Development Of Novel Reaction With Sodium Chlorodifluoroacetate As A Convenient Source Of Difluorocarbene

The particularity of fluorine atom and C-F bond determines the unique properties of fluorine-containing compounds,the insertion of fluorine atoms in organic molecules can greatly change the biological activity and physical properties of the compound.Therefore,the selective insertion of fluorine atoms or fluorine-containing groups into organic molecules has become a routine strategy for drug design and the development of new functional materials,Trifluoromethyl and difluoromethyl are the most widely used fluorinated groups,especially difluoromethyl,The group has an electron withdrawing effect and can affect the electronic effects,chemical properties and biological reactivity of adjacent groups.Therefore,in recent years,relevant scholars in this field have developed a variety of difluorocarbene reagents and successfully applied them in a variety of reactions,the insertion of difluorocarbene into compounds such as alcohols,mercaptans,aldehydes,ketones,carboxylic acids,alkynes,alkenes,etc.,enriches the types of difluorocarbene reagents.Under this research background,we have selected appropriate difluorocarbene reagents and nucleophiles to develop a series of new reactions.The specific work is as follows:First of all,Using Sodium chlorodifluoroacetate as a difluorocarbene source,adding DMF and K₂CO₃,isonitrile was synthesized by reacting primary amine with sodium chlorodifluoroacetate in an oil bath at 100 ^oC for 12 h.The characteristic of this method is that sodium chlorodifluoroacetate undergoes decarboxylation reaction under the action of alkali to generate difluorocarbene,which can react with primary amine to obtain isonitrile.After the product is separated and purified by column chromatography,its structure is determined by NMR,IR and HRMS.Then optimize the reaction conditions,expand the substrate under the best reaction conditions,and explore the applicability of the reaction.Finally,the possible mechanism of the reaction was proposed based on relevant literature and experimental investigation.Subsequently,Based on the synthesis of isonitrile by the reaction of difluorocarbine and primary amine,amidines and heterocyclic compounds were prepared via one-pot method,the process is as follows:（1）In the reaction system,difluorocarbine reacts with primary amine to form isonitrile,and then the isonitrile is inserted into the N-H bond of the primary or secondary amine to synthesize amidine compounds.Isonitriles can also react with tertiary amines to form amidines,which involves the activation of the C-N bond of the tertiary amine.（2）Based on the synthesis of isonitrile,select suitable substrates and synthesize a variety of nitrogen heterocyclic compounds and fused ring compounds through the process of isonitrile insertion/cyclization.Finally,based on the synthesis of isonitrile,we add carboxylic acid to the reaction system,and the carboxylic acid deprotonates under alkaline conditions to form carboxylate ion,it has nucleophilicity and can react with isonitrile and generate amide compounds through atom migration.Adding water to the reaction system,isonitrile or the reaction intermediate in the synthesis of isonitrile can react with water to form formamide.Finally,optimize the reaction conditions,expand the substrate under the best reaction conditions,and explore the applicability of the reaction.In summary,a simple and efficient method for the synthesis of isonitriles was developed using sodium chlorodifluoroacetate as difluorocarbene source.And based on the synthesis of isonitrile,the synthesis methods of amidine,amide,and heterocycle and spiro ring were developed.These works are very original basic research,and play an irreplaceable role in the study of synthesis,application and reactivity of isonitrile.