PIDA/I₂‑Mediated α- and β‑C(sp³)–H Bond Dual Functionalization of Tertiary Amines

The α,β-C­(sp3)–H bond dual functionalization of tertiary amines is still a challenging task for both organic and medicinal chemists. Herein a direct, mild, metal-free, and site-specific method mediated by PIDA/I2 was developed for α,β-C­(sp3)–H bond dual functionalization of tertiary amines, and this method can provide facile access to α-keto lactams or rarely studied α,α-diiodo lactams. Moreover, this method was used for the effective syntheses of three natural products [obscurumine C (13), obscurumine O (17), and strychnocarpine (18)] and direct preparation of mimics of the in vivo metabolites of two FDA-approved drugs (imatinib and donepezil) in 36–60% overall yield. The method represents a promising protocol for the late-stage α,β-C­(sp3)–H bond oxidative dual functionalization of tertiary amine-containing drugs and complex natural products.对于有机化学家和药物化学家而言，叔胺的α,β-碳(sp³)-氢键双官能化仍是一项极具挑战性的研究课题。本文开发了一种由PIDA/I₂介导的直接、温和、无金属且位点特异性的叔胺α,β-碳(sp³)-氢键双官能化方法，该方法可便捷制备α-酮内酰胺或鲜有研究的α,α-二碘代内酰胺。此外，该方法可用于三种天然产物[obscurumine C（13号）、obscurumine O（17号）以及strychnocarpine（18号）]的高效合成，还能以36%~60%的总收率直接制备两种美国食品药品监督管理局（Food and Drug Administration，FDA）获批药物——伊马替尼与多奈哌齐的体内代谢物模拟物。该方法为含叔胺结构的药物及复杂天然产物的后期α,β-碳(sp³)-氢键氧化双官能化提供了一种极具应用前景的合成策略。