Benzothiophene derivatives, synthesis

In 2004, Lemaire[73] developed a new mechanism for the synthesis of benzo[h]thiophene through palladium-catalyzed C-H arylation of benzothiophene derivatives with aryl iodides. Mori [74] discovered a new catalytic system for the... 

The Hurd-Mori cyclization and Lalezari cyclization of a-methylene ketones are by far the most widely used routes to 1,2,3-thiadiazole and 1,2,3-selenodiazole, respectively.This approach has been applied in the synthesis of a variety of 1,2,3-thiadiazoles 129 (13JHC630) andl31 (13OT4038) from the corresponding hydrazones. Thiadiazoles 132, derived from 131, can be effectively converted to benzothiophene derivatives (see Section 5.5.4.2). 

In 2006, Berens et al. reported the synthesis of novel benzothiophene-based DuPHOS analogues, which gave excellent levels of enantioselectivity when applied as the ligands to the asymmetric rhodium-catalysed hydrogenation of various olefins, such as dehydroamino acid derivatives, enamides and itaco-nates (Scheme 8.10). ... 

A versatile and regioselective synthesis of benzo[b]furans, naphthalenes, indoles and benzothiophenes was achieved by reaction of o-alkynylarene and heteroarene carboxaldehyde derivatives in the presence of iodonium ions. The reaction mechanism was also discussed <06CEJ5790>. 

The synthetic methods will be arranged in order of bond formation, beginning with the formation of one bond, between sulfur and carbon-2 of thiophene, and proceeding around the ring, then two bonds, etc. This method is outlined in the chapter by Meth-Cohn (B-79MI31500) who has calculated that there are 19 different ways that thiophenes can be formed by different bond formations. Of these only 11 are of practical value currently. We have treated benzothiophenes and other polycyclic thiophenes as derivatives of thiophene, and discussed their synthesis in the specific bond formation sections. Likewise since methods... 

Another useful source of the CS fragment in this synthesis scheme is dichlorosulfine. It has been shown to react with diaryldiazomethanes to yield 2-chlorobenzo[h]thiophene 1-oxides in reasonable yields (72RTC1345). The reaction is quite successful when X = H, 4-Me, 4-C1 or 3-OMe (Scheme 20) but failed when X = 4-OMe. The reaction presumably proceeds by a [3 + 2] cyclization to form an intermediate thiadiazole derivative, which loses nitrogen to give an episulfoxide that can rearrange to the final product (Scheme 20). Since benzothiophene sulfoxides are easily reduced, this constitutes a new thiophene synthesis. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Similar elimination reactions are employed in the synthesis of the benzologs of five-membered heterocyclic compounds. For example, /3-phenylethyl alcohols having hydroxyl, sulfhydryl, and amino groups in the ortbo position ate cyclized to the dihydro derivatives of benzofuran, benzothiophene, and benzopyrrole, respectively. Likewise, dehydro-halogenation of /3-(o-hydroxyphenyl)-ethyl bromide gives dihydtobenzo-furan in 72% yield. ... 

The heterocyclic 5,5-difluoro-l//-thiacyclopropa / indene (12) was synthesized by eycloaddi-tion of the appropriate cxocyclic diene to l,2-dichloro-3,3-difluorocyclopropene, in analogy to the synthesis of the parent hydrocarbon/°° but was too short-lived to allow full characterization/ The oxa analog, in turn, could not be isolated. No difficulties were encountered with the 1,3-dihydro derivatives of 5,5-difluoro-5//-cyclopropa[/][2]benzothiophene 10a and 10b. "... 

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