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BENZOTHIOPHENES
Benzothiophene
Benzothiophene is an aromatic organic compound with a molecular formula C8H6S and an
odor similar to naphthalene (mothballs). It occurs naturally as a constituent of petroleum-
related deposits such as lignite tar. Benzothiophene has no household use. It is used primarily
in industry and research.
Being a heterocyclic compound, benzothiophene finds use in research as a starting material for
the synthesis of larger, usually bioactive structures. It is found within the chemical structures of
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pharmaceutical drugs such as raloxifene, zileuton, and sertaconazole. It is also used in the
manufacturing of dyes such as thioindigo.
Its aromaticity makes it relatively stable, although as a heterocycle, it has reactive sites which
allow for functionalization
Drug containg benzothiophene nucleous1.Isoxazoles and Cyanopyridines
Introduction
Isoxazole derivatives constitute a unique class of nitrogen and oxygen containing five member
heterocycles while cyanopyridine constitutes a six member heterocycles. During the past years
considerable evidence has accumulated to demonstrate the importance of isoxazole and
cyanopyridine derivatives. They are associated with wide spectrum of biological activities such
as antiviral , anthelmintics , anti-inflammatory , anticonvulsant and insecticidal activity etc.
Hence, it appeared of interest to prepare some new isoxazole and cyanopyridine derivatives
Synthesis
The starting compounds 1-[p-(3-chloro-2-benzo(b)thiophenoylamino)-phenyl]-3-aryl-2-
propen-1-ones (1a-l) were synthesized by the reaction of p-(3-chloro-2-
benzo(b)thiophenoylamino)-acetophenone with different aldehydes. Compounds 1a-l on
cyclization with hydroxylamine hydrochloride in presence of sodium acetate furnished 1-[p-
(3-chloro-2-benzo(b)thiophenoylamino)-phenyl]-5-aryl-isoxazoles (2a-l) while cyclo
condensation of compounds 1a-lwith malononitrile in presence of ammonium acetate
furnished 2-amino-3-cyano-4-p-methoxyphenyl-6-[benzo(b)thiophenoyl amino)-phenyl]-
pyridine. Elemental and spectral analyses supported the constitution of all products. Theproduct was screenedfor their antitubercular and antimicrobial activities
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2 .Thiourea derivatives bearing the benzo[b]thiophene nucleus
Introduction
Attempts have been made to modify the structure of thiohydantoin molecules by introducingcarrier molecules during drug designwith the view of reducing their toxicity. There has been
considerable interest in the thiohydantoin ring system, bothwith regards to heterocyclic
chemistry and the pharmacological activities of several of its derivatives. Thiohydantoin
derivatives have been found to possess potential biological and medicinal activities, such as
antiviral, antifungal and anticonvulsant. Thioxopyrimidine derivatives with significant
therapeutic importance have drawn our attention. The aim was to develop a facile and
convenient route to new deriatives of these molecules in synthetically useful yields. The
increasing potency of thioxopyrimidine derivatives have been explored for the development of
pharmaceutically important molecules with specific biological activities, such as
antiparkinsonian, antiviral, anti-inflammatory andCNSdepressant, as well as antimicrobial8 and
anticonvulsant. The structures of the synthesized compounds were assigned on the basis ofelemental analyses, FTIR, 1H-NMR and mass spectral data. The compounds were screened for
theirin vitro antimicrobial activity
Experimental
Thin layer chromatography was used to monitor the reactions and the purity of the synthesized
compounds. The melting points were determined in open capillary tubes and are uncorrected.
IR spectra were recorded on a Shimadzu FTIR-8400 instrument using the KBr disc technique
and only sharply defined peaks were recorded (_max in cm-1). The 1H-NMR spectra were
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recorded on a Bruker AC-300 MHz FTNMR spectrophotometer using TMS as the internal
reference (chemical shift in_ppm). The mass spectra were taken on a Jeol D-300 spectrometer.
Preparation of N-[(arylamino)thioxomethyl]-3,5-dichlorobenzo[b]thiophene-2-carboxamide
(1)
Ammonium thiocyanate (0.7 g, 0.01 mol) in acetone was added dropwise to a solution of3,5-dichlorobenzo[b]thiophene-2-carbonylchloride (2.6 g, 0.01 mol) in acetone. Aryl amine
(0.01 mol) in acetone was then added to the reaction mixture in small portions. The reaction
mixture was refluxed for 3 h. The mixture was filtered, concentrated under reduced pressure
and the residue crystallized from ethanol
Preparation of 1-aryl-3-[3,5-dichlorobenzo[b]thien-2-yl)carbonyl]-2-thioxoimidazolidin-4-one
(2)
N-[(arylamino)thioxomethyl]-3,5-dichlorobenzo[b]thiophene-2-carboxamide (0.1 mol) was
dissolved in the minimum amount of pyridine. To this solution, chloroacetic acid (0.94 g, 0.1
mol) and 15 ml of a mixture of ethanol and dioxane (1:1) was added. The resulting mixture was
refluxed for 12 h, cooled and the mixture was filtered, concentrated under reduced pressure andthe residue crystallized from ethanol.
