Synthesis of fluorinated 3-aminobenzofurans via a tandem S_NAr-cyclocondensation strategy

A small library of twenty-seven novel 3-amino-2,6-disubstituted-4,5,7-trifluorobenzofurans was successfully synthesized with the compounds formed in low to good yield using a tandem S_NAr-cyclocondensation reaction of 4-substituted perfluorobenzonitriles with α-hydroxycarbonyl compounds employing DBU as base. The compounds were prepared as part of a medicinal chemistry project to develop novel fluorinated heterocyclic leads and were characterised by ¹H and ¹⁹F NMR spectroscopy, IR spectroscopy, high resolution mass spectrometry and elemental analysis. The X-ray crystal structure of the 2-(4-methoxybenzoyl)-6-morpholino derivative was determined, which showed the benzoyl substituent to be coplanar with the benzofuran ring, and to form a hydrogen bond to the 3-amino group. Attempts to synthesise the corresponding 3-unsubstituted or 3-methyl analogues using 4-substituted perfluoro-benzaldehydes or acetophenones were unsuccessful, with cleavage of the carbonyl group occurring. A mechanistic study indicated that alkoxide ions attacked the carbonyl group, rather than effecting S_NAr reaction at C-2, leading to loss of a perfluoroaryl anion which was trapped with D₂O.