Synthesis of pyrazole-substituted chromene analogues with selective anti-leukemic activity

Article abstract of DOI:10.1134/S1070363217100243

We report design and synthesis of a series of flavanone/chromene derivatives containing pyrazoles 6a–6h and 8a–8e with potent anti-leukemic activity. Anti-leukemic activity of novel flavanone derivatives was tested using the K562 cell line. The parental flavanone was selected as the reference compound in identification of analogues with superior anti-leukemic activity. More than two-thirds of the derivatives displayed higher activity than the initial flavanone. Positions of substituents that promoted anti-leukemic activity were identified on both the chromene and pyrazole fragments. Compounds 6b and 6c showed the highest activity against K562 cell line, with IC₅₀ values 3.0 and 0.5 μM respectively. Notably, compounds 6b and 6c displayed very high selectivity in inhibition of leukemic cells (K562) but not of healthy HEK293 cells or solid cancer cell lines HeLa, MCF7 and BT474. Moreover, both the 6b and 6c compounds were predicted to have good ADME properties.

Full text of DOI:10.1134/S1070363217100243

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 10, pp. 2421–2428. © Pleiades Publishing, Ltd., 2017.
Synthesis of Pyrazole-Substituted Chromene Analogues
with Selective Anti-Leukemic Activity1
G. Madhua, M. Sudhakara, K. Santosh Kumara, G. Rajashekher Reddya,
A. Sravanib, K. Ramakrishnab, and Ch. Prasad Raoa*
a Natural Products Laboratory, Department of Chemistry,
Osmania Univeristy, Hyderabad, Telangana, 500007 India
*e-mail: prasadraoou@yahoo.com
b Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology,
Osmania Univeristy, Hyderabad, Telangana, 500007 India
Received June 5, 2017
Abstract—We report design and synthesis of a series of flavanone/chromene derivatives containing pyrazoles
6a–6h and 8a–8e with potent anti-leukemic activity. Anti-leukemic activity of novel flavanone derivatives was
tested using the K562 cell line. The parental flavanone was selected as the reference compound in identification
of analogues with superior anti-leukemic activity. More than two-thirds of the derivatives displayed higher
activity than the initial flavanone. Positions of substituents that promoted anti-leukemic activity were identified
on both the chromene and pyrazole fragments. Compounds 6b and 6c showed the highest activity against K562
cell line, with IC50 values 3.0 and 0.5 µM respectively. Notably, compounds 6b and 6c displayed very high
selectivity in inhibition of leukemic cells (K562) but not of healthy HEK293 cells or solid cancer cell lines
HeLa, MCF7 and BT474. Moreover, both the 6b and 6c compounds were predicted to have good ADME
properties.
Keywords: chalcones, flavanone, pyrazoles, K562 cell line, anti-leukemic activity
DOI: 10.1134/S1070363217100243
INTRODUCTION
RESULTS AND DISCUSSION
There is a number of natural compounds of anti-
cancer potential, for example, naringenin, hesperetin
and hesperidin demonstrated cancer cell proliferation
inhibition, cell cycle arrest and reduction of in vivo
metastatic potential [1–5]. Flavanone is among im-
portant natural compounds of significant anti-cancer
activity [6–8]. Most studies so far dealt with anti-
cancer activity of flavonoids [9–12] but not flava-
nones. In this study, we synthesized flavanone deriva-
tives with potential anti-leukemic activity.
The initial flavanones and their derivatives 4a–4c
were synthesized in accordance with the earlier
developed two-step method [14] (Scheme 1). Basic
and substituted pyrazoles were synthesized using two
different pathways [15, 16] (Schemes 2 and 3). The
products 6a–6h and 8a–8e were characterized by IR,
1
1H and 13C NMR, and mass spectral data. In H NMR
spectra of compound 6d proton of the pyrazole ring
was recorded as a singlet at 8.41 ppm whereas in the
spectrum of compound 8c, proton of the pyrazole ring
appeared at 7.73 ppm as a doublet.
Due to very high bioactivity and wide range of
applications of pyrazole derivatives [13], we syn-
thesized substituted pyrazoles on chromene moiety (a
flavanone) using two different approaches and evaluated
their anti-leukemic activity using K562 cell line.
Selective anti-leukemic activity of two highly active
flavanone analogues was confirmed by their lack of
significant activity against healthy HEK293 and solid
cancer cell lines HeLa, MCF7, and BT474.
