Synthesis of Highly Functionalized Pyrrolidines via a Selective Iodide-Mediated Ring Expansion of Methylenecyclopropyl Amides

This manuscript describes a highly selective iodide-mediated, tandem Mannich/cyclization to afford trans-2,3-disubstituted pyrrolidines from methylenecyclopropyl amides in good to excellent yields and selectivities. The reaction scope has been drastically expanded to include a wide array of aromatic, heteroaromatic and α,β-unsaturated imines, as well as a variety of methylenecyclopropyl amides. Additionally, mechanistic studies were carried out to ascertain the nature of the ring-opening/ring-closing mechanism using deuterated substrates. Results from these studies indicate that the primary mechanism is an SN2/SN2 ring opening/ring closing and that iodine- or iodide-mediated isomerization of the iodo enolate is likely occurring.本研究报道了一种高选择性碘离子介导的串联Mannich/环化反应，该反应可由亚甲基环丙基酰胺制备反式-2,3-二取代吡咯烷，产物收率良好至优异且选择性优良。该反应的底物适配范围已大幅拓展，可涵盖多种芳香族、杂芳香族及α,β-不饱和亚胺类底物，同时也兼容多种亚甲基环丙基酰胺底物。此外，本研究借助氘代底物开展机理实验，以明确开环/闭环过程的反应本质。研究结果表明，该反应的主导机理为SN2/SN2型开环-闭环过程，且碘或碘离子介导的碘代烯醇负离子异构化过程大概率存在。