Efficient Synthesis of New Benzofuran-based Thiazoles and Investigation of their Cytotoxic Activity Against Human Breast Carcinoma Cell Lines

Article abstract of DOI:10.1002/jhet.3131

A new series of 1,3-thiazole-benzofuran derivatives was synthesized via heterocyclization of 2-(1-(6-alkoxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)-2-methyl-2l4-diazane-1-carbothioamides with hydrazonoyl halides. Also, 1-(4,7-dimethoxybenzofuran-5-yl)-3-

Full text of DOI:10.1002/jhet.3131

Month 2018 Efficient Synthesis of New Benzofuran-based Thiazoles and Investigation
of their Cytotoxic Activity Against Human Breast Carcinoma Cell Lines
a
Abdou O. Abdelhamid,a Nadia A. Abdelrehem,a and Sahar M. Kandeelb
*
Sobhi M. Gomha,
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
bDepartment of Natural Compounds, National Research Center, Dokki, Cairo, Egypt
*
E-mail: s.m.gomha@gmail.com
Received October 30, 2017
DOI 10.1002/jhet.3131
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new series of 1,3-thiazole-benzofuran derivatives was synthesized via heterocyclization of 2-(1-(6-alk-
oxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)-2-methyl-2l4-diazane-1-carbothioamides with hydrazonoyl
halides. Also, 1-(4,7-dimethoxybenzofuran-5-yl)-3-phenylprop-2-en-1-one derivatives were used for synthe-
sis of another series of 1,3-thiazole-pyrazole-benzofuran. The structure of the newly synthesized products
was elucidated via elemental analysis, spectral data, and alternative routes whenever possible. Seven new
compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell
lines compared with doxorubicin drug. The results revealed that some new compounds showed promising
anticancer activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antifeedant activities [9]. In order to explore diverse
biological activities, investigating various methods for
synthesis and structural modification of benzofuran ring
have now become important goal of several research
groups. Thus, benzofuran moiety can be taken as lead
compound for the synthesis of novel derivatives with a
variety of biological activities. Recently, benzofurans
have been identified to exhibit potent cytotoxic activities
against human breast cancer cells and ovarian cancer cells
[10,11]. Wan et al. [12] prepared a series of novel
benzofuran derivatives and evaluated in vitro against a
panel of human tumor cell lines. It was found that the
existence of 2-methylimidazole or 2-ethylimidazole ring
and substitution of the imidazolyl-3-position with a
naphthylacyl or methoxyphenacyl group were essential
for modulating cytotoxic activity. Hranjec et al. [13]
prepared a series of novel heteroaromatic benzofuran-2-
carboxamide derivatives. It was observed that
replacement of benzo[b]thiophene with benzo[b]furan
seems to be detrimental for the antitumor activity (I–IV)
(Fig. 1). Thiazole derivatives are reported to exhibit
diverse biological activities as antimicrobial, antioxidant,
antitubercular, and anticonvulsant, anticonvulsant,
anticancer, and anti-inflammatory agents [14–22]. Many
reports indicated that 1,3-thiazole derivatives exhibited
potential anticancer activity against various cancer types
Cancer is a disease characterized by the uncontrolled
growth of abnormal cells. It is now documented that the
most cytotoxic anticancer agents induce apoptosis which
is the programmed cell death. The identification of novel,
more potent, selective and less toxic antitumor agents is
the most important aim for the researchers because of its
widespread, rapid development and the severe infection
of the tumor diseases. Various natural and synthetic
benzofuran derivatives are found to possess diverse
applications in the field of medicine. Benzofuran
derivatives display potent biological properties including
analgesic, antiparasitic, antihyperglycemic, antimicrobial,
antitumor, and kinase inhibitor activities [1–5]. In
addition, substituted benzofurans find application such as
of fluorescent sensor [6], oxidant [7], antioxidants,
brightening agents, a variety of drugs, and in other field
of chemistry and agriculture [8]. Moreover, many of the
natural benzofurans have physiological, pharmacological,
and toxic properties. The most recognized benzofurans
are ailanthoidol, amiodarone, and bufuralol compounds.
Ailanthoidol,
a neolignan with a 2-arylbenzofuran
skeleton, has been reported to possess a variety of
biological activities such as anticancer, antiviral,
immunosuppressive,
antioxidant,
antifungal,
and
© 2018 Wiley Periodicals, Inc.

S. M. Gomha, A. O. Abdelhamid, N. A. Abdelrehem, and S. M. Kandeel
Vol 000
Figure 1. Reported benzofuran and 1,3,4-thiadiazole derivatives as antitumor agents.
