Synthesis and Anticancer Activity of 2-Aryl-3-methylbenzofuro[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione and 2-Aryl-3,7,9-trimethylpyrido[3',2':4,5]thieno[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones

Article abstract of DOI:10.1134/S1070428020050139

Abstract: The reactions of ethyl 1-aryl-4-(2-bromoacetyl)-5-methyl-1H-pyrazolocarboxylates with ortho-hydroxybenzonitrile and 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile gave previously unknown 2-aryl-3-methylbenzofuro[3,2-b]pyrazolo[4,3-e]az

Full text of DOI:10.1134/S1070428020050139

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 5, pp. 813–818. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 5, pp. 766–772.
Synthesis and Anticancer Activity of 2-Aryl-3-methyl-
benzofuro[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione
and 2-Aryl-3,7,9-trimethylpyrido[3',2':4,5]thieno-
[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones
T. I. Chabana,*, Y. E. Matiichuka, V. Ya. Horishnya, I. G. Chabana, and V. S. Matiychukb
a Danylo Halytsky Lviv National Medical University, Lviv, 79010 Ukraine
b Ivan Franko National University of Lviv, Lviv, 79005 Ukraine
*e-mail: chabantaras@ukr.net
Received January 10, 2020; revised February 18, 2020; accepted February 22, 2020
Abstract—The reactions of ethyl 1-aryl-4-(2-bromoacetyl)-5-methyl-1H-pyrazolocarboxylates with ortho-hyd-
roxybenzonitrile and 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile gave previously unknown 2-aryl-
3-methylbenzofuro[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones and 2-aryl-3,7,9-trimethylpyrido[3',2':4,5]-
thieno[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones, respectively. It was found that this reaction occurred
as a tandem process. The synthesized compounds were sceened for anticancer activity and exhibited moderate
activity against the most part of malignant cancer cells.
Keywords: organic synthesis, heterocyclization, tandem reactions, anticancer activity
DOI: 10.1134/S1070428020050139
Tandem reactions are of great importance in organic
chemistry, since they make it possible to obtain com-
pounds of complex structure in one stage and high atom
economy [1–4]. Such reactions are easy to perform and
usually give high yields of products. Tandem reactions
are widely used in the synthesis of heterocyclic com-
pounds, drugs, as well as complete synthesis of natural
compounds.
b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones and
2-aryl-3,7,9-trimethylpyrido[3',2':4,5]thieno[3,2-b]py-
razolo[4,3-e]azepine-4,11(2H,10H)-diones. To this end,
we reacted ethyl 1-aryl-4-(2-bromoacetyl)-5-methyl-1H-
pyrazolocarboxylates 2a–2f with ortho-hydroxybenzonit-
rile (3) and 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-
3-carbonitrile (4). The starting bromoketones 2a–2f were
prepared by bromination of ethyl 4-acetyl-5-methyl-1-
aryl-1H-pyrazole-3-carboxylates 1a–1f [16] in acetic
acid.
Ortho-hydroxybenzonitrile reacts with α-halocarbonyl
compounds to afford 3-amino-2-acyl-1-benzofuran de-
rivatives [5–7]. In this case, the amino group at the C3
position of benzofuran, formed in this reaction, exhibits
nucleophilic properties and can undergo, provided the
starting haloketone contains an ester group, tandem
lactamization reaction. In particular, benzofuro[3,2-c]-
[2]benzoazepine-6,11-dione derivatives [8] are obtained
in this way.
It was found that the reactions of bromoketones 2a–2f
with ortho-hydroxybenzonitrile (3) in the presence of
potassium carbonate involved tandem heterocycliza-
tion with consecutive closure of the furan and azepine
rings and formed 2-aryl-3-methylbenzofuro[3,2-b]py-
razolo[4,3-e]azepine-4,11(2H,10H)-diones 7a–7f. In the
same way, compounds 2a–2f reacted with 4,6-dimethyl-
2-thioxo-1,2-dihydropyridine-3-carbonitrile (4), yelding
2-aryl-3,7,9-trimethylpyrido[3',2':4,5]thieno[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones 10a–10f
(Scheme 1).
Proceeding with our research into the synthesis and
biological activity of fused azaheterocycles [9–20],
we developed a simple one-pot method of synthesis
of previously unknown 2-aryl-3-methylbenzofuro[3,2-
813

814
CHABAN et al.
Scheme 1.
