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Updated: Jul 17, 2025

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
Published on: January 19, 2016
Aryl (β,β',β″-Trifluoro)-tert-butyl: A Candidate Motif for the Discovery of Bioactives
Luca S Dobson1, Qingzhi Zhang1, Benjamin A McKay1
1School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
Abstract:
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.
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