Research On C(sp~3)-C(sp~3) Bond Construction Based On Monoalkylation And Asymmetric Michael Addition Of Active Methylene Compounds

Active methylene compounds are widely used in organic synthesis,and the construction of their carbon-carbon bonds plays an important role in the synthesis of drugs,natural product active ingredients and functional molecules.This thesis mainly explores the C（sp³）-C（sp³）bond construction method of active methylene compounds from two parts:1.Based on the monoalkylation of C（sp³）-C（sp³）bonds by active methylene compounds,the following studies were conducted.The traditional alkylation method requires the use of halogen-containing reagents,which produces toxic waste;and some functional groups have poor tolerance under strong alkaline condition.At the same time,this method is difficult to achieve selective monoalkylation.In this thesis,the O-O bond of alkylsilyl peroxide is homogenized in the reaction system to form oxygen free radicals,and then the alkyl source is provided byβ-cleavage.Thus active methylene compounds can be selectively monoalkylation with alkylsilyl peroxide catalyzed by low-toxic and easily-available copper catalyst to create C（sp³）-C（sp³）bond.After screening the ligand,solvent,reaction temperature and other conditions,the optimal reaction condition is,1.0 m L of N,N-dimethylformamide（DMF）as the solvent,and 5 mol%cuprous iodide（Cu I）,1.0equivalent of 4-dimethylaminopyridine（DMAP）,1.0 equivalent of active methylene compound and 1.4 equivalent of alkylsilyl peroxide were reacted at 50°C for 1 hour under argon.With this conditon,all products got by the ractions of active methylene compounds4a-4k and alkylsilyl peroxides 3a-3j,were monoalkylated products,and the yield was as high as 99%.In this paper,the monoalkylation reaction of nitro hydrocarbons evolved methylene compounds was further studied.（1）In a solvent-free reaction system,1.0 m L of nitroalkane was used as the solvent,and 10 mol%cuprous iodide（Cu I）,1.0 equivalent of4-dimethylaminopyridine（DMAP）and 1.0 equivalent of alkylsilyl peroxide were reacted at50°C for 1 hour,yields 62%,72%and 56%were obtained respectively.（2）At the same time,in order to increase the scope of application of nitroalkanes,optimization of reaction conditions involving solvents was carried out.The optimal conditions is:0.2 m L of benzene（C₆H₆）as a solvent,added 5.0 equivalent of nitroalkane,10 mol%cuprous iodide（Cu I）,1.0equivalent of DMAP and 1.0 equivalent of alkylsilyl peroxide reacted for 12 hours at room temperature.With this condition,the expansion of substrates was carried out,and the reaction products are all monoalkylated products,the maximum yield was 60%.Based on the research of constructing C（sp³）-C（sp³）bonds by monoalkylation of active methylene compounds,more than 30 compounds were obtained,all of which were monoalkylated products,and the highest yield could reach 99%.2.The C（sp³）-C（sp³）bond was constructed based on the asymmetric Michael addition of active methylene compounds,and the following studies were carried out.2-indolinone is the core skeleton of many drugs,but there are few methods for constructing intermediates with high stereoselectivity.Therefore,this paper explores the construction of C（sp³）-C（sp³）bonds by the asymmetric double Michael addition of N-Boc-2-indolinone and dienone derivatives catalyzed by a chiral phase transfer catalyst.By further screening the conditions of base and phase transfer catalyst,the product yield was 94%,the diastereoselectivity was as high as 100%,and the enantiomer ee value was 33%.In this paper,the successful development of the method of constructing carbon-carbon bonds through monoalkylation,and the exploration of the highly stereoselective asymmetric Michael addition method of N-Boc-2-indolinone and dienone,are expected to be used in the synthesis of biological activities molecules,and provide new ideas for the efficient,environmentally friendly and selective construction of C（sp³）-C（sp³）bond.