Diastereoselective Cross-dehydrogenative-coupling Of Tetrahydropyridines With 1,3-Dicarbonyl Compounds

In recent years,with the emergence of the concept of atom economy and green chemistry,to construct carbon-carbon bonds by direct activating carbon-hydrogen bonds has become a research hotspot.Cross-dehydrogenation coupling as a new efficient synthesis strategy gets more and more attention of' organic chemists,due to the advantages of the mild conditions,less by-products,high atomic efficiency.Through the efforts of organic chemists,multiple types of cross-dehydrogenation coupling reactions have been developed.However,due to the large bond energy of C-H bonds,the reactivity of this kind of reaction is low,and its chemical selectivity is also difficult to control.At present.there are only a few reports on intramolecular regioselectivity and diastereoselectivity of' the cross-dehydrogenation coupling reaction,and of which there are few intermolccular study,so this kind of cross-dehydrogenation coupling reaction has attracted much attention.Cis-or transs-2,6-or 2,4-substituted tetrahydropyridines and piperidines are key units spread across numerous bioactive natural products.We have found that these compounds often possess methylene carbonyl moiety at C2 or C4 position,such as?(-)-methyl palustramate,(-)-andrachcinidine.calvine.In general,the synthesis of the above disubstituted tetrahydropiperidine with a carbonyl methylene group at the 2-position or 4-position is often carried out by prefunctioned the respective components.Thus,the problem of' increase in reaction steps and reduction of atom economy will be inevitably.It is envisaged that as long as the nitrogen atom a-position C-H of tetrahydropyridine compound and the active C-H of dicarbonyl compound are simultaneously activated?a diastereoselective selective cross-dehydrogenation coupling reaction can be achieved,after a further simple decarboxylation these disubstituted tetrahydropyridine can be obtained quickly.Once this idea is realization,reaction steps will be greatly shorten and atom economy will be greatly enhanced.However,it is full of challenges and opportunities to achieve control and enhance the activation and stereoselectivity of this reaction.This thesis studied based on this idea.First,tetrahydropyridine and dimethyl malonate were selected as the initial substrate to explore the reaction,and then the reaction mainly studied from the following aspects:the types of metal additive,the amount of additive,the kind of oxidant,and the kind of solvent.Through the study,the best reaction conditions of stereoselectivity and yield can be obtained.In order to verify the applicability of this reaction,the optimum reaction conditions were obtained.First,different kinds of dicarbonyl compounds and different side chains of tetrahydropyridine were used to expand the substrate range of the reaction system and found that they were well The reaction conditions were obtained to obtain cis-2,6-disubstituted tetrahydropyridine with good diastereoselectivity.Then we synthesized the trans-2,6-disubstituted tetrahydropyridine by a simple one-step retro-aza-Michael/aza-Michael reaction.Replacement of ?-keto ester as a nucleophile.we unexpectedly synthesized cis-2,4-disubstituted tetrahydropyridine,completed the synthesis of tetrahydropyridine with a selectivity for stereoselective regions.In addition,we have also developed the stereoselective cross-dehydrogenation coupling reaction system,successfully applied to the synthesis of tetrahydropyridine natural products and analogues.Verify the good application of this system and practical value.