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

5 years ago

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

Bas de Bruin, Petrus F. Kuijpers, Willem B. Breukelaar, Nicolaas P. van Leest, Martijn J. Tiekink, Joost N. H. Reek, Jarl Ivar van der Vlugt, Daniël L. J. Broere

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 (Boc2O) 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 [Boc2O]. 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. It's all in the azides: Cobalt-catalysed activation of aliphatic azides enables the direct synthesis of various heterocycles from aliphatic azides in good to excellent yields. Detailed mechanistic investigations reveal a metallo-radical intramolecular C−H activation mechanism. Enantioselective radical-type ring closure C−H amination of aliphatic azides proved possible.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201700358