A facile synthesis of 7,8-di aryl coumarino and flavano benzo-thiophenes

Article abstract of DOI:10.1080/10426500210246

The key step for the synthesis of 7-hydroxy 2,3-diarylsubstituted benzothiophenes 5a-f, by starting from substituted 2-aryl-2-((2-methoxy phenyl)thio)acetophenones 3a-f as an intermediate, consists of a Friedel-Crafts cyclization followed by demethylation by Lewis acids like BF₃OEt₂ and AlCl₃ in DCM.

Full text of DOI:10.1080/10426500210246

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Phosphorus, Sulfur, and Silicon and the Related
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A Facile Synthesis of 7,8-DI Aryl Coumarino and
Flavano Benzo-Thiophenes
G. V. P. Chandramouli a , B. Prasanna a , P. Naveen Kumar a & P. Vijayakumar Reddy a
a Department of Chemistry, Regional Engineering College, Warangal, 506 004, India
Version of record first published: 27 Oct 2010.
To cite this article: G. V. P. Chandramouli , B. Prasanna , P. Naveen Kumar & P. Vijayakumar Reddy (2002): A Facile Synthesis
of 7,8-DI Aryl Coumarino and Flavano Benzo-Thiophenes, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:2,
511-522
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Phosphorus, Sulfur and Silicon, 2002, 177:511–522
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Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
A FACILE SYNTHESIS OF 7,8-DI ARYL COUMARINO
AND FLAVANO BENZO-THIOPHENES
G. V. P. Chandramouli, B. Prasanna, P. Naveen Kumar,
and P. Vijayakumar Reddy
Department of Chemistry, Regional Engineering College,
Warangal 506 004, India
(Received April 10 2001.)
The key step for the synthesis of 7-hydroxy 2,3-diarylsubstituted ben-
zothiophenes 5a–f, by starting from substituted 2-aryl-2-((2-methoxy
phenyl)thio)acetophenones 3a–f as an intermediate, consists of a
Friedel-Crafts cyclization followed by demethylation by Lewis acids like
BF3OEt2 and AlCl3 in DCM.
Keywords: Benzopyranones; benzothiophenes; condensation; demethy-
lation; Friedel crafts cyclization
Substituted benzothiophenes are of interest in many pharmaceutical
areas. They exhibit a variety of biological properties such as anti-
allergic1 and occular hypotensive activities.2 In addition, they
also to serve as bioisosters of indoles.3 Recently Reloxifene (Ly
139481 HCl)4, a polysubstituted-2-aryl benzothiophene was ap-
proved for the prevention of osteoporosis in postmenopausal women.
Substituted Coumarino benzothiophenes were known to exhibit
antiinflammatory,5 analgesic,6 and antipyretic activities.7 There are
relatively few methods8,9 for the preparation of 3-aryl benzothio-
phenes reported in literature. In this communication, we report a
convenient procedure for the preparation of 7-hydroxy-2,3-diaryl
benzothiophenes 5a–f by condensation and demethylation of sub-
stituted 2-aryl-2-{{2-methoxyphenyl}thio}acetophenones 3a–f with
Lewis acids like borontrifloride-etherate and aluminium chloride at
room temperature.
Initially, we attempted the cyclization of 3a–f with alcoholic KOH
refluxed for 14–15 h which gave 7-methoxy-2,3-diarylbenzothiophenes
Address correspondence to G. V. P. Chandramouli, Department of Chemistry, Regional
Engineering College, Warangal 506 004, India.
Raloxifene was approved by the FDA in Jan. 1998, and is marketed as Evista by Eli
Lilley.
511

512
G. V. P. Chandramouli et al.
4a–f with low yield (20–25%). Then followed by demethylation by a
known procedure10 gave the corresponding compounds 5a–f with lower
yields. These compounds were later condensed with ethylacetoacetate
in the presence of polyposphoric acid11 to produce the corresponding
coumarino benzothiophenes 6a–f about 30% yield.
Finally, after some experimentation, we synthesised the compounds
5a–f and 6a–f by a convenient route by using a Lewis acid. The clo-
sure of the benzothiophene ring was accomplished by treatment of
3a–f with borontrifluoride-etherate (BF3OEt2) at room temperature,
which afforded 7-methoxy-2,3-diarylbenzothiophenes 4a–f in consid-
erable yield. By the reaction of 4a–f with aluminium chloride in the
presence of DCM at room temperature, demethylation12 took place pro-
ducing the corresponding 7-hydroxy2,3-diarylbenzothiophenes 5a–f in
acceptable to good yields when these compounds were condensed with
etylacetoacetate in the presence of AlCl3, in DCM at room temperature
the corresponding coumarino benzothiophenes 6a–f were obtained.
SCHEME 1
Substituted 7-hydroxybenzothiophenes 5a–f were acetylated with
acetyl chloride in the presence the of AlCl3 in dry DCM. The acyl
compounds 7a–f were later condensed with benzaldehyde in the pres-
ence of alcoholic KOH(40%) to give rise to the corresponding flavano
benzothiophenes 8a–f.

