Ni-Catalyzed Enantioselective Intramolecular Mizoroki-Heck Reaction for the Synthesis of Phenanthridinone Derivatives

J Org Chem. 2023 Jul 7;88(13):8203-8226. doi: 10.1021/acs.joc.3c00202. Epub 2023 Jun 15.

Abstract

A Ni-catalyzed enantioselective intramolecular Mizoroki-Heck reaction has been developed to transform symmetrical 1,4-cyclohexadienes with attached aryl halides into phenanthridinone analogues containing quaternary stereocenters. Herein, we report important advances in reaction optimization enabling control of unwanted proto-dehalogenation and alkene reduction side products. Moreover, this approach provides direct access to six-membered ring heterocyclic systems bearing all-carbon quaternary stereocenters, which have been much more challenging to form enantioselectively with nickel-catalyzed Heck reactions. A wide range of substrates were demonstrated to work in good to excellent yields. Good enantioselectivity was demonstrated using a new synthesized chiral iQuinox-type bidentate ligand (L27). The sustainability, low price of nickel catalysts, and significantly faster reaction rate (1 h) versus that of a recently reported palladium-catalyzed reaction (20 h) make this process an attractive alternative.

MeSH terms

  • Catalysis
  • Molecular Structure
  • Nickel* / chemistry
  • Palladium* / chemistry
  • Stereoisomerism

Substances

  • Nickel
  • Palladium