Anti-leukemic activity of novel flavanone/chromene
derivatives was tested using K562 cell line. The parental
flavanone 4a was used as a reference compound to
compare the potency of reaction intermediates 5a–5c
and 7a, 7b and final products 6a–6h and 8a–8e. The
parental flavanone failed to affect survival of K562
cells even at the concentration as high as 100 µM. Of
18 flavanone derivatives, 12 compounds displayed anti-
leukemic activity in a dose-dependent manner while
1 The text was submitted by the authors in English.
2421

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MADHU et al.
Scheme 1. Synthesis of flavanones 4a–4c.
R
CHO
OH
O
OH
O
R
O
a
b
O
R
1
2a−2c
3a−3c
4a−4c
Reagents and conditions: (a) KOH, EtOH, H2O, room temperature, 8 h, 60–70%; (b) EtOH, HCl, reflux overnight, 80–90%;
R = H, Me, OMe.
Scheme 2. Synthesis of pyrazole derivatives of flavanones 4a–4c.
R
R
R
O
O
O
c
d
CHO
N
N
O
Cl
R1
4a−4c
5a−5c
6a−6h
Reagents and conditions: (c) DMF, POCl3, 0°C–room temperature, 2 h, 80%; (d) R1NHNH2·H2O, CH3COOH, reflux, 4 h,
75%. a: R = H, R1 = H, Ph, p-Cl-Ph; b: R = Me, R1= H , Ph; c: R = OMe, R1 = H, Ph, p-Cl-Ph.
Scheme 3. Synthesis of pyrazole derivatives of flavanone.
R
R
R
O
O
O
f
e
N
O
O
N
N
R1
7a, 7b
4a, 4b
8a−8e
Reagents and conditions: (e) DMF–DMA, xylene, reflux, 7 h; 50%; (f) R1NHNH2·H2O, CH3COOH, reflux, 4 h, 80%. a: R =
H, R1= H , Ph; b: R = Me, R1= H , Ph , p-Cl-Ph.
the remaining 6 compounds 6a, 7a, 7b, 8b, 8d, and 8e
demonstrated no biological activity at 100 µM.
Notably, the flavanone derivatives 6b, 6c, 6e, 6g, 6h,
and 8c demonstrated higher activity with an IC50 value
below 50 µM. Among these, 6b (IC50 = 3 µM) and 6c
(IC50 = 0.5 µM) displayed highest anti-leukemic
activity at sub-micromolar concentrations.
cell growth inhibition of HEK 293 cells with IC50
values of 38 and 21 µM respectively. The compounds
6b and 6c demonstrated high selectivity index (SI) for
K562 cells (Table 2). SI was calculated as a ratio of
IC50 of a compound with K562 (leukemic) to that of
the HEK293 (healthy) cell line (Table 2). Thus,
compounds 6b and 6c were characterized by very high
selective toxicity towards leukemic cells but not
towards healthy cells. In addition, the possible broad
anti-cancer activity of these compounds was tested
using additional solid tumor cell lines HeLa, MCF7
and BT474 and they displayed SI≤ 2 against HeLa,
To assess non-specific toxicity, a non-cancerous
HEK293 cell line was chosen as a control. Parental
compound 4a showed no effect at concentration of
100 µM (Table 2). However, both 6b and 6c displayed
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SYNTHESIS OF PYRAZOLE-SUBSTITUTED CHROMENE ANALOGUES
2423
Table 1. Anti-leukemic activity of 2-arylchromene analogues against K562 cell line
Structure
N2
Drug-likeness score
miLogP n-violation TPSA
26.3
Anti-leukemic
activity IC50
Comp. no.
N1
p-tolyl p-OCH3
MW
224.2
270.7
284.7
300.7
279.3
293.3
248.2
324.3
358.8
262.3
338.4
278.3
354.4
388.8
248.2
324.3
262.3
338.4
372.8
4a
5a
5b
5c
7a
7b
6a
6b
6c
6d
6e
6f
–
–
–
–
+
–
–
–
–
–
–
+
+
–
–
–
–
–
+
+
+
–
–
–
+
–
+
–
–
–
-
>100
80
3.1
3.9
4.4
4.0
3.0
3.5
3.3
4.6
5.3
3.7
5.1
3.4
4.7
5.4
3.3
4.6
3.7
5.1
5.8
0
0
0
0
0
0
0
0
1
0
1
0
0
1
0
0
0
1
1
–
–
26.3
26.3
35.5
29.5
29.5
37.9
27.0
27.0
37.9
27.0
47.1
36.2
36.2
37.9
27.0
37.9
27.0
27.0
–
–
83
–
–
81
–
–
>100
>100
>100
3
–
–
H
–
Phenyl
–
p-Cl-phenyl
–
0.5
H
–
69
Phenyl
–
-
19
H
–
+
+
+
–
–
–
–
–
59
6g
6h
8a
8b
8c
8d
8e
Phenyl
–
14
p-Cl-phenyl
–
H
17
–
–
–
–
–
63
Phenyl
H
>100
30
Phenyl
p-Cl-phenyl
>100
>100
Table 2. Selectivity index of compounds 4a, 6b, and 6c against HEK293, K562, HeLa, MCF7, and BT474 cell lines
HEK293
IC50
>100
38
K562
HeLa
MCF7
SI
No activity >100 No activity
BT474
Comp. no.
