Cobalt‐Porphyrin‐Catalysed Intramolecular Ring‐Closing C−H Amination of Aliphatic Azides: A Nitrene‐Radical Approach to Saturated Heterocycles

Cobalt-porphyrin-catalysed intramolecular ring-closing C-H bond amination enables direct synthesis of various N-heterocycles from aliphatic azides. Pyrrolidines, oxazolidines, imidazolidines, isoindolines and tetrahydroisoquinoline can be obtained in good to excellent yields in a single reaction step with an air- and moisture-stable catalyst. Kinetic studies of the reaction in combination with DFT calculations reveal a metallo-radical-type mechanism involving rate-limiting azide activation to form the key cobalt(III)-nitrene radical intermediate. A subsequent low barrier intramolecular hydrogen-atom transfer from a benzylic C-H bond to the nitrene-radical intermediate followed by a radical rebound step leads to formation of the desired N-heterocyclic ring products. Kinetic isotope competition experiments are in agreement with a radical-type C-H bond-activation step (intramolecular KIE=7), which occurs after the rate-limiting azide activation step. The use of di-tert-butyldicarbonate (Boc2 O) significantly enhances the reaction rate by preventing competitive binding of the formed amine product. Under these conditions, the reaction shows clean first-order kinetics in both the [catalyst] and the [azide substrate], and is zero-order in [Boc2 O]. Modest enantioselectivities (29-46 % ee in the temperature range of 100-80 °C) could be achieved in the ring closure of (4-azidobutyl)benzene using a new chiral cobalt-porphyrin catalyst equipped with four (1S)-(-)-camphanic-ester groups.