(V–VIII) (Fig. 1) [23–27]. In the light of the
aforementioned findings and in continuation of our efforts
to synthesize new antitumor compounds [28–37], this
work aims to the synthesis of a new series of 1,3-
thiazole-benzofuran and 1,3-thiazole-pyrazole-benzofuran,
which is expected to be active as antitumor agents.
Treatment of 1-(6-hydroxy-4,7-dimethoxybenzofuran-5-
yl)-3-phenylprop-2-en-1-one (11a) [40] and 3-phenyl-
1-(4,6,7-trimethoxybenzofuran-5-yl)prop-2-en-1-one (11b)
[40] with thiosemicarbazide gave 3-(6-hydroxy-4,7-
dimethoxybenzofuran-5-yl)-5-phenyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (12a) and 5-phenyl-3-(4,6,
7-trimethoxybenzofuran-5-yl)-4,5-dihydro-1H-pyrazole-
1-carbothioamide (12b), respectively (Scheme 2).
Structures 12 were confirmed via elemental analysis,
spectral data, and chemical transformation. Thus,
RESULTS AND DISCUSSION
compound
12a
was
reacted
with
2-oxo-N-
Chemistry.
Interaction
of
1-(6-hydroxy-4,7-
phenylpropanehydrazonoyl chloride (4a) in ethanolic
triethylamine afforded 4,7-dimethoxy-5-(1-(4-methyl-5-
(phenyldiazenyl)thiazol-2-yl)-5-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)benzofuran-6-ol 13a.
Analogously, 12a was reacted with the appropriate
hydrazonoyl chloride 4b and 4c gave 5-(1-(5-
(aryldiazenyl)-4-methylthiazol-2-yl)-5-phenyl-4,5-dihydro-
1H-pyrazol-3-yl)-4,7-dimethoxybenzofuran-6-ols 13b,c,
respectively. Structures 13a-c were elucidated by
elemental analysis and spectral data. Moreover, 4,7-
dimethoxy-5-(1-(4-methylthiazol-2-yl)-5-phenyl-4,5-dihydro-
1H-pyrazol-3-yl)benzofuran-6-ol (14) was prepared by
reaction of 12a with ω-bromoacetophenone.
dimethoxybenzofuran-5-yl)ethan-1-one (1a) [38] and
1-(4,6,7-trimethoxybenzofuran-5-yl)ethan-1-one (1b) [38]
with thiosemicarbazide (2) ethanol gave 2-(1-(6-hydroxy-4,
7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbo-
thioamide (3a) [39] and 2-(1-(4,6,7-trimethoxybenzofuran-
5-yl)ethylidene)hydrazine-1-carbothioamide (3b), respectively
(Scheme 1). Structures 3a and 3b were confirmed by
elemental analysis, spectral data, and chemical
transformation. Compound 3 was proven to be a versatile
material for the synthesis of some novel substituted
thiazole derivatives. Thus, cyclization thioamides 3a and
3b with the appropriate hydrazonoyl halides 4a–d in
ethanolic triethylamine afforded 5-((E)-1-(2-(5-((E)-
aryldiazenyl)-4-substituted thiazol-2-yl)hydrazono)ethyl)-4,
Biological screening (cytotoxic activity).
The in vitro
7-dimethoxybenzofuran-6-ols
aryldiazenyl)-4-substituted-2-(2-((E)-1-(4,6,7-trimethoxyben-
6a–d
and
5-((E)-
growth inhibitory rates (%) and inhibitory growth activity
(as measured by IC50) of the newly synthesized
compounds were determined against the MCF-7 human
breast carcinoma cell line in comparison with the well-
known anticancer drug doxorubicin as the standard, using
the MTT viability assay. Data generated were used to
plot a dose–response curve of which the concentration
(μM) of test compounds required to kill 50% of cell
population (IC50) was determined. Cytotoxic activity was
expressed as the mean IC50 of three independent
experiments. The difference between inhibitory activities
of all compounds with different concentrations was
statistically significant P < 0.001.
zofuran-5-yl)ethylidene)
respectively (Scheme 1).