1a–1f
8
5
2a–2f
7a–7f
1a–1f, 2a–2f, 7a–7f, 10a–10f, R = H (a), 3-Cl (b), 4-Cl (c), 2,4-Cl2 (d), 4-Br (e), 4-CH3O (f).
6
9
10a–10f
The synthesized compounds are high-melting yellow
according to the National Cancer Institute Developmental
Therapeutic Program international research program of
the U.S. National Institute of Health [21–24] in vitro
against 60 cell lines embracing almost the entire spec-
trum of human cancers (including leukemia, non-small
cell lung cancer, epithelial colon cancer, melanoma, and
ovarian and breast cancer). The concentrations of the test
compounds were 10–5 M. The activity of the test com-
pounds was quantified in terms the growth percentage of
substances readily soluble in DMF and DMSO, soluble
with heating in acetic acid and alcohols, and insoluble in
apolar solvents and water. The structure of compounds
1
2a–2f, 7a–7f, and 10a–10f was proved by H NMR
spectroscopy.
Anticancer activity testing of the synthesized com-
pounds was performed by high-throughput screening
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SYNTHESIS AND ANTICANCER ACTIVITY
815
Table 1. Cytotoxicity of synthesized compounds at a concentration of 10–5 M on 60 cancer cell lines
Mitotic activity on 60 lines, GP, %
Compound no.
The most sensitive lines (cancer line/type), GP, %
average
76.16
range
OVCAR-4 (Ovarian cancer) 10.25
T-47D (Breast cancer) 28.89
SK-OV-3 (Ovarian cancer) 37.86
SR (Leukemia) 45.66
7a
7b
10.25–100.91
SNB-75 (CNS tumor) 48.76
SR(Leukemia) 27.90
SF-539 (CNS tumor) 38.08
82.52
27.90–111.86
7с
7d
7e
94.47
95.52
92.78
53.44–110.73
51.24–112.23
46.78–109.77
SR (Leukemia) 53.44
SR (Leukemia) 51.24
SR (Leukemia) 46.78
OVCAR-4 (Ovarian cancer) 3.57
HCT-116 (Colon cancer) 37.72
MDA-MB-231/ATCC (Breast cancer) 37.91
786-0 (Kidney cancer) 39.66
7f
71.94
3.57–102.76
SR (Leukemia) 40.76
HCT-116 (Colon cancer) 48.44
SR (Leukemia) 49.19
10a
97.60
71.93–108.12
10b
10c
10d
10e
102.93
98.61
99.03
98.09
86.53–107.76
75.44–122.28
81.33–109.20
60.89–116.11
UO-31 (Kidney cancer) 86.53
SR (Leukemia) 75.44
SR (Leukemia) 81.33
SR (Leukemia) 60.89
HOP-62 (Non-small cell lung cancer) 6.06
NCI-H226 (Non-small cell lung cancer) 16.52
SF-268 (CNS tumor) 35.13
10f
63.58
6.06–107.37
OVCAR-4 (Ovarian cancer) 32.69
T-47D (Breast cancer) 39.03
cancer cells (GP, %) compared to control [21–24]. The
resulting data are listed in the Table 1.
2-hydroxybenzonitrile or 4,6-dimethyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile, that occurred as tandem
heterocyclizations, allowed us to prepare previously un-
known 2-aryl-3-methylbenzofuro[3,2-b]pyrazolo[4,3-e]-
azepine-4,11(2H,10H)-diones and 2-aryl-3,7,9-trime-
thylpyrido[3',2':4,5]thieno[3,2-b]pyrazolo[4,3-e]azepine-
4,11(2H,10H)-diones. The synthesized compounds were
screened for anticancer activity and exhibited moderate
anticancer effect.
The synthesized compounds exhibited moderate an-
ticancer activity. Among compounds 7a–7f, the highest
activity was found in compounds 7a and 7f (mean GP
values 76.16 and 71.94%, respectively). The OVCAR-4
ovarian cancer cell line proved to be the most sensitive to
these compounds.Among derivatives 10a–10f, the high-
est activity was found in compound 10f with respect to
HOP-62 and NCI-H226 non-small cell lung cancer cell
lines. It was noted that the MeO group in the test com-
pounds had a positive effect of their anticancer activity.
EXPERIMENTAL
1
The H NMR spectra of DMSO-d6 solutions were
measured on a Varian Mercury VX-400 spectrometer
(400 MHz), internal reference TMS. Elemental analysis
Thus, the reactions of bromoketones 2a–2f with
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CHABAN et al.
Ethyl 4-(bromoacetyl)-1-(4-bromophenyl)-5-me-
was performed on an Elementar Vario L cube analyzer.
