K-region oxides and imines of benzo[b]phenanthro[2,3-d]thiophene and benzo[b]phenanthro[3,2-d]thiophene

The syntheses of the K-oxides and K-imine derivatives of benzo[b]phenanthro[2,3-d]thiophene and benzo-[b]phenanthro[3,2-d]thiophene are described. The parent hydrocarbons 1 and 2 were oxidized with osmium tetroxide and sodium metaperiodate, and the dialdehydes 12 and 18 so formed, cyclized to the corresponding epoxides 1a,12b-dihydrobenz[b]oxireno[9,10]phenanthro[2,3-d]thiophene ( 7 ) and 1a,12b-dihydrobenz-[b]oxireno[9,10]phenanthro[3,2-d]thiophene ( 13 ). Reaction of the oxiranes with sodium azide gave mixtures of azido-alcohols that, in turn, were transformed to the thiaarene imines 1a,12b-dihydro-1H-benz[b]azirino-[9,10]phenanthro[2,3-d]thiophene ( 8 ) and 1a,12b-dihydro-1H-benz[b]azirino[9,10]phenanthro[3,2-d]thiophene ( 14 ), respectively, with the aid of tri-n-butylphosphine.     

3-Aminoalkyl-5-methyl-benzo[b]thiophene

Zusammenfassung Ausgehend von -[5-Methyl-benzo[b]thienyl-(3)]-propionsäure wurde eine Reihe von 5-Methyl-benzo[b]thiophenen mit einer Aminoalkylsubstitution in 3-Stellung dargestellt: 3-(-Aminoäthyl)-5-methyl-benzo[b]thiophen durchCurtius-Abbau des Azids und 3-(-Aminopropyl)-5-methyl-benzo[b]thiophen sowie N-Substitutionsprodukte davon durch LiAlH₄-Reduktion der entsprechenden Amide.

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5-Methyl-benzo[b]thiophenes having an aminoalkyl substituent in position 3 were prepared from -[5-methyl-benzo[b]-thienyl-(3)]-propionic acid: 3-(-aminoethyl)-5-methyl-benzo[b]-thiophene byCurtius rearrangement of the azide, and 3-(-aminopropyl)-5-methyl-benzo[b]thiophene as well as some of its N-derivatives by reduction of the corresponding amides with LiAlH₄.

     

Benzo[b] thiophene derivatives XVII. Electrophilic substitution of 4-hydroxybenzo[b] thiophene derivatives

A variety of eleclrophilic substitution reactions have been carried out on 4-methoxybenzo[b]-thiophene (IIIa) and 4-benzoyloxybenzo[b ] thiophene (IVa). Substitution occurs in the 7-position of IIIa and, with the exception of bromination, in the 7-position of IVa. Bromination of IVa occurs in the 3-position. Bromination of 4-hydroxybenzo[b] thiophene (IIa) occurs in the 5-position. The nmr spectra of eleven disubstituted benzo[b] thiophenes have been tabulated.     

A facile synthesis of benzo[b]thiophene derivatives

Lithiation of S-(2-methylphenyl) N,N,N',N'-tetramethylphosphorodiamidothioate with sec-BuLi at -105° gave the corresponding benzylic anion which was acylated with various aromatic esters to give various deoxybenzoin derivatives in moderate to high yields. Acidic treatment of these products in refluxing formic acid gave 2-arylbenzo[b]thiophene derivatives. 2-Methylbenzo[b]thiophene and benzo[b]thiophen-2(3H)-one were also prepared using the similar procedure.     

N-Substituierte Benzo [b]thiophen-3-acetamide und 3-(β-Aminoäthyl)-benzo [b]thiophene

Zusammenfassung Die Synthese der Titelverbindungen erfolgte über die Benzo[b]thiophen-3-essigsäure, deren Chlorid mit Diäthylamin und N-Methylpiperazin zu den entsprechenden N-substituierten Benzo[b]thiophen-3-acetamiden reagierte; diese wurden mit LiAlH₄ zu tertiären Aminen reduziert.Die Synthese der homologen 2-Methylverbindungen ging vom 2-Methyl-3-acetyl-benzo[b]thiophen aus: Haloformreaktion gab 2-Methyl-benzo[b]thiophen-3-carbonsäure;Wolff-Umlagerung des entsprechenden Diazomethylketons in Gegenwart von sekundären Aminen lieferte verschiedene N-substituierte 2-Methyl-benzo[b]thiophen-3-acetamide, von denen drei mit LiAlH₄ zu tertiären Aminen reduziert wurden.