hydrazinyl)thiazole
6e–h,
Compounds 6a–h were established according to
elemental analysis, spectral data, and alternative
synthetic route. Compound 3a was reacted with ω-
bromoacetophenone in ethanol afforded 4,7-dimethoxy-
5-(1-(2-(4-phenylthiazol-2-yl)hydrazono)ethyl)benzofuran-6-ol
(8a) in a good yield. Compound 8a was coupled with 4-
methylbenzenediazonium chloride in pyridine at 0–5°C
gave product identical in all aspects (mp, mixed mp, and
spectra) with 6d.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis of New Benzofuran-based Thiazoles and Investigation of their
Cytotoxic Activity Against Human Breast Carcinoma Cell Lines
Scheme 1. Synthesis of thiazoles 6a–h. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. Synthesis of thiazoles 13a–c and 14.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. Gomha, A. O. Abdelhamid, N. A. Abdelrehem, and S. M. Kandeel
Vol 000
Table 1
CONCLUSIONS
The antitumor activities of the tested compounds 6a–g against MCF-7.
In the present paper, a series of 1,3-thiazole-benzofuran
and 1,3-thiazole-pyrazole-benzofuran derivatives were
synthesized. The structure of the newly synthesized
products was elucidated via elemental analysis, spectral
data, and alternative routes whenever possible. Some of
the new compounds were tested in vitro against the
human breast carcinoma (MCF-7) cell lines compared
with doxorubicin as the standard, using the MTT viability
assay. Most of the tested compounds were found to have
moderate to high anticancer activity.
Compound No.
R
R`
X
IC50 (μM)
6a
6b
6c
6d
6e
6f
6g
H
H
H
Me
Me
Me
Ph
Me
Me
Me
—
H
Me
Cl
Me
H
Me
Cl
—
6.49 1.42
1.35 1.13
9.42 2.20
15.37 1.46
3.71 1.33
0.69 1.10
19.05 1.84
0.44 1.07
H
Me
Me
Me
—
EXPERIMENTAL
Doxorubicin
Melting points were measured on an Electrothermal IA
9000 series digital melting point apparatus. IR spectra
were recorded in potassium bromide discs on Pye
Unicam SP 3300 and Shimadzu FTIR 8101 PC infrared
The results revealed that the tested compounds showed
high variation in the inhibitory growth rates and activities
against the tested tumor cell lines in a concentration
dependent manner compared with the reference drug as
shown in Table 1.
The descending order of activity of the newly synthesized
compoundswasasfollows:6f>6b>6e>6a>6c>6d>6g.
Examination of the compound activities leads to the
following conclusions (Fig. 2):
1
spectrophotometers. The H and 13C NMR spectra were
recorded on
a Varian 6 Mercury VX-300 NMR
1
spectrometer (Karlsruhe, Germany). H NMR (300 MHz)
and 13C NMR (75 MHz) were run in DMSO-d6, and chem-
ical shifts are expressed in ppm units using TMS as an in-
ternal reference. Mass spectra were recorded on a
Shimadzu GCMS-QP1000 EX mass spectrometer at
70 eV. Elemental analyses were measured by using a Ger-
man made Elementar vario LIII CHNS analyzer. Antitumor
activity was evaluated at the Regional Center for Mycol-
ogy and Biotechnology at Al-Azhar University, Cairo,
Egypt.
• The activities of the synthesized compounds depend on
structural skeleton and electronic environment of the
molecules.
• The introduction of electron-donating group (methyl) at
C4 of the phenyl group at position 5 in the 1,3-thiazole
ring enhances the antitumor activity. In contrast, intro-
duction of an electron-withdrawing group (chlorine) de-
creases the antitumor activity (6b > 6a > 6c).
• The in vitro inhibitory activity of the 6-methoxybenzofuran
>6-hydroxybenzofuran (6e > 6a, 6f > 6b and 6g > 6c).
This may be due to the +I effect of the methyl group (in-
crease activity).
Chemistry. Synthesis of 2-(1-(4,7-dimethoxybenzofuran-5-
yl)ethylidene)hydrazine-1-carbothioamides
(3a,b).
A
catalytic amounts of concentrated hydrochloric acid was
added to a mixture of 1-(4,7-dimethoxybenzofuran-5-yl)
ethan-1-ones (1a,b) (10 mmol) and thiosemicarbazide 2
(0.91 g, 10 mmol) in 50 mL of ethanol. The solution was
refluxed for 4 h (monitored by TLC). The precipitate
which formed after cooling was filtered, washed with
ethanol, and recrystallized from dioxane to give The solid
product was filtered off and recrystallized from ethanol to
• The in vitro inhibitory activity of the 4-methylthiazole >4-
phenylthiazole (6b > 6d). This may be due to the +I effect
of the methyl group (increase activity).
afford the respective products 3a,b.
