Highly Cumulated Radical Cascade Reaction of aza‐1,6‐Enyenes: Stereoselective Synthesis of exo‐Methylene Piperidines

Abstract

Treatment of 1,6‐azaeneyne compounds with Ph3SnH resulted in the stereoselective formation of 5‐(E)‐alkylidene‐2,3‐cis‐piperidine in moderate to good yields. Intermediate products including methylenepyrrolidine and stannomethylene pyrrolidine were also detected in the reaction mixture, suggesting that the reaction progressed via a highly cumulated radical cascade process involving sequential six radical processes, i.e. radical addition, 5‐exo cyclization, substitution (1,4‐tin migration), 3‐exo cyclization, ring cleavage of cycloprolane, and hydrogen abstraction from Ph3SnH. The product distribution depended on the lower Ph3SnH concentration, resulting in higher piperidine yields. The E/Z selectivity of the exo‐methylene unit was also sensitive to the reaction temperature. The vinylic triphenyltin group was converted into hydrogen and iodine. A kinetic analysis of the reaction indicated that the 1,4‐tin migration and ring expansion progressed as irreversible reactions and that their reaction rates were large enough to progress the cascade reaction smoothly and to prevent side reactions such as hydrogen abstraction from Ph3SnH.

Radical Cascade Reaction in Heterocyclic Synthesis: Formation of Bicyclic 2,3‐dihydrostannoles and Other Heterocyclic Compounds from Amide‐type 1,6‐Enyne Compounds

“…Interestingly, the isomeric ratio of E/ Z-3 did not change significantly and the ratio was almost constant in from 1 : 1 to 4 : 6 regardless the reaction conditions. Compared to our previous results obtained for the formation of a piperidine ring using triphenyltin hydride, [10] these results were surprising result that is going to be discussed in a later section.…”

“…[9] When triphenyltin radical was used instead, the radical cascade reaction provided the formation of alkylidenepiperidine in moderate yields. [9,10] These reactions offer a unique methodology for the preparation of heterocyclic compounds in a few steps from 1,6-enyne compounds as precursors, although chiral precursors require relatively long steps for the preparation. [11] We envisaged that this radical cascade synthetic strategy may become convenient if the precursors could be prepared in short steps.…”