ZnBr2-Catalyzed Rearrangement of a-Haloketones to Terminal Carboxylic Acids

1 ZnBr2-Catalyzed Rearrangement of a-Haloketones to Terminal Carboxylic Acids 

Reagents and conditions Mel (2.4 equiv.)/NaH (3 equiv.),THF //.3-butyn-1-ol, Pd(0)CU2Br2/TEA, reflux  

In this step, the sodium salt of 2-(4-bromophenyl)-2,2-dimethylacetic acid 13 was lithiated via a metal-halogen exchange using f-BuLi, and subsequently 4-[4-(hydroxydiphenylmethyl)piperidini-l-yl]butyraldehyde 14 was arylated to afford fexofenadine. 

15 h vi ethylene glycol, p-TsOH, benzene, reflux, 24 h vii. NaOH, MeOH r.l. 30 min viii. Jones oxydation. 

The reaction proceeds via ZnBr2 catalysis with formation of an acetal intermediate 15A, and polarization of the C-Br bond. Transposition of the hemiacetal intermediate 15B and 1,2-migration of phenyl group affords the 2,2-dimethlyphe-nylacetic acid ester 16. 

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