2-(1-(4,6,7-Trimetho-xybenzofuran-5-yl)ethylidene)
hydrazine-1-carbothioamide (3b). Beige solid, 65% yield,
mp 186–188°C; IR (KBr) ν cmÀ1: 3398–3273 (NH2 and
NH), 3159, 2941, 2841 (C─H), 1595 (C═N), 1482,
1
1066; H NMR (DMSO-d6) δ: 2.20 (s, 3H, CH3), 3.80
(s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 7.12 (d, 1H, Furan-H3), 7.63 (s,br, 2H, NH2),
7.96 (d, 1H, Furan-H2), 10.17 (br s, 1H, NH); 13C
NMR (75 MHz, DMSO-d6): δ = 19.72 (CH3), 61.21,
61.30, 62.21 (OCH3), 105.54, 117.48, 122.29, 134.71,
145.28, 145.95, 146.03, 147.26, 147.86 (Ar─C),
Figure 2. Activities of tested compounds against the MCF-7 breast can-
cer cell line. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis of New Benzofuran-based Thiazoles and Investigation of their
Cytotoxic Activity Against Human Breast Carcinoma Cell Lines
180.04 (C═S); MS m/z (%): 323 (M+, 74), 278 (38),
233 (100), 217 (51), 60 (14). Anal. Calcd for
C14H17N3O4S (323.37): C, 52.00; H, 5.30; N, 12.99;
found: C, 51.85; H, 5.13; N, 12.75%.
146.25, 147.13, 148.83, 166.94, 167.41 (Ar-C); MS m/z
(%): 487 (M++2, 22), 485 (M+, 72), 454 (100), 300 (19),
218 (17), 111 (26), 55 (35). Anal. Calcd for
C22H20ClN5O4S (485.94): C, 54.38; H, 4.15; N, 14.41;
found: C, 54.46; H, 4.03; N, 14.27%.
Synthesis of 1,3-thiazols 6a–h. General procedure. To
a mixture of thiosemicarbazones 3a,b (1 mmol) and the
appropriate hydrazonoyl halides 4a–d (1 mmol) in
dioxane (20 mL), TEA (0.07 mL) was added and the
obtained solution was refluxed for 6 h, allowed to cool
and the solid formed was filtered off, washed with EtOH,
dried and recrystallized from the proper solvent to give
the corresponding products 6a–h. The products 6a–h
together with their physical constants are listed in the
following.
4,7-Dimethoxy-5-(1-(2-(4-phenyl-5-(p-tolyldiazenyl)thiazol-
2-yl)hydrazono)ethyl)benzofuran-6-ol (6d).
Orange solid,
75% yield, mp 226–228°C (DMF); IR (KBr) ν cmÀ1
:
3443–3236 (NH and OH), 3153, 2928, 2840 (C─H),
1
1617 (C═N), 1478, 1063; H NMR (DMSO-d6) δ: 2.32
(s, 3H, CH3), 2.62 (s, 3H, CH3), 3.81 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 7.02–8.09 (m, 11H, Ar─H), 10.63,
11.28 (s,br.,2H, NH and OH); MS m/z (%): 527 (M+, 44),
496 (100), 468 (29), 293 (14), 218 (24), 91 (66). Anal.
Calcd for C28H25N5O4S (527.60): C, 63.74; H, 4.78; N,
13.27; found: C, 63.66; H, 4.59; N, 13.14%.
4,7-Dimethoxy-5-(1-(2-(4-methyl-5-(phenyldiazenyl)
thiazol-2-yl)hydrazono)ethyl)benzofuran-6-ol (6a). Brown
4-Methyl-5-(phenyldiazenyl)-2-(2-(1-(4,6,7-
solid, 70% yield, mp 221–223°C (EtOH); IR (KBr) ν
trimethoxybenzofuran-5-yl)ethylidene)
hydrazinyl)thiazole
cmÀ1: 3428–3288 (NH and OH), 2935, 2841 (C─H),
(6e). Brown solid, 70% yield, mp 132–135°C (EtOH);
1
1603 (C═N), 1482, 1060; H NMR (DMSO-d6) δ: 2.33
IR (KBr) ν cmÀ1: 3435 (NH), 2935, 2841 (C─H), 1604
(s, 3H, CH3), 2.51 (s, 3H, CH3), 3.85 (s, 3H, OCH3),
3.92 (s, 3H, OCH3), 6.98–8.02 (m, 7H, Ar─H), 9.14,
10.26 (s,br., 2H, NH and OH); 13C NMR (75 MHz,
DMSO-d6): δ = 19.72 (CH3), 61.21, 62.21 (OCH3),
105.54, 117.48, 122.29, 134.71, 145.28, 145.95, 146.03,
147.26, 147.86 (Ar─C), 180.04 (C═S); MS m/z (%): 451
(M+, 38), 420 (100), 300 (26), 218 (26), 204 (30), 105
(23), 77 (69). Anal. Calcd for C22H21N5O4S (451.50): C,
58.53; H, 4.69; N, 15.51; found: C, 58.44; H, 4.60; N,
15.39%.
