Mn-Mediated Radical-Ionic Annulations of Chiral N‑Acylhydrazones

• Published in: Journal of organic chemistry 2015-06, Vol.80 (12), p.6432-6440
• Main Authors: Slater, Kara A, Friestad, Gregory K
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.5b00863

Sequencing a free radical addition and nucleophilic substitution enables [3 + 2] and [4 + 2] annulations of N-acylhydrazones to afford substituted pyrrolidines and piperidines. Photolysis of alkyl iodides in the presence of Mn2(CO)10 leads to chemoselective iodine atom abstraction and radical addition to N-acylhydrazones without affecting alkyl chloride functionality. Using radical precursors or acceptors bearing a suitably positioned alkyl chloride, the radical addition is followed by further bond construction enabled by radical–polar crossover. After the alkyl radical adds to the imine bond, the resulting N-nucleophile displaces the alkyl chloride leaving group via 5-exo-tet or 6-exo-tet cyclizations, furnishing either pyrrolidine or piperidine, respectively. When both 5-exo-tet and 6-exo-tet pathways are available, the 5-exo-tet cyclization is preferred. Isolation of the intermediate radical adduct, still bearing the alkyl chloride functionality, confirms the order of events in this radical–polar crossover annulation. A chiral oxazolidinone stereocontrol element in the N-acylhydrazones provides excellent stereocontrol in these reactions.