Preparation of 3-aryl-1-[(3,5-dichlorobenzo[b]thien-2-yl)carbonyl]dihydro-2-
thioxopyrimidine-4,6(1H,5H)-dione (3)
N-_(Arylamino)thioxomethil)_-3,5-dichlorobenzo[b]thiophene-2-carboxamide (0.01mol) and
malonic acid (2.6 g, 0.01 mol) in acetyl chloride (15 ml) were refluxed for 6 h on a steam bath.
After cooling, the mixture was filtered, concentrated under reduced pressure and the residue
crystallized from ethanol.
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3.Non-symmetrical 2,5-disubstituted 1,3,4-oxadiazoles bearing a benzo[b]thiophene
moiety
Introduction
2,5-Disubstituted-1,3,4-oxadiazoles have been reported as remarkable antidepressive,
anticonvulsive, antiinflamatory, antimitotic, hypoglycemic, antifungal, antimicrobial agents, as
well as insecticides. Moreover, they present interesting electrochemical and fluorescent
properties.The benzothiophene nucleus has a great potential in medicinal chemistry due to its
low toxicity and good lipophilicity. The biological activity of many structures containing this
motif is increased by its presence. Several 1,3,4-oxadiazoles bearing the 3-chloro-
benzo[b]thienyl moiety are known and were screened for antimicrobial activity. The 2-amino-
5-(3-chloro-benzothienyl) derivatives were synthesized by cyclodesulfurization of
thiosemicarbazides, while the corresponding 2-thioether-derivatives were obtained by
alkylation of an 1,3,4-oxadiazole-2-thione.
To our knowledge a study concerning the synthesis of unsymmetrical 2,5-diaryl-1,3,4-oxadiazoles substituted with a benzo[b]thiophene ring has not been reported. Herein, we
describe the synthesis and characterization of 2,5-disubstituted-1,3,4-oxadiazoles bearing a
benzo[b]thiophene ring by dehydration of unsymmetricalN,N- diacylhydrazines.
N,N-diacylhydrazines are easily accessible starting from acids, acid chlorides or esters and
respectively various hydrazides and are valuable intermediates in the synthesis of cyclic
compounds. The most common synthetic strategy for preparing 2,5-substituted-1,3,4-
oxadiazoles involves the dehydrative cyclization ofN,N-diacylhydrazines using strong acids
(dehydration agents) such as POCl SOCl2 P2O5
or H2SO4. There have been also reported
reactions of N,N-diacylhydrazines grafted onto polymer support or under microwave
irradiation, leading to 2,5-disubstituted-1,3,4-oxadiazoles in good yields. Recently, Katritzky et
al. described an efficient one pot synthesis of 1,3,4-oxadiazoles from acylhydrazides and N-
acylbenzotriazoles.
Synthesis
Synthesis of the 2,5-disubstituted-1,3,4-oxadiazoles required in a first step the preparation of
the starting materials, namely the 3-chlorobenzo[b]thiophene-2-carboxyl chloride 1 and the
acylhydrazides 2. The synthesis of 1 was described by Higa and Krusbsak and consists in
treatment of cinnamic acid with thionyl chloride, in chlorobenzene at reflux, in presence of
pyridine. The acylhydrazides 2 were obtained from ethyl esters in reaction with 100%hydrazine hydrate in very good yields, according to the literature. All known compounds were
characterized by NMR spectral analysis to confirm the structure.The key intermediates for the synthesis of the 2,5-disubstituted-1,3,4-oxadiazoles 4 are the
N,N-diacylhydrazines 3, which form as a result of the reaction between the acid chloride of 3-
chlorobenzo[b]thiophene-2-carboxylic acid 1 and acylhydrazides 2, in tetrahydrofuran, in
presence of sodium bicarbonate (Scheme 2). All compounds are colorless crystals, except the
compound 3f, which is yellow. The melting points are high, over 180 C in all cases. The
compounds bearing nitro groups have the highest melting points.The synthesis of 2,5-disubstituted-1,3,4-oxadiazoles was performed by treatment ofN,N-
diacylhydrazines 3 with an excess of POCl3 in toluene at reflux.By this method the new
compounds 4 were obtained in good yield as colorless crystals, except from the compound 4f,which is yellow, similar to the correspondingN,N-diacylhydrazine.