1
(C═N), 1490, 1062; H NMR (DMSO-d6) δ: 2.31 (s, 3H,
CH3), 2.59 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.85 (s,
3H, OCH3), 3.96 (s, 3H, OCH3), 6.96 (d, 1H, Furan-H3),
7.14 (m, 1H, Ar─H), 7.30–7.36 (m, 4H, Ar─H),7.99 (d,
1H, Furan-H2), 10.45 (s,br., 1H, NH); MS m/z (%): 465
(M+, 31), 434 (100), 248 (33), 233 (47), 218 (22), 105
(18), 77 (61). Anal. Calcd for C23H23N5O4S (465.53): C,
59.34; H, 4.98; N, 15.04; found: C, 59.47; H, 4.91; N,
14.88%.
4-Methyl-5-(p-tolyldiazenyl)-2-(2-(1-(4,6,7-
trimethoxybenzofuran-5-yl)ethylidene)hydrazinyl)thiazole
(6f). Brown solid, 72% yield, mp 110–112°C (Dioxane);
4,7-Dimethoxy-5-(1-(2-(4-methyl-5-(p-tolyldiazenyl)thiazol-
2-yl)hydrazono)ethyl)benzofuran-6-ol (6b).
Yellow solid,
72% yield, mp 229–231°C (Dioxane); IR (KBr) ν cmÀ1
:
IR (KBr) ν cmÀ1: 3437 (NH), 3150, 2927, 2849 (C─H),
1
3417–3235 (NH and OH), 3156, 2921, 2845 (C─H),
1611 (C═N), 1473, 1062; H NMR (DMSO-d6) δ: 2.24
1
1615 (C═N), 1480, 1063; H NMR (DMSO-d6) δ: 2.25
(s, 3H, CH3), 2.35 (s, 3H, CH3), 2.57 (s, 3H, CH3),
3.73 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.00 (s, 3H,
OCH3), 7.12–7.25 (m, 5H, Furan-H3 and Ar─H), 7.98
(d, 1H, Furan-H2),10.39 (s,br.,1H, NH); MS m/z (%):
479 (M+, 39), 448 (100), 271 (16), 218 (18), 106
(14), 91 (30). Anal. Calcd for C24H25N5O4S (479.56):
C, 60.11; H, 5.25; N, 14.60; found: C, 60.00; H, 5.14;
(s, 3H, CH3), 2.29 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.83
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 7.06 (d, 1H, Furan-
H3), 7.11 (d, 2H, Ar─H), 7.22 (d, 2H, Ar─H),7.85 (d,
1H, Furan-H2), 9.11, 10.34 (s,br., 2H, NH and OH); MS
m/z (%): 465 (M+, 77), 434 (100), 300 (16), 218 (15),
106 (18), 91 (47). Anal. Calcd for C23H23N5O4S
(465.53): C, 59.34; H, 4.98; N, 15.04; found: C, 59.18;
H, 4.82; N, 15.01%.
N, 14.43%.
5-((4-Chlorophenyl)diazenyl)-4-methyl-2-(2-(1-(4,6,7-
trimethoxybenzofuran-5-yl)ethylidene)hydrazinyl)thiazole
(6g). Brown solid, 74% yield, mp 126–128°C (EtOH);
5-(1-(2-(5-((4-Chlorophenyl)diazenyl)-4-methylthiazol-2-yl)
hydrazono)ethyl)-4,7-dimethoxybenzofuran-6-ol
(6c).
