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A general strategy for C(sp³)-H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor.

ABSTRACT: Photoredox catalysis has provided many approaches to C(sp³)-H functionalization that enable selective oxidation and C(sp³)-C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp³)-H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp³)-H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles-including halides, water, alcohols, thiols, an electron-rich arene, and an azide-to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical-a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis-enabling new site-selectivity for late-stage C(sp³)-H functionalization.

SUBMITTER: Leibler IN

PROVIDER: S-EPMC8630022 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Iron-catalyzed remote functionalization of inert C(sp3)-H bonds of alkenes via 1,n-hydrogen-atom-transfer by C-centered radical relay.

Project description:As an alternative approach to traditional C-H activation that often involved harsh conditions, and vicinal or primary C-H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)-H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido-ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

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