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The title substances were synthesized using benzo[b]thiophene-3-acetic acid as an intermediate, the acid chloride of which reacted with diethylamine and N-methylpiperazine to give the corresponding N-substituted benzo[b]thiophene-3-acetamides; these were reduced by LiAlH₄ to tertiary amines.The synthesis of the homologous 2-methyl compounds started from 2-methyl-3-acetyl-benzo[b]thiophene: haloform reaction gave 2-methyl-benzo[b]thiophene-3-carboxylic acid;Wolff-rearrangement of the corresponding diazomethyl ketone in the presence of secondary amines yielded various N-substituted 2-methyl-benzo[b]thiophene-3-acetamides; three of them were reduced by LiAlH₄ to tertiary amines.

     

The synthesis of the monomethyl isomers of benzo[b]naphth[2,1-d]thiophene

All isomers of the monomethylbenzo[b]naphth[2,1-d]thiophenes were synthesized using photocyclization of 3-styrylbenzo[b]thiophenes. The 1-, 3-, 4-, and 5-methylbenzo[b]naphtho[2,1-d]thiophenes were synthesized by irradiation of the corresponding methylated 3-styrylbenzo[b]thiophenes which were prepared by the Wadsworth-Emmons reaction of diethyl benzo[b]thenylphosphonate with o-, m-, p-tolualdehyde and acetophenone. The 7-, 8-, 9- and 10-methylbenzo[b]naphtho[2,1-d]thiophenes were synthesized by decarboxylation of 7-, 8-, 9- and 10-methylbenzo[b]naphtho[2,1-d]thiophene-6-carboxylic acid with copper in quinoline. These carboxylic acids were prepared by photocyclization of the corresponding 2-(benzo[b]thiophen-3-yl)-3-phenylpropenoic acids which were prepared by the condensation of the methylated benzo[b]thiophene-3-ylacetic acids with benzaldehyde in the presence of triethylamine in acetic anhydride.     

Benzo[b]thiophene derivatives. XXV. Condensation and reductive alkylation of 3-aminoalkylbenzo[b]thiophenes with formaldehyde

The reductive alkylation of 3-aminomethylbenzo[b]thiophene by the Eschweiler-Clarke (formaldehyde-formic acid) method and of 3-β-aminoethylbenzo[b]thiophene by the Borch (formaldehyde-cyanoborohydride) method proceeded in good yields. However, the Eschweiler-Clarke reaction with 3-β-aminoethylbenzo[b]thiophene gave the Pictet-Spengler cyclized product, N-methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3c]pyridine. Mechanistic aspects of the latter reaction were investigated.     

Benzo[B]thiophene derivatives XXIV. Oxidation of o-dihydroxybenzo[b]thiophene methyl ethers

The attempted oxidative demethylation of a series of o-dihydroxybenzo[b]thiophene methyl ethers with cerium (IV), argentic oxide, periodale and thallate usually led to intractable mixtures. However, in one ease, use of ceric ammonium nitrate resulted in nitration of the benzo[b]-thiophene ring. In another example, treatment with aqueous periodate or thallate resulted in oxidative hydroxylation of benzo[b]thiophene.     

Benzo[b]thiophene mit Halogensubstitution in 5-Stellung

Zusammenfassung Cyclisierung von -(p-Chlor-phenylthio)-acetessigester und -(p-Brom-phenylthio)-acetessigester mit Polyphosphorsäure und anschließende Hydrolyse gab 5-Chlor- und 5-Brom-benzo[b]-thiophen-3-essigsäure. Deren Säurechloride wurden mit verschiedenen sekundären Aminen zu den entsprechenden N-substituierten 5-Chlor-und 5-Brom-benzo[b]thiophen-3-acetamiden umgesetzt. Diese wurden mit LiAlH₄ zu den tertiären Aminen reduziert.Ähnlich wie im Fall des -(p-Methoxy-phenylthio)-acetessigesters konnte auch die entsprechende Fluorverbindung nicht zu einem Benzo[b]thiophen-Derivat ringgeschlossen werden.

