Researchs For β-Aza-benzyl Elimination Of Unstrained Alcohol

The formation of carbon-carbon bonds has received much attention among chemists,which can transform simple and readily available small molecules into more valuable complex compounds in organic synthesis.At the same time,the chemistry of carbon-carbon cleavage is very important since carbon-carbon bond is widely existed as the skeleton of organic compounds.It is a very valuable topic how to efficiently transform this kind of inert chemical bond,which can not only be applied to the synthesis of drugs and bioactive molecules,but also serve the degradation of organic polymers and the transformation of materials science.Among them,transition metal-catalyzed carbon-carbon bond cleavage is widely noted,which include oxidation addition andβ-carbon elimination.It is of great research value to use alcohols as synthetic precursors efficiently.Transition metal-catalyzedβ-carbon elimination enables the conversion of alcohols to C-metal species and carbonyl compounds,and the former participating in the formation of new carbon-carbon bonds.The main types ofβ-carbon elimination include small ring-opening reactions driven by ring strain andβ-carbon elimination by unstrained molecules.In the latter,β-alkyne,cyanide elimination based on C（sp³）-C（sp）bond cleavage andβ-aryl,alkenyl elimination based on C（sp³）-C（sp²）bond cleavage have attracted people’s attention and have phased progress.However,development has been relatively slow since the C（sp³）-C（sp³）key is more difficult to cut.Therefore,we selected aza-benzyl alcohol as the research substrate,and adopted chelation-assisted strategy to achieve the inert C（sp³）-C（sp³）bond cleavage under the metal catalyst to generate aza-benzyl metal species,and used various acceptors to capture the active species.Therefore,this paper uses this strategy to complete the relevant transformation of three parts:Part I:Copper-catalyzed aza-benzyl transfer reaction.The hydrogen transfer process between alcohols and carbonyl compounds byβ-H elimination strategy is widely used in organic synthesis,but the hydrocarbon transfer process between alcohols and carbonyl compounds byβ-H elimination strategy is less reported.Although aryl,alkyne and allyl groups could underwent such transformations,benzyl transfer remains a challenge.In this study,we used chelate-assisted strategy to select trifluoroaryl ethyl ketone and various aldehydes as transfer acceptors to achieve aza-benzyl transfer process.When ketones and aza-benzyl-metal species are produced after theβ-carbon elimination of tertiary alcohol,the species preferentially react with the more active trifluoroaryl ethyl ketones or aldehydes,which is a kinetic advantage.On the other hand,the product is thermodynamically more stable than the feedstock,which is the driving force of this transfer strategy.Part II:Silver-catalyzed 1,3-aza-benzyl migration of allyl alcohol.The isomerization of allyl alcohol is one of the most effective strategies in synthetic chemistry since its excellent atomic economy.In recent years,the carbon migration mediated by hydrogen and free radicals has developed rapidly and has a good application prospect.The latter is difficult to produce the 1,3-migration reaction of carbon free radicals due to the unstable transition state of the four-membered ring.On the other hand,compared with free radical mediated carbon migration reactions,there are few reports on metal-catalyzed carbanion migration reactions,among which sp hybrid carbanion migration reactions have achieved 1,3-migration with alkyne and cyanide groups.Can we achieve benzyl 1,3-migration in the presence of transition metals?The difficulty lies in selective fracture of C（sp³）-C（sp³）bond,dehydration and high activity of C（sp³）-metallic species.We found that the silver/PCy₃ complexes were able to achieve this reaction despite the need for the use of coordination atoms on the benzyl group and the use of chelate-assisted strategies.We achieved a silver-catalyzed benzyl 1,3-migration reaction via unstrained C（sp³）-C（sp³）bond cleavage,with the advantages of high atomic economy,activation reagent no need to add and cheap silver catalyst.Part III:Base-promoted aza-benzyl borrowing reactions.The formation of a molecule of carbonyl compound that is not normally utilized,which is the one of most significant problem in theβ-carbon elimination of unstrained alcohols.In order to utilize this by-product and achieve maximum atomic utilization efficiency,by inspired to our group’s previous successful cases of cyano borrowing,alkynyl borrowing and aryl borrowing reactions,we designed the aza-benzyl reaction.The process is that under the transition metal,the C（sp³）-C（sp³）bond of the alcohol is cleavage,producing a molecule of carbonyl compound and C（sp³）-metallic species.The resulting carbonyl compound reacts with the added ketone to formα,β-unsaturated ketone.Finally,the Michael addition of C（sp³）-metallic species withα,β-unsaturated ketone completes the benzyl borrowing reaction.Compared with cyano borrowing,alkynyl borrowing and aryl borrowing reactions,aza-benzyl borrowing is more challenge,cause of the C（sp³）-C（sp³）bond has a higher bond energy and more difficult to cleavage.The formed C（sp³）-metal species are unstable,which easily quenched by protons and difficult to capture.In the experiment,palladium was used to complete the reaction,but it was further found that base could promote the reaction alone,the mechanism experiment also confirmed the rationality of the process.This process involves the cleavage and formation of C（sp³）-C（sp³）bonds,it exhibited high atomic economy with the water as the only by-product,a wide range of substrates and the use of expensive transition metals was avoided..