Halo-benzothiophenes

Like Larock, Flynn and co-workers utilized various electrophilic cyclization reactions to produce desirable halo-benzothiophenes for use in cross-coupling reactions. The following benzothiophene synthesis involved a Suzuki cross-coupling reaction to form new aryl-aryl bonds at the C3 position. The product has been investigated in the search for potent tubulinbinding agents. ... 

Rejnak M, Klima J, Svodoba J et al (2004) Synthesis and electrochemical reduction of methyl 3-halo-l-benzothiophene-2-carboxylates. Collect Czech Chem Commum 69 242-260... 

Benzofurans and benzothiophenes are sometimes obtained by condensation of active methylene and aldehyde groups in ortho substituents on the benzene ring. " The starting materials in the furan series are conveniently prepared in situ torn phenolic aldehydes and a-halo ketones or CL-halo esters. 

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. ... 

Palladium(0)-catalysed coupling of an orf/to-halophenolic ether (thioether) with a terminal alkyne (or with an alkynylboronic ester ) and ring closure promoted with an electrophile - iodine has been most often used - is an excellent method to make both benzothiophenes °° ° and benzofurans. ortfto-AIkynyl-phenols can be comparably closed with palladium catalysis in the presence of copper(II) halides to give the corresponding 3-halo-benzofurans, ° and ortfto-alkynyl pyridin-2- and -3-yl acetates likewise ring close with iodine, generating furopyridines. ... 

---