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Cyclization reactions of -(p-chloro-phenylthio)-acetoacetate and -(p-bromo-phenylthio)-acetoacetate withPPA followed by hydrolysis gave 5-chloro- and 5-bromobenzo[b]thiopheneacetic acid. The acid chlorides reacted with various secondary amines to give the corresponding N-substituted 5-chloro- and 5-bromo-benzo[b]thiophene-3-acetamides. These were reduced by LiAlH₄ to tertiary amines.Similar to -(p-methoxy-phenylthio)-acetoacetate the fluoro compound gave no cyclization to a benzo[b]thiophene derivative.

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Mit 1 Abbildung     

Synthesis of 6-aminobenzo[b]naphtho[2,1-d]thiophene

6-Aminobenzo[b]naphtho[2,1-d]thiophene has been prepared by two different routes, one, a one-pot synthesis.     

Benzo[b]thiophene. Derivatives. XXVIII. 5-bromo-3-benzo[b]thienylalanine and derivatives

A potential inhibitor of gelation of sickle hemoglobin, 5-bromo-3-benzo[b]thienylalanine, has been synthesized along with several derivatives. Several hydrolytic pathways from the intermediate ethyl 5-bromo-3-benzo[b]thienylformamidomalonate have been examined, and that involving alcoholysis to ethyl N-formyl-5-bromo-3-benzo[b]thienylalanine shown to be superior.     

N-Substituierte 2-Methyl-3-aminoacetyl-benzo[b]thiophene und 2-Methyl-3-(α-hydroxy-β-amino-äthyl)-benzo[b]thiophene

Zusammenfassung Bromierung von 2-Methyl-3-acetyl-benzo[b]thiophen ergab 2-Methyl-3-bromacetyl-benzo[b]thiophen, das beim Umsetzen mit Dimethylamin, Morpholin und N-Methylpiperazin die entsprechend basisch substituierten 3-Acetylverbindungen lieferte. Diese wurden mit LiAlH₄ zu den -Hydroxyverbindungen reduziert.In ähnlicher Weise wurde auch 3-Diäthylaminoacetyl-benzo[b]thiophen dargestellt.

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Bromination of 2-methyl-3-acetyl-benzo[b]thiophene gave 2-methyl-3-bromacetyl-benzo[b]thiophene, which reacted with dimethylamine, morpholine and N-methylpiperazine to give the corresponding base-substituted 3-acetyl derivatives. These were reduced by LiAlH₄ to the -hydroxy compounds.Similarily 3-diethylaminoacetyl-benzo[b]thiophene was synthesized.

     

Synthesis of new 4-quinolone-type compounds in the benzo[b]thiophene series

Some new derivatives of 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid (quinolone-type compounds) 5 and 13 have been prepared in the benzo[b]thiophene series. The key step was the construction of the pyridine ring starting from 2-aminobenzo[b]thiophene derivatives. The synthesis of amine 9 , was performed by using an original “animation” reaction.     

Synthesis of trans‐dihydrodiol derivatives of phenanthro[3,4‐b]‐thiophene and phenanthro[4,3‐b]thiophene

The present study describes the synthesis of phenanthro[3,4‐b]thiophene (3) , phenanthro[4,3‐b]thiophene (4) and its potential dihydrodiol metabolites, trans‐6,7‐dihydroxy‐6,7‐dihydrophenanthro[3,4‐b]thiophene (5) and trans‐8,9‐dihydroxy‐8,9‐dihydrophenanthro[3,4‐b]thiophene (6) , trans–6,7‐dihydroxy‐6,7‐dihydro‐phenanthro[4,3‐b]thiophene (7) and trans‐8,9‐dihydroxy‐8,9‐dihydrophenanthro[4,3‐b]thiophene (8) from Suzuki coupled intermediates. The UV spectra of these dihydrodiols are presented. These spectra are useful tools for identifying these dihydrodiols among unknown metabolites of 1 and 2 produced in vitro or in vivo.     

