Microwave-assisted one-pot synthesis in water of carbonylpyrazolo[3,4-: B] pyridine derivatives catalyzed by InCl3 and sonochemical assisted condensation with aldehydes to obtain new chalcone derivatives containing the pyrazolopyridinic moiety

Article abstract of DOI:10.1039/c7ra10127a

Pyrazolo[3,4-b]pyridine derivatives have been synthesized via one-pot condensation of 3-methyl-1-phenyl-1H-pyrazolo-5-amine (1), formaldehyde (as paraformaldehyde) (2) and β-diketones (3) under microwave irradiation in aqueous media catalyzed by InCl₃. This process has been found to be useful in the preparation of new N-fused heterocycle products in good to excellent yields. Further treatment of pyrazolopyridines (4a and 4e) with aldehyde aromatics (5a-l) afforded chalcone analogs.

Full text of DOI:10.1039/c7ra10127a

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PAPER
Microwave-assisted one-pot synthesis in water of
carbonylpyrazolo[3,4-b]pyridine derivatives
catalyzed by InCl3 and sonochemical assisted
condensation with aldehydes to obtain new
chalcone derivatives containing the
Cite this: RSC Adv., 2017, 7, 50044
pyrazolopyridinic moiety†
a
c
d
Efrain Polo,
Karoll Ferrer-Pertuz,bc Jorge Trilleras,
Jairo Quiroga
a
*
and Margarita Gutierrez
´
Pyrazolo[3,4-b]pyridine derivatives have been synthesized via one-pot condensation of 3-methyl-1-
phenyl-1H-pyrazolo-5-amine (1), formaldehyde (as paraformaldehyde) (2) and b-diketones (3) under
microwave irradiation in aqueous media catalyzed by InCl3. This process has been found to be useful in
the preparation of new N-fused heterocycle products in good to excellent yields. Further treatment of
pyrazolopyridines (4a and 4e) with aldehyde aromatics (5a–l) afforded chalcone analogs.
Received 11th September 2017
Accepted 16th October 2017
DOI: 10.1039/c7ra10127a
rsc.li/rsc-advances
activities associated with it. Analgesic, anti-microbial, antipy-
retic, anxiolytic, antagonists stereoselective of A1 receptors in
Introduction
humans, vasodilating, anti-chagasic, respiration stimulating,
inhibitors of phosphodiesterase 4B (PDBE4B), bronchodilating,
and of this system have been reported in the literature
(Fig. 2).6–14
Over the years it has been found in the literature that nitrogen-
containing heterocycles have shown wide spectrums of biolog-
ical activities for accessing pharmaceutical and medicinal
products. Recent studies have shown that greater than 90% of
molecules currently under analysis by pharmaceutical compa-
nies include nitrogen heterocycles, where pyrrole, imidazole,
pyrazole, pyrimidine, pyridine, and derivatives constitute the
most important family of these compounds.1 Fused pyridine
systems such as pyrazolopyridines and their related derivatives
have been identied as a potentially interesting scaffold for
biologically active compounds because of their structural
analogy to purine bases, an important constituent of DNA and
RNA nucleosides.2–5 The pyrazolopyridines, which comprise ve
isomers (I–V); [3,4-b], [3,4-c], [4,3-c], [4,3-b] and [1,5-a] (Fig. 1).
In particular pyrazolo[3,4-b]pyridines (I) has aroused great
interest in recent years due to a wide variety of biological
Due to their attractive pharmacological properties, pyrazolo
[3,4-b]pyridines have attracted the attention of chemists who
have researched ways to obtain the desired properties through
different synthetic strategies. The most common reactions
include: (a) condensation of pyrazole-5-amine derivatives and
activated carbonyl groups;15–17 (b) reaction of 5-aminopyrazoles,
1,3-dicarbonyl derivatives or equivalents and aldehydes through
of Hantzsch-type reaction;18–20 (c) through Povarov-type [4 + 2],
cycloaddition between 5-aminopyrazoles, aromatic aldehydes,
and cycloalkanones in acetic acid;21 and (d) Friedlander
¨
condensation of 5-aminopyrazole-4-carbaldehydes with a-
aOrganic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of
Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca 3460000,
Chile. E-mail: mgutierrez@utalca.cl; Tel: +56-071-220-0448
b
´
´
´
˜
Departamento de Quımica, Universidad Tecnica Federico Santa Marıa, Av. Espana
´
No. 1680, Valparaıso 2340000, Chile
cGrupo/Semillero de Investigacion en Compuestos Heterocıclicos, Programa de
´
´
´
´
´
Quımica, Facultad de Ciencias Basicas, Universidad del Atlantico, Puerto Colombia,
´
Atlantico, Colombia
dHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del
Valle, Cali A.A. 25360, Colombia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra10127a
Fig. 1 Pyrazolopyridine Isomers.
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Results and discussion
Initially, held the synthesis of compound 1; prepared from (2E)-
3-aminobut-2-enenitrile and 1-phenyl hydrazine was
7
8
synthesized by conventional methods according to the litera-
ture (Scheme 1).42
Fig. 2 Examples of pyrazolo[3,4-b]pyridines biologically actives.
The three-component coupling reaction of 1, para-
formaldehyde 2 and indandione 3e under MWI in water was
studied comprehensively as a representative example for
obtaining pyrazolo[3,4-b]pyridines. For comparison was studied
the effect of three different reaction conditions: reux using
AcOH, reux using water and InCl3 and the use of water and
InCl3 with MWI (Scheme 2 and Table 1).
Previously, Dzvinchuk et al.43 synthesized 4a in 87% yield
from the reaction of 1,3-cyclohexanedione 3a, 1 and 4-
(dimethylamino)-benzaldehyde in boiling acetic acid for 2 h. In
this reaction N,N-dimethylaniline was obtained as a byproduct.
Zheng et al.44 reported the synthesis of 4b in 15% yield from
a two-step reaction. Recently Sumesh et al.,45 reported the
synthesis of 4a and 4b in 98% yield a one-step using L-proline,
and water for 2 h.
methylene ketones such as acetone or acetophenones with
potassium hydroxide as basic catalyst.22–24
The methods described in the literature presents several
disadvantages such as the use of toxic solvents for the envi-
ronment, long reaction times, several steps of synthesis, these
contradict the current trends of green chemistry,25 as a result
of the importance that presents these heterocycles in the
medicinal eld, different researchers have designed envi-
ronmentally friendly and efficient synthetic routes, for
example have used water as solvent under microwave irradi-
ation (MWI) using catalysts organic or inorganic.26,27 Recently,
InCl3 has emerged as useful Lewis acid catalyst in organic
synthesis due to its compatibility with both organic and
aqueous media in comparison with frequently used Lewis
acids such as BF3, TiCl4, and AlCl3 react violently with water
and cannot be used under aqueous conditions. The fact that
its non-toxic nature enables the chemists to handle its reac-
tions very easily and its lower heterophilicity makes it an ideal
catalyst or reagent for the C–C bond formation reactions. In
this context, over the past few years, InCl3 has received
increasing attention as a novel type of water tolerant Lewis
acid catalyst for organic synthesis with high chemo-, regio-,
and stereoselectivity.
In order to understand how the working temperature and the
presence of different amounts of catalyst inuence the perfor-
mance and reaction time under MWI conditions was studied
the behavior of compound 4e which facilitated establish the
optimal reaction conditions (Table 2).
As shown in Table 2, the expected product was obtained in
good yield in water under MWI when is working with
ꢀ
a temperature of 150 C; InCl3 at 15% mol. It is also observed
that by inducing the reaction at the same temperature (150 ꢀC),
For example, InCl3 has been utilized in Diels–Alder,28 Frie-
del–Cras,29,30 Michael-type,31–34 Mannich type,35,36 Mukaiyama-
aldol,37,38 von Pechmann reaction,39 Hosomi–Sakurai allylation
reactions,40,41 neat or in water under mild conditions. As InCl3
has these unique properties compared to other Lewis acids
which include stability and recoverability from water, we are
interested to apply it to other carbon–carbon bond formation
reactions in water.
In general, the synthetic methodologies described in the Scheme 1 Synthesis of starting material 1 needed for synthesis of
pyrazolo[3,4-b]pyridine derivatives 4a–i.
literature are based on the starting materials. Starting from the
variety of a,b-unsaturated synthons can build diverse pyrazolo
[3,4-b]pyridine core. Herein, we wish to report a simple method
for the synthesis of pyrazolo[3,4-b]pyridines derivatives via one-
pot three-component reaction between 5-aminopyrazoles
derivatives 1, paraformaldehyde 2 and b-diketones 3 catalyzed
by InCl3 in aqueous media. Low environmental impact strategy,
based on the construction of pyridine ring onto pyrazole
combining reuse of catalyst, water and microwave irradiation.
