L-Proline-catalyzed three-component domino reactions in the regioselective synthesis of novel densely functionalized pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1039/c3ra00136a

The l-proline-catalyzed three-component synthesis of novel 3-methyl-1-aryl-1H-pyrazolo[3,4-b]pyridines in good yields from the reaction of 3-methyl-1-aryl-1H-pyrazol-5-amines, 1,3-dicarbonyl compounds and aromatic aldehydes in ethanol is described. This domino transformation presumably involves the formation of two C-C bonds and one C-N bond in a single synthetic operation.

Full text of DOI:10.1039/c3ra00136a

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L-Proline-catalyzed three-component domino reactions
in the regioselective synthesis of novel densely
functionalized pyrazolo[3,4-b]pyridines3
Cite this: DOI: 10.1039/c3ra00136a
Pethaiah Gunasekaran, Sethuraman Indumathi and Subbu Perumal*
Received 9th January 2013,
Accepted 11th March 2013
The L-proline-catalyzed three-component synthesis of novel 3-methyl-1-aryl-1H-pyrazolo[3,4-b]pyridines in
good yields from the reaction of 3-methyl-1-aryl-1H-pyrazol-5-amines, 1,3-dicarbonyl compounds and
aromatic aldehydes in ethanol is described. This domino transformation presumably involves the
formation of two C–C bonds and one C–N bond in a single synthetic operation.
DOI: 10.1039/c3ra00136a
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ving two or more steps.16 These methods suffer from one or
more disadvantages such as environmentally unfriendly
Introduction
The chemistry of pyrazolopyridine derivatives has attracted
much attention in view of their importance as bio-active drug
targets1 in the pharmaceutical industry and their prevalence as
the core structure of numerous biologically active com-
pounds.2 Pyrazolopyridines act as potent cyclin dependent
kinase 1 (CDK1) inhibitors,3 HIV reverse transcriptase inhibi-
tors,4 CCR1 antagonists,5 protein kinase inhibitors,6 inhibitors
of cGMP degradation, dopamine D3 receptor antagonists,
besides possessing antiherpetic and antiallergic,7 herbicidal
and fungicidal activities.8 In particular, pyrazolo[3,4-b]pyri-
dines viz. cartazolate, etazolate and tracazolate (Fig. 1) are
known as anxiolytic drugs.9
Previously reported methods for the synthesis of variously
functionalized pyrazolo[3,4-b]pyridines include: (i) hetero
Diels–Alder reactions of azadienes with alkynes and alkenes,10
(ii) reactions of pyrazolamines with electron-deficient alkenes,
isoflavones and coumarinaldehydes,11 (iii) three-component
reaction of pyrazolamines with (a) isatin and cyclic diketones
in presence of CAN catalyst12 and (b) salicylaldehyde and ethyl
acetoacetate in the presence of piperidine and acetic acid,13
(iv) reactions of pyrazolamines having a benzotriazolylmethyl
group at the 4-position/amino nitrogen with unactivated and
electron-rich alkenes in the presence of p-TSA followed by
heterocyclization,14 (v) four-component reactions of indolin-2-
one, 3-oxo-3-phenylpropanenitrile, hydrazines and aldehydes
in the presence of p-TSA catalyst15 in ionic liquid, ([BMIm]Br)
as solvent and (vii) transformations using appropriately
substituted pyridines as synthons via linear synthesis invol-
catalysts (metal, corrosive acid and toxic substances) low or
inconsistent yields, lack of convergence and tedious work up.
Fluorinated organic compounds have gained significant
importance due to their unique chemical and biological
properties.17 In particular, the reactions of fluorinated 1,3-
dicarbonyl compounds as synthons are attractive18 in the
assembly of heterocycles19,20 of medicinal and agricultural
relevance.21
The biological importance of pyrazolopyridines and fluori-
nated heterocycles, in conjunction with our recently embarked
research programme on the construction of novel heterocycles of
varying complexity and diversity employing novel green transfor-
mations22 and domino processes23 led us to report in this
manuscript the synthesis of 1-aryl-3-methyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridines (Table 2) as promising candidates for
biological evaluation in good yields from the three-component
reactions of 1,3-dicarbonyl compounds, viz. 4,4,4-trifluoro-1-
(thiophen-2-yl)butane-1,3-dione/1-phenylbutane-1,3-dione/methyl
acetoacetate 1, aromatic aldehydes
2 and 3-methyl-1-aryl-
1H-pyrazol-5-amines 3 in ethanol employing organocatalyst,
L-proline (Table 2).
It is pertinent to note that L-proline is an abundant,
inexpensive and eco-friendly amino acid capable of catalyzing
diverse organic reactions24 and domino transformations.25
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai-625 021, Tamil Nadu, India. E-mail: subbu.perum@gmail.com;
Fax: +91-452-2459845; Tel: +91-452-2459845
Electronic supplementary information (ESI) available. CCDC reference number
3
909204. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ra00136a
Fig. 1 Some pyrazolopyridine drugs.
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either water or ethanol failed to afford the product (entry 1).
The reaction in the presence of pyrrolidine, Et3N and
ammonium acetate afforded a low/no yield of the product 4a
(Table 1, entries 10–14 and 20–29), whilst with HCOOH, acetic
acid, p-TSA, pyrrolidine–acetic acid mixture (1 : 1) and
pyrrolidine–HCOOH mixture (1 : 1) in ethanol (Table 1, entries
16–20) the reaction failed to occur. This reaction afforded a
maximum yield (78%) of 4a with 20 mol% of L-proline in
ethanol at 80 uC (entry 6). The data in Table 1 also disclose that
the yield of 4a remains almost the same, when the amount of
L-proline was increased to 100 mol%, albeit different reaction
times were required (Table 1, entries 4–6). From these
observations, the L-proline–ethanol pair emerges as the most
suitable catalyst–solvent combination, among those examined.
