Iron-Catalyzed Intermolecular C–N Cross-Coupling Reactions via Radical Activation Mechanism

Abstract

A concept for intermolecular C–N cross-coupling amination has been discovered using tetrazoles and aromatic and aliphatic azides with boronic acids under iron-catalyzed conditions. The amination follows an unprecedented metalloradical activation mechanism that is different from traditional metal-catalyzed C–N cross-coupling reactions. The scope of the reaction has been demonstrated by the employment of a large number of tetrazoles, azides, and boronic acids. Moreover, several late-stage aminations and a short synthesis of a drug candidate have been showcased for further synthetic utility. Collectively, this iron-catalyzed C–N cross-coupling should have wide applications in the context of medicinal chemistry, drug discovery, and pharmaceutical industries.

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

“…It has been shown that Fe(II) complexes of porphyrins, generated in situ from the reduction of Fe(III) complexes with zinc dust, can effectively activate 1,2,3,4-tetrazoles, which serve as the surrogates for organic azides, to generate the corresponding α-Fe(III)-aminyl radicals ( Scheme 15 ). [ 93 – 95 ] These α-Fe(III)-aminyl radicals are capable of engaging radical addition to both C=C and C≡C bonds, as well as abstracting hydrogen atoms from a variety of C–H bonds, leading to catalytic cyclization and amination processes via a stepwise radical pathway ( Scheme 16 ). For instance, the Fe(II)-based metalloradical system has been applied to intermolecular denitrogenative annulation of 1,2,3,4-tetrazoles with alkynes, where radical addition to C≡C bonds is a key step, giving rise to the general synthesis of functionalized imidazopyridines ( 81 ) in good to high yields.…”

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

“…It has been shown that Fe(II) complexes of porphyrins, generated in situ from the reduction of Fe(III) complexes with zinc dust, can effectively activate 1,2,3,4‐tetrazoles, which serve as the surrogates for organic azides, to generate the corresponding α‐Fe(III)‐aminyl radicals (Scheme 15). [93–95] These α‐Fe(III)‐aminyl radicals are capable of engaging radical addition to both C=C and C≡C bonds, as well as abstracting hydrogen atoms from a variety of C−H bonds, leading to catalytic cyclization and amination processes via a stepwise radical pathway (Scheme 16). For instance, the Fe(II)‐based metalloradical system has been applied to intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles with alkynes, where radical addition to C≡C bonds is a key step, giving rise to the general synthesis of functionalized imidazopyridines ( 81 ) in good to high yields [96] .…”

The Recent Advances in Iron‐Catalyzed C(sp3)−H Functionalization

“…[33] Iron complexes efficiently catalyze a range of C(sp 3 )À H activation reactions through the radical pathway and are also compatible with the synthesis of biologically active compounds due to their higher earth abundance and low biological toxicity. [34,35] Iron complexes have a unique reactivity profile in the context of combining both iron chemistry and iron catalysis, which has grabbed significant attention from researchers and become an emerging field in organic chemistry. An iron-based catalytic system exhibited two different modes of reactivity.…”