Orange solid, 72% yield, mp 244–246°C (Dioxane); IR
(KBr) ν cmÀ1: 3432–3249 (NH and OH), 3153, 2929,
2840 (C─H), 1615 (C═N), 1482, 1067; 1H NMR
(DMSO-d6) δ: 2.46 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.94
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 7.10 (d, 1H, Furan-
H3), 7.36 (d, 2H, Ar─H), 7.62 (d, 2H, Ar─H),7.88 (d,
1H, Furan-H2), 10.14, 10.80 (s,br., 2H, NH and OH); 13C
NMR (75 MHz, DMSO-d6): δ = 16.91, 20.62 (CH3),
61.12, 61.47 (OCH3), 105.74, 112.70, 115.12, 116.22,
126.23, 129.10, 131.39, 132.24, 139.24, 142.91, 144.69,
IR (KBr) ν cmÀ1: 3440 (NH), 3151, 2937, 2849 (C─H),
1
1615 (C═N), 1488, 1069; H NMR (DMSO-d6) δ: 2.31
(s, 3H, CH3), 2.58 (s, 3H, CH3), 3.74 (s, 3H, OCH3),
3.83 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 7.14 (d, 1H,
Furan-H3), 7.30–7.35 (m, 4H, Ar─H), 8.00 (d, 1H,
Furan-H2),10.52 (s,br.,1H, NH); MS m/z (%): 501 (M++2,
21), 499 (M+, 60), 248 (100), 233 (98), 218 (42), 111
(42), 65 (31). Anal. Calcd for C23H22ClN5O4S (499.97):
C, 55.25; H, 4.44; N, 14.01; found: C, 55.14; H, 4.40; N,
13.93%.
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S. M. Gomha, A. O. Abdelhamid, N. A. Abdelrehem, and S. M. Kandeel
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4-Phenyl-5-(p-tolyldiazenyl)-2-(2-(1-(4,6,7-
3-(6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)-5-phenyl-4,5-
dihydro-1H-pyrazole-1-carbothioamide (12a).
trimethoxybenzofuran-5-yl)ethylidene)hydrazinyl)thiazole
(6h). Brown solid, 69% yield, mp 203–205°C (Dioxane);
Beige solid,
74% yield, mp 110–112°C (EtOH); IR (KBr) ν cmÀ1
:
IR (KBr) ν cmÀ1: 3432 (NH), 3151, 2932, 2840 (C─H),
3434–3240 (OH and NH2), 3060, 2938 (C─H), 1617
1
1
1612 (C═N), 1479, 1068; H NMR (DMSO-d6) δ: 2.26
(C═N), 1477, 1061; H NMR (CDCl3) δ: 3.17 (dd, 1H,
(s, 3H, CH3), 2.39 (s, 3H, CH3), 3.79 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 7.01–8.16 (m,
11H, Ar─H), 10.82 (s,br.,1H, NH); MS m/z (%): 541
(M+, 97), 510 (100), 480 (18), 332 (25), 248 (29), 218
(16), 91 (72). Anal. Calcd for C29H27N5O4S (541.63): C,
64.31; H, 5.02; N, 12.93; found: C, 64.16; H, 5.14; N,
HA, J = 17.6, 6.1 Hz), 3.94 (s, 3H, OCH3), 4.08 (s, 3H,
OCH3), 4.26 (dd, 1H, HB, J = 17.6, 12.2 Hz), 5.89 (dd,
1H, HX, J = 12.4, 6.1 Hz), 6.83 (d, 1H, Furan-H3), 7.24–
7.81 (m, 8H, Ar─H, and NH2), 11.26 (s,br., 1H, OH);
MS m/z (%): 397 (M+, 28), 347 (19), 228 (23), 169
(100), 77 (64). Anal. Calcd for C20H19N3O4S (397.45):
C, 60.34; H, 4.82; N, 10.57. Found: C, 60.28; H, 4.75;
12.75%.
Alternate synthesis of 6d. i) Synthesis of 4-phenyl-2-(2-(1-
(4,6,7-trimethoxybenzofuran-5-yl)ethylidene)hydrazinyl)thiazole
(8a). A mixture of 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-
N, 10.50%.
5-Phenyl-3-(4,6,7-trimethoxybenzofuran-5-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide (12b).
White solid, 68%
yield, mp 106–108°C (Dioxane); IR (KBr) ν cmÀ1: 3370,
3251 (NH2), 3153, 3026, 2975, 2836 (C─H), 1617
(C═N), 1477, 1061; MS m/z (%): 411 (M+, 100), 378
(73), 351 (53), 321 (20), 233 (24), 163 (23), 60 (38).
Anal. Calcd for C21H21N3O4S (411.48): C, 61.30; H,
5.14; N, 10.21. Found: C, 61.18; H, 5.03; N, 10.08%.