We report the use of this nucleus of pyrazolo[3,4-b]pyridines
for structural diversication from carbonyl carbon coupled
aromatic aldehydes generating analogs of chalcones. Compar-
ison yields and reaction times are reported by using a conven-
tional method and use ultrasound for the obtaining of new
derivatives. The target molecules were obtained in good to
excellent isolated yields.
Scheme 2 Reaction conditions to obtain pyrazolo[3,4-b]pyridines
4a–i.
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Table 1 Comparison of yields pyrazolo[3,4-b]pyridines (4a–i)
Microwave irradiation
method
Conventional method
Time (h)/yield (%)
Time (min)/yield (%)
H2O/InCl3
Compound
m/z
Mp (ꢀC)
AcOH
H2O/InCl3
128–130
123–124 (ref. 45)
4a
277
4/60
16/33
4/75
15/75
15/85
152–154
165–166 (ref. 45)
164.5–166 (ref. 43)
4b
4c
305
339
4/62
9/48
211–213
7/52
10/80
4d
4e
263
311
215–217
246–248
8/66
1/44
7/60
5/72
15/82
10/91
98–100
96 (ref. 46)
4f
265
227
293
6/50
4/47
3/52
10/65
8/50
7/60
17/90
12/67
15/95
4g
4h
276–278
300–302
4i
309
>300
3/44
8/45
20/91
and increasing the amount of catalyst (20% mol), the yield does
The possibility to recover and recycle InCl3 also offers
not change. With these results in hand, different pyrazolo[3,4-b] another signicant advantage. Because InCl3 is soluble in
pyridine derivatives 4a–i were prepared using various b-dike- reaction medium and the products are insoluble in water, the
tones 3a–i (Table 1).
recovered ltrate containing the catalyst could be recycled.
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Table 2 Temperature screening for the synthesis of 3-methyl-1-
phenylindeno[2,3-e]pyrazolo[3,4-b]pyridin-5(1H)-one 4e in MWI at
300 W. Reactions are performed on a 1 mmol scale of the reactants
under MWI
Catalyst
(mol%)
Reaction
Reaction time
(min)
Isolated yield
(%)
Fig. 3 Structural determination of compound 4a.
Entry
temp. ꢀ
C
1
2
3
4
5
6
0
5
10
15
20
25
80
45
30
10
10
15
10
0
100
120
150
150
150
23
80
90
90
87
Studies using amine (1), formaldehyde (2), and diketone (3e) as
model substrates showed that the recovered ltrate could be
successively recycled in subsequent reactions without any
signicant decrease of yield of 4e. A marginal loss of the yield
was observed in rst two runs (91% and 89%), while in third
and fourth run the yield dropped to 75% and 65%, respectively.
With the optimized protocol in hand, the scope of this
domino process was then assessed through the variation of b-
diketones 3a–i (Table 1). As a general trend, this reaction is
tolerant to a large variety of b-diketones (linear, cyclical,
heterocycles). Diversely adducts could be prepared in good
yields (up to 95%), demonstrating the versatility of this one-pot
process. This variety results very attractively for the establish-
ment of structure–activity relationships aer biological
evaluation.
Scheme 4 Plausible mechanism for the formation of pyrazolo[3,4-b]
pyridine 4g.
MWI technique. Microwave irradiation method facilitates the
polarization of the reacting molecule causing reactions to occur
at higher rate.
A reasonable mechanism for the formation of product 4a is
outlined in Scheme 3. The formation of 4a is expected to
proceed via initial condensation of aldehyde 2 with b-diketones
3a to give an intermediate [9], it may be proposed that the InCl3
catalyst facilitates the formation the intermediate [9] by
increasing the electrophilicity of the carbonyl group of the
aldehyde which further undergoes Michael addition with 1 to
give an open-chain intermediate [10], which is subsequently
cyclized, dehydrated and dehydrogenated to afford the aroma-
tized product 4a (Fig. 3).
InCl3 in water under microwave radiation turns out to be
advantageous for the synthesis of these compounds as shown in
the Table 1. In conventional method, the yield of all the prod-
ucts is lower as compared to the yield obtained by synthesis by
Scheme 3 Plausible mechanism for the formation of pyrazolo[3,4-b]
pyridine derivate 4a.
Scheme 5 Synthetic versatility of carbonyl carbon.
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Table 3 Synthesis of heterocyclic analogues of chalcones
Conventional method
(h per yield)
Ultrasonic method
(min per yield)
Entry
Estructure
Mp (ꢀC)
6a
2/50
2/52
10/50
20/65
175–177
6b
6c
187–189
210–212
3/48
2/51
10/72
15/52
6d
165–167
6e
6f
2/65
3/67
3/50
15/72
10/80
15/61
123–125
189–191
178–180
6g
6h
6i
2/61
2/49
10/83
15/90
180–182
179–181
6j
3/57
4/37
15/92
20/72
177–179
176–178
6k
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Table 3 (Contd.)
Conventional method
(h per yield)
Ultrasonic method
(min per yield)
Entry
Estructure
Mp (ꢀC)
6l
3/45
4/75
3/62
20/67
15/98
15/87
108–110
6m
6n
170–172
211–213
6o
6p
4.5/65
3/79
10/63
10/82
134–136
230–232
6q
6r
6s
4/88
2/70
3/81
15/93
10/72
15/91
150–152
186–188
180–182
6t
2.5/85
4/83
10/87
10/90
195–197
6u
>300
6v
2.5/68
10/75
>300
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However, the compound 4g does not t this mechanism. synthesized pyrazolopyridines derivatives 4 and 6 showed bands
Derivatives of Meldrum's acid (1,3-dioxane-4,6-dione) are at stretching frequencies in the range of 1584–1598 cmꢁ1 and
excellent precursors for the production of a variety of ketones, 1488–1502 cmꢁ1, which are characteristic of (–C]N) and (–C]C)
propadienones, iminopropadienones, and other reactive mole- groups. 1H-NMR spectra were similar between them in each set,
cules by ash vacuum thermolysis (FVT),47 via a pseudo-retro- and were characterized by the presence of three groups of signals
Diels–Alder reaction, eliminating acetone and carbon dioxide. (aromatics protons, protons near heteroatoms and aliphatic
Mechanistically the formation of the product (4g) can be visu- protons). Each series was identied a signal around 8 ppm,
alized by initial Knoevenagel condensation of aldehyde 2 and typical for g-unsubstituted pyridine ring shown as in Fig. 3 and 4.
6,6-dimethyl-1,3,5-trioxane-2,4-dione (3h) resulting in adduct
11, followed by a Michael type nucleophilic addition of C-5 of
the pyrazole ring (1) to the enone intermediate [11]; in the next
Experimental
step loss of acetone and CO2 and subsequent cyclodehydration
to furnish the desired compound (Scheme 4).
The experiments were performed in a discover microwave
apparatus (CEM Corporation, Matthews, NC, USA); the ultra-
Ketones engage in many organic reactions. The most important
sonic irradiation was performed by using a Branson ultrasonic
reactions follow from the susceptibility of the carbonyl carbon
cleaner bath, model 1510, 115 v, 1.9 L with mechanical timer
toward nucleophilic addition and the tendency for the enolates to
(60 min with continuous hold) and heater switch, 47 kHz. All
1
add to electrophiles, most reactions of carbonyl compounds take
the products were characterized by spectral data (IR, MS, H-
NMR, 13C-NMR). 1H and 13C NMR spectra (400 MHz for
place by one of four general mechanisms: nucleophilic addition
(12–17), nucleophilic acyl substitution, alpha substitution (18), and
carbonyl condensation (6a–v) (Scheme 5).
In order to create structural diversity from the carbonyl
carbon available, we synthesize chalcones derivatives using
pyrazolopyridine 4f or 4a and aldehydes aromatic 5a–l in
a typical condensation of Claisen–Schmidt in ethanol with basic
catalysis. In this reaction, we evaluate the advantages of sono-
chemical method over conventional method as is shows in
Table 3.
