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

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.

Figure 1

Bioactive Nortopsentins A–C and pyridyl–imidazole kinase inhibitor SB-633825 (1).

Figure 2

Modular access to 2,4,5-trisubstituted imidazoles.

Scheme 1. Scope of the Oxidation–Condensation Approach to 2,4(5)-Disubstituted Imidazoles

Reaction scale: 0.30 mmol. Reactions performed employing the ketone (1.25 equiv), aldehyde (1.00 equiv), NH₄OAc (5.00 equiv), DMSO (0.75 mL), MeOH (2.75 mL). Yields described correspond to isolated yields after column cromatography. Ketone (1.25 equiv), 48% aq HBr (10 mol %), DMSO, 85 °C, 18 h then aldehyde (1.00 equiv), NH₄OAc (5.00 equiv), MeOH, rt, 24 h. Ketone (1.25 equiv), 48% aq HBr (300 mol %), DMSO, 85 °C, 8 h then aldehyde (1.00 equiv), NH₄OAc (5.00 equiv), MeOH, rt, 24 h. Ketone (1.75 equiv), 48% aq HBr (300 mol %), DMSO, 85 °C, 18 h then aldehyde (1.00 equiv), NH₄OAc (10.00 equiv), MeOH, rt, 24 h.

Scheme 2. Synthesis of 2,4,5-Trisubstituted Imidazole STK10 Kinase Inhibitors