Consequently, for all subsequent reactions, 20 mol% of L-
proline was employed in ethanol at 80 uC. With these results in
hand, the scope of the reaction was investigated under the
optimal conditions established above using diketones/keto
ester, pyrazolamines and aromatic aldehydes bearing different
substituents in the aryl rings (Table 2). Typically, the reaction
of a mixture of 1,3-dicarbonyl compound 1 (1 mmol), aromatic
aldehyde 2 (1 mmol) and 3-methyl-1-aryl-1H-pyrazol-5-amine 3
(1 mmol) in presence of L-proline (0.20 mmol) in ethanol (15
ml) at 80 uC for 10–19 h afforded a library of novel 3-methyl-1-
aryl-1H-pyrazolo[3,4-b]pyridines 4 in 70–85% yields. In the case
of 3-methyl-1-aryl-1H-pyrazol-5-amines having p-F, p-Cl and
p-OMe phenyl rings on the nitrogen, the above reaction
resulted in the formation of either pyrazolopyridines 4 or
dihydropyrazolopyridines 5 lacking a trifluoroacetyl group
(Table 2, entries 18–22) or both 4 and 5 disclosing that the
product-selectivity of the reaction is subtly influenced by the
nature of the substituent present in the aryl ring of the
pyrazolamine as well as the aromatic aldehyde (Table 2, entries
19–21). The reaction of a representative b-ketoester, viz. methyl
acetoacetate with 4-chlorobenzaldehyde and 3-methyl-1-phe-
nyl-1H-pyrazol-5-amine in the presence of L-proline at 80 uC
also furnished the corresponding methyl pyrazolopyridine
carboxylate ester, viz. methyl 4-(4-chlorophenyl)-3,6-dimethyl-
1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4w) in 71%
yield. The reaction of 1-phenylbutane-1,3-dione, an unsymme-
trical 1,3-diketone, with a methyl group in place of a
trifluoromethyl group, with p-anisaldehyde and 3-methyl-1-
phenyl-1H-pyrazol-5-amine in the presence of L-proline at 80
uC also afforded a good yield of the product 4x in 85% yield.
However, the reaction of acetylacetone in the above reaction
led to a complex mixture of products, presumably due to self-
condensation of the 1,3-diketone having only alkyl groups
linked to carbonyl.
Scheme 1 Plausible mechanistic pathway for L-proline-catalyzed formation of
pyrazolopyridines 4 and dihydropyrazolopyridines 5.
The unique catalytic efficacy of L-proline in a variety of organic
transformations is ascribable to its multiple catalytic functions
as an acid or a base or both simultaneously, as a nucleophile
and its ability to form enamine/iminium intermediates upon
reaction with carbonyl/a,b-unsaturated carbonyl compounds
respectively.26
Results and discussion
We started our study by examining the model reaction of 4,4,4-
trifluoro-1-(thiophen-2-yl)butane-1,3-dione
1
(1 mmol),
The structure and regiochemistry of all the products 4 and
5 were unambiguously determined from combustion data and
one- and two-dimensional NMR spectroscopic data (see
4-chlorobenzaldehyde 2 (1 mmol) and 3-methyl-1-phenyl-
1H-pyrazol-5-amine 3 (1 mmol) in presence of L-proline (1
mmol), which afforded compound 4a (Table 1). Initially, the
reaction was investigated using different catalysts, solvents
and under solvent- as well as catalyst-free conditions (Table 1)
with a view to finding optimal conditions to maximize the
yield of the product. The reaction in the absence of catalyst in
supporting information ). A single crystal X-ray crystallo-
3
graphic study of 4o confirmed the structure deduced from
NMR spectroscopic data (Fig. 2).
It is pertinent to note that all the products 4 generated from
1,3-diketones had the same regiochemistry with the trifluor-
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Table 1 Optimization of catalyst,a solvent and reaction conditions for the synthesis of 4a
Entry
Catalyst
Solvent
Time (h)
Yield of 4ab (%)
c
1
2
—
Water/ethanol
Water
Acetonitrile
20
14
7
6
—
35
55
78
75
78
55
45
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine–HOAc mixture (1 : 1)
Pyrrolidine-HCOOH mixture (1 : 1)
HCOOH
HOAc
p-TSA
Et3N
Et3N
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Ethanol (100)d
Ethanol (50)d
Ethanol (20)d
Ethanol (15)d
Ethanol (10)d
Chloroform
6
12
14
15
20
20
20
20
20
15
16
21
21
16
20
7
c
—
—
c
Solvent-free
Acetonitrile
Ethanol
Chloroform
Water
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Acetonitrile
Ethanol
Chloroform
Solvent-free
Water
Acetonitrile
Ethanol
Chloroform
Solvent-free
Water
15
33
c
—
—
—
—
—
—
—
c
c
c
c
c
c
10
31
25
10
8
Et3N
Et3N
Et3N
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
20
20
18
11
14
20
15
15
c
—
12
15
c
—
—
—
c
c
a
b
c
d
100 mol% of catalyst was employed in these reactions unless mentioned. Yield of isolated product. Reaction failed to occur. Values in
parentheses indicate mol% of L-Proline.
omethyl/methyl group at the 6-position and the carbonyl
linked to the aryl/thienyl group at the 5-position of the
pyrazolopyridine ring system. This regiochemistry is explicable
on the basis of the greater electrophilicity of the carbonyl of
COCF3 and COCH3 groups than the carbonyl of ArCO (Ar =
2-thienyl/substituted phenyl) groups. In the case of the
reaction of the ketoester, CH3COCH2COOMe, in place of
diketone, with p-chlorobenzaldehyde and 3-methyl-1-phenyl-
1H-pyrazol-5-amine, the regiochemistry of the product, methyl
4-(4-chlorophenyl)-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-
5-carboxylate (4w) is controlled by the higher electrophilicity of the
CH3CO group than COOMe function.
dihydropyrazolopyridine intermediate 11 via 10. Subsequently,
the intermediate 11 undergoes air oxidation to afford the final
product 4. Our efforts to obtain evidence for the formation of
(i) either the Knoevenagel intermediate 8 from the reaction of
4,4,4-trifluoro-1-phenylbutane-1,3-dione 1 (1 mmol), p-chlor-
obenzaldehyde (1 mmol) and L-proline (1 mmol) and (ii)
dihydropyrazolopyridine intermediate 11 (Scheme 1) from the
reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol),
4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione (1 mmol),
p-chlorobenzaldehyde (1 mmol) and L-proline (0.2 mmol)
under nitrogen atmosphere did not succeed leading to an
inseparable mixture of products.
