Benzo[b]thiophene derivatives. XXVII. 5-methoxy-6-halo-3-β-acetamidoethylbenzo[b]thiophenes,blocked analogs of melatonin

The preparation of the 6-fluoro and 6-chloro analogs of the title compound is described, in a seven-step synthesis giving 30-40% overall yields. All intermediates have been isolated and characterized, including important by-products, such as the corresponding benzo[b]thienyl-3-acetic acids, and 3-methylbenzo[b]thiophenes. Cyclization of the 3-halo-4-methoxyphenylthioacetoacetic esters gave more ortho-cyclization in the chlorine case than was observed for the fluorine derivative. The title compounds were shown to have weak antiovulatory action, with the fluoro analog most active.     

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 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. XXII. Synthesis of the isomeric 5-methyl-6-methoxy- and 5-methoxy-6-methylbenzo[b] thiophene-2-carboxylic acids

The two isomeric benzo[b] thiophene-2-carboxylie acids having methyl and methoxy groups at positions 5 and 6 have been prepared and characterized. Both acids have been decarboxylated to the corresponding isomeric 5,6-disubstituted benzo[b]thophenes, and esterified to their methyl esters. The intermediate rhodanines, α-mercaptocinnamic acids and corresponding disulfides are described. An unusual by-product in the oxidative cyclization of β-3-methyl-4-methoxyphenyl-α-mercaptoacrylic acid with iodine is shown to be trans-3-methyl-4-methoxycinnamic acid, which can also be formed directly from the mercaptoacrylic acid by reduction with hydrogen iodide.     

Some methyl substituted benzo[b]naphtho[2,3-d]thiophenes

Seven benzo[b]naphtho[2,3-d]thiophenes have been prepared with methyl groups substituted in the 6,7, and 8-positions. These compounds are structurally related to the sulfur analogs of cholanthrene and methylcholanthrene.     

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.     

The synthesis of benzo[b]phenanthro[d]thiophenes and anthra[b]benzo[d]thiophenes

The synthesis of benzo[b]phenanthro[2, 3-d]thiophene ( 5 ), benzo[b]phenanthro[4, 3-d]thiophene ( 6 ), benzo-[b]phenanthro[2, 1-d]thiophene ( 9 ), benzo[b]phenanthro[3, 2-d]thiophene ( 14a ), anthra[1, 2-b]benzo[d]thiophene ( 24 ), anthra[2, 3-b]benzo[d]thiophene ( 29 ) and anthra[2, 1-b]benzo[d]thiophene ( 30 ) is described as well as the preparation of 13-methylbenzo[b]phenanthro[3, 2-d]thiophene ( 14b ).     

Benzo[b]thiophene derivatives I. 6-methoxybenzo[b]thiophene analogs of plant growth regulators

The acid catalyzed ring closure of an appropriately substituted phenyl ketoester sulfide served as the initial reaction in the synthesis of several 3,4- and 3,6-disubstituted benzo[b]thiophenes. One of these compounds, 4-methoxybenzo[b]thienyl-3-acetic acid, showed marked plant growth enhancement.     

Synthesis of benzo[b]phenanthro[d]thiophenes

The synthesis of benzo[b]phenanthro[1,2-d]thiphene ( 1 ), benzo[b]phenanthro[4,3-d]thiophene ( 2 ), benzo-[b]phenanthro[2,1-d]thiophene ( 3 ) and benzo[b]phenanthro[3,4-d]thiophene ( 4 ) from appropriately substituted olefines by photochemical cyclodehydrogenation is described. The photolysis of olefin 9 gave a mixture of 4 and anthra[1,2-b]benzo[d]thiophene ( 5 ).     

