Synthesis of benzofurans and benzopyrans

Abstract

Syntheses of 2,3-dihydrobenzofurans and 3,4-dihydrobenzopyrans normally involve several stages, therefore efficient syntheses of these compounds are desirable. A number of 3,4-dihydrobenzopyrans derivatives were prepared in one pot syntheses. The reaction is thought to proceed through cation intermediates, involving allylic cations generated by the reaction of allyl alcohols, 1,3-dienes, or diols in the presence of acids such as trifluoroacetic acid (TFA), or in a solution of glacial acetic and a metal catalyst or glacial acetic acid and sulphuric acid, followed by reaction with nucleophiles such as phenols or hydroquinones. This leads to the formation of allyl aryl ethers which rearrange via a [3,3]-sigmatropic reanangement and acid-catalysed intramolecular cyclisation, to give the conesponding 3,4-dihydrobenzopyrans. 5-Formyl-2,3-dihydrobenzofuran and 6-formylamino-3,4-dihydrobenzopyran were synthesized by several routes and the isolated products exhibited cis-trans isomerism. It was found that the introduction of an alkyl substituent at carbon-4 in the model benzopyran locks the 2,3,4-alkyl substituents into axial and equatorial orientations. This may influence the peroxyl-radical scavenging activity of these compounds by altering the extent of orbital overlap between the 2p-type lone pair on the pyran oxygen and the aromatic 1t-electron system. 2,3-Dihydrobenzofurans such as 5-hydroxy-2,3-dihydrobenzofuran have been shown to have better antioxidant activity than alpha-tocopherol due to the influence of the smaller, more strained ring, which allows better overlap of the oxygen lone pair and the 1t-electrons in the aromatic system. 5-Hydroxy-2,3-dihydrobenzofuran was efficiently synthesised in an improvement on the yields previously reported in the literature. A series of substituted 2,3-dihydrobenzofurans were synthesised by the reaction of phenols with allylic alcohols or aldehydes in the presence of trifluoroacetic acid or catalytic amounts of sulphmic acid, which also promoted the acid-catalysed intramolecular cyclisation.