Synthesis of Benzothiophenes and Benzofurans

1 From 2-Arylthio- or 2-Aryloxy-Aldehydes, -Ketones or -Acids 

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 order to produce hetero-ring unsubstituted benzothiophenes an arylthioacetaldehyde acetal is generally employed, prepared in turn, from bromoacetaldehyde acetal and the thiophenol. An exactly parallel sequence produces 2,3-unsubstitutedbenzofurans. 2-Aryloxy-acetates (or 1-aryloxy-acetones) heated with DMFDMA, produce enamines which cycUse on treatment with zinc chloride, giving 3-unsubstituted benzofuran-2-carboxylates (3-unsubstituted 2-acetyl-benzofurans).  

Comparable acid- (or Lewis acid) -catalysed ring closures of 2-arylthio- and 2-aryloxy- -ketones, and -2-arylthio- and 2-aryloxyacetyl- chlorides lead to 3-substituted heterocycles and 3-oxygenated heterocycles, respectively. It is possible to combine the preparation of the arylthio-ketone and the ring closure steps utilising two solid-supported reagents in a one-pot procedure, as illustrated. Formation of 3-aryl-benzothiophenes by this route can be complicated by partial or complete isomerisation to the 2-aryl-heterocycle,however using boron trifluoride as the Lewis acid produces only the 3-aryl-isomer. 3-Tosylamino-benzofurans can be prepared from aryl glyoxal hydrates.  

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