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 petroleumrelated 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

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 nucleous

1.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-2propen-1-ones (1a-l) were synthesized by the reaction of p-(3-chloro-2benzo(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. The product was screenedfor their antitubercular and antimicrobial activities

2.Thiourea derivatives bearing the benzo[b]thiophene nucleus Introduction Attempts have been made to modify the structure of thiohydantoin molecules by introducing carrier 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 of elemental analyses, FTIR, 1H-NMR and mass spectral data. The compounds were screened for their in 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

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 of 3,5-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 and the residue crystallized from ethanol. Preparation of 3-aryl-1-[(3,5-dichlorobenzo[b]thien-2-yl)carbonyl]dihydro-2thioxopyrimidine-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.

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-chlorobenzo[b]thienyl moiety are known and were screened for antimicrobial activity. The 2-amino5-(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-1,3,4oxadiazoles 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 unsymmetrical N,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-1,3,4oxadiazoles involves the dehydrative cyclization of N,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 Nacylbenzotriazoles. 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 3chlorobenzo[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 of N,Ndiacylhydrazines 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 corresponding N,N-diacylhydrazine.

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 on benzo[b]thiophene nucleus , it was contemplated to synthesized some new 1,2,4-triazoles and imidazolones derivatives bearing benzo[b]thiophene moiety. Condensation of 2hydrazinocarbonyl-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)-4arylidine-5-imidazolone (2a-l). Reaction of 1 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)-4aryl-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

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-5imidazolones (2a-l) A mixture of 2-hydrazinocarbonyl-3,5- dichlorobenzo[b]thiophene (2.61 g, 0.01 M) and 4arylidine-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 4arylisothiocynate (0.01 M) was refluxed in ethanol for 6 h. The resulting solution was then cooled 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.

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 of Leishmania 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 quinonoid compounds 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. Dimer 2i was obtained in 72% yield by condensation of 2e 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

introduction

Synthesis

Some trivia on benzothiones

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 petroleumrelated 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

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, and I. 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 by Rhodococcus 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 of Rhodococcus 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.