The melting points were measured in open capillaries on
a Büchi B-545 apparatus.
thyl-1H-pyrazole-3-carboxylate (2e). Yield 77%, mp
1
149–150°C. H NMR spectrum, δ, ppm: 1.44 t (3H,
CH3CH2, J 7.2 Hz), 2.43 s (3H, CH3), 4.47 q (2H,
Synthesis of 4-(bromoacetyl)-5-methyl-1-aryl-1H-
pyrazole-3-carboxylates 2a–2f (general procedure).
Three drops of conc. H2SO4 were added to a solution
of 0.03 mol of acetylpyrazole 1a–1f in 80 mL of glacial
acetic acid. A solution of 1.55 mL (0.03 mol) of bromine
in 20 mL of acetic acid was then added dropwise to the
resulting solution. The mixture was stirred for an addi-
tional 5 h and then poured into 300 mL of water. In the
case of compound 2a, the reaction mixture was diluted
with 300 mL of water and extracted with methylene
chloride (3 × 300 mL). The organic layer was washed in
succession with water and K2CO3 and NaCl solutions,
dried, concentrated, and purified by column chromatog-
raphy (eluent hexane–ethyl acetate, 8 : 1). In the case of
compounds 2b–2f, the precipitate that formed, dried, and
recrystallized from ethanol.
CH3CH2O, J 7.2 Hz), 4.58 s (2H, CH2Br), 7.33 d (2Harom
,
J 8.4 Hz), 7.67 d (2Harom, J 8.4 Hz). Found, %: C 41.82;
H 3.31; N 6.53. C15H14Br2N2O3. Calculated, %: C 41.89;
H 3.28; N 6.51.
Ethyl 4-(bromoacetyl)-5-methyl-1-(4-methoxy-
phenyl)-1H-pyrazole-3-carboxylate (2f). Yield 85%,
1
mp 81–82°C. H NMR spectrum, δ, ppm: 1.43 t (3H,
CH3CH2, J 7.1 Hz), 2.39 s (3H, CH3), 3.87 s (3H, CH3O),
4.46 q (2H, CH3CH2O, J 7.1 Hz), 4.60 s (2H, CH2Br),
7.00 d (2Harom, J 8.8 Hz), 7.34 d (2Harom, J 8.8 Hz).
Found, %: C 50.57; H 4.41; N 7.28. C16H17BrN2O4. Cal-
culated, %: C 50.41; H 4.49; N 7.35.
Synthesis of 2-aryl-3-methylbenzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones and
2-aryl-3,7,9-trimethylpyrido[3',2':4,5]thieno[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-diones. Ethyl
4-(bromoacetyl)-5-methyl-1-aryl-1H-pyrazole-3-car-
boxylate 2a–2f (0.001 mol) and 207 mg (0.0015 mol) of
K2CO3 were added to a mixture of 119 mg (0.001 mol)
of 2-hydroxybenzonitrile (3) or 164 mg (0.001 mol) of
4,6-dimethyl-2-thioxo-1,2-dihydripyridine-3-carbonitrile
(4) in 10 mL of anhydrous acetonitrile. The mixture was
refluxed for 4 h, cooled, and diluted with 20 mL of water.
The precipitate that formed and recrystallized from DMF.
Ethyl 4-(bromoacetyl)-5-methyl-1-phenyl-1H-
pyrazole-3-carboxylate (2a). Yield 82%, mp 65–66°C.
1H NMR spectrum, δ, ppm: 1.43 t (3H, CH2CH3, J
7.1 Hz), 2.43 s (3H, CH3), 4.47 q (2H, CH2CH3, J
7.1 Hz), 4.60 s (2H, CH2Br), 7.41–7.56 m (5Harom).
Found, %: C 51.18; H 4.39; N 7.84. C15H15BrN2O3.
Calculated, %: C 51.30; H 4.31; N 7.98.
Ethyl 4-(bromoacetyl)-5-methyl-1-(3-chloro-
phenyl)-1H-pyrazole-3-carboxylate (2b). Yield 93%,
1
mp 104–105°C. H NMR spectrum, δ, ppm: 1.39 t
3-Methyl-2-phenyl-benzofuro[3,2-b]pyrazolo[4,3-
e]azepine-4,11(2H,10H)-dione (7a). Yield 87%, mp >
(3H, CH3CH2, J 7.2 Hz), 2.43 s (3H, CH3), 4.38 q
(2H, CH3CH2O, J 7.2 Hz), 4.60 s (2H, CH2Br), 7.53–
7.69 m (4Harom). Found, %: C 46.80; H 3.78; N 7.04.
