Remote Functionalization: Palladium-Catalyzed C5(sp3)-H Arylation of 1-Boc-3-aminopiperidine through the Use of a Bidentate Directing Group

A protocol for the Pd-catalyzed CS(sp(3))-H arylation of readily available 1-Boc-3-(picolinoylamino)piperidine with iodo(hetero)arenes is reported. The substrate can be obtained from a biorenewable feedstock, namely L-arginine. The use of the right N1 protective group is decisive to get arylation. The addition of a catalytic amount of 2,6-dimethylbenzoic acid and performing the reaction at high concentration are important to achieve a high conversion and yield. The procedure gives arylated 1-Boc-3-(picolinoylamino)piperidines in a regiospecific (C5) and stereo-specific (cis) manner. Orthogonal cleavage of the amide over the carbamate group allows one to further selectively derivatize the amino moieties of the piperidine scaffold.