A comparison of the results obtained under ultrasonic irra-
singlet; d, doublet; q quartet; t, triplet; m, multiplet. IR spectra
diations with those of conventional stirring in ethanol (Table 3)
revealed that the reaction under ultrasonic irradiation proceeds
in much lower reaction times and excellent yields. The rate
High-resolution mass spectrometry ESI-MS and ESI-MS/MS
acceleration using ultrasonic irradiations may be due to cavi-
tation phenomena, in which the energy being transmitted more
efficiently to the substrates.48–50
The yields of compound 6 were excellent. It is worth noting
that the electronic nature of the substituents affects only to
a lesser extent the yields of the products and the reaction
proceeds quite well with both electron-withdrawing and
proton and 100 MHz for carbon) were recorded on an AM-400
spectrometer (Bruker, Rheinstetten, Germany), using CDCl3,
DMSO-d6 and CD3OD as solvents. Tetramethylsilane (TMS) was
used as an internal standard. Chemical shis (d) and J values
are reported in ppm and Hz, respectively, relative to the solvent
peak CDCl3 at 7.24 ppm for protons and 77 ppm for carbon
atoms; DMSO-d6 2.5 ppm for protons and 39.7 ppm for carbon
atoms, and CD3OD with 3.35 and 4.78 ppm for protons and
49.3 ppm for carbon. Signals are designated as follows: s,
(KBr pellets, 500–4000 cmꢁ1) were recorded on a NEXUS 670 FT-
IR spectrophotometer (Thermo Nicolet, Madison, WI, USA).
analyses were conducted in a high-resolution hybrid quadru-
pole (Q) and orthogonal time-of-ight (TOF) mass spectrometer
(Waters/Micromass Q-TOF micro, Manchester, UK) with
a constant nebulizer temperature of 100 ꢀC. Melting points
(uncorrected) were measured on a Electrothermal IA9100
melting point apparatus (Stone, Staffs, UK). Reaction progress
was monitored by means of thin-layer chromatography using
silica gel 60 (Merck, Darmstadt, Germany). All reagents were
electron-releasing substituents on chalcones analogues.
Compounds of the series 4 and 6 were easily characterized by
purchased from either Merck or Sigma Aldrich (St. Louis, MO,
USA) and used without further purication. Final purication of
1H-NMR, 13C-NMR, IR and mass spectra. The FT-IR spectra of
all products for analysis was carried out by recrystallization.
General procedure for the preparation of pyrazolopyridine 4a–
j
Conventional method (reux). (a) A solution of 5-amino-
pyrazole (1, 1 mmol), p-formaldehyde (2, 1 mmol) and b-dike-
ꢀ
tone (3, 1 mmol) in acetic acid (15 mL)was heated at 80 C (oil
bath) for 4–11 h. Then, the reaction mixture was ltered hot and
the resulting solid products were washed with ethanol, dried in
air and recrystallized from ethanol.
(b) A mixture of 5-aminopyrazole (1, 1 mmol), p-formalde-
hyde (2, 1 mmol) and b-diketone (3, 1 mmol) was placed in
a 50 mL round-bottomed ask; 10 mL of water and InCl3 (15%
mol) were added. The mixture was stirred under reux for 4–
Fig.
4 HMBC-assisted NMR-based structural determination of
compound 6p.
16 h. The progress of the reaction was monitored by TLC using
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petroleum ether/ethylacetate (60 : 40) as eluent. The reaction (CH), 127.2 (2ꢂ CH), 129.2 (CH), 138.6 (C), 145.8 (C), 152.9 (C),
mixture was allowed to cool to room temperature. The precipi- 174.6 (C), 203.4 (C); HRMS (ESI, m/z): calcd for C16H13N3ONa
tate formed was collected by ltration at pump washed with [M + Na]+ 286.0956 found 286.0114.
a mixture hexane/ethanol.
3-Methyl-1-phenylindeno[2,3-e]pyrazolo[3,4-b]pyridin-5(1H)-
one (4e). Yield: 91% (283.3 mg); yellow solid; mp 246–248 ꢀC; IR
(KBr, cmꢁ1): 3390, 3054, 2923, 1716, 1613, 1589, 1502, 1337,
Synthesis assisted by microwave
1
1290, 1138, 1028, 809, 781, 727, 636, 553; H NMR (400 MHz,
A mixture of 5-aminopyrazole (1, 1 mmol), p-formaldehyde (2, 1 DMSO-d6): dH ¼ 2.61 (s, 3H, CH3), 7.38 (t, J ¼ 7.4 Hz, 1H), 7.95
mmol), b-diketone (3, 1 mmol), InCl3 (15% mol), and water (3 (d, J ¼ 7.2 Hz, 1H), 8.28 (d, J ¼ 7.7 Hz, 2H), 8.47 (s, 1H); 13CNMR
mL) were subjected to MWI (maximum power 300 W during 10– (100 MHz, DMSO-d6) dC: 11.3 (CH3), 116.0 (C), 120.5 (2ꢂ CH),
20 min at a controlled temperature of 483 K) using a focused 120.7 (CH), 122.6 (C), 122.9 (CH), 125.7 (CH), 126.4 (CH), 128.5
microwave reactor (CEM Discover, Matthews, NC, USA). The (2ꢂ CH), 131.3 (CH), 134.8 (CH), 136.3 (C), 138.3 (C), 141.8 (C),
aqueous phase extracted with EtOAc (2 ꢂ 10 mL). The 145.5 (C), 152.2 (C), 163.5 (C), 188.9 (C); HRMS (ESI, m/z): calcd
combined organic layers was dried over Na2SO4 and evaporated; for C20H13N3OK [M + K]+ 350.4350 found 349.4350.
to give the corresponding derivatives 4a–j.
1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-il)etanone
3-Methyl-1-phenyl-7,8-dihydrociclohexa[2,3-e]pyrazolo[3,4-b] (4f). Yield: 90% (238.7 mg); yellow solid; mp 100–102 ꢀC; IR
pyridin-5(6H)-one (4a). Yield: 75% (207.9 mg); orange crystals; (KBr, cmꢁ1): 3065, 2960, 2924, 2853, 1679, 1611, 1592, 1503,
1
mp 128–130 C; IR (KBr, cmꢁ1): 3063, 2949, 2883, 1680, 1593, 1436, 1236, 1119, 1026, 944, 755, 692, 585; H NMR (400 MHz,
ꢀ
1
1505, 1419, 1260, 1183, 1015, 904, 778, 748, 667, 559, 530; H DMSO-d6): dH ¼ 2.63 (s, 3H, CH3), 2.67 (s, 3H, CH3), 2.77 (s, 3H,
NMR (400 MHz, DMSO-d6): dH ¼ 2.11 (q, J ¼ 6.0 Hz, 2H), 2.57 (s, CH3), 7.31 (t, J ¼ 7.4 Hz, 1H), 7.54 (t, J ¼ 8.0 Hz, 2H), 8.25 (d, J ¼
3H, CH3), 2.68 (t, J ¼ 6.5 Hz, 1H), 3.15 (t, J ¼ 6.5 Hz, 2H), 7.31 (t, J 7.7 Hz, 2H), 8.87 (s, 1H); 13CNMR (100 MHz, DMSO-d6) dC: 12.2
¼ 7.4 Hz, 1H), 7.53 (t, J ¼ 8.0 Hz, 2H), 8.23 (d, J ¼ 8.7 Hz, 2H), (CH3), 25.8 (CH3), 29.4 (CH3), 114.4 (C), 120.1 (2ꢂ CH), 125.7
8.68 (s, 1H); 13CNMR (100 MHz DMSO-d6) dC: 12.1 (CH3), 21.3 (CH), 127.2 (C) 129.1 (2ꢂ CH), 133.3 (CH), 138.9 (C), 144.3 (C),
(CH2), 33.0 (CH2), 38.2 (CH2), 116.1 (C), 120.1 (2ꢂ CH), 122.9 149.5 (C), 158.5 (C), 199.6 (C); HRMS (ESI, m/z): calcd for
(C), 125.7 (CH), 129.1 (2ꢂ CH), 130.3 (CH), 138.7 (C), 145.1 (C),
150.4 (C), 163.9 (C), 196.5 (C); HRMS (ESI, m/z): calcd for
C
16H16N3O [M + H]+ 266.1293 found 266.2751.
3-Methyl-1-phenyl-4,5-dihydro-1H-pyrazol[3,4-b]pyridine (4g).
Yield: 67% (152.2 mg); green crystals; mp 276–278 ꢀC; IR
C
17H15N3OK [M + K]+ 316.0858 found 316.4317.