IC50
>100
3
SI
IC50
SI
IC50
89
IC50 SI
4a
6b
6c
No activity
12.6
>100 No activity
39
17
0.9
1.2
22
1.7
1.2
61
33
0.6
0.6
21
0.5
42
17
MCF7 and BT474 cell lines indicating their lack of
potential selective anti-cancer activity (Table 2).
Overall, the above data indicated very high selective
activity of compounds 6b and 6c against leukemic
cells but not towards healthy non-cancerous cells as
well as solid cancer cells.
phenyl or p-chlorophenyl substitutions on the pyrazole
N1 demonstrated high activity (IC50 < 50 µM). On the
contrary, the derivatives with phenyl or p-chlorophenyl
substitutions on the pyrazole N2 8b, 8d, and 8e
exhibited no anti-leukemic activity with cellular IC50
≥100 µM. Importantly, hydrogen attached to N2 (8a)
rather than N1 6a of pyrazole moiety resulted in the
enhanced activity (Table 1). Similarly, a 2-fold
enhancement in activity was observed for 8c with H on
N2 over 6d with H on N1, both of those had p-tolyl
substituent on the chromene backbone (Table 1). So,
Mechanistic studies indicated that the structures of
pyrazole to chromene backbone 6a did not induce anti-
leukemic activity (IC50 > 100 µM). However, all 5
flavanone derivatives 6b, 6c, 6e, 6g, and 6h with either
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2424
MADHU et al.
the role of substituents, specifically on N1 and N2 of
the flavanone moiety, influenced biological activity of
the compounds.
(4.02 g, 38 mmol) were dissolved in 100 mL of
ethanol. 60% KOH was added drop wise until the
solution was alkaline. The reaction mixture was stored
for 8 h. Neutralization with dilute HCl gave a solid,
which was chromatographed on silica gel (eluent
petroleum ether : chloroform, 8 : 2). The similar
procedure was used for producing compounds 3b and
3c from 2b and 2c, accordingly.
All tested compounds had distinctive pharmacolo-
gical properties confirming to Lipinski’s rule of 5
(nviolation ≤1) [17]. 13 Of overall 18 compounds were
in good agreement with all the Lipinski’s rules while 5
derivatives violated only one rule, miLogP value > 5.
Among two most active flavanone derivatives tested in
this study, 6b showed complete agreement with best
drug-likeliness (nviolation = 0), while the compound
6c had a miLogP score of >5 (nviolation = 1). All
flavanone derivatives showed a TPSA (polar surface
area) value of < 63A02 predicting a high (>90%) oral
absorption rate, Caco2 permeability, and blood-brain
barrier penetration [18]. The presence of fewer
rotatable bonds (≤10) reinforced the drug-likeness of
these flavanone analogues [19].
Synthesis of flavan-4-ones (4a–4c). (E)-1-(2-Hyd-
roxyphenyl)-3-phenylprop-2-enone 3a (5g, 10 mmol)
was dissolved in ethanol (100 mL). To the resulting
solution conc. HCl (10 mL) was added and the mixture
was refluxed overnight on a water bath. Upon comple-
tion of the reaction ethanol was distilled off and water
added. The residual solid was filtered off, chromato-
graphed on silica gel (petroleum ether : chloroform,
8 : 2). The similar procedure was used or the synthesis
of compounds 4b, 4c from 3b, 3c accordingly.
Previous studies have shown that 7-methoxy-
flavanone and 7-hydroxyflavanone have several-fold
activity than that of the parental flavanone [20–22].