A plausible mechanism for the formation of the 3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridines 4 depicted in Scheme 1,
envisages the intervention of a Knoevenagel intermediate 8
(Scheme 1), which subsequently undergoes Michael addition
with pyrazolamine and concomitant condensation to afford a
The probable mechanism for the formation of dihydropyr-
azolopyridines 5 lacking a trifluoroacetyl group (Table 2
entries 18–20) from the reaction of 3-methyl-1-aryl-
1H-pyrazol-5-amines with p-MeO and p-Cl phenyl rings is also
depicted in Scheme 1. Presumably, the extended conjugation
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Table 2 Synthesis of pyrazolo[3,4-b]pyridines 4 and 5a
failed to catalyse this reaction (Table 1). This suggests that the
presence of both secondary amino and carboxyl functions in
the same catalyst molecule is crucial for the success of this
transformation. This, in turn, discloses that both the carboxyl
as well as secondary amino functions are involved in catalysing
the reactions in concert as shown in the Michael addition and
condensation steps (Scheme 1). Presumably, catalysis by L-
proline and the lack of it by an equimolar mixture of
pyrrolidine and formic/acetic acid is ascribable to a favourable
entropy factor on going to the transition state in the case of L-
proline, as both the amino and carboxyl functions are present
in the same molecule leading to less loss of entropy than that
involved in the catalysis by pyrrolidine and formic/acetic acid.
This protocol furnishing a series of novel 3-methyl-1-aryl-
1H-pyrazolo[3,4-b]pyridines proceeds via a one pot three-
component reaction. It is pertinent to note that multi-
component reactions (MCRs),28 endowed with powerful bond
forming and atom efficacies can afford libraries of new
chemical entities of structural complexity and diversity
facilitating new lead identification and optimization in drug
discovery programmes.29 As isolation and characterization of
the intermediates of these MCRs are obviated in this protocol,
considerable savings in solvent, adsorbent, energy, time and
cost are achieved enabling them to conform to the tenets of
green chemistry.
Yield (%)b
Time (h) 4 (5)
Entry Comp R1
R2
R3
R4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
CF3 2-Thc
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 2-Th
CF3 Ph
CF3 Ph
CF3 Ph
CF3 Ph
CF3 Ph
CF3 Ph
CF3 Ph
CF3 Ph
CF3 2-Th 4-Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Cl
4-O2N 14
4-F
4-Br
4-MeO 18
3-Br
3-F
12
78
82
11
16
85
81
82
16
11
16
79
75
79
82
2-Br
2-MeO 18
2-Me 13
2,3-Cl2 19
15
4-O2N 10
82
70
80
H
78
75
79
4-Cl
4-Me
4-MeO 14
3-Br
12
13
82
84
(85)
(83)
39 (61)
82
13
8
6
7
8
4-OMe 4-O2N
4-Cl
4-Cl
4s
4t
4u
4v
4w
4x
4-MeO
4-O2N
4-Cl
4-Cl
4-Cl
CF3 Ph
CH3 OMe
CH3 Ph
4-F
H
H
8
12
6
78
71
85
Conclusions
4-MeO
In conclusion, we have developed an expedient three-compo-
nent domino protocol for the synthesis of novel 3-methyl-1-
aryl-1H-pyrazolo[3,4-b]pyridines in good yields from the reac-
tion of 3-methyl-1-aryl-1H-pyrazol-5-amines, 1,3-diketones/
b-ketoester and aromatic aldehydes in the presence of a
catalytic amount of green catalyst, L-proline. This one-pot
transformation via a domino sequence of reactions involves
the formation of two C–C bonds and one C–N bond in a single
synthetic operation.
a
Reaction conditions: dicarbonyl compound (1 mmol), aldehyde (1
mmol), pyrazol-5-amine (1 mmol) and L-proline (0.20 mmol) in
b
c
ethanol (15 ml) stirred at 80 uC. Yield of isolated product. 2-Th =
2-Thienyl.
confers greater stability for 5 than 12, which provides the
impetus for the tautomeric equilibrium to lie in favour of 5.27
Further, the lack of a trifluoroacetyl group at position 6 in
compound 5 is likely to diminish the acidity of the hydrogen in
the same position which, in turn, renders aromatization
difficult.
Experimental section
Melting points were measured in open capillary tubes and are
uncorrected. The 1H-NMR, 13C-NMR, DEPT, H,H-COSY and
C,H-COSY were recorded on a Bruker (Avance) 300 MHz NMR
instrument using TMS as internal standard and CDCl3 as
solvent. Standard Bruker software was used throughout.
Chemical shifts are given in parts per million (d-scale) and
the coupling constants are given in Hertz. 19F NMR spectra
were measured at 235 MHz in Bruker AC-250 NMR instrument.
Silica gel-G plates (Merck) were used for TLC analysis with a
mixture of petroleum ether (60–80 uC) and ethyl acetate as
eluent. Elemental analyses were performed on a Perkin Elmer
2400 Series II Elemental CHNS analyzer. Mass spectra were
recorded in a LCQ Fleet mass spectrometer, Thermo Fisher
Instruments Limited, US. Electrospray ionisation mass spec-
It is pertinent to note that L-proline catalyses the above
transformation efficiently, whilst either pyrrolidine or formic/
acetic acid or an equimolar mixture of the base and these acids
Fig. 2 Ortep diagram for compound 4o.
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trometry (ESI-MS) analysis was performed in the positive ion
mode on a liquid chromatography ion trap.
(4-(4-Bromophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4d).
Yellow solid; yield 81%; mp 230 uC; 1H NMR (300 MHz, CDCl3)
dH: 2.11 (s, 3H, CH3), 6.98-7.01 (m, 2H, Ar–H), 7.20–7.21 (m,
1H, Ar–H), 7.26–7.29 (m, 1H, Ar–H), 7.33–7.41 (m, 2H, Ar–H),
7.53–7.59 (m, 3H, Ar–H), 7.66 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Ar–H),
8.33 (dd, 2H, J = 7.8 Hz, 1.2 Hz, Ar–H); 13C NMR (75 MHz,
CDCl3) dC: 14.6, 116.2, 120.8, 121.6 (1JC,F = 274.8 Hz, CF3),
123.8, 126.4, 126.6, 128.0, 129.2, 130.5, 130.9, 131.5, 131.7,
131.9, 135.0, 135.6, 138.7, 143.2 (2JC,F = 34.7 Hz, CF3), 143.3,
144.6, 144.9, 148.5, 185.5. ESI-MS m/z calcd for
C25H15BrF3N3OS [M +2H]+ 544.37, found 544.63. Anal. Calcd
for C25H15BrF3N3OS: C, 55.36; H, 2.79; N, 7.75%. Found C,
55.288; H, 2.93; N, 7.88%.
