An Efficient Synthesis of 2- and 2,6-Substituted Piperidines Using PdII-Catalyzed 1,3-Chirality Transfer Reaction

An efficient and general method for 2- and 2,6-substituted piperidine syntheses using Pd(II)-catalyzed 1,3-chirality transfer reaction has been developed. The various N-protected zeta-amino allylic alcohols cyclize in the presence of PdCl2(CH3CN)2 to give substituted piperidines with high stereoselectivities. The syntheses of (S)-(+)- and (R)-(-)-coniine were achieved in 3 steps from the optically pure allylic alcohols (S)-14c and (R)-14c, respectively. Although the rates of reactions were significantly accelerated in CH2Cl2, THF gave the highest stereoselectivity. PdCl2(CH3CN)2 was found to be the best catalyst for this transformation. A plausible reaction pathway involving the formation of the Pd pi-complex directed by the chiral secondary allylic alcohol followed by syn-azapalladation, and subsequent syn-elimination of PdCl(OH) is proposed.