2-Hydroxyflavanone derivatives were shown to exhibit
anti-inflammatory activity [23]. The present study
reports 13 flavanone analogues with superior biolo-
gical activity than that of the parental flavanone using
a representative CML (chronic myeloid leukemia) cell
line. K562 Cells were previously shown to be sensitive
to natural flavanones such as naringenin at high con-
centrations [24]. Thus, this cell line offers a potential
approach to anti-leukemic compounds that can act as
lead molecules for further drug development.
Synthesis of 4-chloro-2-aryl-2H-chromene-3-
carbaldehydes (5a–5c). To 2-phenylchroman-4-one
4a (10 mmol) in dry dimethyl formamide (50 mmol) a
freshly distilled dry phosphorus oxychloride (9 mmol)
was added with constant stirring at 0°C. The reaction
mixture stirred for 2h then poured on to crushed ice.
The yellow residue was filtered off, washed with water
and purified by chromatography on silica gel (eluent
petroleum ether) to give 4-chloro-2-phenyl-2H-chro-
mene-3-carbaldehyde (5a). The product was recrys-
tallized from methanol as pale yellow needles. The
similar procedure was used for the synthesis of
compounds 5b, 5c from 4b, 4c accordingly.
Overall, this study identified key flavanone deri-
vatives with biological activity superior than the reference
parental flavanone specifically against leukemic cells
that can be used in development of improved anti-
leukemic therapeutics.
Synthesis of (E)-3-[(dimethylamino)methylene]-
2-phenylchroman-4-one (7a) and (E)-3-[(dimethyl-
amino)methylene]-2-(4-methylphenyl)phenylchroman-
4-one (7b). A compound 4a or 4b (0.3 mmol) was con-
densed with dimethylformamide dimethylacetal
(0.9 mmol) by refluxing in xylene for 7 h [24]. Upon
completion of the process (TLC monitoring), xylene
was distilled off, water was added, the mixture was
extracted with ethylacetate, and the residual product
was purified by column chromatography.
EXPERIMENTAL
All reagents and solvents were purchased from com-
mercial sources and used without further purification.
Melting points were determined in open capillaries on
an electrical melting point apparatus. 1H and 13C NMR
Synthesis of compounds 6a–6h and 8a–8e. A
mixture of a compound 5a–5c or 7a, 7b (0.5 mmol)
with acetic acid (10 mL) was refluxed for 4h. Upon
completion of the reaction (monitored by TLC) the
mixture was poured into ice cold water. The residue
was filtered off and purified by column chromato-
graphy on silica gel (5% ethyl acetate in hexane) to
give a derivative 6a–6h or 8a–8e respectively.
spectra were measured on
a
Bruker-DPX-400
spectrometer in CDCl3 using TMS as the standard. MS
(ESI) spectra were measured on a LCMS 2010 VG
mass spectrometer.
Synthesis of chalcones (3a–3c). 2-Hydroxyaceto-
phenone 1 (5.0 g, 36.76 mmol) and benzaldehyde 2a
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SYNTHESIS OF PYRAZOLE-SUBSTITUTED CHROMENE ANALOGUES
2425
(E)-1-(2-Hydroxyphenyl)-3-phenylprop-2-enone
(3a). Yellow solid, yield 60%. H NMR spectrum, δ,
7.50 m (1H), 7.95 d.d (J = 10.0, 2.0 Hz, 1H). 13C NMR
spectrum, δ, ppm: 44.2, 55.0, 79.1, 114.0, 117.9,
120.7, 121.2, 126.7, 127.5, 130.6, 135.8, 159.7, 161.4,
191.8. MS (ESI): m/z 245 [M + H]+.
1
ppm: 7.20 m (2H), 7.65 m (4H), 7.77 m (3H), 7.95 m
(2H), 12.72 s (1H). MS (ESI): m/z 225 [M + H]+.
(E)-1-(2-Hydoxyphenyl)-3-(4-methylphenyl)prop-
2-enone (3b). Light yellow solid, yield 65%, mp 114°C.
IR spectrum, ν, cm–1: 1635 (C=O). 1H NMR spectrum,
δ, ppm: 2.3 s (3H), 6.90 d.d.d (J = 8.2, 7.7, 1.2 Hz,
1H), 7.00 d.d (J = 8.5, 1.0 Hz, 1H), 7.21 d (J = 8.0 Hz,
2H), 7.47 d.d.d (J = 8.5, 7.7, 1.5 Hz, 1H), 7.53 d (J =
8.0 Hz, 2H), 7.58 d (J = 15.3 Hz, 1H), 7.87 d (J =
15.5 Hz, 1H), 7.91 d.d (J = 8.0, 1.5 Hz, 1H), 12.90 s
(1H). 13C NMR spectrum, δ, ppm: 21.6, 118.6, 118.9,
120.0, 128.7, 129.6, 129.8, 131.8, 136.2, 141.6, 145.5,
163.6, 193.7. MS (ESI): m/z 239 [M + H]+.