(4-(4-Methoxyphenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4e).
White solid; yield 82%; mp 185 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.14 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 6.76–6.80 (m,
1H, Ar–H), 6.90–7.01 (m, 2H, Ar–H), 7.05 (d, 1H, J = 8.1 Hz, Ar–
H), 7.18 (d, 1H, J = 3.9 Hz, Ar–H), 7.29–7.37 (m, 2H, Ar–H),
7.53–7.61 (m, 3H, Ar–H), 8.34 (d, 2H, J = 8.4 Hz, Ar–H); 13C
NMR (75 MHz, CDCl3) dC: 14.6, 55.2, 113.4, 113.7, 116.8, 120.8,
125.2, 126.2, 127.1, 127.8, 129.1, 130.5, 131.3, 134.6, 135.0,
138.9, 143.6, 145.2, 146.0, 148.7, 160.2, 185.9. 19F NMR (235
MHz, CDCl3) dF 262.3 (s, CF3). ESI-MS m/z calcd for
C26H18F3N3O2S [M + H]+ 494.50, found 494.35. Anal. Calcd
for C26H18F3N3O2S: C, 63.28; H, 3.68; N, 8.51%. Found C,
63.41; H, 3.80; N, 8.74%.
General procedure for the synthesis of 3-methyl-1-phenyl-
1H-pyrazolo[3,4-b]pyridines 4
A mixture of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione 1
(1 mmol), aromatic aldehyde 2 (1 mmol), 3-methyl-1-aryl-
1H-pyrazol-5-amine 3 (1 mmol) and L-proline (0.20 mmol) in
ethanol (15 ml) was stirred at 60 uC for the time given in
Table 2. After completion of the reaction (TLC), the reaction
mixture was extracted with ethyl acetate (2 6 40 ml) and the
residue after removal of the solvent was chromatographed over
silica gel (230–400 mesh) using a petroleum ether–ethyl
acetate mixture (4 : 1 v/v), which afforded pure product 4.
The spectroscopic data for compounds 4 are given below.
(4-(4-Chlorophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4a).
White solid; yield 78%; mp 223 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.12 (s, 3H, CH3), 7.01 (t, 1H, J = 3.9 Hz, Ar-H), 7.05–
7.08 (m, 1H, Ar–H), 7.20–7.23 (m, 2H, Ar–H), 7.33–7.42 (m, 3H,
Ar–H), 7.56 (t, 2H, J = 8.3 Hz, Ar–H), 7.65 (d, 1H, J = 3.9 Hz, Ar–
H), 8.34 (d, 2H, J = 8.3 Hz, Ar–H); 13C NMR (75 MHz, CDCl3) dC:
14.6, 116.3, 120.8, 121.3 (1JC,F = 275.6 Hz, CF3), 126.5, 126.9,
128.0, 128.8, 129.2, 129.3, 130.4, 131.3, 131.6, 134.9, 135.6,
138.8, 143.3, 144.7, 145.1, 148.7, 185.4. ESI-MS m/z calcd for
C25H15ClF3N3OS [M + H]+ 498.05, found 498.17. Anal. Calcd for
C25H15ClF3N3OS: C, 60.30; H, 3.04; N, 8.44%. Found C, 60.42;
H, 3.18; N, 8.31%.
(4-(3-Bromophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4f).
Yellow solid; yield 79%; mp 200 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.12 (s, 3H, CH3), 7.02–7.13 (m, 2H, Ar–H), 7.22–
7.39 (m, 4H, Ar–H), 7.54 (d, 1H, J = 6.9 Hz, Ar–H), 7.54–7.60 (m,
2H, Ar–H), 7.67 (s, 1H, Ar–H), 8.33 (d, 2H, J = 8.4 Hz, Ar–H), 13C
(3-Methyl-4-(4-nitrophenyl)-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4b).
Yellow solid; yield 82%; mp 185 uC; 1H NMR (300 MHz, CDCl3)
dH: 2.10 (s, 3H, CH3), 7.02 (td, 1H, J = 4.5 Hz, 0.9 Hz, Ar–H),
7.23 (dd, 1H, J = 4.5 Hz, 0.9 Hz, Ar–H), 7.32–7.41 (m, 2H, Ar–H),
7.55–7.63 (m, 3H, Ar–H), 7.67 (dd, 1H, J = 5.4 Hz, 0.9 Hz, Ar–H),
8.14 (dd, 1H, J = 8.4 Hz, 2.1 Hz, Ar–H), 8.29–8.34 (m, 3H, Ar–H);
13C NMR (75 MHz, CDCl3) dC: 14.6, 115.7, 121.0, 122.8, 123.6,
126.5, 126.7, 128.2, 129.4, 130.1, 131.3, 135.2, 136.3, 138.6,
139.7, 142.8, 143.2, 144.8, 148.2, 148.5, 185.0. ESI-MS m/z calcd
for C25H15F3N4O3S [M + H]+ 509.47, found 509.39. Anal. Calcd
for C25H15F3N4O3S: C, 59.05; H, 2.97; N, 11.02%. Found C,
59.22; H, 3.07; N, 11.16%.
NMR (75 MHz, CDCl3) dC: 14.6, 116.1, 120.8, 121.3 (1JC,F
=
274.9 Hz, CF3), 121.7, 122.5, 126.4, 126.7, 127.4, 128.0, 128.5,
129.1, 129.2, 130.1, 132.1, 132.2, 132.7, 138.7, 143.2, 143.3
(2JC,F = 34.9 Hz, CF3), 144.0, 148.5, 185.6. ESI-MS m/z calcd for
C25H15BrF3N3OS [M +2H]+ 544.37, found 544.23. Anal. Calcd
for C25H15BrF3N3OS: C, 55.36; H, 2.79; N, 7.75%. Found C,
55.22; H, 2.63; N, 7.64%.
(4-(3-Fluorophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4g).
