.34 (C-10b), 143.98 (C-10), 145.91 (C-6a), 149.27
(C-2), 151.98 (C-8), 162.15 (C-4), 169.06 (CO2Et), 195.78
(COPh), 113.44, 126.95, 128.51, 128.81, 130.61, 131.82,
160.31 (arom. C’s). MS: (M+) 481 (63.9%), 105 (100%).
Anal. calcd. for C27H23N5O4 (481): C 67.36, H 4.78, N
14.55; found: C 67.06; H 4.45, N 14.30.
Ethyl-3-{[(N,N-dimethylamino)methylene]amino}-4-(4-
methoxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (15)
This compound was synthesized from compound 2
(10 mmol) and DMF–DMA (12 mmol) in a manner similar
to that described for the preparation of compound 5. It was
crystallized from ethanol to give yellow crystals (76%), mp
174 °C. IR υ (cm–1): 3195 (NH), 1734 (C=O). 1632 (C=N).
1H NMR (CDCl3): δ 0.99 (t, J = 7.2 Hz, 3H, CH2CH3), 2.72
(s, 3H, CH3), 2.75 (s, 3H, CH3, N(CH3)2), 2.80 (s, 3H, CH3,
N(CH3)2), 3.83 (s, 3H, OCH3), 4.08 (q, J = 7.2 Hz, 2H,
CH2CH3), 6.91 (d, J = 8.6 Hz, 2H, Ar–H), 7.38 (d, J =
8.6 Hz, 2H, Ar–H), 7.63 (s, 1H, N=CH), 11.74 (s, 1H, NH).
Anal. calcd. for C20H23N5O3 (381): C 62.99, H 6.03, N
18.37; found: C 62.70, H 5.80, N 18.09.
Ethyl-4-amino-3-(4-chlorobenzoyl)-10-(4-methoxyphenyl)-
8-methylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-
carboxylate (23b)
Yellow crystals from acetic acid (65%,), mp 301–302 °C.
IR υ (cm–1): 3373, 3237 (NH2), 1711 (ester C=O), 1648 (Ar.
1
C=O), 1626 (C=N). H NMR (DMSO-d6): δ 1.02 (t, J =
7.25 Hz, 3H, CH2CH3), 2.65 (s, 3H, CH3), 3.81 (s, 3H,
OCH3), 4.08 (q, J = 7.25 Hz, 2H, CH2CH3), 7.02–7.74 (m,
8H, Ar–H), 8.34 (s, 1H, C(2)–H), 9.25 (br., 2H, NH2). Anal.
calcd. for C27H22N5O4Cl (515.5): C 62.85, H 4.26, N 13.57,
Cl 6.88; found: C 63.15, H 4.00, N 13.27, Cl 6.61.
Synthesis of ethyl-4-amino-3-cyano-10-(4-methoxyphenyl)-
8-methylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-
carboxylate (18)
A mixture of compound 15 (10 mmol) and either of
cyanothioacetamide (16a) or malononitrile (16b) (10 mmol)
in ethanol (30 mL) containing 0.5 mL of triethylamine, as a
catalyst, was heated under reflux for 2 h. The solid product
obtained on hot was filtered off and crystallized from
dioxane to give compound 18 as yellow crystals (67%), mp
309–310 °C. IR υ (cm–1): 3427, 3391 (NH2), 2223 (CϵN),
Ethyl-4-amino-3-(4-methylbenzoyl)-10-(4-methoxyphenyl)-
8-methylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-
carboxylate (23c)
Yellow crystals, (63%, dioxane), mp 317–318 °C. IR υ
(cm–1): 3376, 3238 (NH2), 1713 (ester C=O), 1648 (Ar.
C=O). 1H NMR (CDCl3): δ 1.05 (t, J = 7.2 Hz, 3H,
CH2CH3), 2.44 (s, 3H, CH3, aroyl), 2.82 (s, 3H, CH3), 3.87
(s, 3H, OCH3), 4.15 (q, J = 7.2 Hz, 2H, CH2CH3), 7.28 (d,
J = 8.4 Hz, 2H, Ar–H), 7.53–7.59 (m, 6H, Ar–H), 8.66 (s,
1H, C(2)–H), 9.46 (br., 2H, NH2, lost after D2O-exchange).
