A site selective functionalisation of 1,3-bis(trifluoromethyl)benzene

Abstract

1,3-Bis(trifluoromethyl)benzene was regioselectively metalated and subsequently carboxylated at position 2 to give 2,6-bis(trifluoromethyl)benzoic acid. Treatment of the acid with sulphur tetrafluoride gave 2,6-bis(trifluoromethyl)benzoyl fluoride which was readily converted to 2,6-bis(trifluoromethyl)benzyl alcohol and further to 2,6-bis(trifluoromethyl)benzaldehyde. Bromination of 2,6-bis(trifluoromethyl)benzoic acid with 1,1-dibromo-5,5-dimethylhydantoin proceeded regioselectively affording 4-bromo-2,6-bis(trifluoromethyl)benzoic acid almost quantitavely. The latter was fluorinated to the corresponding acid fluoride which on treatment with methanolic sodium methoxide gave 4-methoxy-2,6-bis(trifluoromethyl)benzoic acid or its methyl ester, depending on the reaction conditions. 4-Methoxy-2,6-bis(trifluoromethyl)benzoic acid, via its acid fluoride, was also transformed, first to the corrsponding benzyl alcohol, then to the benzaldehyde. Lithiation of 4-methoxy-2,6-bis(trifluoromethyl)benzoic acid, followed by methylation, proceeded with low selectivity, nevertheless, methyl 4-methoxy-3-methyl-2,6-bis(trifluoromethyl)benzoate was formed as the main product which was stepwise converted to 4-methoxy-3-methyl-2,6-bis(trifluoromethyl)benzyl alcohol and 4-methoxy-3-methyl-2,6-bis(trifluoromethyl)-benzaldehyde, albeit in low total yield.