The (β,β′,β″-trifluoro)-tert-butyl (TFTB) group has received very little attention
in the literature. This work presents a direct synthesis of this group
and explores its properties. The TFTB group arises when the methyl
groups of a tert-butyl moiety are exchanged for fluoromethyl
groups. Sequential fluoromethylations result in a decrease of Log P (increasing hydrophilicity), ultimately by 1.7 Log P units in the TFTB group relative to that of tert-butyl benzene itself. A focus is placed on synthetic transformations,
conformational analysis, and metabolism of the TFTB group in the context
of presenting a favorable profile as a motif for the discovery of
bioactives.