White solid; yield 75%; mp 145 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.12 (s, 3H, CH3), 6.83–6.92 (m, 1H, Ar–H), 6.97–
7.26 (m, 4H, Ar–H), 7.36 (t, 2H, J = 7.5 Hz, Ar–H), 7.57 (t, 2H, J =
8.2 Hz, Ar–H), 7.67 (s (br), 1H, Ar–H), 8.33 (dd, 2H, J = 8.7 Hz,
0.9 Hz, Ar–H). 13C NMR (75 MHz, CDCl3) dC: 14.4, 115.8, 116.2
(2JC,F = 20.8 Hz, Ar–F), 117.3 (2JC,F = 23.2 Hz, Ar–F), 120.7, 121.3
(1JC,F = 274.9 Hz, CF3), 124.9, 125.8, 126.4, 126.6, 128.0, 129.2,
(4-(4-Fluorophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4c).
Yellow solid; yield 85%; mp 164 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.10 (s, 3H, CH3), 6.93–7.01 (m, 2H, Ar–H), 7.10–
7.15 (m, 2H, Ar–H), 7.20 (dd, 1H, J = 3.9 Hz, 0.9 Hz, Ar–H),
7.33–7.40 (m, 2H, Ar–H), 7.56 (t, 2H, J = 8.1 Hz, Ar–H), 7.26 (dd,
1H, J = 5.4 Hz, 1.2 Hz, Ar–H), 8.34 (dd, 2H, J = 5.4 Hz, 1.2 Hz,
Ar–H). 13C NMR (75 MHz, CDCl3) dC: 14.5, 114.9 (2JC,F = 21.7
Hz, Ar–F), 116.1 (2JC,F = 21.7 Hz, Ar–F), 116.5, 120.7, 121.3 (1JC,F
130.2 (3JC,F = 8.3 Hz, Ar–F), 134.9, 135.2, 138.6, 143.2 (2JC,F
=
= 274.7 Hz, CF3), 126.3, 126.9, 128.0, 128.1, 129.1, 130.9 (3JC,F
=
34.7 Hz, CF3), 143.3, 144.2, 144.9, 148.5, 162.1 (1JC,F = 248.9 Hz,
Ar–F), 185.7. ESI-MS m/z calcd for C25H15F4N3OS [M + H]+
482.46, found 482.32. Anal. Calcd for C25H15F4N3OS: C, 62.37;
H, 3.14; N, 8.73%. Found C, 62.49; H, 3.26; N, 8.80%.
8.3 Hz, Ar–F), 131.7 (3JC,F = 8.3 Hz, Ar–F), 135.0, 135.6, 138.7,
143.0, 143.3, 143.4, 145.0, 148.5, 163.0 (1JC,F = 248.7 Hz, Ar–F),
185.7. 19F NMR (235 MHz, CDCl3) dF 262.4 (s, CF3), dF 111.6–
111.7 (m, Ar–CF). ESI-MS m/z calcd for C25H15F4N3OS [M + H]+
482.46, found 482.58. Anal. Calcd for C25H15F4N3OS: C, 62.37;
H, 3.14; N, 8.73%. Found C, 62.51; H, 3.31; N, 8.85%.
(4-(2-Bromophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4h).
White solid; yield 79%; mp 153 uC; 1H NMR (300 MHz, CDCl3)
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dH: 2.14 (s, 3H, CH3), 7.01–7.02 (m, 1H, Ar–H), 7.24–7.26 (m,
2H, Ar–H), 7.33–7.50 (m, 4H, Ar–H), 7.54–7.68 (m, 3H, Ar–H),
8.36 (d, 2H, J = 8.1 Hz, Ar–H). 13C NMR (75 MHz, CDCl3) dC:
13.4, 116.6, 119.5, 120.7, 121.3, 122.8, 126.3, 126.6, 127.4,
127.8, 129.2, 130.8, 132.1, 132.5, 133.7, 135.7, 136.0, 143.6,
144.1, 148.5, 185.7. 19F NMR (235 MHz, CDCl3) dF 262.3 (s,
CF3). ESI-MS m/z calcd for C25H15BrF3N3OS [M + 2H]+ 544.37,
found 544.73. Anal. Calcd for C25H15BrF3N3OS: C, 55.36; H,
2.79; N, 7.75%. Found C, 55.22; H, 2.88; N, 7.88%.
C
25H16F3N3OS [M + H]+ 464.47, found 464.38. Anal. Calcd
C25H16F3N3OS: C, 64.79; H, 3.48; N, 9.07%. Found C, 64.68; H,
3.39; N, 9.01%.
(3-Methyl-4-(4-nitrophenyl)-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4m). White
solid; yield 78%; mp 205 uC; 1H NMR (300 MHz, CDCl3) dH:
2.08 (s, 3H, CH3), 7.26–7.41 (m, 5H, Ar–H), 7.49–7.61 (m, 5H,
Ar–H), 8.15 (s (br), 2H, Ar–H), 8.33 (dd, 2H, J = 8.7 Hz, 1.2 Hz,
Ar–H); 13C NMR (75 MHz, CDCl3) dC: 14.4, 115.6, 120.8, 121.1,
126.6, 126.8, 128.5, 129.2, 130.5, 134.1, 137.2, 138.5, 139.7,
(4-(2-Methoxyphenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone(4i).
Yellow solid; yield 82%; mp 213 uC; 1H NMR (300 MHz, CDCl3)
dH: 2.12 (s, 3H, CH3), 3.58 (s, 3H, OCH3), 6.71 (d, 1H, J = 8.2 Hz,
Ar–H), 6.90–6.92 (m, 1H, Ar–H), 7.01 (t, 1H, J = 7.5 Hz, Ar–H),
7.19 (d, 1H, J = 7.5 Hz, Ar–H), 7.25–7.36 (m, 3H, Ar–H), 7.52–
7.58 (m, 3H, Ar–H), 8.35 (d, 2H, J = 9.0 Hz, Ar–H). 13C NMR (75
142.6, 142.8, 143.5 (2JC,F = 34.8 Hz, CF3), 148.0, 148.5, 193.3. 19
F
NMR (235 MHz, CDCl3) dF 262.3 (s, CF3). ESI-MS m/z calcd for
C27H17F3N4O3 [M + H]+ 503.44, found 503.41. Anal. Calcd for
C27H17F3N4O3: C, 64.54; H, 3.41; N, 11.15%. Found C, 64.66; H,
3.28; N, 11.29%.
