O-Aryl carbamates of 2-substituted piperidines: anionic Fries rearrangement and kinetic resolution by lithiation

Abstract

Piperidines and their 2-substituted derivatives are fundamental intermediates for the development of new active pharmaceutical ingredients with improved pharmacokinetic profiles and unique three-dimensional properties. Consequently, the design of synthetic methodologies for their selective transformations into highly valuable scaffolds, aimed at increasing the molecular diversity, is of high importance. We disclose herein a general and efficient organolithium-mediated protocol to promote chemo- and regioselective anionic Fries rearrangement or kinetic resolution processes starting from O-aryl carbamates of 2-substituted piperidines. The use of t-BuLi allows a regioselective ortho-metalation of the O-aryl carbamate followed by an intramolecular carbamoyl migration, thereby delivering a series of functionalized N-piperidinyl salicylamides in yields of 33 to 95%. The protocol has been successfully extended to 5- and 7-membered saturated N-heterocyclic scaffolds with comparable yields and selectivity. Mechanistic aspects and studies on the use of bench-type aerobic conditions are also detailed. In addition, the chiral n-BuLi/(+)-sparteine complex promotes the kinetic resolution of the O-aryl carbamate by regioselective lithiation at the 2-position of the piperidine ring. Upon electrophilic quench, the enantioenriched starting material is recovered with a good level of stereoselectivity (up to 85 : 15 er).