Modular Synthesis of Di- and Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors

J Org Chem. 2019 Nov 1;84(21):14187-14201. doi: 10.1021/acs.joc.9b01844. Epub 2019 Sep 30.

Abstract

A one-pot and modular approach to the synthesis of 2,4(5)-disubstituted imidazoles was developed based on ketone oxidation, employing catalytic HBr and DMSO, followed by imidazole condensation with aldehydes. This methodology afforded twenty-nine disubstituted NH-imidazoles (23%-85% yield). A three-step synthesis of 20 kinase inhibitors was achieved by employing this oxidation-condensation protocol, followed by bromination and Suzuki coupling in the imidazole ring to yield trisubstituted NH-imidazoles (23%-69%, three steps). This approach was also employed in the synthesis of known inhibitor GSK3037619A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry*
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry*
  • Ketones / chemistry*
  • Oxidation-Reduction
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry*

Substances

  • Aldehydes
  • Imidazoles
  • Ketones
  • Protein Kinase Inhibitors