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4.Synthesis of some New Imidazolones and 1,2,4-Triazoles Bearing Benzo[b]thiophene
Nucleus
Introduction
Imidazolones and their derivatives are known fortheir potential biological and pharmacological
properties. Synthesis of imidazolones from the respective oxazoline-5(4H)-ones and
appropriate primary amines under different experimental conditions has been investigated by
Islam et al. . Derivatives of 1,2,4-triazoles are of current interest
in view of their wide ranging of biological activities exhibited by these compounds . Search of
more biologically effective agent and industrial utility, led chemists to explore a variety of
chemical entities with biological properties. In continuous of our work onbenzo[b]thiophene nucleus , it was contemplated to synthesized some new 1,2,4-triazoles and
imidazolones derivatives bearing benzo[b]thiophene moiety. Condensation of 2-
hydrazinocarbonyl-3,5-dichlorobenzo[ b]thiophene 1 with different aromatic oxazolinones
led to the required compounds 2-phenyl-1-(3,5-dichloro-2-benzo[b]thiophenoylamino)-4-
arylidine-5-imidazolone (2a-l). Reaction of1 with different aromatic isothiocyanates yielded
N1-(3,5-dichloro-2- benzo[b]thiophenyl)-N4-substituted aryl thiosemicarbazides (3a-j),
which on reaction with sodium hydroxide yielded 3-(3,5-dichlorobenzo[b]thiophen-2-yl)-4-
aryl-5-mercapto-1,2,4-triazoles(4a-j). The structures of the synthesized compounds were
assigned on the basis of elemental analyses, IR, 1HNMR and Mass spectral data. The
compounds were screened for their antitubercular and antimicrobial activities
synthesis
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synthesis of 4-arilidine-2-phenyl oxazolinones
These compounds were prepared from condensation of substituted benzaldehyde with benzoyl
glycine in the presence of sodiuam acetate and vogel decribed acetic anhydride.
Synthesis of 2-Phenyl-1-(3,5-dichloro-2-benzo[b]thiophenoylamino)-4-arylidine-5-
imidazolones (2a-l)
A mixture of 2-hydrazinocarbonyl-3,5- dichlorobenzo[b]thiophene (2.61 g, 0.01 M) and 4-
arylidine-2-phenyl-5-oxazolinone (0.01 M) in pyridine (20 ml) was refluxed for 6-8 h. The
excess of solvent was removed under reduce pressure and reaction mixture was poured onto
crushed ice. The product was isolated and crystallized from benzene.
Synthesis of N1-(3,5-dichloro-2-benzo[b]thiophenyl)- N4-substituted-aryl thiosemicarbazides
(3a-j)
A mixture of 2-hydrazinocarbonyl-3,5- dichlorobenzo(b)thiophene (2.61 g, 0.01 M) and 4-
arylisothiocynate (0.01 M) was refluxed in ethanol for 6 h. The resulting solution was thencooled and separated solid was crystallized from ethanol
Synthesis of 3-(3,5-Dichloro-2-benzo[b]thiophenyl)-
4-aryl-5-mercapto-1,2,4-triazoles (4a-j)
N1-(3,5-dichlorobenzo[b]thiophen-2-yl)-N4- substituted aryl thiosemicarba-zide (0.01 M)
was refluxed with sodium hydroxide solution (8%, 20 ml) for 8 h. The content was cooled,
poured into cold water, stirred and filtered. The filtrate on neutralizing yielded solid, which was
crystallized from ethanol.
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Thiophene Ring-Containing Quinones
Introduction
Leishmaniasis and Chagas disease are common protozoal parasitic diseases in South America
which cause considerable morbidity and mortality. Leishmaniasis is initiated by inoculation ofLeishmania species into the skin via sand fly bites. Drugs currently available for treatment of
Leishmaniasis are potentially toxic, inconvenient to administer and frequently give rise to
clinical resistance.1,2) The infection is classically treated with pentavalent antimony in the
form of sodium stibogluconate (Pentostam) or N-methylglucamine antimonate
(Glucantime) and with pentamidine or amphotericin
B. Chagas disease is a widespread infection in Latin America which currently infects 16 to 20
millions people leading to over 45000 deaths each year.3) It is caused by Trypanosoma
cruzi and is naturally transmitted by Reduviidae bugs. The chemotherapy of Chagas disease is
limited to the drugs benznidazole and nifurtimox. Both drugs are not very active and have
severe side effects. The absence of new drugs to control Chagas disease makes the search for
active chemotherapeutic agents an urgent priority in parasitic research. The quinonoidcompounds occupy a special place among the broad variety of natural and synthetic agents with
antibacterial, antifungal, antiprotozoal, and antitumor activity. Some of these pharmacological
effects have been attributed to the formation of DNA-damaging anionradical intermediates by
bioreduction of the quinone system.9) Among the diversity of quinones with cytotoxic activity,
those having a thiophene nucleus fused to a quinone system
have received relatively little attention10,11) despite the antitumoral activity of thiophene
analogues of daunomycin and mitoxantrone
.
