Remote C-H Functionalization via Selective Hydrogen Atom Transfer

Abstract

The selective functionalization of remote C-H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C-H functionalization. This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena.

Keywords: hydrogen atom transfer; nitrogen-centered radicals; oxygen-centered radicals; radicals; remote C–H functionalization.

Scheme 1

Fundamental mechanistic steps of intramolecular hydrogen atom transfer (HAT)

Scheme 2

δ C–H Amination via N-centered radicals by N–X homolysis

Scheme 3

δ C–H Amination via in situ N–I formation and homolysis

Scheme 4

Modern improvements to Suarez’s δ C–H amination

Scheme 5

Triiodide strategy for δ C–H amination of methylenes

Scheme 6

δ C–H Amination via azide-derived N-radicals and nitrenes

Scheme 7

δ C–H Halogenation via halide radical traps

Scheme 8

γ C–H Halogenation of alcohols via N–X homolysis

Scheme 9

γ,δ-Amino-iodination of amides via amination/scission cascade

Scheme 10

Photoredox-catalyzed γ or δ C–H alkylation via amidyl radicals

Scheme 11

γ C–H Functionalization via iminyl N(sp²) radicals

Scheme 12

C–H Arylation via vinyl azide-derived N(sp²) radicals

Scheme 13

β C–H Functionalization of amines via amidine radicals

Scheme 14

β C–H Amination of alcohols via imidate radicals

Scheme 15

Norrish photochemical strategy for C–H functionalization

Scheme 16

The Barton reaction: δ C–H amination via O-centered radicals

Scheme 17

δ C–H Halogenation via metal-mediated O–X cleavage

Scheme 18

δ C–H Oxygenation of alcohols via in situ O–X formation

Scheme 19

δ C–H Alkylation via O–SPh or O–NPhth cleavage

Scheme 20

δ C–H Oxygenation via in situ oxime-derived radicals

Scheme 21

δ C–H Oxygenation via in situ hydroxylamine radicals

Scheme 22

δ C–H Lactonization via in situ carboxylate O–H oxidation

Scheme 23

δ Alkylation via vinyl bromide derived C(sp²) radicals

Scheme 24

α-Ether C–H functionalization via HAT from aryl radicals

Scheme 25

C–H Functionalization of α-amides via HAT from aryl radicals

Scheme 26

C–H Alkylation of α-amines and α-amides via aryl radicals

Scheme 27

Metal-catalyzed α C–H functionalization via aryl radicals

Scheme 28

α-Amino C–H functionalization via arenediazonium-derived radicals

Scheme 29

Remote C–H functionalization via ArN₂-derived radicals

Scheme 30

Anomeric radicals derived from alkyl bromides

Scheme 31

δ C–H Alkylation via atom-transfer of an C(sp³)–I

Scheme 32

Pd-Catalyzed, remote desaturation via C(sp³)–I