3,7,7-Trimethyl-1-phenyl-7,8-dihydrociclohexa[2,3-e]pyrazolo- (KBr, cmꢁ1): 3063, 2938, 2917, 2860, 1595, 1570, 1503, 1435,
1
[3,4-b]pyridin-5(6H)-one (4b). Yield: 85% (259.5 mg); yellow solid; 1385, 1144, 1123, 1062, 950, 911, 785, 712, 690; H NMR (400
mp 152–154 ꢀC; IR (KBr, cmꢁ1): 3064, 2954, 2929, 2869, 1678, 1591, MHz, DMSO-d6): dH ¼ 1.95 (s, 3H), 3.16 (d, J ¼ 3.7 Hz, 2H), 3.57
1507, 1374, 1244, 1119, 1023, 936, 757, 672, 556, 511; 1H NMR (400 (d, J ¼ 15.8 Hz, 1H), 4.26 (t, J ¼ 14.3 Hz, 2H), 7.28 (t, J ¼ 6.9 Hz,
MHz, DMSO-d6) dH: 1.02 (s, 6H), 2.58 (m, 5H), 3.07 (s, 2H), 7.30 (t, J 1H), 7.49 (t, J ¼ 7.5 Hz, 2H), 7.95 (d, J ¼ 8.53 Hz, 2H); 13C NMR
¼ 7.2 Hz, 1H), 7.53 (t, J ¼ 7.7 Hz, 2H), 8.24 (d, J ¼ 8.2 Hz, 2H), 8.68 (100 MHz, DMSO-d6) dC: 12.1 (CH3), 47.5 (CH2), 63.0 (CH2), 104.3
(s, 1H); 13CNMR (100 MHz, DMSO-d6) dC: 12.2 (CH3), 27.7 (CH3), (C), 119.8 (2ꢂ CH), 125.6 (CH), 129.3 (2ꢂ CH), 135.8 (C), 139.2
32.5 (CH3), 46.6 (CH2), 51.5 (CH2), 99.5 (C), 116.1 (C), 120.3 (2ꢂ (C), 144.8 (C), 145.0 (C); HRMS (ESI, m/z): calcd for C15H13N5O2
CH), 122.0 (C), 125.9 (CH), 129.2 (2ꢂ CH), 130.2 (CH), 138.8 (C), [M + 2H]+ 229.1215 found 229.1577.
145.4 (C), 151.0 (C), 162.8 (C), 196.7 (C); HRMS (ESI, m/z): calcd for
3-Methyl-1-phenyl-1H-pyrazolo[40,30:5,6]pyrido[2,3-d]pyrimi-
dine-5,7(6H,8H)-dione (4h). Yield: 95% (278.6 mg); yellow solid;
C19H19N3O [M]+ 305.1528 found 305.2056.
3-Methyl-1-phenylnaalen[2,3-e]pyrazolo[3,4-b]pyridin-5,10- mp 300–302 C; IR (KBr, cmꢁ1): 3169, 3050, 2822, 1716, 1618,
dione (4c). Yield: 80% (271.4 mg); brown solid; mp 211–213 ꢀC; 1592, 1493, 1418, 1381, 1242, 1166, 1030, 851, 796, 761, 575; 1H
IR (KBr, cmꢁ1): 3476, 3052, 2921, 1683, 1665, 1505, 1290, 1276, NMR (400 MHz, DMSO-d6): dH 2.24 (s, 3H), 7.51 (m, 4H), 7.71 (s,
ꢀ
1114, 1094, 1027, 971, 785, 756, 661, 592; H NMR (400 MHz, 1H), 8.11 (s, 1H), 12.14 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
1
DMSO-d6): dH ¼ 2.58 (s, 3H, CH3), 7.32 (t, J ¼ 7.2 Hz, 1H), 8.22 dC: 12.3 (CH3), 103.9 (C), 114.3 (C), 120.3 (2ꢂ CH), 125.9 (CH),
(d, J ¼ 8.3 Hz, 2H), 8.24 (s, 1H); 13CNMR (100 MHz, DMSO-d6) 129.2 (2ꢂ CH), 132.8 (C), 138.8 (CH), 145.4 (C), 150.7 (C), 151.1
dC: 12.0 (CH3), 118.5 (C), 120.0 (2ꢂ CH), 124.6 (C), 126.0 (CH), (C), 161.1 (C), 162.4 (C); HRMS (ESI, m/z): calcd for C15H13N5O2
126.5 (CH), 126.8 (CH), 128.1 (CH), 129.0 (2ꢂ CH), 131.0 (CH), [M + 2H]+ 295.1069 found 295.1305.
132.5 (C), 133.4 (C), 134.4 (C), 138.2 (C), 145.4 (C), 147.5 (C),
3-Methyl-1-phenyl-7-sulfanylidene-1,6,7,8-tetrahydro-5H-
150.2 (C), 180.4 (C), 181.3 (C); HRMS (ESI, m/z): calcd for pyrazolo[40,30:5,6]pyrido[2,3-d]pyrimidin-5-one (4i). Yield:
21H13N3O2Na [M + Na]+ 362.0905 found 362.2862. 91% (281.5 mg); red solid; mp > 300 ꢀC; IR (KBr, cmꢁ1): 3322,
C
3-Methyl-1-phenyl-6,7-dihydrociclopenta[2,3-e]pyrazolo[3,4- 3108, 3045, 2917, 1641, 1600, 1496, 1415, 1378, 1337, 1152,
b]pyridin-5(1H)-one (4d). Yield: 82% (215.9 mg); yellow solid, 1094, 920, 781, 698, 677, 527; 1H NMR (400 MHz, DMSO-d6):
mp 215–217 C; IR (KBr, cmꢁ1): 3392, 3036, 2919, 1735, 1630, dH 2.60 (s, 3H), 7.31 (t, J ¼ 8.0 Hz, 1H), 7.51 (t, J ¼ 8.0 Hz, 2H),
ꢀ
1592, 1493, 1423, 1292, 1241, 1153, 1021, 754, 664, 615, 528; 1H 8.23 (d, J ¼ 8.0 Hz, 2H), 8.82 (s, 1H), 11.46 (s, 1H), 11.77 (s,
NMR (400 MHz, DMSO-d6): dH ¼ 2.59 (s, 3H, CH3), 7.35 (t, J ¼ 1H); 13C NMR (100 MHz, DMSO-d6) dC: 12.7 (CH3), 104.3 (C),
7.4 Hz, 1H), 7.57 (t, J ¼ 7.9 Hz, 2H), 8.21 (d, J ¼ 7.7 Hz, 2H), 8.54 106.7 (C), 124.6 (2ꢂ CH), 128.3 (CH), 129.7 (2ꢂ CH), 136.8
(s, 1H); 13CNMR (100 MHz, DMSO-d6) dC: 12.2 (CH3), 28.5 (CH), 143.8 (CH), 151.1 (C), 153.6 (C), 162.0 (C), 177.1 (C);
(CH2), 36.1 (CH2), 116.9 (C), 120.5 (2ꢂ CH), 125.0 (C), 126.0 calcd for C30H23N10O2S2 [2M + H]+ 619.1447 found 619.1970.
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7.44 (t, J ¼ 7.8 Hz, 2H), 7.70 (d, J ¼ 8.0 Hz, 1H), 7.59 (s, 1H), 7.80
(s, 1H), 8.22 (d, J ¼ 8.0 Hz, 2H), 8.53 (s, 1H); 8.67 (s, 1H); 8.74 (s,
1H); 13C NMR (100 MHz, CD3Cl); 12.8 (CH3), 26.5 (CH2), 32.9
(CH2), 117.4 (C), 121.2 (2ꢂ CH), 123.6 (CH), 126.3 (CH), 129.3 (2ꢂ
CH), 131.8 (CH), 133.7 (CH), 136.8 (CH), 137.0 (C), 139.3 (C),
145.4 (C), 149.7 (CH), 150.9 (CH), 151.4 (C), 162.7 (C), 186.8 (C);
HRMS (ESI, m/z): calcd for C23H18N4ONa [M + Na]+ 389.1373
found 389.1219.
General procedure for the synthesis of chalcones 6a–i
A mixture of pyrazolo[3,4-b]pyridine (4a or 4f 1 mmol), appro-
priate aromatic aldehyde (1 mmol), KOH (1 mmol) and ethanol
(2 mL), was sonicated for 5–20 min in the water bath of an
ultrasonic cleaner bath. The progress of the reaction was
monitored by TLC using dichloromethane : ethyl acetate (9 : 1
v/v) as eluent. The reaction mixture was cooled in ice-water
bath. The formed precipitate was ltered, washed with
mixture water : ethanol (1 : 1) and puried by recrystallization
with mixture ethanol : hexane (1 : 1) to give the target
compounds in high yields of 50–98%.