Synthesis
The benzo[b]thiophenes 2ag were prepared from o-acylnitroarenes 1a, b and methyl
thioglycolate according to a recently reported method.14) Compound 2h was prepared in 75%
yield by reaction of 2e with excess triethylene glycol and N,N9 dicyclohexylcarbodiimide
(DCC) as shown in Chart 2. Dimer2i was obtained in 72% yield by condensation of2e and 2h
with DCC. Benzo[b]thiophene- 4,7-quinones 3ai were prepared by oxidative demethylation
of the corresponding benzo[b]thiophenes 2ai with ceric ammonium nitrate (CAN) in
acetonitrilewater solution following the procedure reported recently
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introduction
Synthesis
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.
Some trivia on benzothiones
Benzothiophene is an aromatic organic compound with a molecular formula C8H6S and an
odor similar tonaphthalene(mothballs). It occurs naturally as a constituent of petroleum-
related deposits such aslignite tar. Benzothiophene has no household use. It is used primarily
in industry and research.
Being a heterocyclic compound, benzothiophene finds use in research as a starting material forthe synthesis of larger, usually bioactive structures. It is found within the chemical structures of
http://www.absoluteastronomy.com/topics/Organic_compoundhttp://www.absoluteastronomy.com/topics/Naphthalenehttp://www.absoluteastronomy.com/topics/Naphthalenehttp://www.absoluteastronomy.com/topics/Naphthalenehttp://www.absoluteastronomy.com/topics/Lignitehttp://www.absoluteastronomy.com/topics/Lignitehttp://www.absoluteastronomy.com/topics/Organic_compoundhttp://www.absoluteastronomy.com/topics/Naphthalenehttp://www.absoluteastronomy.com/topics/Lignite7/31/2019 Benzo Thio Phene
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pharmaceutical drugs such as raloxifene,zileuton, and sertaconazole. It is also used in the
manufacturing of dyes such as thioindigo.
Its aromaticity makes it relatively stable, although as a heterocycle, it has reactive sites which
allow for functionalization.
References
1. Gray, K. A., O. S. Pogrebinsky, G. T. Mrachko, L. Xi, D. J. Monticello, and
C. H. Squires. 1996. Molecular mechanisms of biocatalytic desulfurization of
fossil fuels. Nat. Biotechnol. 14:17051709.
2. Grossman, M. J. 1996. Microbial removal of organic sulfur from fuels: a
review of past and present approaches, p. 345359.In M. L. Occelli and R.
Chianelli (ed.), Hydrotreating technology for pollution control: catalysts,
catalysis, and processes. Marcel Dekker, New York, N.Y.
3. Grossman, M. J., M. K. Lee, R. C. Prince, K. K. Garrett, G. N. George, andI. J. Pickering. 1999. Microbial desulfurization of a crude oil middle-distillate
fraction: analysis of the extent of sulfur removal and the effect of
removal on remaining sulfur. Appl. Environ. Microbiol. 65:181188.
4. Hanson, G., and D. S. Kemp. 1981. Convenient routes to 4,40-functionalized
O-terphenyls and 2,29-functionalized biphenyls. J. Org. Chem. 46:54415443.
5. Hartdegen, F. J., J. M. Coburn, and R. L. Roberts. 1984. The microbial
desulfurization of petroleum. Chem. Eng. Prog. 80:6367.
6. Hou, C. T., and A. I. Laskin. 1976. Microbial conversion of dibenzothiophene.
Dev. Ind. Microbiol. 17:351362.
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desulfurization of dibenzothiophene byRhodococcus erythropolis D-1. Appl.
Environ. Microbiol. 60:223 226.
8. Kabe, T., A. Ishihara, and H. Tajima. 1992. Hydrodesulfurization of sulfurcontaining
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9. Kayser, K. J., B. A. Bielaga-Jones, K. Jackowski, O. Odusan, and J. J.
Kilbane II. 1993. Utilization of organosulfur compounds by axenic and
mixed cultures ofRhodococcus rhodochrous IGTS8. J. Gen. Microbiol. 139:
31233129.
10. Kilbane, J. J., and B. A. Bielaga. 1990. Toward sulfur-free fuels.
CHEMTECH 20:747751.11. Kodama, K., S. Nakatani, K. Umehara, K. Shimizu, Y. Minoda, and K.
Yamada. 1970. Microbial conversion of petrosulfur compounds. Part III.
Isolation and identification of products from dibenzothiophene. Agric. Biol.
Chem. 34:13201324.
12. Kodama, K., K. Umehara, K. Shimizu, S. Nakatani, Y. Minoda, and K.
Yamada. 1973. Identification of microbial products from dibenzothiophene
and its proposed oxidation pathway. Agric. Biol. Chem. 37:4550.
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