Synthesis Of Alkylated/Arylated N-heterocyclic Derivatives Based On Free Radical Reactions

N-Heterocyclic compounds are an important backbone in natural products and drugs with a wide range of biological activities,such as antibacterial,anticancer,anticoagulant,antiviral and antithrombotic effects.In recent years,studies on the functionalation of N-heterocyclic derivatives including N-aryl propargylamides,quinoxalinones and quinazolinones have received extensive attention.At the same time,toluene,acetone and3-aminoindazole are cheap and readily available as alkylating and arylating reagents.Therefore,it is important to find a simple and efficient method to synthesize alkyl or aryl-substituted N-heterocyclic derivatives.In this thesis,N-aryl propargylamides,quinoxalinones and alkenyl-containing quinazolinones were used to synthesise alkylated and arylated N-heterocyclic compounds via the radical reactions.These reactions are characterised by short reaction times,wide substrate range and simple steps.The specific contents are as follows:（1）Transition-metal catalyzed synthesis of benzylated spiro[4.5]trienone derivativesThe reaction of N-（4-methoxyphenyl）-N-methyl-3-phenylpropionic acid amine and m-xylene is used as a template reaction,and the conditions including oxidant,reaction temperature and reaction time are optimized.The optimal reaction conditions:the ratio of N-（4-methoxyphenyl）-N-methyl-3-phenylpropionic acid amine and toluene is 0.2 mmol:0.5m L,TBPB（tert-butyl peroxybenzoate）2.0 equiv,Cu Br（0.15 eq）+Ag NO₃（0.2 eq）as the catalyst,at 130°C for 70 min,and the yield is 55%.Thirty-four target compounds are successfully synthesized,and their structures are confirmed by IR,NMR and HR MS.The highest yield is up to 65%.The reaction mechanism is presumed to be a free radical reaction by controlled experiments.The advantages of this method are a wide range of substrates,simple steps and short reaction time.This approach provides a simple and efficient method for the synthesis of 3-benzylazaspiro[4,5]trienone derivatives.（2）Copper-catalyzed synthesis of o-cyanoarylated quinoxalinone derivativesThe reaction of N-methylquinoxalinone and 3-aminoindazole is used as a template reaction,and the reaction conditions such as the oxidant,catalyst and solvent are optimized.The optimal reaction conditions:the ratio of N-methylquinoxalinone and 3-aminoindazole is0.2 mmol:0.3 mmol,TBPB（2.5 eq）as the oxidant,Cu（OAc）₂（0.15 eq）as the catalyst at100℃for 60 min,the yield can reach 63%.Under the optimal reaction conditions,313-o-cyanoarylated quinoxalinone derivatives are successfully obtained,and their structures are elucidated by IR,NMR and HR MS.The best yield is up to 78%.The reaction mechanism is proposed to be a free radical reaction by some controlled experiments.The method is characterized by a wide range of substrates,simple steps,short reaction time and cheap and easy availability of raw materials.（3）Microwave-assisted synthesis of alkylated polycyclic quinazolinone derivativesThe reaction of N-（1-butenyl）quinazolinone with acetone is used as a template reaction,and the oxidant,catalyst and reaction temperature are optimized.The optimal reaction conditions:the ratio of N-（1-butenyl）quinazolinone with acetone is 0.2 mmol:1.0 m L,TBHP（2.0 eq）as the oxidant,at 120℃for 40 min and the yield was 72%.Under the optimal reaction conditions,28 alkylated polycyclic quinazolinones are synthesized and their structures were confirmed by IR,NMR and HR MS.The mechanism of the reaction was presumed to be a free radical reaction by controlled experiments.This method is characterized by a simple operation and short reaction time,and provides a simple and efficient way to synthesize alkylated polycyclic quinazolinone derivatives.