4-((E)-(7,8-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazolo[3,4-
b]quinolin-6(5H)-ylidene)methyl)benzonitrile (6e). Yield: 72%
(281.1 mg); brown solid; mp 123–125 C; IR (KBr, cmꢁ1): 3062,
ꢀ
2949, 2920, 2851, 2231, 1942, 1867, 1667, 1595, 1508, 1485,
1328, 1268, 1204, 1120, 1022, 854, 755; 1H NMR (400 MHz,
CD3Cl) 2.65 (s, 3H), 3.13–3.20 (m, 4H), 7.28 (t, J ¼ 8.0 Hz, 1H),
7.47–7.52 (m, 4H), 7.70 (d, J ¼ 8.0 Hz, 2H), 7.84 (s, 1H), 8.26 (d, J
¼ 8.0 Hz, 2H), 8.78 (s, 1H); 13C NMR (100 MHz, CD3Cl); 12.7
(CH3), 26.5 (CH2), 32.8 (CH2), 112.3 (C), 117.4 (C), 118.7 (C),
121.1 (C), 121.1 (2ꢂ CH), 123.5 (C), 126.3 (CH), 129.3 (2ꢂ CH),
130.5 (2ꢂ CH), 131.8 (CH), 132.5 (2ꢂ CH), 135.1 (CH), 137.4 (C),
139.2 (C), 140.4 (C), 145.4 (C), 151.3 (C), 162.5 (C), 186.7 (C);
HRMS (ESI, m/z): calcd for C25H18N4O [M + H]+ 391.1559 found
390.9908.
(E)-6-((Benzo[d][1,3]dioxol-5-yl)methylene)-7,8-dihydro-3-methyl-
1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (6a). Yield: 50%
(204.7 mg); yellow solid; mp 221–223 C; IR (KBr, cmꢁ1): 3065,
ꢀ
2897, 1658, 1592, 1488, 1317, 1239, 1036, 923, 816, 747; 1H NMR
(400 MHz, CD3Cl); dH 2.67 (s, 3H), 3.24 (s, 4H), 6.02 (s, 2H), 6.88
(d, J ¼ 8.0 Hz, 1H), 7.00 (m, 2H), 7.29 (d, J ¼ 8.0 Hz, 1H), 7.50 (t, J
¼ 8.0 Hz, 2H), 7.86 (s, 1H), 8.28 (d, J ¼ 8.0 Hz, 2H), 8.81 (s, 1H);
13C NMR (100 MHz, CD3Cl); 12.5 (CH3), 26.3 (CH2), 32.7 (CH2),
101.4 (CH2), 108.5 (CH), 109.8 (CH), 117.0 (C), 120.9 (2ꢂ CH),
123.8 (C), 125.3 (CH), 125.9 (CH), 129.0 (2ꢂ CH), 129.6 (CH),
131.3 (C), 133.0 (CH), 137.6 (C), 139.1 (C), 145.1 (C), 147.8 (C),
148.3 (C), 151.0 (C), 162.5 (C), 187.0 (C); HRMS (ESI, m/z): calcd
for C25H19N3O3Na [M + Na]+ 432.1324 found 432.1360.
(E)-6-Benzylidene-7,8-dihydro-3-methyl-1-phenyl-1H-pyrazolo-
[3,4-b]quinolin-5(6H)-one (6f). Yield: 80% (292.3 mg); white solid;
mp 189–191 ꢀC; IR (KBr, cmꢁ1): 3062, 3045, 2966, 2940, 2920,
1661, 1609, 1583, 1511, 1485, 1418, 1268, 1201, 1016, 941, 790,
(E)-6-(4-Morpholinobenzylidene)-7,8-dihydro-3-methyl-1-phenyl-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (6b). Yield: 65% (292.9
1
764; H NMR (400 MHz, CD3Cl) 2.48 (s, 3H), 3.03 (s, 4H), 7.05–
mg); yellow solid; mp 175–177 C IR (KBr, cmꢁ1): 3062, 2955,
ꢀ
7.10 (m, 1H), 7.15–732 (m, 6H), 7.74 (s, 1H), 8.08 (d, J ¼ 8.0 Hz,
2H), 8.61 (s, 1H); 13C NMR (100 MHz, CD3Cl); 12.5 (CH3), 26.1
(CH2), 32.7 (CH2), 117.0 (C), 120.8 (2ꢂ CH), 123.6 (CH), 125.9
(CH), 128.5 (2ꢂ CH), 128.8 (CH), 129.0 (2ꢂ CH), 129.9 (2ꢂ CH),
131.3 (CH), 134.5 (C), 135.5 (C), 137.5 (CH), 139.1 (C), 145.0 (C),
151.0 (C), 162.5 (C), 187.0 (C); HRMS (ESI, m/z): calcd for
C24H19N3ONa [M + Na]+ 388.1426 found 388.1700.
2920, 2894, 2851, 1664, 1589, 1508, 1421, 1378, 1184, 1114, 923;
1H NMR (400 MHz, CD3Cl); dH 2.45 (s, 3H), 3.03 (s, 8H) 3.63–3.66
(m, 4H), 6.53 (s, 1H), 6.68 (d, J ¼ 8.0 Hz, 2H), 7.04–7.09 (m, 1H),
7.23–7.31 (m, 4H), 7.68 (s, 1H), 8.08 (d, J ¼ 7.8 Hz, 2H), 8.58 (s,
1H); 13C NMR (100 MHz, CD3Cl); 12.5 (CH3), 26.3 (CH2), 32.7
(CH2), 48.1 (CH2), 66.6 (CH2), 114.4 (2ꢂ CH), 116.9 (CH), 120.8
(CH), 124.0 (C), 125.8 (CH), 126.4 (C), 129.0 (2ꢂ CH), 131.1 (CH),
131.6 (C), 131.9 (2ꢂ CH), 137.9 (CH), 139.1 (C), 145.0 (C), 151.0
(C), 151.4 (C), 162.5 (C), 187.0 (C); HRMS (ESI, m/z): calcd for
(E)-3-Methyl-6-(4-methylbenzylidene)-1-phenyl-1,6,7,8-tetra-
hydro-5H-pyrazolo[3,4-b]quinolin-5-one (6g). Yield: 61% (231.4
mg); white solid; mp 178–180 C; IR (KBr, cmꢁ1): 3045, 2952,
ꢀ
C
28H26N4O2Na [M + Na]+ 473.1948 found 473.1105.
2923, 1658, 1589, 1418, 1265, 1172, 1016, 813, 753; 1H NMR
(400 MHz, CD3Cl); 2.40 (s, 3H), 2.66 (s, 3H), 3.23 (s, 4H), 7.23–
7.30 (m, 3H), 7.38 (d, J ¼ 8.0 Hz, 2H), 7.48–7.50 (m, 2H), 7.92 (s,
1H), 8.29 (d, J ¼ 8.0 Hz, 2H), 8.80 (s, 1H); 13C NMR (100 MHz,
CD3Cl); 12.5 (CH3), 21.4 (CH3), 26.2 (CH2), 32.7 (CH2), 117.0 (C),
120.8 (2ꢂ CH), 123.7 (C), 125.9 (CH), 129.0 (2ꢂ CH), 129.2(2ꢂ
CH), 130.0 (2ꢂ CH), 131.2 (CH), 132.6 (C), 133.7 (C), 137.6 (CH),
139.1 (C), 139.1 (C), 145.0 (C), 151.0 (C), 162.5 (C), 187.1 (C);
HRMS (ESI, m/z): calcd for C25H22N3O [M + H]+ 380.1763 found
380.1763.
(E)-7,8-Dihydro-3-methyl-6-((1-methyl-1H-imidazol-2-yl)methy-
lene)-1-phenyl-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (6c). Yield:
72% (265.9 mg); yellow solid; mp 210–212 ꢀC; IR (KBr, cmꢁ1):
3097, 3062, 2952, 2920, 2877, 1676, 1612, 1592, 1505, 1415, 1256,
1
1210, 1111, 1016, 889, 750; H NMR (400 MHz, CD3Cl) 2.62 (s,
3H), 3.26 (t, J ¼ 6.6 Hz, 1H), 3.74 (m, 5H), 6.95 (s, 1H), 7.22 (d, J ¼
6.6 Hz, 2H), 7.45 (t, J ¼ 7.3 Hz, 1H), 7.60 (s, 1H), 7.80 (s, 1H), 8.24
(d, J ¼ 8.0 Hz, 2H), 8.74 (s, 1H); 13C NMR (100 MHz, CD3Cl); 12.5
(CH3), 25.7 (CH2), 32.3 (CH2), 33.2 (CH3), 116.9 (C), 119.2 (CH),
120.8 (CH), 120.9 (2ꢂ H), 122.9 (CH), 123.5 (C), 125.8 (C), 125.9
(CH), 129.0 (2ꢂ CH), 130.2 (CH), 131.2 (CH), 136.1 (C), 139.0 (C),
143.9 (C), 145.0 (C), 151.0 (C), 163.3 (C), 187.0 (C); HRMS (ESI,
m/z): calcd for C22H19N5O [M + K]+ 408.1221 found 408.1104.
