Intermolecular 1,2-Difunctionalization of Alkenes Enabled by Fluoroamide-Directed Remote Benzyl C(sp³)–H Functionalization

Abstract

A copper-catalyzed remote benzylic C−H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite siteselectivity, broad substrate scope, and wide utilizations of latestage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in twocomponent alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f ][1,2]thiazepine 1,1-dioxides.

The synthesis of seven- and eight-membered rings by radical strategies

“…In 2020, Sun, Song, Li, and co-workers described a unique seven-membered ring formation strategy via Cu-mediated C(sp 3 )–H functionalization, leading to the seven-membered cyclization of N -fluoro- o -alkylarylamide derivatives (Scheme 10). 29 The functionalization of benzylic C(sp 3 )–H needs to be achieved in this method, which was more difficult and innovative than before. However, it is worth noting that the reaction conditions did not become harsh, and only the copper catalyst, substituted bipyridines as the ligands, and Na 2 HPO 4 as the base were required.…”

Divergent regioselective Heck-type reaction of unactivated alkenes and N-fluoro-sulfonamides

“…However, the interaction of N -fluoro-amides with alkenes has rarely been explored. A seminal work was disclosed very recently by Li in benzylic radical-initiated difunctionalization of styrene derivatives 54 .…”

A three-component difunctionalization of N-alkenyl amides via organophotoredox radical-polar crossover

“…One-pot syntheses of such complex molecules lead to the rapid preparation of natural products and bioactive molecules. The 1,2-difunctionalization of alkenes via three-component transformations is thus becoming a well-established method that has been undertaken using transition metal catalysis, 1 photocatalysis, 2 or hypervalent iodine reagents. 3…”