Photocatalytic hydrogen atom transfer: the philosopher's stone for late-stage functionalization?

Abstract

Applications of photocatalytic Hydrogen Atom Transfer (HAT) methodologies for the Late-Stage Functionalization (LSF) of complex molecules have been discussed in this perspective.

Photochemical C–H Silylation and Hydroxymethylation of Pyridines and Related Structures: Synthetic Scope and Mechanisms

“…35 A milder version of this photochemical process was recently disclosed by DiRocco, Krska and co-workers by using 4 [Ir(dF-CF3-ppy)2(dtbpy)]PF6 as the photocatalyst an benzoyl peroxide (PBO) as the terminal oxidant. 39 Based on the dual reactivity of N-alkoxypyridinium ions (NAPs), 40,41,[42][43][44][45] as alkoxy radical precursors that are good hydrogen abstractors 46,47,48 and as electrophilic partners in Minisci reactions, as previously reported by Hong and co-workers [49][50][51][52][53][54][55]56 we hypothesized that NAPs should be good partner with silanes or methanol to accomplish photocatalytic C-H silylation and hydroxymethylation, respectively (Scheme 1).…”

Tyrosine and Drug-like Late-stage Benzylic Functionalization via Photoredox Catalysis

“…4 Recently, LSF via photoredox catalysis has gained great attention. [5][6][7][8] In this regard, various selective photocatalyzed LSF methodologies, e.g. for the functionalization of C(sp 2 )-H bonds, [9][10] α-heteroatom positions, [11][12][13] or decarboxylation reactions, [14][15] have been developed.…”

“…However, benzylic photocatalyzed LSF is signi cantly underrepresented. 5 In particular, the benzylic functionalization of electron rich compounds such as in tyrosine or other phenolic drug-like derivatives is highly appealing, since this type benzylic C-H bonds are ubiquitous in biomolecules and pharmaceuticals ( Fig. 1, a).…”

“…However, C-H bond discrimination issues often lead to a poor site-selectivity for benzylic positions. 5 In fact, other C-H bonds like in tertiary or α-heteroatom positions are modi ed under similar HAT conditions, which compromises the potential for benzylic LSF. [23][24][25][26] Therefore, alternative methods to overcome the current reactivity and selectivity issues are highly demanded.…”

Bromine as a Visible-Light-Mediated Polarity-Reversal Catalyst for the Functionalization of Aldehydes

“…[4][5][6][7][8] In this context, the emergence of photocatalysis has provided enormous opportunities for C-H functionalization through direct photo hydrogen atom transfer (HAT) catalysis or by the synergistic combinations of photoredox with HAT catalysis. [9][10][11][12][13][14][15][16][17][18] Aldehydes, one of the most abundant and readily available feedstocks, are enabled to generate acyl radicals to achieve umpolung reactivity by photo-induced HAT in a step-and atom-economic fashion. [19][20] However, the acceptors of acyl radicals were limited to electron-de cient alkenes and radical trappers containing electron-withdrawing leaving groups, [21][22][23][24][25] to result in an electrophilic radical intermediate to turn over the redox-neutral photocatalytic cycle ( Fig.…”