benzo thio phene

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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/Lignite


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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.

7. Izumi, Y., T. Ohshiro, H. Ogino, Y. Hine, and M. Shimao. 1994. Selective

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

polyaromatic compounds in light oil. Ind. Eng. Chem. Res. 31:

15771580.

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.
http://www.absoluteastronomy.com/topics/Raloxifenehttp://www.absoluteastronomy.com/topics/Zileutonhttp://www.absoluteastronomy.com/topics/Zileutonhttp://www.absoluteastronomy.com/topics/Zileutonhttp://www.absoluteastronomy.com/topics/Sertaconazolehttp://www.absoluteastronomy.com/topics/Raloxifenehttp://www.absoluteastronomy.com/topics/Zileutonhttp://www.absoluteastronomy.com/topics/Sertaconazole

benzo thio phene

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