1,4-Dioxane → 1-{[(5S,7S)-7-methyl-2-oxo-3-(2-propyn-1-yl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile

Participants

Reaction Conditions

Reaction Steps

To a 20 mL microwave tube was added 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (840 mg, 2.99 mmol) and propargyl amine (822 mg, 14.93 mmol) in MeOH (5 mL). The tube was sealed and heated at 100° C. for 2 h on a hotplate. The reaction mixture was then evaporated down directly to a crispy foam, codistilled 2× with DCM, and left on highvac for 3 h to remove any residual MeOH and the volatile amine. The yellow residue was then treated with CDI (2.42 g, 14.93 mmol) and 1,4-dioxane (5 mL) was added. The reaction mixture was stirred and heated at 100° C. for 2 h, then left at RT overnight. LCMS then indicated the reaction was not complete. The reaction mixture was then heated at 120° C. for 6 h. The mixture (dark orange oil) was loaded onto florisil and purified using silica gel chromatography CISCO): 0.5-5% MeOH/DCM (30 min), 5% (10 min), 120 g silica. The desired product eluted at 18 min. The product was dried under vacuum at RT overnight to yield 1-{[(5S,7S)-7-methyl-2-oxo-3-(2-propyn-1-yl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an yellow oil (109 mg, 5% yield). MS (m/z) 363 (M+H+).

Provenance & Evidence