(4-(4-Chlorophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4n). White
solid; yield 75%; mp 204 uC; 1H NMR (300 MHz, CDCl3) dH:
2.13 (s, 3H, CH3), 7.26–7.38 (m, 6H, Ar–H), 7.50–7.60 (m, 6H,
Ar–H), 8.40 (d, 2H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3)
dC: 14.5, 116.3, 120.8, 121.4 (1JC,F = 274.5 Hz, CF3), 126.4, 127.1,
128.4, 129.2, 129.3, 130.7, 131.6, 133.7, 135.5, 137.6, 138.8,
143.5 (2JC,F = 34.7 Hz, CF3), 144.4, 148.7, 193.9. 19F NMR (235
MHz, CDCl3) dF 262.3 (s, CF3). ESI-MS m/z calcd for
C27H17ClF3N3O [M + H]+ 492.10, found 492.22. Anal. Calcd
for C27H17ClF3N3O: C, 65.93; H, 3.48; N, 8.54%. Found C,
65.80; H, 3.36; N, 8.48%.
(3-Methyl-1-phenyl-4-p-tolyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4o). White
solid; yield 79%; mp 155 uC; 1H NMR (300 MHz, CDCl3) dH:
2.10 (s, 3H, CH3), 2.29 (s, 3H, CH3), 6.95–7.15 (m (br), 4H, Ar–
H), 7.26–7.37 (m, 3H, Ar–H), 7.47 (tt, 2H, J = 5.2 Hz, 1.2 Hz, Ar–
H), 7.53–7.57 (m, 4H, Ar–H), 8.35 (dd, 2H, J = 8.7 Hz, 1.2 Hz,
Ar–H). 13C NMR (75 MHz, CDCl3) dC: 14.5, 21.1, 116.6, 120.6,
121.4 126.1, 127.1, 128.2, 128.7(br), 128.9(br), 129.1, 129.3,
130.0, 133.4, 137.6, 138.8, 139.0, 143.3 (2JC,F = 34.5 Hz, CF3),
143.6, 146.1, 148.6, 194.3. ESI-MS m/z calcd for C28H20F3N3O
[M + H]+ 472.15, found 472.38. Anal. Calcd for C28H20F3N3O: C,
71.33; H, 4.28; N, 8.91%. Found C, 71.39; H, 4.38; N, 8.99%.
(4-(4-Methoxyphenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4p). White
solid; yield 82%; mp 152 uC; 1H NMR (300 MHz, CDCl3) dH:
2.13 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 6.73–7.03 (m (br), 4H, Ar–
H), 7.26–7.37 (m, 2H, Ar–H), 7.46 (td, 2H, J = 6.6 Hz, 1.2 Hz, Ar–
H), 7.54–7.59 (m, 4H, Ar–H), 8.35 (dd, 2H, J = 8.7 Hz, 1.2 Hz,
Ar–H). 13C NMR (75 MHz, CDCl3) dC: 14.6, 53.2, 113.5, 116.9,
120.8, 125.3, 126.2, 127.4, 128.3, 129.2, 129.3, 130.9, 133.4,
137.8, 139.0, 143.3, 145.9, 148.8, 160.2, 194.3. ESI-MS m/z calcd
for C28H20F3N3O2 [M + H]+ 488.47, found 488.58. Anal. Calcd
for C28H20F3N3O2: C, 68.99; H, 4.14; N, 8.62%. Found C, 68.87;
H, 4.24; N, 8.76%.
MHz, CDCl3) dC: 13.1, 54.7, 109.9, 117.5, 120.6, 121.4 (1JC,F
=
274.7 Hz, CF3), 121.9, 126.0, 127.1, 127.2, 127.8, 129.1, 131.1,
132.2, 134.8, 135.2, 139.0, 143.1, 143.5, 144.0, 144.5, 148.3,
155.7, 186.2. ESI-MS m/z calcd for C26H18F3N3O2S [M + H]+
494.50, found 494.30. Anal. Calcd for C26H18F3N3O2S: C, 63.28;
H, 3.68; N, 8.51%. Found C, 63.17; H, 3.59; N, 8.44%.
(3-Methyl-1-phenyl-4-(2-tolyl)-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4j).
Yellow solid; yield 82%; mp 173 uC; 1H NMR (300 MHz,
CDCl3) dH: 2.10 (s, 3H, CH3), 2.33 (s, 3H, CH3), 7.01–7.06 (m,
3H, Ar–H), 7.19–7.20 (m, 2H, Ar–H), 7.25–7.26 (m, 1H, Ar–H),
7.35 (t, 1H, J = 7.5 Hz, Ar–H), 7.53–7.61 (m, 3H, Ar–H), 8.34 (dd,
2H, J = 9.0 Hz, 1.2 Hz, Ar–H). 13C NMR (75 MHz, CDCl3) dC:
14.5, 21.2, 115.9, 116.7, 120.8, 121.1 (1JC,F = 274.8 Hz, CF3),
126.2, 126.9, 127.8, 128.3, 129.0, 129.2, 129.8, 130,1, 134.8,
135.1, 138.9, 139.1, 143.2 (2JC,F = 34.6 Hz, CF3), 143.7, 144.0,
145.2, 146.4, 148.7, 185.8. 19F NMR (235 MHz, CDCl3) dF 262.3
(s, CF3). ESI-MS m/z calcd for C26H18F3N3OS [M + H]+ 478.11,
found 478.36. Anal. Calcd for C26H18F3N3OS: C, 65.40; H, 3.80;
N, 8.80%. Found C, 65.28; H, 3.69; N, 8.72%.
