Preparation of 4-aryl-β-carboline-3-carboxamides by Suzuki–Miyaura cross-coupling applied to a 4-iodo precursor obtained by ortho- directed lithiation

Abstract

The 4-iodo-β-carboline-3-carboxamide derivative 2 was obtained by ortho-directed metalation of the phenylcarboxamide precursor 5 using methyllithium and iodine followed by in situ Nmethylation with methyl iodide. Compound 2 reacted with a variety of aryl-and heteroarylboronic acids under classical Suzuki-Miyaura palladium-catalyzed coupling conditions to give the corresponding 4-aryl (7a-d, 7f) and 4-heteroaryl (7g, 7h) β-carboline-3-carboxamides. While this reaction failed in the case of 3,4,5-trimethoxyphenylboronic acid, conditions were found [Pd(OAc) 2 , dppf, CsF in dioxane-ethanol] which allowed formation of the coupled product 7e in high yield. The N,N-dimethylsulfamoyl protecting group was easily removed using a trifluoroacetic acid-trifluoromethanesulfonic acid mixture. Reductive amination of the 4-(2-formylphenyl)-β-carboline derivative 7f with benzylamine followed by sodium hydride-promoted cyclization provided the novel benzazepino-β-carboline derivative 9.