Synthesis of 2-Aryl Azetidines through Pd-Catalyzed Migration/Coupling of 3-Iodoazetidines and Aryl Boronic Acids

Abstract

A palladium-catalyzed cross-coupling of 3-iodoazetidines and nonheteroaryl boronic acids was reported. The [1,1′biphenyl]-2-yldicyclohexylphosphane ligand enabled the reaction that favored the formation of 2-aryl azetidines. The control experiments indicated that the reaction can proceed through either a palladiumhydride/dihydroazete complex or free dihydroazete intermediate followed by hydropalladation.

Desymmetrization of Vicinal Bis(boronic) Esters by Enantioselective Suzuki–Miyaura Cross-Coupling Reaction

“…Aside from five-membered cyclic substrates, those containing four- and six-membered rings are also effective coupling partners. Even though, chain-walking in cross-coupling of four-membered ring substrates has been observed, reactions of diborylcyclobutanes with Pd/ L5 provide single regioisomer products. Of note, the efficiency and selectivity for the reactions were found to be dependent on the nature of the electrophile: a number of bromoarenes react with good stereocontrol; however, reactions with pyridine-based electrophiles occur with diminished enantioselectivity ( 19 , 27 ).…”

A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry

“…However, most studies to date have focused on elaborating the 3-position with a dearth of examples focused on the 2-position . Existing approaches toward 2-substituted azetidines through de novo construction or late-stage functionalization include intramolecular alkylative cyclization, − formation or functionalization of a β-lactam then reduction, , C–H activation, , functionalization of azetines, − functionalization of α-lithiated intermediates, , aza Paternò-Büchi [2 + 2] cycloaddition, − ring expansion of aziridines, − and oxidative hydrogen-atom abstraction followed by cross-coupling. , Advances toward constructing 2-heteroaryl azetidines are comparatively fewer with recent examples using oxidative hydrogen-atom abstraction followed by a Minisci reaction (Figure a) , and decarboxylation of the carboxylic acid (Figure b) or redox-active ester with subsequent cross-coupling (Figure c). − These approaches offer an initial framework, but suffer from issues with regioselectivity, superstoichiometric quantities of azetidine reagents, prefunctionalization of coupling partners, and limited exploration into heteroaryl substrates with diverse functional groups, among other difficulties.…”