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

Author(s)

de Toledo, Ian ^[1] ; Grigolo, Thiago ^[1] ; Bennett, James M. ^[2] ; Elkins, Jonathan M. ^{[2, 3]} ; Pilli, Ronaldo A. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, Dept Organ Chem, UNICAMP, BR-13083970 Campinas, SP - Brazil

^[2] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Old Rd Campus Res Bldg, Roosevelt Dr, Oxford OX3 7DQ - England

^[3] Univ Estadual Campinas, Dept Genet & Evolucao, Inst Biol, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

• Document type: Journal article
• Source: Journal of Organic Chemistry; v. 84, n. 21, p. 14187-14201, NOV 1 2019.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/13104-5 - Planning and synthesis of inhibitors based on biological targets: the case of neglected kinases
• Grantee: Ronaldo Aloise Pilli
• Support Opportunities: Regular Research Grants