Study On Synthesis And Reaction Of α-Hydroxyl Homoallylic Difluorohydrins Building Block

Fluorine atoms and fluorine-containing groups are widely found in medicine,pesticides and material molecules.Fluorine incorporation into the molecule can increase the lipophilicity of small-molecule drugs,improve drug permeability in the organism,regulate molecule spatial configuration,and improve drug molecules’metabolic stability and biological activity.Among them,the difluoromethyl group is generally considered to be the bioelectronic groups of oxygen atoms and polar functional groups(such as carbonyl group).Precise incorporation of difluoromethylene into biologically active molecules can significantly alter molecular conformation,improve metabolic stability,and increase the acidity of groups adjacent to it in the molecule.Therefore,selective synthesis of fluorinated organic molecules is of great significance for the development of bioactive compounds(agricultural chemicals and drugs)and materials which have special performance.In this paper,the barbier reaction mediated by indium was studied.The highly functional allyl difluoro alcohol was formed using halogenated bifluoromethyl ketones and allyl halides as substrates.The method is widely applicable to various substrates,with mild reaction conditions and high yield.This paper is divided into two parts.In the first part,the Barbier reaction of iododifluoromethyl ketones with allyl bromides as substrates in the presence of indium was investigated.The screening of metal reagents,reaction solvents,and reaction time required for the reaction were introduced.The optimum conditions were obtained as follows:under nitrogen atmosphere,with metal indium as the mediator and DMSO as the solvent,the reaction was carried out at room temperature for 3-5 hours.Under optimal conditions,20homoallylic difluorohydrins with different structures were synthesized with yields of30%-98%.At the same time,14 iododifluoromethyl ketones with different structures,as well as chlorodifluoromethyl ketones and bromodifluoromethyl ketones were synthesized.In the second part,the C(sp~3)-H bond activation reaction between the homoallylic difluorohydrins building block and various substituents of o-nitrobenzoic acid was investigated under palladium catalytic system,29 difluorooxy allyl esters with novel structures were synthesized at 32%-51%yields.The model reaction was selected,and the optimization of catalyst,oxidant,solvent and temperature of the system was performed.Optimal conditions were determined as follows:the reaction of homoallylic difluorohydrins and o-nitrobenzoic acid with hexafluoroisopropanol as solvent,palladium acetate as catalyst,silver oxide as oxidant,and the reaction lasted for 10-12hours.