(E)-7,8-Dihydro-3-methyl-1-phenyl-6-((pyridin-3-yl)methylene)-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (6d). Yield: 52% (190.5
mg); beige solid; mp 165–167 ꢀC; IR (KBr, cmꢁ1): 3050, 2937,
2917, 2842, 1951, 1872, 1751, 1658, 1615, 1514, 1482, 1418, 1328,
(E)-6-((Furan-2-yl)methylene)-7,8-dihydro-3-methyl-1-phenyl-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (6h). Yield: 83% (294.9
mg); beige solid; mp 180–182 ꢀC; IR (KBr, cmꢁ1): 3140, 3123,
3053, 2955, 2897, 2842, 1742, 1658, 1664, 1609, 1545, 1499,
1317, 1265, 1198, 1068, 961, 880; 1H NMR (400 MHz, CD3Cl)
2.65 (s, 3H), 3.30 (t, J ¼ 6.0 Hz, 2H) 3.40–3.44 (m, 2H), 6.53 (s,
1H), 6.74 (s, 1H), 7.28 (d, J ¼ 8.0 Hz, 1H), 7.50 (t, J ¼ 8.0 Hz, 2H),
7.59 (s, 1H), 7.64 (s, 1H), 8.29 (d, J ¼ 8.0 Hz, 2H), 8.78 (s, 1H); 13
C
1
1268, 1195, 1097, 1016, 758; H NMR (400 MHz, CD3Cl) 2.61 (s,
NMR (100 MHz, CD3Cl); 12.5 (CH3), 25.6 (CH2), 32.3 (CH2),
3H), 3.14–3.21 (m, 4H), 7.23 (t, J ¼ 8.0 Hz, 1H), 7.30–7.33 (m, 1H),
112.3 (CH), 116.9 (C), 117.2 (CH), 120.9 (2ꢂ CH), 123.4 (CH),
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123.8 (C), 125.9 (CH), 129.0 (2ꢂ CH), 130.7 (C), 131.2 (CH), 139.1
(C), 144.7 (CH), 145.0 (C), 150.9 (C), 152.2 (C), 162.8 (C), 186.7
(C); HRMS (ESI, m/z): calcd for C22H17N3O2Na [M + Na]+
378.1218 found 378.0209.
(E)-6-((5-(4-Chlorophenyl)furan-2-yl)methylene)-3-methyl-1-
phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (6m).
Yield: 98% (456.6 mg); yellow solid; mp 170–172 ꢀC; IR
(KBr, cmꢁ1): 3065, 2949, 1664, 1589, 1421, 1320, 1239, 1201, 1091,
1036, 912, 787; 1H NMR (400 MHz, CD3Cl) 2.65 (s, 3H), 3.35 (t, J ¼
6.1 Hz, 2H), 3.46 (m, 2H) 6.77 (s, 1H), 6.82 (s, 1H), 7.28 (t, J ¼
7.2 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz, 2H), 7.50 (t, J ¼ 7.3 Hz, 2H), 7.63
(d, J ¼ 8.0 Hz, 3H), 8.30 (d, J ¼ 8.0 Hz, 2H), 8.77 (s, 1H); 13C NMR
(101 MHz, CDCl3) d 12.5 (CH3), 25.8 (CH2), 108.3 (CH), 117.0 (C),
119.8 (CH), 120.9 (2ꢂ CH), 123.1 (CH), 123.8 (C), 125.4 (2ꢂ CH),
125.9 (CH), 128.3 (C), 129.0 (2ꢂ CH), 129.1(2ꢂ CH), 130.6 (C),
131.1 (CH), 134.2 (C), 139.2 (C), 145.0 (C), 151.0 (C), 152.0 (C),
155.0 (C), 162.7 (C), 186.4 (C); HRMS (ESI, m/z): calcd for
C28H20ClN3O2 [M]+ 465.1244 found 465.1226.
(E)-6-(3,5-Dimethoxybenzylidene)-3-methyl-1-phenyl-1,6,7,8-
tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (6i). Yield: 90%
(382.9 mg); yellow Solid; mp 179–181 ꢀC; IR (KBr, cmꢁ1): 3004,
2935, 2833, 1653, 1598, 1519, 1421, 1328, 1253, 1143, 1022, 764;
1H NMR (400 MHz, CD3Cl) 2.90 (s, 3H), 3.50 (s, 4H) 4.17 (s, 6H)
7.16 (d, J ¼ 8.0 Hz, 1H), 7.35 (d, J ¼ 8.0 Hz, 1H), 7.52 (m, 1H),
7.74 (t, J ¼ 8.0 Hz, 2H), 8.13 (s, 1H), 8.53 (d, J ¼ 8.0 Hz, 2H), 9.04
(m, 1H); 13C NMR (100 MHz, CD3Cl); 12.4 (CH3), 26.2 (CH2),
32.6 (CH2), 55.9 (CH3), 110.9 (CH), 113.3 (CH), 116.9 (C), 120.8
(2ꢂ CH), 123.4 (CH), 123.7 (C), 125.8 (CH), 128.3 (C), 128.9 (2ꢂ
CH), 131.1 (CH), 132.7 (C), 137.7 (CH), 139.1 (C), 145.0 (C),
148.7 (C), 149.8 (C), 150.9 (C), 162.4 (C), 186.9 (C); HRMS (ESI,
m/z): calcd for C26H24N3O3 [M + H]+ 426.1818 found 426.1818.
(E)-3-Methyl-1-phenyl-6-(3,4,5-trimethoxybenzylidene)-1,6,7,8-
tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (6j). Yield: 92%
(E)-3-Methyl-1-phenyl-6-(quinolin-3-ylmethylene)-1,6,7,8-tet-
rahydro-5H-pyrazolo[3,4-b]quinolin-5-one (6n). Yield: 87%
(362.3 mg); yellow solid; mp 211–213 C; IR (KBr, cmꢁ1): 3053,
ꢀ
1
2961, 2917, 1667, 1600, 1514, 1253, 1114, 1022, 747; H NMR
(400 MHz, CD3Cl) 2.68 (s, 3H), 3.30 (s, 4H), 7.29 (t, J ¼ 8.0 Hz,
1H), 7.50 (t, J ¼ 8.0 Hz, 2H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.76 (t, J ¼
8.0 Hz, 1H), 7.86 (d, J ¼ 8.0 Hz, 1H), 8.04 (s, 1H), 8.12 (d, J ¼
8.0 Hz, 1H), 8.21 (s, 1H), 8.28 (d, J ¼ 8.0 Hz, 2H), 8.84 (s, 1H),
9.01 (s, 1H); 13C NMR (100 MHz, CD3Cl); 12.8 (CH3), 26.7 (CH2),
32.9 (CH2), 117.4 (C), 121.2 (2ꢂ CH), 123.7 (C), 126.3 (CH), 127.6
(CH), 127.7 (C), 128.4 (CH), 129.0 (C), 129.3 (2ꢂ CH), 129.6 (CH),
130.7 (CH), 131.8 (CH), 133.9 (CH), 136.8 (CH), 136.9 (C), 139.3
(C), 145.4 (C), 147.8 (C), 151.4 (C), 151.6 (CH), 162.6 (C), 186.8
(C); HRMS (ESI, m/z): calcd for C27H20N4OK [M + K]+ 455.1274
found 455.1271.
(419.1 mg); yellow solid; mp 177–179 C; IR (KBr, cmꢁ1): 2935,
ꢀ
2836, 2593, 1661, 1598, 1505, 1323, 1259, 1123, 1007, 834, 747; 1H
NMR (400 MHz, CD3Cl) 2.60 (s, 3H), 3.20 (s, 4H) 3.83 (s, 9H) 6.64
(s, 2H), 7.22 (m, 1H), 7.44 (t, J ¼ 7.5 Hz, 2H), 7.81 (s, 1H), 8.23 (d, J
¼ 8.0 Hz, 2H), 8.74 (s, 1H); 13C NMR (100 MHz, CD3Cl); 12.4
(CH3), 26.2 (CH2), 32.7 (CH2) 56.2 (CH3), 60.9 (CH3), 107.4 (2ꢂ
CH), 117.0 (C), 120.8 (2ꢂ CH), 123.6 (C), 125.9 (CH), 129.0 (2ꢂ
CH), 130.9 (C), 131.2 (CH), 133.8 (C), 137.7 (CH), 138.9 (C), 139.0
(C), 145.0 (C), 151.0 (C), 153.1 (C), 162.4 (C), 186.9 (C); (ESI, m/z):
calcd for C27H25N3O4K [M + K]+ 494.1482 found 494.1456.
