Benzothiophenes ring synthesis

A related approach has been used for the synthesis of poly(thiaacene)s, which are novel helical aromatic polymers comprised of fused benzothiophene rings, poly(thiaheterohelicene) <20050L755>. 

Cyclisation of 2-arylthio- or 2-aryloxy-aldehydes, -ketones or -acids via intramolecular electrophilic attack on the aromatic ring, with loss of water, creates the heterocyclic ring this route is a common method for the ring synthesis of benzothiophenes. 

In pursuit of additional derivatives, Eli Lilly scientists sought to synthesize constrained analogues of raloxifene. The synthesis of these analogues used a unique method of constructing the benzothiophene ring system through an acid-promoted dehydrative carbocationic cyclization of the hydroxythioacetamide using methanesulfonic acid as illustrated below. 

The synthesis of photochromic compounds containing combinations of benzothiophene and thiophene 70 (04JPP(A)97, 09JMS100), indene 71 (06TL1267), or benzofuran rings 72 and 73 (06BCJ1100, 08BCSJ644) was documented (Scheme 22). 

Reports detailing the chemistry and syntheses of thiophenes, benzothiophenes, and related ring systems that have appeared during the past year are the primary focus of this review. The synthesis of heterocycles including thiophenes has been reviewed <99JCS(P1)2849, 99JH1469>. As always, the author apologizes in advance for all errors and omissions. 

This approach is used for the syntheses of fused heterocycles which have a [l,3]-heteroatom juxtaposition in one of the rings <1996CHEC-II(7)49>. The unambiguous synthesis of tetrahydro-3//-benzothieno[2,3- / imidazole 87, as a target for the potential treatment of anxiety disorders, was accomplished starting from commercially available ethyl 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylate 85 the key formation of the bicyclic heterocycle occurred through a final acid-mediated cyclization of 86 (Scheme 17) <1997SC473>. 

Unlike in the case of the preparation of indoles and benzofuranes, the synthesis of benzothiophenes from o-ethynyl-thiophenols is not known. A close analogy was reported by Larock, where phenylacetylene was coupled with 2-iodothioanisole. Ring closure of the formed o-ethynyl-sulfide was initiated by the addition of different electrophiles. The reaction led to the formation of the benzothiophene core bearing the electrophile in the... 

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... 

SYNTHESIS OF BENZOTHIOPHENES BY FUSION OF SIX-MEMBERED CARBOCYCLIC RINGS TO THIOPHENES... 

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). 

Anodic methoxylation of aromatic ethers via the EEQCp mechanism has found its widest application in the synthesis of quinone bisketals (LXX) from para-dimethox-ybenzenes (LXIX) [79]. Yields are generally excellent, and the reaction is conveniently carried out at constant current in a single cell [42,80]. The reaction has also been shown to work well for naphthalenes [81] and benzothiophenes [82]. As shown in Table 4, a variety of substituents may be present on the ring. When substituents sensitive to cathodic reduction such as -CHO and -CH CHCO Me are present, a divided cell apparatus may be required to obtain reasonable yields of the corresponding bisketals. 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

A synthesis of (+)-estradiol from an alkyl 1,3-dihydrobenzo[c]thiophene-2,2-dioxide involving o-quinodimethane formation by thermal extrusion of SO2 and subsequent cycloaddition has been achieved in an overall yield of 50% (ref. 143). Thus a chiral cyclopentanone component (ref. 144) was used to alkylate the appropriate benzothiophene dioxide and the required tetracyclic stucture obtained directly with avoidance of the customary hydrogenation. It was found desirable at the alkylation stage to enhance deprotonation at Cl by having a cyano group in the benzenoid ring. The ( anotetracycle (R CN) was reacted... 

Synthesis of Benzothiophens by Ring-closure Reactions.—A review of the chemistry of benzothiophens, covering the period 1952—1968, has appeared. ... 

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