Syntheses of 4-(benzo[b]furan-2 or 3-yl)- and 4-(benzo[b]-thiophen-3-yl)piperidines with 5-HT2 antagonist activity

The syntheses of 4-(benzo[b]furan-3-yl)piperidines, 4-(benzo[b]furan-2-yl)piperidines and 4-(benzo[b]thiophen-3-yl)piperidines with 5-HT₂ antagonist activity are described. Reaction of 1-acetyl-4-(2,4-difluorobenzo-yl)piperidine 2 with methyl glycolate gave methyl 6-fluoro-3-(1-acetylpiperidin-4-yl)benzo[b]furan-2-carboxylate 3 , which was converted to 2-[2-[4-(benzo[b]furan-3-yi)piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyridin-3(2H)-one hydrochloride 9 . Analogous benzo[b]furans 17a-d and benzo[b]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4-fluoro-2-(4-pyridinylmethoxy)acetophenones 20a,b afforded 4-(benzo[b]furan-2-yl)pyridines 21a,b , which were converted to 2-[2-[4-(benzo[b]furan-2-yl)-piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochlorides 24a,b. Among them, benzo[b]furans 9 and 17a,d and benzo[b]thiophenes 10 and 18a showed potent 5-HT₂ antagonist activity in vitro.     

Benzo[b]thiophene derivatives. XXVI. 5-methoxy-6-chloro-3-β-acetamidoethylbenzo[b ]thiophene,a blocked analog of melatonin

A potential anti-ovulatory agent, 5-methoxy-6-chloro-3-β-acetamidoethylbenzo[b]thiophene, a sulfur analog of melatonin having the 6-position blocked to inhibit oxidative metabolism, has been synthesized from 3-hydroxy-4-chloroacetophenone.     

Benzo[b] thiophene derivatives. XVIII. The sulfur isosteres of harmaline,harmine and related isomers

The sulfur analogs of harmaline, 7-methoxy-3,4-dihydro-1-methyl[1]benzothieno[2,3-c]-pyridine (Ib), harmine, 7-methoxy-1-methyl[1]benzothieno[2,3- c ]pyridine (IIb), and corresponding 6-methoxy isomers (Ic and IIc) have been synthesized for pharmacological evaluation as monoamine oxidase inhibitors.     

Novel Route for Obtaining Isomeric Benzo[b]thiophenoindoles

We describe a novel route for synthesis of benzo[b]thiopheno[2,3-e]- and benzo[b]thiopheno[3,2-f]indoles. As the starting compounds, we used the corresponding annelated isatins obtained by the Sandmeyer reaction. We have established that reduction of the latter to the corresponding unsubstituted benzo[b]thiophenoindoles depends both on the nature of the substituent and on the reaction conditions.     

The nitrobenzo [b] thiophenes

Syntheses, and infrared and nuclear magnetic resonance spectral data for the six mononitrobenzo[b] thiophenes are described. Sulfonation of benzo[b] thiophene has been demonstrated to produce the 2- and 3-isomers.     

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.

     

Antifilarial and antimalarial agents. Basically substituted 10-aminobenzo[b] [1,5] naphthyridines, 10-Aminobenzo[b] [1,5] naphthyridine N-Oxides,and 8-Amino-1,5-naphthyridines

Various 2-alkoxy 7-chloro-10-[[[(dialkylamino)alkyl]amino]]benzo[b][1,5]naphthyridines (XI) and N-oxides (XV, XVII, XVIII, XXII), 4-[(2-alkoxy-7-chlorobenzo[b][1,5]naphthyridin-10-yl)-amino]-α-(diethylamino)-o-cresol derivatives (XII-XIV, XXI) and N-oxides (XIX, XX, XXV), 2-butoxy-8-[[[(dialkylamino)alkyl]amino]]-1,5-naphthyridines (XXVIa and b), and 2-butoxy-8–[[3-[(diethylamino)methyl]-p-anisidino]]-1,5-naphthyridine (XXVII) were synthesized for antifilarial and antimalarial evaluation. The compounds were obtained in 13–91% yield by the condensation of 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridines, 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridine 5-oxides, and 2-butoxy-8-chloro-1,5-naphthyridine with the appropriate diamine in phenol, or by perbenzoic acid oxidation of the parent 10-amino-7-chlorobenzo-[b][1,5] naphthyridines in chloroform. Among them, eight compounds killed adult Litomosoides carinii in gerbils when administered in daily gavage doses of 25–400 mg./kg. for 5 days. Azacrine 5-oxide (XVII), the most active compound, was equipotent with amodiaquine (1a), azacrine (IX), and quinacrine 10-oxide (VI). Twelve substances were active orally against Plasmodium berghei in mice at doses ranging from 3.8–155 mg./kg./day for 6 days. 7-Chloro-10-[[-3-[(diethylamino)-methyl]-p-anisidino]]-2-methoxybenzo[b][1,5]naphthyridine 5-oxide dihydrochloride (XX) was approximately 12 times as potent as quinine against P. berghei, but was highly cross-resistant with chloroquine (IV). Structure-activity relationships are discussed.     