(E)-3-Methyl-1-phenyl-6-(4-(prop-2-yn-1-yloxy)benzylidene)-
1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (6k). Yield:
72% (302.0 mg); white solid; mp 176–178 ꢀC; IR (KBr, cmꢁ1):
3288, 3241, 2932, 1658, 1505, 1412, 1276, 1218, 1178, 1019, 842,
764; 1H NMR (400 MHz, CD3Cl) 2.25 (s, 1H), 2.67 (s, 3H), 3.24 (s,
4H) 4.73 (s, 2H) 7.04 (d, J ¼ 8.0 Hz, 2H), 7.28 (t, J ¼ 7.3 Hz, 1H),
7.52 (m, 4H), 7.90 (s, 1H), 8.29 (d, J ¼ 8.0 Hz, 2H), 8.80 (m, 1H);
13C NMR (100 MHz, CD3Cl); 12.5 (CH3), 26.2 (CH2), 32.7 (CH2),
55.8 (CH2), 75.9 (CH), 78.1 (C), 114.9 (2ꢂ CH), 117.0 (C), 120.9
(2ꢂ CH), 123.8 (C), 125.9 (CH), 128.9 (C), 129.0 (2ꢂ CH), 131.2
(2ꢂ CH), 131.8 (CH), 132.9 (C), 137.2 (CH), 139.1 (C), 145.0 (C),
151.0 (C), 158.0 (C), 162.5 (C), 187.0 (C); (ESI, m/z): calcd for
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridin-5-yl)prop-2-en-1-one (6o). Yield: 63%
(250.3 mg); yellow solid; mp 186–188 ꢀC; IR (KBr, cmꢁ1): 3082,
2990, 2894, 2787, 1655, 1589, 1577, 1444, 1308, 1184, 1033, 984,
1
754; H NMR (CDCl3, 400 MHz) dH: 2.63 (s, 3H), 2.81 (s, 3H),
6.01 (s, 2H), 6.82 (d, J ¼ 8.0 Hz, 1H), 7.12–7.04 (m, 3H), 7.28 (t, J
¼ 7.4 Hz, 1H), 7.52–7.45 (m, 3H), 8.16 (s, 1H), 8.32 (d, J ¼
7.5 Hz, 2H). 13C NMR (CDCl3, 100 MHz) dC: 12.4 (CH3), 24.7
(CH3), 101.6 (CH2), 106.5 (CH), 108.5 (CH), 114.2 (C), 120.6 (2ꢂ
CH), 123.9 (CH), 125.3 (CH), 125.5 (CH), 128.7 (C), 128.7 (C),
128.9 (2ꢂ CH), 129.8 (CH), 139.2 (C), 143.3 (C), 145.7 (CH),
148.4 (C), 150.1 (C), 150.1 (C), 158.0 (C), 193.8 (C); HRMS (ESI,
m/z): calcd for C24H19N3O3Na [M + Na]+ 420.1324 found
420.0670.
C
27H21N3O2K [M + K]+ 458.1271 found 458.1261.
tert-Butyl-(E)-4-(4-((3-methyl-5-oxo-1-phenyl-1,5,7,8-tetrahy-
dro-6H-pyrazolo[3,4-b]quinolin-6-ylidene)methyl)phenyl)pipera-
zine-1-carboxylate (6l). Yield: 67% (326.5 mg); brown solid; mp
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(4-morpholinophenyl)prop-2-en-1-one (6p). Yield: 82% (359.6
108–110 C; IR (KBr, cmꢁ1): 3065, 2958, 2877, 1681, 1592, 1517,
mg); yellow solid; mp 230–232 C; IR (KBr, cmꢁ1): 3069, 2961,
ꢀ
ꢀ
1421, 1265, 1175, 1106, 906, 750; 1H NMR (400 MHz, CD3Cl); 1.44
(s, 9H), 2.16 (m, 2H), 2.58 (s, 3H), 2.68 (t, J ¼ 6.0 Hz, 2H), 7.19 (m,
6H), 3.54 (bs, 2H), 6.87 (d, J ¼ 8.0 Hz, 1H), 7.22 (d, J ¼ 8.0 Hz, 1H),
7.39 (d, J ¼ 8.0 Hz, 1H), 7.45 (t, J ¼ 8.0 Hz, 3H), 8.23 (m, 3H), 8.66
(s, 1H); 13C NMR (100 MHz, CD3Cl); 12.5 (CH3), 21.9 (CH2), 26.3
(CH2), 28.4 (CH3), 32.7 (CH2), 33.7 (CH2), 38.8 (CH2), 48.0 (CH2),
80.0 (C), 115.1 (CH), 116.7 (C), 120.8 (2ꢂ CH), 123.0 (C), 124.0 (C),
125.8 (CH), 125.9 (CH), 126.5 (C), 129.0 (2ꢂ CH), 130.4 (CH),
131.1 (CH), 131.6 (C), 131.9 (CH), 137.9 (CH), 139.2 (C), 145.1 (C),
151.2 (C), 154.6 (C), 163.8 (C), 187.0 (C); HRMS (ESI, m/z): calcd
for C33H36N5O3 [M + H]+ 550.2818 found 550.2818.
2921, 2892, 2849, 1953, 1885, 1737, 1668, 1600, 1508, 1380,
1303, 1180, 1123, 923, 761; 1H NMR (CDCl3, 400 MHz) dH: 2.65
(s, 3H), 2.81 (s, 3H, CH3), 3.27 (t, J ¼ 4.6 Hz, 4H), 3.86 (t, J ¼
4.5 Hz, 4H), 6.89 (d, J ¼ 8.3 Hz, 2H), 7.07 (d, J ¼ 15.9 Hz, 1H),
7.29 (t, J ¼ 7.4 Hz, 1H), 7.46 (d, J ¼ 16.1 Hz, 1H), 7.53–7.50 (m,
4H), 8.15 (s, 1H), 8.33 (d, J ¼ 8.3 Hz, 2H); 13C NMR (CDCl3, 100
MHz) dC: 12.5 (CH3), 24.6 (CH3), 47.8 (2ꢂ CH2), 66.5 (2ꢂ CH2),
114.2 (C), 114.5 (2ꢂ CH), 120.7 (2ꢂ CH), 122.9 (CH), 125.0 (C),
125.6 (CH), 129.0 (2ꢂ CH), 129.3 (C), 129.7 (CH), 130.2 (2ꢂ CH),
139.4 (C), 143.3 (C), 146.5 (CH), 150.2 (C), 152.9 (C), 157.8 (C),
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194.7 (C); HRMS (ESI, m/z): calcd for C27H26N4O2Na [M + Na]+
461.1953 found 461.8987.
