Study On The Synthesis Of 4-Fluoropyridine Derivatives From Geminal Difluorocyclopropene And Isocyanoacetate

Pyridine is one of the most prevalent heterocyclic skeletons in biologically active molecules.The fluorine atom has high electronegativity and small atomic radius,and its combination with pyridine significantly improves lipophilicity,metabolic stability,bioavailability and,in some cases,the potency of known biologically active molecules for use as Primary scaffold for drug molecules.Despite their increasing importance in pharmaceuticals and agrochemicals,there are few efficient and facile synthetic methods to develop a simple and practical method for the preparation of fluoropyridines,especially the synthesis of 4-fluoropyridines.In this paper,a new method for the synthesis of 4-fluoropyridine was mainly studied.Using gem-difluorocyclopropene and isocyanate as raw materials,[3+3] cycloaddition was carried out under the action of Ag catalysis and alkali at room temperature.A series of 4-fluoropyridine derivatives were synthesized in a simple and efficient manner.The optimal reaction conditions,substrate adaptability range,derivatization experiments,and application in drug molecules were explored,and the possible reaction mechanism was proposed,which further enriched the synthesis methods of 4-fluoropyridine compounds.This paper mainly includes two parts,the main contents are as follows:1.The first part introduces several synthetic methods and existing problems of 4-fluoropyridine compounds introduced in the literature,and briefly describes the synthetic methods and reaction studies of gem-difluorocyclopropenes,and the cyclization reactions involving isocyanates.Studies are reviewed and ideas for the design of our responses are presented.2.In the second part,the research work on a new method for the synthesis of 4-fluoropyridine compounds was carried out,through the [3+3] cycloaddition of geminal difluorocyclopropene and isocyanoacetate under the action of Ag catalysis and alkali After the reaction,a series of 4-fluoropyridine derivatives were synthesized,which further enriched the synthesis methods of 4-fluoropyridine.The optimal reaction conditions,substrate adaptability range,derivatization experiments,and application in drug molecules were explored,and the possible reaction mechanism was proposed.Through the research work in this paper,a new method for synthesizing 4-fluoropyridine is proposed,which provides a simple and efficient synthetic method for the construction of 4-fluoropyridine.