CONVENIENT SYNTHESIS OF BIPHENYL-2-CARBOXYLIC ACIDS VIA THE NUCLEOPHILIC AROMATIC-SUBSTITUTION REACTION OF 2-METHOXYBENZOATES BY ARYL GRIGNARD-REAGENTS

Nucleophilic aromatic substitution (S(N)Ar) of 2-methoxybenzoic esters derived from 2,6-dialkylphenols by aryl Grignard reagents affords 1,1'-biphenyl-2-carboxylates in excellent yields by proper choice of the bulk of the 2,6-dialkyl-substituents. The phenoxyl protecting groups can be easily removed from the resulting biphenyl-2-carboxylates to the free acids by treatment with potassium hydroxide in aqueous ethanol (2,4,6-trimethylphenyl and 2,6-diisopropylphenyl esters) or sodium methoxide in toluene-hexamethylphosphoric triamide (2,6-di-t-butyl-4-methylphenyl esters). The regioselective biphenyl coupling reaction via the SNAr process is utilized for the key-step construction of the biphenyl skeleton in a formal synthesis of cannabinol.