Hydroxy-directed fluorination of remote unactivated C(sp³)–H bonds: a new age of diastereoselective radical fluorination

Abstract

We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.

Benzoates as photosensitization catalysts and auxiliaries in efficient, practical, light-powered direct C(sp3)–H fluorinations

“…1b ), free alcohols ( 5a , 5b′ , 5c–5e , 5g ) and free amines ( 6a–6d ) all failed under photocatalytic C(sp 3 )–H fluorinations (Table 3). We note that in the earlier reports of Chen, 8 Tan, 9 a and Lectka, 10 a–e free 1° or 2° alcohols were never reported, only hindered 3° alcohols were tolerated. Neither were free 1°/2°/3° amine moieties; 1° and 2° amines always required protection.…”

“…These data corroborate an energy transfer between MFB and SF , in line with that proposed for previous arylketone catalysts. 9,10 This suggests 3 MFB* is the excited state involved, and its T 1 energy is well matched with that of SF (see Table 4, vide infra ). A radical trapping experiment with 1.5 eq.…”

“…Lu, Soo, Tan and co-workers also observed that the emission peak shape of AQN differed in the presence of SF . 9 b Mixing MFB with larger excesses of SF (Fig. 4C–E) led to buildup of a peak at λ = 467 nm that more closely resembled SF .…”

“…Therefore, our PSAux auxiliary strategy offers future promise as an attachable handle to direct late-stage C(sp 3 )–H fluorination selectivity which (i) is not possible by previous catalytic methods and (ii) allows fluorination to be exogenously directed by the chemist, rather than endogenously directed by the molecule via its inherent functionality. 9 a ,10,12 Of key importance and justifying the use of a PSAux strategy, the 4-fluorobenzoate auxiliaries can be cleaved by known methods 17 to give alcohols or amines in near-quantitative (93–98%) yields (Fig. 3).…”

“…Fluorination regioselectivity was governed by thermodynamic factors endogenous to the substrate; the most electron-rich C(sp 3 )–H bond that forms a stable 2° radical intermediate is fluorinated. Lectka used benzil as an alternative PSCat for the late-stage photocatalytic fluorination of complex molecules, 10 including steroid derivatives, and found that ketones/enones innate to the substrate could direct regioselective C(sp 3 )–H fluorination in a proximal or distal fashion ( Fig. 1A ).…”