4-Chloro-2-phenyl-2H-3-chromene-3-carbaldehyde
(5a). Yield 80%. IR spectrum, ν, cm–1: 1661 (CHO),
1601 (C=C). H NMR spectrum, δ, ppm: 6.30 s (1H),
6.70 m (2H), 7.20 m (6H), 7.48 d.d (J = 9.0, 2.0 Hz,
1H), 10.27 s (1H). 13C NMR spectrum, δ, ppm: 74.8,
117.2, 119.7, 121.7, 126.3, 126.6, 128.5, 128.3, 134.3,
137.9, 143.5, 154.8, 187.8. MS(ESI): m/z 270 [M] and
272 [M + 2].
1
4-Chloro-2-(4-methyphenyl)-2H-chromene-3-
carbaldehyde (5b). Light yellow solid, yield 80%, mp
98°C. IR spectrum, ν, cm–1: 1667 (CHO), 1603 (C=C).
1H NMR spectrum, δ, ppm: 2.22 s (3H), 6.25 s (1H),
6.68 d.d (J = 10.0 Hz, 1H), 6.95 m (1H), 7.00 d (J =
10.0 Hz, 2H), 7.10 d (J = 10.0 Hz, 2H), 7.30 m (1H),
7.65 d.d (J = 10.0 Hz, 1H), 10.22 s (1H). 13C NMR
spectrum, δ, ppm: 21.0, 74.9, 117.5, 120.0, 122.0,
126.2, 126.5, 129.20, 134.0, 135.0, 138.5, 143.5,
155.0, 188.0. MS(ESI): m/z 284 [M], 286 [M + 2].
(E)-1-(2-Hydroxyphenyl)-3-(4-methoxyphenyl)-1-
phenylprop-2-enone (3c). Yellow solid, yield 70%,
mp 87°C. IR spectrum, ν, cm–1: 1637 (C=O). 1H NMR
spectrum, δ, ppm: 3.85 s (3H), 6.90 m (2H), 6.96 d
(J = 9.0 Hz, 2H), 7.50 m (2H), 7.58 d (J = 9,0 Hz, 2H),
7.90 d (J = 16.0 Hz, 1H), 7.95 d.d (J = 9.0, 2.0 Hz,
1H), 12.85 s (1H). 13C NMR spectrum, δ, ppm: 55.2,
114.3, 117.4, 118.3, 118.5, 119.9, 127.8, 129.3, 130.3,
135.9, 145.1, 161.8, 163.4, 193.4. MS (ESI): m/z 245
[M + H]+.
4-Chloro-2-(4-methoxylphenyl)-2H-chromene-3-
carbaldehyde (5c). Pale yellow needles, yield 80%,
mp 85°C. IR spectrum, ν, cm–1: 1660 (CHO), 1600
(C=C). 1H NMR spectrum, δ, ppm: 3.75 s (3H), 6.30 s
(1H), 6.75 m (3H), 7.25 m (3H), 7.70 d.d (J = 10.0, 2.0
Hz, 1H), 10.30 s (1H). 13C NMR spectrum, δ, ppm:
54.9, 74.7, 113.7, 117.3, 119.8, 121.7, 126.2, 126.8,
128.2, 130.0, 134.2, 143.3, 154.8, 159.8, 187.8. MS
(ESI): m/z 300 [M], 302 [M + 2].
2-Phenylchroman-4-one (4a). White crystals, yield
1
89%, mp 73°C. IR spectrum, ν, cm–1: 1689 (C=O). H
NMR spectrum, δ, ppm: 2.85 d.d (J = 17.0, 4.0 Hz,
He3), 3.08 d.d (J = 17.0, 14.0 Hz, Ha3), 5.50 d.d (J =
17.0, 4.0 Hz, 1H), 7.05 m (2H), 7.45 m (3H), 7.93 d.d
(J = 10.0, 2.0 Hz, 1H). MS (ESI): m/z 225 [M + H]+.
