Metalloradical Catalysis: General Approach for Controlling Reactivity and Selectivity of Homolytic Radical Reactions

Abstract

Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two-electron heterolytic ionic chemistry. While one-electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high-energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal-centered radicals present in open-shell metal complexes as one-electron catalysts for homolytic activation of substrates to generate metal-entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two-electron catalysis by transition metal complexes, MRC operates through one-electron chemistry utilizing stepwise radical mechanisms.

Keywords: C−H functionalization; aziridination; cyclopropanation; metalloradical catalysis; radical reaction.

Scheme 1.

General catalytic mechanism of metalloradical catalysis.

Scheme 2.

Metalloporphyrins: general platform for metalloradical catalysts.

Scheme 3.

Generation of α-Co(III)-alkyl radicals and α-Co(III)-aminyl radicals.

Scheme 4.

Representative examples of Co(II) complexes of D₂-symmetric chiral amidoporphyrins with tuneable pocket- and cavity-like environments.

Scheme 5.

General mechanism for radical olefin cyclopropanation with diazo compounds via Co(II)-based MRC. Reprinted from ref. [4] with permission from Elsevier.

Scheme 6.

Selected examples of chiral cyclopropanes from catalytic radical cyclopropanation, cyclopropenation and bicyclization via Co(II)-based MRC.

Scheme 7.

General mechanism of radical aziridination of alkenes with organic azides via Co(II)-based MRC and selected examples of substrates.

Scheme 8.

Selected examples of chiral aziridines from catalytic radical aziridination and bicyclization via Co(II)-based MRC.

Scheme 9.

General mechanism for radical C–H alkylation via Co(II)-based MRC.

Scheme 10.

Selected examples of carbocyclic and heterocyclic compounds from catalytic intramolecular radical C–H alkylation via Co(II)-based MRC.

Scheme 11.

General mechanism for radical C–H amination via Co(II)-based MRC.

Scheme 12.

Selected examples of N-heterocyclic compounds from catalytic intramolecular radical C–H amination via Co(II)-based MRC.

Scheme 13.

Selected examples of amine compounds from catalytic intermolecular radical C–H amination via Co(II)-based MRC.

Scheme 14.

Selected examples of cyclic compounds from catalytic radical cyclization reactions via Co(II)-based MRC.

Scheme 15.

Fe(II)-based MRC involving α-Fe(III)-aminyl radicals generated from activation of tetrazoles by in situ-reduced Fe(II) complexes of porphyrins.

Scheme 16.

Selected examples of N-heterocyclic and amine compounds from catalytic radical cyclization reactions via Fe(II)-based MRC.

Scheme 17.

Radical cyclopropanation of alkenes with diazo compounds via Fe(III)-based MRC involving α-Fe(IV)-alkyl radicals and γ-Fe(IV)-alkyl radicals.