(4-(2,3-Dichlorophenyl)-3-methyl-1-phenyl-6-(trifluoro-
methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)metha-
1
none (4k). Yellow solid; yield 70%; mp 188 uC; H NMR (300
MHz, CDCl3) dH: 2.10 (s, 3H, CH3), 7.01–7.03 (m, 1H, Ar–H),
7.25–7.39 (m, 4H, Ar–H), 7.49 (t, 1H, J = 4.8 Hz, Ar–H), 7.57 (td,
2H, J = 7.5 Hz, 1.8 Hz, Ar–H), 7.65 (d, 1H, J = 4.2 Hz, Ar–H), 8.34
(dd, 2H, J = 8.7 Hz, 1.2 Hz, Ar–H). 13C NMR (75 MHz, CDCl3)
dC: 13.1, 115.8, 116.3, 120.8, 121.3 (1JC,F = 274.7 Hz, CF3), 126.4,
127.4, 127.9, 129.2, 130.3, 131.5, 133.5, 134.1, 135.5, 135.8,
138.8, 141.7, 143.2, 143.6, 144.0, 148.5, 185.3. Anal. Calcd for
C25H14Cl2F3N3OS: C, 56.40; H, 2.65; N, 7.89%. Found 56.57; H,
2.78; N, 7.78%.
(3-Methyl-1,4-diphenyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridin-5-yl)(thiophen-2-yl)methanone (4l). White solid;
yield 80%; mp 178 uC; 1H NMR (300 MHz, CDCl3) dH: 2.10
(s, 3H, CH3), 6.95–6.98 (m, 1H, Ar–H), 7.10–7.13 (m, 1H, Ar–H),
7.19–7.26 (m, 2H, Ar–H), 7.32–7.39 (m, 4H, Ar–H), 7.53–7.61
(m, 3H, Ar–H), 8.35 (d, 2H, J = 8.1 Hz, Ar–H); 13C NMR (75
MHz, CDCl3) dC: 14.4, 116.5, 120.8, 121.5 (1JC,F = 274.9 Hz, CF3)
126.3, 126.9, 127.6, 127.9, 128.4, 129.1, 129.2, 129.9, 133.1,
134.8, 135.2, 138.9, 143.7, 145.2, 146.1, 148.7, 185.7. 19F NMR
(235 MHz, CDCl3) dF 262.3 (s, CF3). ESI-MS m/z calcd for
(4-(3-Bromophenyl)-3-methyl-1-phenyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4q). White
solid; yield 84%; mp 159 uC; 1H NMR (300 MHz, CDCl3) dH:
2.12 (s, 3H, CH3), 7.16–7.20 (m (br), 2H, Ar–H), 7.30–7.60 (m,
10H, Ar–H), 8.34 (dd, 2H, J = 8.4 Hz, 0.9 Hz, Ar–H). 13C NMR
(75 MHz, CDCl3) dC: 14.6, 116.1, 120.8, 121.3 (1JC,F = 275.0 Hz,
CF3), 122.0, 123.1, 126.4, 126.9, 128.4, 129.2, 129.3, 132.1,
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133.7, 135.0, 137.5, 138.7, 143.2, 143.3, 143.7, 148.6, 193.9. 19F
NMR (235 MHz, CDCl3) dF 262.3 (s, CF3). ESI-MS m/z calcd for
C27H17BrF3N3O [M]+ 536.34, found 536.29, [M + 2H]+ 538.27.
Anal. Calcd for C27H17BrF3N3O: C, 60.46; H, 3.19; N, 7.83%.
Found C, 60.32; H, 3.08; N, 7.71%.
1-(4-Methoxyphenyl)-3-methyl-4-(4-nitrophenyl)-6-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-b]pyridine (5r). White solid; yield
85%; mp 187 uC;1H NMR (300 MHz, CDCl3) dH: 1.99 (s, 3H,
CH3), 3.15 (qd, J = 17.2, 8.0 Hz, 2H), 3.83 (s, 3H, OCH3), 4.19 (t,
J = 7.9 Hz, 1H), 6.99 (dd, J = 7.0, 2.1 Hz, 2H, Ar–H), 7.12 (d, J =
8.4 Hz, 2H, Ar–H), 7.23 (d, J = 8.4 Hz, 2H, Ar–H), 7.39 (d, J = 7.0
Hz, 3H, Ar–H), 7.99–7.82 (m, 4H, Ar–H).13C NMR (75 MHz,
CDCl3) dC: 12.5, 34.6, 55.4, 105.0, 113.9, 123.7, 127.1, 128.5,
128.5, 128.8, 130.9, 132.7, 132.8, 137.9, 141.9, 144.7, 146.1,
157.8, 165.1.Anal. Calcd for C26H22N4O3: C, 71.22; H, 5.04; N,
12.78%. Found C, 71.29; H, 5.12; N, 12.70%.
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-methyl-6-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-b]pyridine (5s). White solid; yield
83%; mp 145 uC;1H NMR (300 MHz, CDCl3) dH 2.06 (s, 3H,
CH3), 3. 12–3. 37 (m, 2H), 3.78 (s, 3H, OCH3), 4.20 (t, J = 7.9 Hz,
1H), 6.83 (d, J = 8.6 Hz, 2H, Ar–H), 7.13 (d, J = 8.5 Hz, 2H, Ar–
H), 7.26 (s, 1H, Ar–H), 7.42–7.54 (m, 5H, Ar–H), 7.90–8.01 (m,
3H, Ar–H). 13C NMR (75 MHz, CDCl3) dC:12.6, 34.4, 35.1, 55.2,
106.7, 113.3, 114.2, 121.6, 123.2, 127.2, 128.2, 128.6, 128.8,
129.3, 131.1, 131.2, 133.4, 135.2, 138.0, 145.8, 146.6, 158.9,
166.0. Anal. Calcd for C26H22ClN3O: C, 72.97; H, 5.18; N,
9.82%. Found C, 72.97; H, 5.18; N, 9.82%.
1-(4-Chlorophenyl)-3-methyl-4-(4-nitrophenyl)-6-phenyl-4,5-
dihydro-1H-pyrazolo[3,4-b]pyridine (5t). White solid; yield
61%; mp 187 uC; 1H NMR (300 MHz, CDCl3) dH 2.02 (s, 3H,
CH3). 3.19–3.36 (m, 2H), 4.37 (t, J = 6.7 Hz, 1H), 7. 36–7. 46 (m,
7H, Ar–H), 7.91–8.02 (m, 4H, Ar–H), 8.15 (d, J = 6.2 Hz, 2H, Ar–
H). 13C NMR (75 MHz, CDCl3) dC:12.6, 34.3, 34.9, 76.6, 77.0,
77.4, 97.3, 104.8, 123.3, 124.4, 127.2, 128.0, 128.7, 128.9, 131.5,
131.6, 137.6, 137.7, 144.3, 145.5, 146.6, 147.1, 150.6, 165.3.
