Directed Palladium-Catalyzed γ-C(sp~3)-H Alkenylation of(Aza and Oxa)Cyclohexanamines with Bromoalkenes:Bromide Precipitation as an Alternative to Silver Scavenging

摘要

Directed palladium-catalyzed coupling of remote C(sp~3)-H bonds of aliphatic amines with organohalides is a powerful synthetic tool.However,these reactions still possess limitations with respect to cost and resource efciency,requiring more reactive iodinated reactants and superstoichiometric silver salt reagents.In this work,an efcient regio-and stereospecifc silver-free Pd-catalyzed γ-C(sp~3)-H alkenylation of cyclo-hexanamines and heterocyclic analogues with bromoalkenes is reported,which can also be applied on fve-and seven-membered rings.DFT methods revealed that the oxidative addition of the organobromide to Pd(II)is not the rate-limiting step but rather γ-C(sp~3)-H bond activation in the substrate.The lowest energy complex in the catalytic cycle is a Pd(II)-Br complex coordinated with the reaction product(η~2-alkene and a bidentate directing group).The stability of this complex defnes the overall energy span of the reaction.Co-catalyst KOPiv plays a pivotal role by exchanging bromide for pivalate in the complex,via precipitation of the KBr coproduct.This removal of bromide from the reaction media decreases the energy span,avoiding the use of superstoichiometric silver salt reagents and allowing decoordination of the reaction product.In addition,pivalate facilitates the C(sp~3)-H bond activation in the substrate once another substrate molecule is coordinated.The reaction conditions could be directly applied for(hetero)arylation given the weaker coordination of the reaction product,featuring a(hetero)aryl versus alkenyl and change in resting state.The picolinoyl directing group can be removed via amide esterifcation.