Anal. calcd. for C28H25N5O4 (495): C 67.87, H 5.05, N
14.14; found: C 67.60, H 5.36, N 14.39.
1
1722 (C=O), 1645 (C=N). H NMR (CDCl3): δ 1.08 (t, J =
7.2 Hz, 3H, CH2CH3), 2.86 (s, 3H, CH3), 3.91 (s, 3H,
OCH3), 4.16 (q, J = 7.2 Hz, 2H, CH2CH3), 7.02 (d, J =
8.6 Hz, 2H, Ar–H), 7.51 (d, J = 8.6 Hz, 2H, Ar–H), 8.426 (s,
1H, C(2)–H), 9.27 (br, 2H, NH2). 13C NMR (DMSO-d6): δ
13.41 (CH3CH2), 24.07 (8-CH3), 55.09 (OCH3), 60.97
(OCH2CH3), 78.73 (C-3), 101.72 (C-10a), 113.23 (CN),
122.84 (C-9), 143.78 (C-10b), 144.90 (C-10), 149.29 (C-6a),
158.89 (C-8), 159.78 (C-2), 160.01 (C-4), 168.16 (CO),
114.93, 126.42, 130.26, 155.22 (arom. C’s). Anal. calcd. for
C21H18N6O3 (402): C 62.68, H 4.47, N 20.89; found: C
62.39, H 4.21, N 20.62.
Diethyl-4-amino-10-(4-methoxyphenyl)-8-methylpyrido-
[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3,9-dicarboxylate (23d)
Yellow crystals, (66%, dioxane), mp 258–259 °C. IR υ
(cm–1): 3402, 3284 (NH2), 1715 (ester C=O, C(9)), 1700
1
(ester C=O, C(3)), 1642 (C=N). H NMR (CDCl3): δ 1.04
(t, J = 7.2 Hz, 3H, CH2CH3), 1.41 (t, J = 7.1 Hz, 3H,
CH2CH3), 2.79 (s,3H, CH3),
(s, 3H, OCH3), 4.17 (q,
3.89
Reaction of compound 15 with compounds 20a–20d and
2 with 21a–21d
J = 7.2 Hz, 2H, CH2CH3), 4.44 (q, J = 7.1 Hz, 2H,
CH2CH3), 7.0 (d, J = 8.8 Hz, 2H, Ar-H), 7.52 (d, J = 8.8 Hz,
2H, Ar–H), 7.75 (br, 2H, NH2), 8.88 (s, 1H, C(2)–H). 13C
NMR (DMSO-d6): δ 13.41 (2CH3CH2), 23.02 (8-CH3),
55.16 (OCH3), 60.53 (2CH2CH3), 101.43 (C-10a), 120.68
(C-3), 126.87 (C-9), 130.52 (C-10b), 147.81 (C-10), 151.38
(C-6a), 153.04 (C-2), 158.61 (C-8), 159.57 (C-4), 168.27
(2CO2Et), 113.83, 129.39, 142.82, 154.46 (arom. C’s). Anal.
calcd. for C23H23N5O5 (449): C 61.46, H 5.12, N 15.59;
found: C 61.72, H 5.39, N 15.88.
General procedure
A mixture of compound 15 (10 mmol) and each of com-
pounds 20a–20d (10 mmol) in glacial acetic acid (30 mL)
was heated under reflux for 3 h. The solid products obtained
after cooling were filtered off and crystallized from the
proper solvent to afford compounds 23a–23d, respectively.
Reaction of 2 with 21a–21d was preceded in a similar man-
ner to give the same reaction products 23a–23d.
Ethyl-4-amino-3-benzoyl-10-(4-methoxyphenyl)-8-
methylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-9-
carboxylate (23a)
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acid (68%), mp 297–298 °C. IR υ (cm–1): 3369, 3235 (NH2),
1
1714 (ester C=O), 1647 (PhC=O), 1622 (C=N). H NMR
© 2007 NRC Canada

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© 2007 NRC Canada