Publication
Title
Directed palladium-catalyzed γ-C(sp³)–H alkenylation of (Aza and Oxa) cyclohexanamines with bromoalkenes : bromide precipitation as an alternative to silver scavenging
Author
Abstract
Directed palladium-catalyzed coupling of remote C(sp3)–H bonds of aliphatic amines with organohalides is a powerful synthetic tool. However, these reactions still possess limitations with respect to cost and resource efficiency, requiring more reactive iodinated reactants and superstoichiometric silver salt reagents. In this work, an efficient regio- and stereospecific silver-free Pd-catalyzed γ-C(sp3)–H alkenylation of cyclohexanamines and heterocyclic analogues with bromoalkenes is reported, which can also be applied on five- 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(sp3)–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 (η2-alkene and a bidentate directing group). The stability of this complex defines 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(sp3)–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 esterification.
Language
English
Source (journal)
ACS catalysis. - -
Publication
2024
ISSN
2155-5435
DOI
10.1021/ACSCATAL.3C04152
Volume/pages
14 :2 (2024) , p. 1157-1172
ISI
001146469700001
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Synthesis of bicyclic amine scaffolds via tandem catalysis.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Record
Identifier
Creation 10.01.2024
Last edited 01.02.2024
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