Asymmetric Conjugate Addition/Cyclization of Unsaturated Imines through Aromatization

Author:Gu Zuo

Supervisor:jiang guo fang

Database:Doctor

Degree Year:2018

Download:36

Pages:122

Size:3093K

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Chiral compounds are widely distributed in numerous natural products and biologically active molecules,and play an important role in various biological systems.Recently,a significant progress has been made in imine chemistry,which has attracted widespread attention from chemists.However,there have been rarely reported based onα,β-unsaturated imines,which may ascribe to the unstability ofα,β-unsaturated imines,the relatively low reactivity and the difficult control of enantioselectivity and regioselectivity.Considering the good stability and easy control of selectivity ofα,β-unsaturated imines which can recover aromaticity,the conjugate addition/cyclization ofα,β-unsaturated imines have been studied in this dissertation.Results are showed as below.Asymmetric conjugate addition/cyclization is an important method for synthesizing chiral cyclic compounds in organic synthesis.However,the related reactions ofα,β-unsaturated imines have only received the limited attention.We have successfully realized the asymmetric Michael addition/cyclization reaction of aromatizableα,β-unsaturated imines(azadienes)with malononitrile using a chiral bifunctional squaramide as catalyst.The optimized reaction conditions were obtained from the asymmetric conjugate addition/cyclization of azadienes with malononitrile using various solvents,catalysts,temperatures.The optimal condition:CHCl3 as the solvent,5 mol%of quinidine derived squaramide catalyst as the catalyst and a reaction temperature of-20 to 30 oC.The chiral benzofuran-fused heterocycles were obtained in up to 99%ee and up to 99%yield.Furthermore,to further demonstrate the practicality of the Michael addition/cyclization,the gram scale reaction was conducted,giving the desired product in 96%yield and slightly lower enantioselectivity.Based on literature reports and the experimental results,a plausible catalytic cycle was depicted.chiral thioethers play an important role in medical science and organisms.The asymmetric sulfa-Michael addition is one of the most powerful synthetic methodologies for chiral thioethers.However,the Michael addition of sulfur donors toα,β-unsaturated imines has only received the limited attention.An effective catalytic asymmetric sulfa-Michael addition of aromatizableα,β-unsaturated imines(azadienes)with tritylthiol using the squaramide catalyst has been developed.To determine optimized reaction conditions,azadiene was reacted with tritylthiol while varying catalysts,solvents,amounts of catalyst and temperatures.The optimized conditions were established as:10 mol%of hydroquinine derived squaramide catalyst as the catalyst,DCM as the solvent and-20 oC as the reaction temperature.The chiral aminothioethers were obtained in up to 94%ee and up to 99%yield.Based on literature reports and the experimental results,we proposed a plausible transition state for the organocatalytic asymmetric conjugate addition of tritylthiol to azadienes.In recent years,although many effective methods have been developed for asymmetric addition of phosphides,the substrate scope has been limited to the use of imines,aldehydes,ketones andα,β-unsaturated carbonyl compounds.However,the asymmetric conjugate addition of phosphorus nucleophiles toα,β-unsaturated imines has not been described,which may ascribe to the difficult control of regioselectivity.We developed an asymmetric conjugate addition of phosphorus nucleophiles to aromatizableα,β-unsaturated imines(azadienes).The key issue is the excellent selectivity of 1,4-addition of azadienes,which is from driving force of aromatization of azadienes.The optimized reaction conditions were obtained by varying base additives,solvents,catalysts and temperatures.The optimal condition:0.5 equiv of Na2CO3 as the base additive,toluene as the solvent,5 mol%of quinine as the catalyst and-20 oC as the reaction temperature.The chiralγ-aminophosphonates were obtained in up to 94%ee and up to 99%yield.Based on literature reports and the experimental results,we proposed a plausible transition state.Indole is the key motif in natural products and drugs.The vinylogous imine intermediates based on indole skeleton are also aromatizableα,β-unsaturated imines and good nucleophilic receptor.In the dissertation,the vinylogous imine intermediates generated in situ from sulfonylindoles under basic conditions would be captured by alkyl radicals of ethers,resulting in theα-alkylation of ethers.The optimized reaction conditions were obtained through using different bases and temperatures.A variety of sulfonylindoles and ethers were suitable reaction partner under the optimized condition.On the basis of previous publications and the experimental results,a plausible catalytic mechanism was presented.