2-(4-Methylphenyl)chroman-4-one (4b). Light
yellow solid, yield 80%, mp 114°C. IR spectrum, ν,
4-Phenyl-1,4-dihydrochromeno[4,3-c]pyrazole
(6a). Pale yellow solid, yield 70%, mp 210–215°C. 1H
NMR spectrum, δ, ppm: 6.44 s (1H), 6.82 d.d (J = 8.0,
0.9 Hz, 1H), 7.00 d.d.d (J = 15.1, 7.6, 1.0 Hz, 1H),
7.23 d.d.d (J = 15.0, 7.6, 1.5 Hz, 1H), 7.27 m (3H),
7.33 m (2H), 7.60 d.d (J = 7.7, 1.5 Hz, 1H), 8.02 s
(1H), 9.15 s (1H). 13C NMR spectrum, δ, ppm: 76.3,
116.8, 121.0, 121.5, 124.9, 125.7, 127.1, 128.3, 128.5,
130.3, 131.4, 138.3, 138.7, 153.1. MS (ESI): m/z 249
[M + H]+.
1
cm–1: 1692 (C=O). H NMR spectrum, δ, ppm: 2.35 s
(3H), 2.82 d.d (J = 17.0, 4.0 Hz, He3), 3.08 d.d (J =
17.0, 14.0 Hz, Ha3), 5.45 d.d (J = 17.0, 4.0 Hz, 1H),
7.00 d.d (J = 10.0, 10.0 Hz, 2H), 7.25 d (J = 9.0 Hz,
2H), 7.35 d (J = 9.0 Hz, 2H), 7.45 d.d (J = 10.0,
2.0 Hz, 1H), 7.95 d.d (J = 10.0, 2.0 Hz, 1H). 13C NMR
spectrum, δ, ppm: 21.1, 44.4, 79.4, 118.0, 120.8,
121.4, 126.0, 126.9, 129.3, 135.7, 135.9, 138.5, 161.5,
191.8. MS (ESI): m/z 239 [M + H]+.
1,4-Diphenyl-1,4-dihydrochromeno[4,3-c]pyrazole
(6b). Yellow solid, yield 73%, mp 140–145°C. 1H NMR
spectrum, δ, ppm: 6.63 s (1H), 6.84 d.d (J = 8.0,
0.9 Hz, 1H), 6.88 (t, J = 7.3 Hz, 1H), 6.94 m (3H),
7.18 d.d.d (J = 15.1, 7.6, 0.2 Hz, 1H), 7.25 m (4H),
7.42 d.d (J = 8.0, 1.6 Hz, 2H), 7.56 d.d (J = 7.7,
1.5 Hz, 1H), 7.87 s (1H), 7.97 s (1H). 13C NMR
2-(4-Methoxyphenyl)chroman-4-one (4c). Yellow
solid, yield 88%, mp 78°C. IR spectrum, ν, cm–1: 1683
(C=O). 1H NMR spectrum, δ, ppm: 2.80 d.d (J = 17.0,
4.0 Hz, He3), 3.09 d.d (J = 17.0, 14.0 Hz, Ha3), 3.95 s
(3H), 5.45 d.d (J = 17.0, 4.0 Hz, 1H), 6.95 d (J =
9.0 Hz, 2H), 7.00 m (2H), 7.40 d (J = 9.0 Hz, 2H),
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MADHU et al.
spectrum, δ, ppm: 77.0, 115.9, 118.2, 118.5, 121.5, 122.6,
126.2, 127.7, 128.4, 128.7, 129.6, 129.8, 133.5, 136.2,
139.2, 139.6, 153.4. MS (ESI): m/z 341 [M + NH3]+.
115.6, 118.9, 121.4, 122.5, 125.4, 127.0, 128.7, 129.6,
129.8, 131.8, 133.2, 135.6, 142.1, 153.6, 159.7. MS
(ESI): m/z 355 [M + H]+ .
1-(4-Chlorophenyl)-4-methoxy-1,4-dihydrochro-
1-(4-Chlorophenyl)-4-phenyl-1,4-dihydrochromeno-
meno[4,3-c]pyrazole (6h). Gray solid, yield 74%, mp
150–155°C. H NMR spectrum, δ, ppm: 3.72 s (3H),
[4,3-c]pyrazole (6c). Light yellow solid, yield 70%,
mp 150–155°C. H NMR spectrum, δ, ppm: 6.62 s
1
1
6.57 s (1H), 6.72 m (1H), 6.81 m (2H), 6.96–7.00 m
(1H), 7.09–7.16 m (1H), 7.24 s (1H), 7.42–7.57 m (7H).