5-yl)ethylidene)hydrazine-1-carbothioamide (3a) (0.618 g,
2 mmol) and phenacyl bromide (7) (0.398 g, 2 mmol) in
absolute EtOH (30 mL) was refluxed for 4 h. The product
started to separate out during the course of reaction. The
crystalline solid was filtered, washed with water, dried,
and recrystallized from EtOH to give pure thiazole 8a as
pale yellow solid, 72% yield, mp 210–212°C (EtOH); IR
(KBr) ν cmÀ1: 3425, 3268 (NH and OH), 3152, 3121,
3073, 2979, 2937, 2838 (C─H), 1618 (C═N), 1481,
Synthesis of 5-(phenyldiazenyl)thiazol-2-yl)-5-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)benzofuran 13a–c. A mixture of
3-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)-5-phenyl-4,
5-dihydro-1H-pyrazole-1-carbothioamide (12a) (0.397 g,
1 mmol) and the appropriate hydrazonoyl chlorides 4a–c
(1 mmol) in dioxane (20 mL) containing TEA (0.5 mL)
was refluxed for 4 h (monitored by TLC), allowed to
cool, and the solid formed was filtered off, washed with
ethanol, dried, and recrystallized from the proper solvent
1
1063; H NMR (DMSO-d6) δ: 2.20 (s, 3H, CH3), 3.87 (s,
3H, OCH3), 3.91 (s, 3H, OCH3), 7.11–7.84 (m, 8H,
Ar─H), 9.23, 10.09 (s,br., 2H, NH and OH); MS m/z (%):
409 (M+, 435), 378 (100), 361 (65), 286 (34), 133 (29),
77 (25). Anal. Calcd for C21H19N3O4S (409.46): C,
61.60; H, 4.68; N, 10.26; found: C, 61.74; H, 4.58; N,
10.10%.
to give the respective thiazoles 13a–c.
4,7-Dimethoxy-5-(1-(4-methyl-5-(aryldiazenyl)thiazol-2-yl)-
5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzofuran-6-ol (13a).
ii) Coupling of thiazole 8a with p-toluene diazonium chloride
9. To a solution of thiazole 8a (0.409 g, 1 mmol) in
EtOH (20 mL) was added sodium acetate trihydrate
(0.138 g, 1 mmol), and the mixture was cooled to 0–5°C
in an ice bath. To the resulting cold solution was added
portionwise a cold solution of p-toluene diazonium
chloride (prepared by diazotizing p-toluidine (1 mmol)
dissolved in hydrochloric acid (6M, 1 mL) with a
solution of sodium nitrite (0.07 g, 1 mmol) in water
(2 mL). After complete addition of the diazonium salt,
the reaction mixture was stirred for a further 30 min in an
ice bath. The solid that separated was filtered off, washed
with water, and finally recrystallized from DMF to give a
product that proved identical in all respects (mp, mixed
mp, and IR spectra) with compound 6d obtained from
reaction of 3a with 4d.
Orange solid, 68% yield, mp 151–153°C (Dioxane); IR
(KBr) ν cmÀ1: 3434 (OH), 2995, 2937, 2849 (C─H),
1
1620 (C═N), 1288, 1059; H NMR (DMSO-d6) δ: 2.49
(s, 3H, CH3), 3.38 (dd, 1H, HA, J = 17.6, 6.1 Hz), 3.93
(s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.20 (dd, 1H, HB,
J = 17.6, 12.2 Hz), 5.82 (dd, 1H, HX, J = 12.4, 6.1 Hz),
7.14 (d, 1H, Furan-H3), 7.38–7.47(m, 8H, Ar─H), 7.66
(m, 2H, Ar─H), 7.91 (d, 1H, Furan-H2), 10.24 (s,br., 1H,
OH); MS m/z (%): 539 (M+, 100), 508 (27), 462 (27),
292 (17), 204 (140), 77 (68). Anal. Calcd for
C29H25N5O4S (539.61): C, 64.55; H, 4.67; N, 12.98;
found: C, 64.60; H, 4.52 N, 12.71%.
4,7-Dimethoxy-5-(1-(4-methyl-5-(p-tolyldiazenyl)thiazol-2-
yl)-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzofuran-6-ol
(13b). Orange solid, 68% yield, mp 139–141°C (EtOH);
Synthesis of 3-(substituted-benzofuran-5-yl)-5-phenyl-4,5-
dihydro-1H-yrazole-1-carbothioamides 12a,b.
