Synthesis of Piperidine Bound 3,4,5-Trisubstituted Isoxazolines Via 1,3-Dipolar Cycloaddition Reactions Catalyzed By N-Heterocyclic Carbene

A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with piperidine alkene alkaloids was developed for the regioselective synthesis of 3,4,5-trisubstituted isoxazolines. Triethylamine (Et₃N) was employed as an effective base to generate both nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety of substituents, including other biologically active fragments, onto the isoxazoline ring to selectively design multinucleus structures. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of isoxazolines was ascribed to a beneficial zwitterion intermediate developed by the interaction of the strongly nucleophilic organo-NHC catalyst with alkene followed by nitrile oxide.