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

Abstract

Asymmetric cross-electrophile difunctionalization of tethered alkenes has become a powerful tool for the production of chiral cyclic scaffolds; however, the current studies all focus on carbocyclization reactions. Herein, we report an N-cyclization–alkylation reaction and thus showcase the potential of heterocyclization for accessing new enantioenriched cyclic architectures. This work establishes a new approach for enantioselective aza-Heck cyclization/cross-coupling sequence, which remains a long-standing unsolved challenge for the synthetic community. The reaction proceeds with primary, secondary, and a few tertiary alkyl iodides, and the use of newly defined ligands gave highly enantioenriched pyrrolines with improved molecular diversity under mild conditions. The presence of imine functionality allows for further structural variations.

Recent Developments in Enantioselective Domino Reactions. Part B: First Row Metal Catalysts

“…reported a highly enantioselective reductive N ‐cyclization/alkylation of alkene‐tethered oxime esters 205 with alkyl iodides 206 through asymmetric nickel catalysis (Scheme 52). [62] This work represents the first highly enantioselective domino aza‐Heck‐type/cross‐coupling reaction. It required the use of 15 mol% of Ni(PCy 3 ) 2 Cl 2 as precatalyst combined with 17 mol% of chiral pyridinebis‐(oxazoline) ligand 207 in the presence of 1,8‐naphthyridine as an additive and four equivalents of zinc as reductor agent.…”

Recent Advances in N-O Bond Cleavage of Oximes and Hydroxylamines to Construct N-Heterocycle

“…In 2022, Shu’s group [ 52 ] reported the nickel-catalyzed enantioselective iminoalkylation of olefinic oxime esters 66 with alkyl iodides 67 ( Figure 23 ). This method uses a newly defined pyridine bis-(oxazoline) ligand to avoid the β -H elimination of the cyclization intermediate, resulting in a Heck product that can highly enantioselectively generate chiral pyrrolines 68 .…”

Nickel/Quinim Enabled Asymmetric Carbamoyl‐Acylation of Unactivated Alkenes

“…Recently, investigation of this topic has been extended to nonaromatic ring-tethered alkene substrates, providing expedient access to the nonaromatic cyclic molecules. [5][6][7][8][9][10] In particular, difunctionalization of unactivated alkene tethered to carbamoyl chloride recently attracts growing interest, different functionalized chiral γ-or δ-lactams are manufactured via carbamoyl-arylation, [5] -alkylation, [6] -borylation, [7] -cyanation [8] and -alkoxycarbonylation [9] (Scheme 1a). Despite these advances, asymmetric carbamoyl-acylation of unactivated alkene still remains elusive.…”