Benzannelated analogs of phenanthro[1,2-b]- and [2,1-b]thiophene: Synthesis and structural characterization by two-dimensional NMR and X-ray techniques

Syntheses of benzo[3,4]phenanthro[1,2-b]thiophene, benzo[3,4]phenanthro[2,1-b]thiophene and their 1-methyl analogs are reported as potential constituents of solvent refined coal liquids and for mutagenicity testing. The attempted synthesis of the 13-methyl analogs which gave the 11-methyl isomers is also described. Total assignments of the ¹H- and ¹³C-nmr spectra based on long range optimized heteronuclear protoncarbon two-dimensional chemical shift correlation are reported. Carbon assignments obtained for benzo[3,4]-phenanthro[1,2-b]thiophene using this approach were confirmed with a 125 MHz ¹³C–¹³C INADEQUATE spectrum. X-Ray crystal structures were determined for benzo[3,4]phenanthro[1,2-b]thiophene and 1-methyl-benzo[3,4]phenanthro[2,1-b]thiophene. Both molecules were helically distorted from planarity. Close intramolecular contacts between the bay region H1–H13 and ClMe-H13 of 2.03 and 2.28 Å, respectively, were responsible for the distortions. There were no close intermolecular contacts of <3.5Å. both molecules refined to an R value of <0.05.     

Efficient Synthetic Approach to Substituted Benzo[b]furans and Benzo[b]thiophenes by Iodine‐Promoted Cyclization of Enaminones

An efficient synthetic approach to the substituted benzo[b]furan and benzo[b]thiophene scaffolds by iodine‐mediated cyclization of the corresponding enaminones is described. This protocol was applied to a large series of these latter precursors to afford the respective benzoheterocycles substituted at the C‐2 position by a carbonyl group functionality. A study of the factors that control this process reveals that the reactivity depends on the presence of electron‐donor groups in the aryl ring of the aryloxycarbonylic and arylthiocarbonylic moieties.     

Synthesis and Structure–Property Relationships of 2,2′‐Bis(benzo[b]phosphole) and 2,2′‐Benzo[b]phosphole–Benzo[b]heterole Hybrid π Systems

The first comprehensive study of the synthesis and structure–property relationships of 2,2′‐bis(benzo[b]phosphole)s and 2,2′‐benzo[b]phosphole–benzo[b]heterole hybrid π systems is reported. 2‐Bromobenzo[b]phosphole P‐oxide underwent copper‐assisted homocoupling (Ullmann coupling) and palladium‐catalyzed cross‐coupling (Stille coupling) to give new classes of benzo[b]phosphole derivatives. The benzo[b]phosphole–benzo[b]thiophene and ‐indole derivatives were further converted to P,X‐bridged terphenylenes (X=S, N) by a palladium‐catalyzed oxidative cycloaddition reaction with 4‐octyne through the C_β? H activation. X‐ray analyses of three compounds showed that the benzo[b]phosphole‐benzo[b]heterole derivatives have coplanar π planes as a result of the effective conjugation through inter‐ring C? C bonds. The π–π* transition energies and redox potentials of the cis and trans isomers of bis(benzo[b]phosphole) P‐oxide are very close to each other, suggesting that their optical and electrochemical properties are little affected by the relative stereochemistry at the two phosphorus atoms. The optical properties of the benzo[b]phosphole–benzo[b]heterole hybrids are highly dependent on the benzo[b]heterole subunits. Steady‐state UV/Vis absorption/fluorescence spectroscopy, fluorescence lifetime measurements, and theoretical calculations of the non‐fused and acetylene‐fused benzo[b]phosphole–benzo[b]heterole π systems revealed that their emissive excited states consist of two different conformers in rapid equilibrium.     

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.