C15H14BrClN2O3. Calculated, %: C 46.72; H 3.66; N 7.26.
1
300°C. H NMR spectrum, δ, ppm: 2.74 s (3H, CH3),
7.42 t (1Harom, J 7.4 Hz), 7.60–7.70 m (6Harom), 7.72 d
(1Harom, J 8.3 Hz), 8.50 d (1Harom, J 8.0 Hz), 11.91 s (1H,
NH). Found, %: C 69.83; H 3.94; N 12.11. C20H13N3O3.
Calculated, %: C 69.97; H 3.82; N 12.24.
Ethyl 4-(bromoacetyl)-5-methyl-1-(4-chloro-
phenyl)-1H-pyrazole-3-carboxylate (2c). Yield 95%,
1
mp 138–139°C. H NMR spectrum, δ, ppm: 1.38 t
3-Methyl-2-(3-chlorophenyl)benzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione (7b). Yield
73%, mp > 300°C. 1H NMR spectrum, δ, ppm: 2.74 s (3H,
CH3), 7.41 t (1Harom, J 7.2 Hz), 7.56–7.76 m (5Harom),
7.83 s (1Harom), 8.48 d (1Harom, J 7.2 Hz), 11.91 s (1H,
NH). Found, %: C 63.42; H 3.31; N 11.25. C20H12ClN3O3.
Calculated, %: C 63.59; H 3.20; N 11.12.
(3H, CH3CH2, J 7.2 Hz), 2.41 s (3H, CH3), 4.38 q
(2H, CH3CH2O), 4.60 s (2H, CH2Br), 7.60 s (4Harom).
Found, %: C 46.43; H 3.74; N 7.40. C15H14BrClN2O3.
Calculated, %: C 46.72; H 3.66; N 7.26.
Ethyl 4-(bromoacetyl)-1-(2,4-dichlorophenyl)-
5-methyl-1H-pyrazole-3-carboxylate (2d). Yield 77%,
1
mp 77–78°C. H NMR spectrum, δ, ppm: 1.43 t (3H,
3-Methyl-2-(4-chlorophenyl)benzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione (7c). Yield
CH3CH2, J 7.2 Hz), 2.22 s (3H, CH3), 4.40 s (2H, CH2Br),
4.45 q (2H, CH3CH2O, J 7.2 Hz), 7.12–7.48 m (3Harom).
Found, %: C 42.72; H 3.24; N 6.54. C15H13BrCl2N2O3.
Calculated, %: C 42.89; H 3.12; N 6.67.
1
76%, mp > 300°C. H NMR spectrum, δ, ppm: 2.73 s
(3H, CH3), 7.42 t (1Harom, J 8.0 Hz), 7.64 t (1Harom, J
8.0 Hz), 7.71 d (1Harom, J 8.0 Hz), 7.72 s (4Harom), 8.50 d
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SYNTHESIS AND ANTICANCER ACTIVITY
817
(1Harom, J 8.0 Hz), 11.92 s (1H, NH). Found, %: C 63.81;
H 3.08; N 11.23. C20H12ClN3O3. Calculated, %: C 63.59;
H 3.20; N 11.12.
4,11(2H,10H)-dione (10c). Yield 80%, mp > 300°C. 1H
NMR spectrum, δ, ppm: 2.08 s (3H, CH3), 2.71 s (3H,
CH3), 2.97 s (3H, CH3), 7.16 s (1H, Py), 7.72 s (4Harom).
Found, %: C 59.43; H 3.67; N 13.38. C21H15ClN4O2S.
Calculated, %: C 59.64; H 3.58; N 13.25.
2-(2,4-Dichlorophenyl)-3-methylbenzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione (7d). Yield
1
78%, mp > 300°C. H NMR spectrum, δ, ppm: 2.57 s
2-(2,4-Dichlorophenyl)-3,7,9-trimethylpyrido-
[3',2':4,5]thieno[3,2-b]pyrazolo[4,3-e]azepine-
4,11(2H,10H)-dione (10d). Yield 74%, mp > 300°C. 1H
NMR spectrum, δ, ppm: 2.48 s (3H, CH3), 2.52 s (3H,
CH3), 2.97 s (3H, CH3), 6.93 s (1H, Py), 7.68–7.76 m
(2Harom), 8.01 d (1Harom, J 2.1 Hz). Found, %: C 55.41;
H 2.97; N 12.39. C21H14Cl4N4O2S. Calculated, %:
C 55.15; H 3.09; N 12.25.
