A [3+3] Aldol-S_NAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives

A one-pot [3+3] aldol-S_NAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde S_NAr acceptors (dielectrophiles) in the presence of K₂CO₃ in DMF at 65-70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by S_NAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where S_NAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate esters as the products.