Radical Aza-Heck Cyclization of Imidates via Energy Transfer, Electron Transfer, and Cobalt Catalysis

Abstract

A radical aza-Heck cyclization has been developed to afford functionally rich products with four contiguous C-heteroatom bonds. This multicatalytic strategy provides rapid syntheses of dense, medicinally relevant motifs by enabling the conversion of alcohol-derived imidates to heteroatom-rich fragments containing vinyl oxazolines/oxazoles, allyl amines, β-amino alcohols/halides, and combinations thereof. Mechanistic insights of this process show how three distinct photocatalytic cycles cooperate to enable: (1) imidate radical generation by energy transfer, (2) dehydrogenation by Co catalysis, and (3) catalyst turnover by electron transfer.

N–O Bond Activation by Energy Transfer Photocatalysis

“…Furthermore, N-aryl-N-allyloxy oximes were exploited in an Ir/ Co-catalyzed transformation to access functionalized 1,3oxazolines (Scheme 4l). 51 Our laboratory mainly focused on the EnT chemistry of oxime esters. was calculated to be 44.05 kcal/mol, which is lower than triplet excited state energy of 5a (E T = 47.3 kcal/mol), indicating feasible N−O bond homolysis.…”

Enantioselective Reductive N-Cyclization–Alkylation Reaction of Alkene-Tethered Oxime Esters and Alkyl Iodides by Nickel Catalysis

“…Among various methods, the aza-Heck cyclization has been a powerful approach to these compounds . This chemistry was initially developed for the synthesis of pyrroles and later expanded to the production of various N -heterocycles, including pyrrolines that are difficult to access via nucleophilic N -cyclization protocols. , Recent progress on tandem aza-Heck cyclization and cross-couplings led to a further increase in molecular diversity . However, their enantioselective variants are rare. , This can be partly ascribed to the complicated mechanisms involved in these reactions, radical cyclization versus N–M migratory insertion; the former delivers racemic compounds.…”

Pd(II)-Catalyzed Aminoacetoxylation of Alkenes Via Tether Formation

“…Even if the oxyamination was not successful, these Heck-like cyclization products also represent valuable building blocks bearing a versatile alkene. 21 …”

“…Even if the oxyamination was not successful, these Heck-like cyclization products also represent valuable building blocks bearing a versatile alkene. 21 Inspired by a recent work by Beccalli and co-workers, 12g,22 a series of hypervalent iodine reagents (PhI(OCOR) 2 ) other than commercially available PhI(OAc) 2 was investigated as both oxidant and carboxylate source. A lower reactivity was observed when PIDA was replaced with 2 equiv of bis(tertbutylcarbonyloxy)iodobenzene, affording the corresponding pivalate compound 2v in 38% yield as a single diastereoisomer.…”

“…Indeed, exclusive formation of elimination product 2u was observed (52% yield and >20:1 dr). Even if the oxyamination was not successful, these Heck-like cyclization products also represent valuable building blocks bearing a versatile alkene …”