A mixture
IR (KBr) ν cmÀ1: 3434 (OH), 2988, 2936, 2849 (C─H),
1611 (C═N), 1295, 1054; 1H NMR (DMSO-d6) δ: 2.34 (s,
3H, CH3), 2.48 (s, 3H, CH3), 3.41 (dd, 1H, HA, J = 17.6,
6.1 Hz), 3.93 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.18
(dd, 1H, HB, J = 17.6, 12.2 Hz), 5.80 (dd, 1H, HX,
J = 12.4, 6.1 Hz), 7.14 (d, 1H, Furan-H3), 7.25–7.39 (m,
7H, Ar─H), 7.56 (m, 2H, Ar─H), 7.90 (d, 1H, Furan-H2),
of chalcones 11a,b (10 mmol), thiosemicarbazide (0.92 g,
10 mmol), and sodium hydroxide (0.3 g) in ethanol
(20 mL) was heated under reflux for 6 h. The resulting
solid was collected, washed with ethanol, and
recrystallized from ethanol to give the products 12a and
12b, respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Efficient Synthesis of New Benzofuran-based Thiazoles and Investigation of their
Cytotoxic Activity Against Human Breast Carcinoma Cell Lines
10.29 (s,br.,1H, OH); MS m/z (%): 553 (M+, 100), 538 (23),
522 (18), 292 (19), 204 (18), 106 (17), 91 (40), 65 (42).
Anal. Calcd for C30H27N5O4S (553.64): C, 65.08; H, 4.92;
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N, 12.65; found: C, 65.19; H, 4.85; N, 12.44%.
5-(1-(5-((4-Chlorophenyl)diazenyl)-4-methylthiazol-2-yl)-5-
phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4,7-dimethoxybenzofuran-
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6-ol (13c).
Red solid, 69% yield, mp 166–168°C
(Dioxane); IR (KBr) ν cmÀ1: 3438 (OH), 2990, 2935
(C─H), 1619 (C═N), 1283, 1058; 1H NMR (DMSO-d6) δ:
2.49 (s, 3H, CH3), 3.43 (dd, 1H, HA, J = 17.6, 6.1 Hz),
3.93 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.23 (dd, 1H, HB,
J = 17.6, 12.2 Hz), 5.83 (dd, 1H, HX, J = 12.4, 6.1 Hz),
7.14 (d, 1H, Furan-H3), 7.36–7.47 (m, 7H, Ar─H), 7.66
(m, 2H, Ar─H), 7.91 (d, 1H, Furan-H2), 10.26 (s,br., 1H,
OH); MS m/z (%): 576 (M++2, 31), 574 (M+, 100), 508
(47), 522 (18), 404 (25), 292 (15), 204 (15), 112 (13), 77
(59). Anal. Calcd for C29H24ClN5O4S (574.05): C, 60.68;
H, 4.21; N, 12.20; found: C, 60.49; H, 4.05; N, 12.06%.
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Synthesis of 4,7-dimethoxy-5-(5-phenyl-1-(4-phenylthiazol-
2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzofuran-6-ol (14).
A
mixture of 3-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)-
5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide (12a)
(0.397 g, 1 mmol) and phenacyl bromide (7) (0.398 g,
1 mmol) in absolute EtOH (20 mL) was refluxed for 4 h.
The product started to separate out during the course of
reaction. The crystalline solid was filtered, washed with
water, dried, and recrystallized from ethanol to give pure
thiazole 14 as yellow crystals in 73% yield; mp 141–
143°C; IR (KBr) ν cmÀ1: 3438 (OH), 3155, 3056, 2948,
1
2931(C─H), 1616 (C═N), 1294, 1055; H NMR (DMSO-
d6) δ: 3.47 (dd, 1H, HA, J = 17.6, 6.1 Hz), 3.92 (s, 3H,
OCH3), 3.99 (s, 3H, OCH3), 4.09 (dd, 1H, HB, J = 17.6,
12.2 Hz), 5.59 (dd, 1H, HX, J = 12.4, 6.1 Hz), 7.15 (d,
1H, Furan-H3), 7.36–7.25–7.51 (m, 11H, Ar─H and
thiazole-H4), 7.89 (d, 1H, Furan-H2), 10.38 (br s, 1H,
OH); MS m/z (%): 497 (M+, 37), 308 (39), 220 (61),
190 (19), 105 (32), 77 (100). Anal. Calcd for
C28H23N3O4S (497.57): C, 67.59; H, 4.66; N, 8.45;
found: C, 67.46; H, 4.49; N, 8.27%.
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Anticancer activity.
The cytotoxic evaluation of the
synthesized compounds was carried out at the Regional
Center for Mycology and Biotechnology at Al-Azhar
University, Cairo, Egypt, according to the reported
method [41].
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet