Study On CuH-catalyzed Addition Reactionof Unsaturated Hydrocarbons-Derived Nucleophilesto Ketones And α,β-Unsaturated Amides

Although the discovery of copper hydride(CuH)compoundscan date back to the mid-19 th century,it was not until the discovery of Stryker reagent in the 1980 s that CuH chemistry entered people’s field of vision and gradually attracted people’s attention.Especially in the last decade,chemical transformations based on CuH catalysis have achieved rapid development,and a series of efficient chemical transformations catalyzed by CuH have been realized to(asymmetrically)construct a series of C–X(X: H,N,C,B,Si,Br,etc.)compounds,adding yet another effective tool to the chemical bond formation methods described above.The chemical transformation catalyzed by CuH generally goes through the following process: the CuH catalyst generated in situ first undergoes an intercalation reaction with an unsaturated hydrocarbon to generate a catalytic amount of an organocopper reagent,which can interact with various electrophiles(e.g.,protons,alkyl halides,etc.)compounds,alkyl sulfonates,organoboron reagents,organosilicon reagents,aryl halides,nitrogen electrophiles,carbonyl compounds,etc.)are coupled to construct the corresponding C–X bonds.From the perspective of reaction form,the coupling of unsaturated hydrocarbons and various electrophiles under CuH-catalyzed conditions is realized,thereby avoiding the shortcomings of traditional methods that often require stoichiometric amounts of metal-organic reagents in the construction of C–X bonds.Therefore,compared with the traditional methodology,the CuH-catalyzed transformation has the advantages of high atomic and step economy,excellent functional group compatibility,and milder reaction conditions.Although CuH chemistry has made remarkable progress in recent years,it still faces some unsolved problems,such as: 1)when there are multiple unsaturated bonds in the system,how to control its chemical selectivity;2)when the raw material is asymmetric unsaturated hydrocarbons,how to achieve high regioselectivity control;3)when there are two or more stereocenters,how to control the enantioselectivity and diastereoselectivity;4)Although a large number of organic electrophiles can participate in the CuH-catalyzed conversion,however,they have strong electrophilic ability and high reactivity.How to realize the reaction of electrophiles with low reactivity(such as unsaturated amides),while simultaneously controlling their chemical,regio,and stereoselectivity remains a formidable challenge.In view of the above problems,this paper has carried out the following researches:(1)CuH-catalyzed asymmetric reductive allylation was achieved using conjugated olefins and ketones.In the above transformations,asymmetric addition reactions with ketones were achieved by utilizing the catalytic amount of organocopper reagents generated from the CuH catalyst generated in-situ with the copper hydrogenation reaction of conjugated olefins,and a series of optically active allyl-containing tertiary alcohol compounds were constructed.The above transformations have excellent functional group compatibility,mild reaction conditions,and excellent chemical,regio-and diastereoselectivity,and homoallylic alcohol compounds containing quaternary carbon chiral conters are synthesized with up to 20:1 diastereoselectivity and 95% ee.The above strategy avoids the disadvantage of using pre-prepared allyl metallo-organic reagents in traditional methods,thus providing an efficient method for the synthesis of challenging chiral quaternary carbon-containing alcohols.(2)Using 2-isocyanophenylacrylamides as raw materials,the cyclization of isocyanide insertion/ asymmetric addition to unsaturated amides with CuH catalysts in series was realized.In this chapter,the chiral bidentate phosphine ligand(S,S)-Ph-BPE was used as the chiral ligand,and the organic copper intermediate was obtained through the insertion of the LCuH active species into the isonitrile,and then the unsaturated amide in the molecule was used for 1,4-Michael addition reaction,successfully prepared a series of C-3 chiral 2-hydroindole compounds with up to 94% yield and 95% ee.This reaction overcomes the disadvantage of the background reaction caused by the strong coordination ability of the isocyano group,and realizes the asymmetric addition reaction of the low-activity unsaturated amide with isocyanide as a potential carbon nucleophile under the induction of a chiral catalyst.It provides an alternative strategy for the reported dilemma of low enantioselectivity in the synthesis of such compounds.(3)The intermolecular addition reaction of 1,1-disubstituted allenes and unsaturated amides was realized under CuH-catalyzed conditions.In this reaction,the regioselective insertion between CuH catalyst and 1,1-disubstituted allenes generates a catalytic amount of allyl copper reagent,and then an addition reaction occurs to unsaturated amides.Unsaturated amides are among the least active Michael acceptors,and their corresponding Michael addition reactions have always been one of the daunting challenges in organic synthetic chemistry.This method utilizes ligand-regulated on-site generation of active allyl copper reagents,overcomes the challenge of low reactivity of unsaturated amides,and realizes the addition of 1,1-disubstituted allenes as potential allylic electrophiles to unsaturated amides.The method has mild reaction conditions,high chemical and regioselectivity,and excellent functional group compatibility,providing an efficient route for ligand-mediated addition of unsaturated hydrocarbons as potential nucleophiles to low-activity Michael acceptors.