13C NMR spectrum, δ, ppm: 29.6, 76.9, 115.6, 118.1,
118.3, 121.2, 122.3, 127.3, 127.5, 129.2, 129.4, 129.6,
133.8, 134.8, 136.2, 136.6, 138.5, 138.7, 153.4. MS
(ESI): m/z 389 [M + H]+.
(1H), 6.88 m (2H), 6.97 m (3H), 7.18 d.d.d (J = 15.4,
7.9, 1.5 Hz, 1H), 7.24 m (3H), 7.42 d.d (J = 8.0,
1.6 Hz, 2H), 7.55 d.d (J = 7.7, 1.5 Hz, 1H), 7.86 s
(1H), 7.96 s (1H). 13C NMR spectrum, δ, ppm: 76.1,
115.3, 117.7, 118.1, 121.5, 122.3, 127.1, 128.8, 129.4,
129.9, 133.6, 134.5, 134.6, 136.0, 137.8, 138.5, 152.9.
MS (ESI): m/z 359 [M + H]+.
(E)-3-[(Dimethylamino)methylene]-2-phenylchro-
man-4-one (7a). Yellow solid, yield 50%, mp 120°C.
1H NMR spectrum, δ, ppm: 3.07 s (6H), 6.66 s (1H),
6.82 d.d (J = 8.2, 0.7 Hz, 1H), 6.87–6.90 m (1H), 7.19–
7.22 m (1H), 7.28–7.26 m (3H), 7.44–7.46 m (2H),
7.86 m (2H), 7.87 d (J = 1.6 Hz, 1H). MS (ESI): m/z
280 [M + H]+.
4-(4-Methylphenyl)-1,4-dihydrochromeno[4,3-c]-
pyrazole (6d). Yellow solid, yield 74%, mp 215–220°C.
1H NMR spectrum, δ, ppm: 2.28 s (3H), 6.34 s (1H),
6.82 d (J = 8.5 Hz, 1H), 7.08 d (J = 7.9 Hz, 2H), 7.22
m (3H), 7.27 d (J = 2.2 Hz, 1H), 7.54 s (1H), 7.68 d
(J = 2.4 Hz, 1H), 8.41 s (1H). 13C NMR spectrum, δ,
ppm: 21.6, 76.3, 116.8, 121.0, 121.5, 124.9, 125.7,
128.5, 133.7, 135.3, 136.5, 138.3, 139.7, 153.1. MS
(ESI): m/z 263 [M + H]+.
(E)-3-[(Dimethylamino)methylene]-2-(4-methyl-
phenyl)chroman-4-one (7b). Yellow solid, yield 50%,
1
mp 130°C. H NMR spectrum, δ, ppm: 2.25 s (3H),
3.06 s (6H), 6.63 s (1H), 6.78–6.81 m (1H), 6.85–6.90
m (1H), 7.05–7.08 m (2H), 7.26–7.35 m (2H), 7.84–
7.88 m (2H). MS (ESI): m/z 294 [M + H]+.
1-Phenyl-4-(4-methylphenyl)-1,4-dihydrochromeno-
[4,3-c]pyrazole (6e). Light green solid, yield 72%, mp
1
145–150°C. H NMR spectrum, δ, ppm: 2.38 s (3H),
6.34 s (1H), 6.76 m (1H), 6.86 m (1H), 7.01 m (1H),
7.14 m (1H), 7.22 d (J = 8.0 Hz, 2H), 7.30 s (1H), 7.40
d (J = 8.0 Hz, 2H), 7.56 m (5H). 13C NMR spectrum,
δ, ppm: 21.2, 77.4, 115.6, 118.5, 121.2, 122.3, 126.3,
127.4, 128.6, 129.0, 129.3, 129.8, 133.8, 136.3, 137.2,
138.5, 140.6, 153.7. MS (ESI): m/z 339 [M + H]+.
4-Phenyl-2,4-dihydrochromeno[4,3-c]pyrazole (8a).
Pale yellow solid, yield 70%, mp 175–180°C. 1H NMR
spectrum, δ, ppm: 6.35 s (1H), 7.15 m (2H), 7.27 m
(5H), 7.39 d (J = 8.0 Hz, 2H), 7.83 d (J = 6.53 Hz,
1H), 7.98 d (J = 6.53 Hz, 1H). 13C NMR spectrum, δ,
ppm: 77.5, 114.6, 117.2, 117.6, 122.3, 122.6, 126.5,
129.5, 129.8, 137.6, 138.8, 142.5, 153.8. MS (ESI):
m/z 249 [M + H]+ .
