Study On Nucleophilic Reaction Using Acetone Cyanohydrin As Cyanation Reagent

Since the 1970s,with the special function of organic cyanide being gradually discovered,a large number of cyano-containing molecules have been widely used in pharmaceuticals,materials and other fields.The most basic method for introducing a cyano group into a molecule is the nucleophilic reactions（including nucleophilic addition and nucleophilic substitution）between the cyanide reagentand the substrate,so it is of great practical significance to choose a suitable cyanide reagent to enable it to efficiently undergo nucleophilic reaction with the substrate under mild conditions.Acetone cyanohydrin has the advantage of relative lower toxicity,lower price,and higher atomic economic benefits.However,in the current reports,there are few studies on nucleophilic reactions using acetone cyanohydrin as cyanation reagent.Study on the nucleophilic reaction with acetone cyanohydrin as cyanation reagent has important theoretical significance and application value.The specific research content is as follows:1.Preparation of chiral catalyst.Three bifunctional catalysts based on BINOL and five cyclohexanediamine salen catalysts were synthesized.The reported synthetic route of ligand（1R,2R）-3 was improved,the experimental steps were reduced from 5 steps to 3 steps,and the yield was increased to 54%（The literature value was 32%）.2.Asymmetric nucleophilic addition reaction between acetone cyanohydrin and HC=O.The research results showed that among the above 8 chiral catalysts,catalyst 5 had the best catalytic effect on the asymmetric addition reaction of acetone cyanohydrin and phenylpropanal,with a product yield of 99%and an ee value of 81%;catalyst 8 had the best catalytic effect on the asymmetric addition reaction of acetone cyanohydrin and benzaldehyde,with a product yield of 85%and an ee value of 54%.3.Micheal addition reaction between acetone cyanohydrin and C=C.Fifteen kinds of reaction substrates N-α,β-unsaturated acylpyrazole（1a～1o）were synthesized,and the reaction of 1a with acetone cyanohydrin was used as a template reaction to screen the type of catalyst and the amount of catalyst,When 20mol% MgBu₂ was used as a catalyst,85% yield of Michael addition product can be obtained;Methodological research results showed that the 1b～1l and acetone cyanohydrin in the presence of 20mol% MgBu₂ can obtain Michael addition product,the yield was 35%～95%.However,when 1 equivalent of TMG was used as the acid binding agent,acetone cyanohydrin undergoes a nucleophilic substitution reaction with 1a～ll to obtainβ-substituted phenyl cyanohydrin（3a～3l）with a yield of 48%～92%.In the asymmetric Micheal addition reaction study,when using 20mol% MgBu₂-S-BINOL-Cinchonine as the catalyst,acetone cyanohydrin reacted with 1a,the product yield was 70%,and the ee value was 42%.1m～1o and acetone cyanohydrin in the presence of 20mol% MgBu₂ and 1 equivalent TMG,respectively,got Michael addition products,the yield was 8%～99%.