Reactions of 4-substituted-2′-halogenoacetophenones with Grignard reagents

Abstract

The initial reaction of 4-substituted 2′-halogenoacetophenones with an excess of methyl Grignard reagent is shown to be an attack at the 1′-carbonyl to form a halohydrin salt. The various reactions which then follow are substituent dependent. In the 4-hydroxy case [(12) and (16)] the only product is 1-(4-hydroxyphenyl)-2-methylpropan-2-ol (13) which arises via a [1,2]-aryl shift with simultaneous elimination of magnesium halide. When the substituent is 4-methoxy, a second pathway becomes important involving epoxide formation and a subsequent [1,2]-hydride migration to the benzylic position, or attack of the Grignard reagent at the benzylic carbon of the epoxide, When the substituent is 4-bromo, the reaction proceeds exclusively via the epoxide and, following a [1, 2]-hydride shift, leads to the isomeric butanols (33) and (34). The reasons underlying such diversity of reactivity are discussed.