Synthesis Of Structurally And Stereochemically Diverse 2,6-Substituted Piperidines

2,6-substituted piperidines are an important part of nitrogen heterocycles that are widely distributed in nature.They are key units spread across numerous biologically active natural products,and have a broad application in pharmaceutical and agrochemical industries.Because of interesting biological activities,2,6-substituted piperidines have attracted much attention in the synthesis.In the past years,it has developed many methods of synthesis of 2,6-disubstituted piperidines in view of the various stereochemical studies that have been made on these compounds.However,the prevalent syntheses mainly rely on functional group transformations,and always show a limited range of substrates with only a few examples.On the other hand,the direct stereocontrolled C-H functionalization of a-substituted piperidines has made important progress through the a-amino anion and C-H activation pathways.However,the former requires stoichiometric amount of organolithium reagents,the latter suffers from limited functionality and modest diastereocontrol,and both approaches provide trans-2,6-substituted products as the major isomer.We hope that the oxidative C-H functionalization through a-amino cation pathway would be an attractive solution for the objective,generating 2,6-substituted piperidines.The N-carbamoyl tetrahydropyridine and potassium(phenylethynyl)trifluoroborate were initially chosen for seeking the suitable reaction conditions.Finally,the TEMPO oxoammonium salt was found as the best oxidant,and solvent optimization identified CH3CN.Under the optimized conditions,the scope of potassium(phenylethynyl)trifluoroborate and readily available allyltrimethylsilanes as the coupling component was explored,affording cis-2,6-substituted tetrahydropyridine in good yield as a single isomer.Then,the scope of substrates was explored using potassium(phenylethynyl)trifluoroborate or allyltrimethylsilane as the coupling component,enabling highly stereoselective access to either cis-or trans-2,6-substituted tetrahydropyridines.For demonstrating the ability of the method in rapidly preparing stereochemically and structurally diverse 2,6-substituted piperidines derivatives and high-quality,natural product-like libraries,we make some synthetic utilities at a late stage in the method.Additionally,the study also provides a systematical understanding of the geometry of piperidine-based α,β-unsaturated N-acyliminium ions towards nucleophile attack.Herein,a diastereoselectively complementary oxidative C-H functionalization of tetrahydropyridines with a varous of components has been established,affording either cis-or trans-2,6-substituted piperidines derivatives.The mild method has good regio-and diastereoselectivity,tolerated of diverse functional groups.The ability of the method in 2,6-substituted piperidine derivatives were also demonstrated.