Catalyzed and Promoted Aliphatic Fluorination

Abstract

In the last six years, the direct functionalization of aliphatic C-H (and C-C) bonds through user-friendly, radical-based fluorination reactions has emerged as an exciting research area in fluorine chemistry. Considering the historical narratives about the challenges of developing practical radical fluorination in organic frameworks, notable advancements in controlling both reactivity and selectivity have been achieved during this time. As one of the participants in the field, herein, we a provide brief account of research efforts in our laboratory from the initial discovery of radical monofluorination on unactivated C-H bonds in 2012 to more useful strategies to install fluorine on biologically relevant molecules through directed fluorination methods. In addition, accompanying mechanistic studies that have helped guide reaction design are highlighted in context.

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

“…In this context, the advantage of direct C-H fluorination over traditional fluorination methods is that it does not require the introduction of other functional groups. Although many methods have been developed for fluorination reactions [3,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], including the addition of electrophilic fluorine to alkenes [1,28,32], the fluorination of aryl triflates [29] and arylpalladium complexes [2,47], few permit a one-step transformation of unactivated C(sp 3 )-H bonds to C(sp 3 )-F bonds [1,3,36,38,48]. Such a transformation would be highly valuable for the late-stage functionalization (LSF) of complex molecules, such as those in Scheme 1.…”

“…3.3 Directing-group-guided C(sp 3 )-H fluorination 3.3.1 Ketones as directing groups: Related to the curious nearexclusive C2 selectivity of 1-phenylbutan-1-one as reported by Tan and co-workers [198], Lectka and co-workers reported highly selective monofluorination of C(sp 3 )-H bonds that are proximal (β-or γ-) to a carbonyl group [153] (Scheme 21); such selectivity was previously difficult to achieve with PS TTET fluorinations. The ketones, acting as directing groups, served as an elegant method to override the typical polarity matching-governed C(sp 3 )-H fluorination [46,205]. The selectivity for β-or γ-fluorination could be attributed to an interaction of the breaking C(sp 3 )-H bond and the neighboring ketone, which is part of the proposed 5-and 6-membered transition state, respectively.…”

N-Hydroxybenzimidazole as a structurally modifiable platform forN-oxyl radicals for direct C–H functionalization reactions

“… 21 This species can work as a strong hydrogen atom abstraction reagent for C–H activation of various hydrocarbons. 21a – c , 22 Based on recent reports, we conducted the C–H oxidative arylation of cyclooctane with isoquinoline in the presence of a catalytic amount of 1e ( Scheme 5c ). 21b , c As a result, arylated product 13 could be obtained in good yield even without photoirradiation.…”

Regioselective, nucleophilic activation of C F bonds in o-fluoroanilines

“…8,[51][52][53] Much has also been written about the special hydrophobicity and oleophobicity of highly fluorinated aliphatics. [54][55][56] In fluorinated arenes, conjugation and local polarity effects play key roles in governing reactivity and properties.…”