Basisch substituierte 5,6-Dimethoxy- und 4,5,6-Trimethoxy-benzo[b]thiophene

Zusammenfassung N-substituierte -{5,6-Dimethoxy-benzo[b]thienyl-(3)}-äthylamine, -{4,5,6-Trimethoxy-benzo[b]thienyl-(3)}-äthylamine und -{5,6-Dimethoxy-benzo[b]thienyl-(3)}-propylamine wurden mittels LiAlH₄-Reduktion der entsprechenden von uns schon früher synthetisierten Säureamide hergestellt.

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N-substituted -{5,6-dimethoxy-benzo[b]thienyl-(3)}-ethylamines, -{4,5,6-trimethoxy-benzo[b]thienyl-(3)}-ethylamines and -{5,6-dimethoxy-benzo[b]thienyl-(3)}-propylamines were prepared by LiAlH₄ reduction of the corresponding amides previously synthesized by us.

     

Synthesis and biological evaluation of 5-substituted benzo[b]thiophene derivatives as anti-inflammatory agents

Abstract  5-Aminobenzo[b]thiophene-2-carboxylic acid was converted to the corresponding 5-(2-chloroacetamido)benzo[b]thiophene-2-carboxylic acid by reaction with chloroacetyl chloride. This acetamido product was treated with different alkyl, cycloalkyl, aryl, and heterocyclic amines to afford a series of C5-substituted benzo[b]thiophenes. These compounds were found to possess potent anti-inflammatory activity. Graphical abstract        

Synthesis of phenaleno[1,9-bc]thiophene

The cyclization of 2-acetonylthionaphthalene, prepared from 2-mercaptonaphthalene (1) and chloro-acetone in the presence of sodium hydroxide, with polyphosphoric acid gave 1-methylnaphtho[2,1-b]thiophene (4) in 64% overall yield from 1. By bromination with N-bromosuccinimide, 4 was converted in 40% yield into l-bromomethylnaphtho[2,1-b]thiophene (8) . Treatment of 8 with potassium cyanide in a phase-transfer medium gave l-cyanomethylnaphtho[2,1-b]thiophene (10) in good yield. Compound 10 was reduced to the corresponding aldehyde 11 and then cyclized with polyphosphoric acid to phenaleno[l,9-bc]thiophene (12) in 24% overall yield from 10.     

Synthesis of anthra[b]thiophenes and benzo[b]naphtho[d]thiophenes

All isomers of the parent anthra[b]thiophenes and benzo[b]naphtho[d]thiophenes, namely anthra[2,3-b]thio-phene, anthra[2,1-b]thiophene, anthra[1,2-b]thiophene, benzo[b]naphtho[2,3-d]thiophene, benzo[b]naphtho[2,1-d]thiophene and benzo[b]naphtho[1,2-d]thiophene were synthesized using a new procedure.     

The synthesis of all of the monomethyl isomers of benzo[b]naphtho[1,2-d]thiophene

All isomers of the monomethylbenzo[bnaphtho[1,2-d]thiophenes were synthesized by photocyclization of 2-styrylbenzo[b]thiophenes which were prepared by the Wadsworth-Emmons reaction or the Wittig reaction.     

Derivate des 3-Phenyl-benzo[b]thiophens

Zusammenfassung 2-Methylthio-benzophenon reagierte mit Chloressigsäure zu 3-Phenyl-benzo[b]thiophen-2-carbonsäure und mit -Chlorphenylessigsäure zu 2,3-Diphenyl-benzo[b]thiophen. 3-Phenyl-5-methoxy-benzo[b]thiophen-2-carbonsäure wurde aus 3-Phenyl-5-amino-benzo[b]thiophen-2-carbonsäure durch Verkochen des Diazoniumsalzes und Methylierung erhalten; ihr N-Methylpiperazid sowie 3 basisch substituierte Ester wurden dargestellt.

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Derivatives of 3-phenylbenzo[b]thiophene

2-Methylthio-benzophenone reacted with chloroacetic acid to 3-phenyl-benzo[b]thiophene-2-carboxylic acid and with -chloro-phenylacetic acid to 2,3-diphenyl-benzo[b]thiophene. 3-Phenyl-5-methoxy-benzo[b]thiophene-2-carboxylic acid was prepared by diazotation of 3-phenyl-5-amino-benzo[b]thiophene-2-carboxylic acid and hydrolysis to the hydroxy compound followed by methylation; its N-methylpiperazide and three esters with basic substituents were synthesized.