Aryl (β, β', β''-trifluoro)-tert-butyl: a candidate motif for the discovery of bioactives

David O'Hagan*, David Bradford Cordes, Luca Dobson, Oluwayinka Omobolanle Oke, Qingzhi Zhang, Rodrigo Cormanich, Chukwuemeka Isanbor, Benjamin McKay, Mohd Faheem Khan, Bruno Piscelli, Cormac Murphy

*Corresponding author for this work

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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.
Original languageEnglish
Number of pages6802
JournalOrganic Letters
Volume25
Issue number37
Early online date8 Sept 2023
DOIs
Publication statusPublished - 22 Sept 2023

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