(3H, CH3), 7.43 t (1Harom, J 7.9 Hz), 7.65 t (1Harom, J
7.9 Hz), 7.71 d (1Harom, J 7.9 Hz), 7.76 d.d (1Harom, J
8.6, 2.1 Hz), 7.81 d (1Harom, J 8.6 Hz), 8.08 d (1Harom, J
2.1 Hz), 8.51 d (1Harom, J 7.9 Hz), 11.96 s (1H, NH).
Found, %: C 58.02; H 2.43; N 10.25. C20H11Cl2N3O3.
Calculated, %: C 58.27; H 2.69; N 10.19.
2-(4-Bromophenyl)-3-methylbenzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione (7e). Yield
2-(4-Bromophenyl)-3,7,9-trimethylpyrido-
[3',2':4,5]thieno[3,2-b]pyrazolo[4,3-e]azepine-
4,11(2H,10H)-dione (10e). Yield 76%, mp > 300°C. 1H
NMR spectrum, δ, ppm: 2.08 s (3H, CH3), 2.71 s (3H,
1
81%, mp > 300°C. H NMR spectrum, δ, ppm: 2.74 s
(3H, CH3), 7.42 t (1Harom, J 8.0 Hz), 7.62 t (1Harom, J
8.0 Hz), 7.65 d (2Harom, J 8.4 Hz), 7.72 d (1Harom, J
8.0 Hz), 7.86 d (2Harom, J 8.4 Hz), 8.49 d (1Harom, J
8.0 Hz), 11.93 s (1H, NH). Found, %: C 56.65; H 2.98;
N 10.12. C20H12BrN3O3. Calculated, %: C 56.89; H 2.86;
N 9.95.
CH3), 2.97 s (3H, CH3), 7.23 s (1H, Py), 7.65 d (2Harom
,
J 8.8 Hz), 7.86 d (2Harom, J 8.8 Hz), 10.03 s (1H, NH).
Found, %: C 53.86; H 3.08; N 12.14. C21H15BrN4O2S.
Calculated, %: C 53.97; H 3.24; N 11.99.
3-Methyl-2-(4-methoxyphenyl)benzofuro[3,2-b]-
pyrazolo[4,3-e]azepine-4,11(2H,10H)-dione (7f). Yield
86%, mp > 300°C. H NMR spectrum, δ, ppm: 2.70 s
(3H, CH3), 3.87 s (3H, CH3O), 7.17 d (2Harom, J 8.8 Hz),
7.42 t (1Harom, J 7.8 Hz), 7.58 d (2Harom, J 8.8 Hz), 7.63 t
(1Harom, J 7.8 Hz), 7.71 d (1Harom, J 7.8 Hz), 8.50 d
(1Harom, J 7.8 Hz), 11.89 s (1H, NH). Found, %: C 67.33;
H 4.18; N 11.04. C21H15N3O4. Calculated, %: C 67.56;
H 4.05; N 11.25.
2-(4-Methoxyphenyl)-3,7,9-trimethylpyrido-
[3',2':4,5]thieno[3,2-b]pyrazolo[4,3-e]azepine-
4,11(2H,10H)-dione (10f). Yield 82%, mp > 300°C.
1H NMR spectrum, δ, ppm: 2.56 s (3H, CH3), 2.66 s
(3H, CH3), 2.97 s (3H, CH3), 3.87 s (3H, OCH3), 7.17 d
(2Harom, J 9.0 Hz), 7.24 s (1H, Py), 7.58 d (2Harom, J
9.0 Hz), 9.96 s (1H, NH). Found, %: C 63.32; H 4.20;
N 13.31. C22H18N4O3S. Calculated, %: C 63.14; H 4.34;
N 13.39.
1
3,7,9-Trimethyl-2-phenylpyrido[3',2':4,5]-
thieno[3,2-b]pyrazolo[4,3-e]azepine-4,11(2H,10H)-
dione (10a). Yield 79%, mp > 300°C. 1H NMR spectrum,
δ, ppm: 2.56 s (3H, CH3), 2.70 s (3H, CH3), 2.97 s (3H,
CH3), 7.21 s (1H, Py), 7.52–7.55 m (5Harom), 10.00 s (1H,
NH). Found, %: C 64.71; H 4.08; N 14.28. C21H16N4O2S.
Calculated, %: C 64.93; H 4.15; N 14.42.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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