Anal. Calcd for C25H19ClN4O2: C, 67.80; H, 4.32; N, 12.65%.
Found C, 67.75; H, 4.39; N, 12.68%.
148.54, 185.32. Anal. Calcd for C25H14Cl2F3N3OS 3: C, 56.40; H,
2.65; N, 7.89%. Found C, 56.46; H, 2.60; N, 7.94%.
(4-(4-Chlorophenyl)-1-(4-fluorophenyl)-3-methyl-6-(trifluoro-
methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone
(4v). White solid; yield 78%; mp 195 uC; 1H-NMR (300 MHz,
CDCl3) dH 2.10 (s, 1H). 6.70–7.43 (m, 5H), 7.45–7.61 (m, 1H), 8.
21–8. 48 (m, 1H). 13C-NMR (75 MHz, CDCl3) dC 14.5, 115.8,
116.1, 116.2, 122.5, 122.4, 127.1, 128.2, 128.4, 128.5, 129.2,
131.4, 133.7, 134.8, 134.9, 135.4, 137.4, 143.2, 144.5, 148.4,
159.6, 161.8, 193.87. Anal. Calcd for C27H16ClF4N3O: C, 63.60;
H, 3.16; N, 8.24%. Found C, 63.66; H, 3.13; N, 8.29%.
Methyl 4-(4-chlorophenyl)-3,6-dimethyl-1-phenyl-
1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4w). White solid;
1
yield 71%; mp 159 uC; H NMR (300 MHz, CDCl3) dH: 2.08 (s,
3H, CH3), 2.74 (s, 3H, CH3), 3.60 (s, 3H, OCH3), 7.24–7.35 (m,
4H, Ar–H), 7.44–7.54 (m, 3H, Ar–H), 8.25–8.30 (m, 2H, ArH).
13C NMR (75 MHz, CDCl3) dC: 14.6, 23.8, 29.6, 52.0, 113.0,
121.0, 123.5, 125.7, 127.7, 128.3, 128.5, 128.9, 129.9, 133.9,
134.9, 139.3, 143.0, 155.9, 168.8. Anal. Calcd for C22H18ClN3O2:
C, 67.43; H, 4.63; N, 10.72%. Found 67.49; H, 4.60; N, 10.79%.
( 4 - ( 4 - M e t h o x y p h e n y l ) - 3 , 6 - d i m e t h y l - 1 - p h e n y l -
1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone (4x). White
solid; yield 85%; mp 191 uC; 1H NMR (300 MHz, CDCl3) dH:
2.13 (s, 3H, CH3), 2.58 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 6.77 (d,
J = 7.6 Hz, 2H, Ar–H), 7.14 (d, J = 8.2 Hz, 2H, Ar–H), 7.25–7.37
(m, 3H, Ar–H), 7.46 (d, J = 7.5 Hz, 1H, Ar–H), 7.49–7.57 (m, 2H,
Ar–H), 7.61 (d, J = 7.4 Hz, 2H, Ar–H), 8.33 (d, J = 7.6 Hz, 2H, Ar–
H). 13C NMR (75 MHz, CDCl3) dC: 14.8, 23.9, 55.1, 113.3, 114.4,
121.1, 125.6, 126.7, 128.5, 128.9, 129.17, 129.3, 130.7, 133.4,
137.7, 139.5, 143.3, 143.3, 150.4, 155.3, 159.7, 198.4. Anal.
Calcd for C28H23N3O2: C, 77.58; H, 5.35; N, 9.69%. Found C,
77.64; H, 5.39; N, 9.64%.
Acknowledgements
SI thanks the Department of Science and Technology, New
Delhi for sanctioning a Fast Track Project No. SR/FT/CS-103/
2010. SP thanks the Department of Science and Technology,
New Delhi, for a major research project (No. SR/S1/OC-50/
2011) and for funds for the purchase of a high resolution NMR
spectrometer under IRHPA scheme. P.G. thanks CSIR, New
Delhi for Junior and Senior Research Fellowships.
(1-(4-Chlorophenyl)-3-methyl-4-(4-nitrophenyl)-6-(trifluoro-
methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(phenyl)methanone
(4t). White solid; yield 39%; mp 169 uC; 1H NMR (300 MHz,
CDCl3) dH 2.10 (s, 3H, CH3), 7.10–7.40 (m, 4H, Ar–H), 7.50–7.56
(m, 5H, Ar–H), 8.20 (s, 2H, Ar–H), 8.29–8.35 (m, 2H, Ar–H). 13
C
NMR (75 MHz, CDCl3) dC 14.58, 115.91, 119.31, 121.78, 123.13,
127.00, 128.63, 129.31, 129.38, 131.96, 134.22, 137.16, 139.60,
143.05, 143.47, 143.94, 148.13, 148.53, 193.28. Anal. Calcd for
C27H16ClF3N4O3: C, 60.40; H, 3.00; N, 10.44%. Found C, 60.37;
H, 3.08; N, 10.49%.
(1,4-Bis(4-chlorophenyl)-3-methyl-6-(trifluoromethyl)-
1H-pyrazolo[3,4-b]pyridin-5-yl)(thiophen-2-yl)methanone (4u).
White solid; yield 82%; mp 179 uC; 1H NMR (300 MHz, CDCl3)
dH 2.11 (s, 3H, CH3), 6.96–7.03 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H,
Ar–H), 7.23 (dd, J = 14.2, 5.6 Hz, 1H, Ar–H), 7.33 (d, J = 8.2 Hz,
1H, Ar–H), 7.41 (d, J = 7.9 Hz, 1H, Ar–H), 7.52 (d, J = 8.9 Hz, 2H,
Ar–H), 7.65 (d, J = 4.8 Hz, 1H, Ar–H), 8.33 (d, J = 8.9 Hz, 2H, Ar–
H). 13C NMR (75 MHz, CDCl3) dC 14.63. 116.47, 119.35, 121.67,
122.98, 126.97128.04, 128.8, 129.29, 130.25, 131.22, 131.30,
131.69, 135.00, 135.63, 135.80, 137.30, 143.15, 143.66, 144.80,
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