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(5-(4-nitrophenyl)furan-2-yl)prop-2-en-1-one (6u). Yield: 90%
(418.0 mg); yellow solid; mp > 300 ꢀC; IR (KBr, cmꢁ1): 2982,
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(1-methyl-1H imidazol-2-yl)prop-2-en-1-one (6q). Yield: 93%
(332.4 mg); yellow solid; mp 150–152 ꢀC; IR (KBr, cmꢁ1): 3107,
2955, 2923, 2847, 1685, 1602, 1555, 1504, 1376, 1300, 1241,
1175, 1124, 1033, 972, 830, 756; 1H NMR (CDCl3, 400 MHz) dH:
2.86 (s, 3H), 3.12 (s, 3H), 4.02 (s, 3H), 7.51–7.43 (m, 3H), 7.72 (t, J
¼ 7.5 Hz, 2H), 7.85 (d, J ¼ 15.1 Hz, 1H), 8.05 (d, J ¼ 15.1 Hz, 1H),
8.51 (d, J ¼ 8.0 Hz, 2H), 8.67 (s, 1H); 13C NMR (CDCl3, 100 MHz)
dC: 12.5 (CH3), 25.5 (CH3), 33.0 (CH3), 114.4 (C), 120.8 (2ꢂ CH),
124.13 (CH), 125.7 (CH), 125.9 (CH), 127.7 (CH), 128.0 (C), 128.9
(2ꢂ CH), 130.6 (CH), 131.1 (CH), 139.2 (C), 143.5 (C), 143.9 (C),
150.2 (C), 159.4 (C), 191.3 (C); HRMS (ESI, m/z): calcd for
1
2929, 1729, 1684, 1592. H NMR (CDCl3, 400 MHz) dH: 2.67 (s,
3H, CH3), 2.86 (s, 3H), 6.87 (d, J ¼ 3.4 Hz, 1H), 6.99 (d, J ¼
3.4 Hz, 1H), 7.32–7.26 (m, 2H), 7.41 (d, J ¼ 15.6 Hz, 1H), 7.52 (t, J
¼ 7.5 Hz, 2H), 7.88 (d, J ¼ 8.8 Hz, 2H), 8.34–8.25 (m, 6H). 13C
NMR (CDCl3, 100 MHz) dC: 12.5 (CH3), 24.9 (CH3), 111.6 (CH),
114.3 (C), 118.8 (CH), 120.7 (2ꢂ CH), 124.4 (2ꢂ CH), 124.7 (2ꢂ
CH), 125.7 (CH), 125.8 (CH), 128.5 (C), 129.0 (2ꢂ CH), 130.1
(CH), 130.7 (CH), 135.1 (CH), 139.2 (C), 143.5 (C), 147.1 (C),
150.3 (C), 152.3 (C), 153.9 (C), 158.2 (C), 193.0 (C); HRMS (ESI,
m/z): calcd for C27H21N4O4 [M + H]+ 465.1563 found 465.1836.
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(4-nitrophenyl)prop-2-en-1-one (6v). Yield: 75% (298.8 mg);
orange solid; mp > 300 ꢀC; IR (KBr, cmꢁ1): 3063, 2983, 1725,
1626, 1586; 1H NMR (CDCl3, 400 MHz) dH: 2.66 (s, 3H), 2.86 (s,
3H), 7.30 (t, J ¼ 7.3 Hz, 1H), 7.38 (d, J ¼ 15.8 Hz, 1H), 7.52 (t, J ¼
7.7 Hz, 2H), 7.64 (d, J ¼ 15.8 Hz, 1H), 7.76 (d, J ¼ 8.3 Hz, 2H),
8.32–8.26 (m, 5H);$13C NMR (CDCl3, 100 MHz) dC: 12.5 (CH3),
25.1 (CH3), 114.3 (C), 120.8 (CH ꢂ2), 124.2 (CH ꢂ2), 125.9 (CH),
127.8 (C), 129.0 (2ꢂ CH), 129.1 (2ꢂ CH), 129.2 (CH), 130.5 (CH),
139.2 (C), 140.5 (C), 142.2 (CH), 143.6 (C), 148.7 (C), 150.3 (C),
158.6 (C), 192.6 (C). Calcd for C23H18N4O3K [M + K]+ 437.1016
found 437.1286.
C
21H19N5OK [M + K]+ 396.1227 found 396.9227.
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(4-methoxyphenyl)prop-2-en-1-one (6r). Yield: 72% (276.1
mg); yellow solid; mp 134–136 C; IR (KBr, cmꢁ1): 3163, 3069,
ꢀ
3001, 2915, 2841, 1962, 1805, 1739, 1654, 1503, 1420, 1300,
1251, 1169, 1029, 983, 820, 758; 1H NMR (CDCl3, 400 MHz) dH:
2.64 (s, 3H), 2.82 (s, 3H), 3.83 (s, 3H), 6.92 (d, J ¼ 8.8 Hz, 2H),
7.10 (d, J ¼ 15.8 Hz, 1H), 7.28 (t, J ¼ 7.5 Hz, 1H), 7.55–7.48 (m,
5H), 8.16 (s, 1H), 8.32 (d, J ¼ 7.8 Hz, 2H); 13C NMR (CDCl3, 100
MHz) dC: 12.8 (CH3), 25.0 (CH3), 55.6 (CH3), 114.5 (C), 114.7 (2ꢂ
CH), 121.0 (2ꢂ CH), 124.2 (CH), 125.9 (CH), 127.3 (C), 129.2 (2ꢂ
CH), 130.1 (CH), 130.6 (2ꢂ CH), 139.6 (C), 143.7 (C), 146.3 (CH),
150.5 (C), 158.2 (C), 162.2 (C), 194.6 (C); HRMS (ESI, m/z): calcd
for C24H21N3O2Na [M + Na]+ 406.1531 found 406.1426.
Conclusions
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (6s). Yield: 91%
(403.6 mg); yellow solid; mp 180–182 ꢀC; IR (KBr, cmꢁ1): 3062,
2998, 2929, 2836, 1954, 1875, 1760, 1681, 1595, 1508, 1418,
1300, 1239, 1120, 1004, 822, 755; 1H NMR (CDCl3, 400 MHz) dH:
3.09 (s, 3H), 3.25 (s, 3H), 4.34 (s, 9H), 7.55 (d, J ¼ 15.9 Hz, 1H),
7.73 (t, J ¼ 7.3 Hz, 1H), 7.85 (d, J ¼ 15.9 Hz, 1H), 7.98–7.92 (m,
4H), 8.60 (s, 1H), 8.76 (d, J ¼ 8.3 Hz, 2H);$13C NMR (CDCl3, 100
MHz) dC: 12.5 (CH3), 24.7 (CH3), 56.2 (2ꢂ CH3), 61.0 (CH3),
105.7 (2ꢂ CH), 114.3 (C), 120.8 (2ꢂ CH), 125.7 (CH), 125.8 (CH),
128.8 (C), 129.0 (2ꢂ CH), 129.7 (C), 129.9 (CH), 139.3 (C), 140.8
(C), 143.4 (C), 146.5 (CH), 150.3 (C), 153.5 (2ꢂ C), 157.8 (C),
194.7 (C); HRMS (ESI, m/z): calcd for C26H25N3O4Na [M + Na]+
466.1743 found 465.9858.
In summary, we developed an efficient three-component reac-
tion
of
3-methyl-1-phenyl-1H-pyrazolo-5-amine,
para-
formaldehyde and b-diketones under MWI in aqueous media
catalyzed by InCl3. Compared with previous methods, this new
protocol has the advantages of simple operation, higher yields,
low cost and is an environmentally benign procedure. Synthetic
versatility showed for carbonyl group allows generating great
structural variety, which facilitates the obtaining of a greater
number of compounds with biological activity on different
therapeutic targets depending on the group that originates. In
the preparation of chalcones employment of sonication
reduced times reaction from hours to minutes. These new
compounds present a privileged core from a biological point of
view.
(E)-1-(3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-
3-(quinolin-3-yl)prop-2-en-1-one (6t). Yield: 87% (351.9 mg);
brown solid; mp 195–197 ꢀC; IR (KBr, cmꢁ1): 3058, 2918, 2850,
1874, 1793, 1737, 1602, 1511, 1384, 1251, 1126, 1031, 979, 906,
Conflicts of interest
1
866, 756; H NMR (CDCl3, 400 MHz) dH: 2.66 (s, 3H), 2.87 (s,
3H), 7.29 (t, J ¼ 7.4 Hz, 1H), 7.53–7.46 (m, 3H), 7.59 (t, J ¼
7.4 Hz, 1H), 7.79–7.73 (m, 2H), 7.86 (d, J ¼ 8.3 Hz, 1H), 8.12 (d, J
¼ 8.5 Hz, 1H), 8.33–8.27 (m, 4H), 9.17 (s, 1H); 13C NMR (CDCl3,
100 MHz) dC: 12.6 (CH3), 25.0 (CH3), 114.3 (C), 120.8 (2ꢂ CH),
125.8 (CH), 127.30 (C), 127.4 (C), 127.6 (CH), 128.2 (CH), 128.4
There are no conicts to declare.
Acknowledgements
(C), 129.0 (2ꢂ CH), 129.5 (CH), 130.4 (CH), 130.9 (2ꢂ CH), 136.2 This research was supported by a FONDECYT project number
(CH), 139.2 (C), 142.2 (CH), 143.6 (C), 148.8 (C), 149.3 (CH), 1150712, PIEI QUIMBIO, project, Utalca. E. P. and MG thanks
150.3 (C), 158.5 (C), 193.1 (C); HRMS (ESI, m/z): calcd for the CONICYT beca No. 63140046, for nancial support. J. T., K.
´
C
26H21N4O [M + H]+ 405.1715 found 405.0341.
F. and J. Q. thanks to Universidad del Atlantico and Universidad
del Valle.
50054 | RSC Adv., 2017, 7, 50044–50055
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