Iridium-catalyzed Highly Selective Synthesis Of Piperidine Derivatives

Piperidine rings,the most prevalent nitrogen-containing heterocycles,are ubiquitous in drugs and natural products.The alkaloids with piperidine as the parent have various physiological activities,such as anticancer,antibacterial,antiviral and treatment of the diabetes.cis-2,6-Disubstituted dihydropyridinones are important precursors for the de novo synthesis of the corresponding piperidine alkaloids.Although many methods for synthesizing cis-2,6-disubstituted dihydropyridones exist,they often require strong acids or strong oxidizing agents to obtain imine ion intermediates,which renders substrates incompatible with acids or oxidants.Therefore,it is of great significance to develop a process for synthesizing cis-2,6-disubstituted dihydropyridone under mild conditions.In this paper,cis-2,6-disubstituted dihydropyridone was synthesized by a?-allyl-Ir intermediate using a transition metal iridium[Ir?COD?Cl]₂ as a catalyst under mild conditions.This method features a broad reaction scope,excellent regio-and diastereoselectivities,mild reaction conditions and high yields.The main work of this paper is as follows:?1?Using the widely available furfural as starting materials,the reaction precursor was obtained by imidization,Grignard reagent attack,and aza-Achmatowicz rearrangement reaction.Then,using iridium as a catalyst,the etherification reaction of the precursor occurred with oxyl nucleophile such as benzyl alcohol,alkyl alcohol and ally alcohol under mild conditions,with high yield?up to 86%yield?and excellent diastereoselectivity?dr>20:1?to give a series of cis-2,6-disubstituted dihydropyridones.?2?Other types of nucleophiles were screened to furtherly expand the range of substrates.Through the reduction reaction,amination and Grignard reaction,we realized the conversion of the cis-2,6-disubstituted dihydropyridones to corresponding piperidine ring.Thereby,a highly sselective method to prepare piperidine derivatives is developed.