Benzothiophenes
513
SCHEME 2
In conclusion, a convergent procedure for the preparation of Phar-
macologically valuable 7,8-diarylcoumarinobenzothiophenes 6a–f via
a common intermediate 3a–f has been developed. These interme-
diates may also provide a synthetic entry to a variety of flavano
benzothiophenes 8a–f.
EXPERIMENTAL
All melting points were uncorrected. The elementary analysis was car-
ried out by CARLO ERBA STUMENTAZOINE, Itali Model 1108 and
IR spectra ( cm 1) were recorded on Perkin Elmer-282 instrument.
The 1H NMR spectra were recorded on a varian 200MHz spectrome-
ter using tetramethyl silane as internal standard. Chemical shift values
are expressed in ppm. Mass spectra were scanned on a Jeol-JMS-300
spectrometer at 70 eV. The purity of compound were monitered by TLC
performed on a silicagel plates (merck) using ethylacetate and pet.ether.
FIGURE 1 A facile synthesis of 7,8-di aryl coumarino and flavano benzo-
thiophenes.

514

515

516

517

518

519

520

Benzothiophenes
521
Substituted 2-aryl-2-((2-methoxy phenyl)thio)
Acetophenones 3a--f
To a suspension of anhydrous K2CO3 (13.8 g, 0.1 mol) in 100 ml of dry
acetone, a solution of 2-methoxy benzene thiol (0.01 mol) was added.
Later a solution of desyl bromide13,14 (0.01 mol) in 5 ml of dry acetone
was also added slowly. The resulting mixture was refluxed for 12–14 h,
cooled, poured into 100 ml ice water, and extracted with EtOAc. The
organic layer was washed with brine and dried over Na2SO4. The sol-
vent was removed in vacuo, and the resulting oil was purified by column
chromatography (EtOAc\pet.ether 1:9) to give 3a–f (50–60%).
Substituted 7-methoxy-2,3-diaryl Benzo(b)thiophenes
4a--f
15
A solution of 3a–f (0.01 mol) and BF3OEt2 (10 ml) was stirred at
room temperature under N2 atmosphere for 14–15 h. The resulting
mixture was poured into NaHCO3 stirred for 10 min, and extracted with
DCM. The organic layer was washed with brine (2 50 ml) and dried
over Na2SO4. The solvent was removed under vacuum. The residue was
purified by column chromatography (EtOAc\pet.ether 2:8) to result in
the formation of 4a–f (65–75%).
Substituted 7-Hydroxy-2,3-diaryl
Benzo(b)thiophenes 5a--f
A finely powdered anhydrous AlCl3(13.0 g, 0.1 mol) in 5 ml of dry DCM
was added at room temperature to a solution of 4a–f (0.01 mol) in 10 ml
of dry DCM under N2 atmosphere. The resulting mixture was stirred
at room temperature for 4–5 h, poured into 100 ml ice water, acidified,
and extracted with DCM. The organic layer was washed with brine
(2 50 ml) and dried over Na2SO4. The solvent was removed in vacuo,
and residue was 7-hydroxy-2,3-diaryl benzo(b)thiophenes 5a–f: puri-
fied by column chromatography (EtOAc\pet.ether 1:9) to give 5a–f
(55–65%).
7,8-Diaryl-4-methyl Coumarino Benzo(b)thiophenes
6a--f
A mixture of 5a–f (0.01 mol) and ethylacetoacetate (1.18 g, 0.01 mol) in
20 ml of dry DCM was added to a solution of anhydrous AlCl3 in 5 ml of
dry DCM, at room temperature under N2 atmosphere. The solution was
then stirred at room temperature for 6–8 h. This solution was acidified

522
G. V. P. Chandramouli et al.
and extracted with DCM. The organic layer was washed with brine
(2 15 ml) and dried over Na2SO4. The solution was concentrated
in vacuo and the compound was purified by Column chromatography
(EtOAc\pet.ether 1:9) to produce compounds 6a–f (52–60%).
7,8-Diaryl Flavano Benzo(b)thiophenes 8a--f
Compounds 4a–f (0.01 mol) were acylated with acetyl chloride in
the presence of AlCl3 in dry DCM to produce the corresponding
compounds 7a–f.
A mixture of 7a–f (0.01 mol) and benzaldehyde (0.01 mol) was taken
in a solution of ethanol and 40% KOH. The solution was stirred at
room temperature for 5 h, then left at room temperature. The result-
ing mixture was acidified with conc. H2SO4 and extracted with DCM
(2
50 ml). The solvent was concentrated in vacuo, the precipitate
was filtered, then purified by recrystallization from methanol to give
8a–f (56–61%).
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