4-(4-Methoxyphenyl)-1,4-dihydrochromeno[4,3-
c]pyrazole (6f). Yellow solid, yield 77%, mp 195–
200°C. 1H NMR spectrum, δ, ppm: 3.74 s (3H), 6.39 s
(1H), 6.80 m (3H), 7.00 d.d.d (J = 14.9, 7.5, 0.7 Hz,
2H), 7.22 d.d (J = 10.3, 2.4 Hz, 2H), 7.61 d.d (J = 7.7,
1.3 Hz, 1H), 9.17 s (1H), 8.00 s (1H). 13C NMR spec-
trum, δ, ppm: 55.0, 79.1, 114.0, 117.9, 120.7, 121.2,
126.7, 127.5, 129.6, 132.8, 135.7, 150.4, 157.8. MS
(ESI): m/z 279 [M + H]+.
2,4-Diphenyl-2,4-dihydrochromeno[4,3-c]pyra-
1
zole (8b). White solid, yield 72%, mp 130–135°C. H
NMR spectrum, δ, ppm: 6.38 s (1H), 6.76 d.d.d (J =
15.1, 7.6, 1.2 Hz, 1H), 6.86 d.d (J = 7.7, 1.5 Hz, 1H),
7.17 m (1H), 7.18 d.d (J = 8.0, 1.0 Hz, 1H), 7.32 s
(1H), 7.44 m (3H), 7.55 m (7H). 13C NMR spectrum,
δ, ppm: 77.2, 117.4, 117.8, 118.9, 119.4, 122.0, 122.6,
123.2, 126.0, 127.7, 128.6, 128.9, 129.3, 129.5, 140.6,
141.2, 144.6, 154.2. MS (ESI): m/z 325 [M + H]+.
4-(4-Methoxyphenyl)-1-phenyl-1,4-dihydrochro-
meno[4,3-c]pyrazole (6g). Gray solid, yield 78%, mp
1
4-(p-Tolyl)-2,4-dihydrochromeno[4,3-c]pyrazole
(8c). White solid, yield 76%, mp 170–175°C. 1H NMR
spectrum, δ, ppm: 2.36 s (3H), 6.34 s (1H), 7.01 m
(2H), 7.22 m (5H), 7.36 d (J = 8.0 Hz, 2H), 7.73 d (J =
6.53 Hz, 1H). 13C NMR spectrum, δ, ppm: 21.2, 76.5,
115.6, 117.2, 117.6, 122.1, 122.7, 127.5, 129.3, 129.7,
137.3, 138.6, 141.8, 153.8. MS (ESI): m/z 263 [M + H]+.
155–160°C. H NMR spectrum, δ, ppm: 3.72 s (3H),
6.57 s (1H), 6.81 m (3H), 6.88 t.t.t (J = 14.6, 7.4,
1.0 Hz, 1H), 6.94 m (2H), 6.97 d.d (J = 7.6, 1.0 Hz,
1H), 7.17 d.d.d (J = 15.4, 7.9, 1.5 Hz, 1H), 7.24 d.d.d
(J = 14.0, 7.4, 1.8 Hz, 2H), 7.33 d.d (J = 6.7, 1.9 Hz,
1H), 7.56 d.d (J = 7.7, 1.5 Hz, 1H), 7.85 s (1H), 7.94 s
(1H). 13C NMR spectrum, δ, ppm: 54.6, 76.9, 112.9,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 10 2017

SYNTHESIS OF PYRAZOLE-SUBSTITUTED CHROMENE ANALOGUES
2427
2-Phenyl-4-(p-tolyl)-2,4-dihydrochromeno[4,3-c]-
pyrazole (8d). Brown solid, yield 72%, mp 135–140°C.
1H NMR spectrum, δ, ppm: 2.37 s (3H), 6.34 s (1H),
6.69–7.13 (m,6H), 7.40–7.52 m (6H), 7.89 d (J =
6.5 Hz, 1H), 8.01 s (1H). 13C NMR spectrum, δ, ppm:
21.2, 76.9, 115.8, 118.1, 120.4, 121.3, 122.5, 125.2,
126.1, 127.7, 128.9, 129.4, 129.7, 131.5, 132.0, 136.1,
138.7, 142.9, 153.5. MS (ESI): m/z 339 [M + H]+.
and CFRD, O.U, Hyderabad, India for providing
spectral data. RKK is supported by grants from UGC-
FRP [no. F.4-5(136-FRP)/2014(BSR)] and DST-SERB
(no. EMR/2014/000904).
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meno[4,3-c]pyrazole (8e). Pale yellow solid, yield
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