Difluoromethyl substituted matte ylide: a broad range of electrophilic difluoromethylation reagents

In the past two decades, fluoride has been called "small atom with big self" in the field of medicine and agricultural chemistry due to its magical "fluorine effect" The introduction of fluorine atoms into the molecular structure of drugs has become a conventional means of new drug development Accordingly, organic chemists have developed a variety of fluorination means and reagents to achieve the preparation of fluorides with different structures Source of fluoxetine capsule (antidepressant): in recent years, Wikipedia has made great breakthroughs in the methods of trifluoromethylation and difluoromethylation For example, Professor F Dean toste of the University of California, Berkeley, prepared the trifluoromethyl products (Science) of aliphatic hydrocarbons through the reduction and elimination of trifluoromethyl Au (III) complexes, 2017 doi: 10.1126/science.aan1411); Professor Tang Pingping from the school of chemistry, Nankai University used TFMS as a trifluoromethylation reagent to trifluoromethylate olefins, 2017 doi: 10.1038/nchem.2711); Zhang Xingang's team from Shanghai Institute of organic science, Chinese Academy of Sciences, used cheap industrial raw material clcf2h to achieve difluoromethylation of aromatic compounds (nature chemistry, 2017 doi: 10.1038/nchem.2746) In contrast, the direct introduction of monochloromethyl (ch2f) is less developed The direct electrophilic reaction of electrophilic monofluoromethyl reagent is one of the feasible strategies for the introduction of monofluoromethyl In the early stage of electrophilic monofluoromethylation, fluoromethanol and its derivative, trifluoromethylsulfonate, or halomethanes (clch2f, ICH 2f) are usually used, but their applications are limited The reaction conditions of fluorocarbinol and trifluoromethylsulfonate are harsh, and the range of substrate application is narrow Although chlorofluoromethane can react with a large number of nucleophiles, it is an ozone depleting gas, and its application prospect remains to be discussed However, fiuoiodomethane is mainly used to synthesize 18 f-labeled radiopharmaceuticals In order to overcome these shortcomings of electrophilic mono fluoromethylsulfonium reagents, mono fluoromethylsulfonium salts 1 and 2 came into being Among them, 1 reacts well with amines, phosphines, sulfonic acids, carboxylic acids and phenols, but poorly with alcohols and nucleophilic C C Although it can be used in a wide range, it can not react with conventional alcohols Recently, Shen Qilong, a research team from Shanghai Key Laboratory of organic chemistry, Chinese Academy of Sciences, published a paper in angelw Chem Int ed., reporting on the electrophilic mono fluoromethylated reagent mono fluoromethylsubstituted matte ylide (3a - B ）It can react with a series of nucleophiles, such as alcohol, malonic acid derivative, sulfonic acid, carboxylic acid, phenol, amine, azaaromatic ring, etc under mild reaction conditions, the substrate can be widely used The sulfonium ylide substituted by fluoromethyl can be obtained by the reaction of fluoromethyl phenylthioether and dimethyl diazomallate After treatment, the crystal product can be obtained The structure of the product is confirmed by 1H, 13C and 19F NMR spectra and single crystal X-ray analysis The prepared matte leaf Lide is stable and can be stored at room temperature for more than one month The mechanism of deuterium substitution shows that the monofluoromethylation is carried out by electrophilic substitution Source of reaction between sulfonium ylide reagent 3a and alcohol: angelw Chem Int ed source of reaction between sulfonium ylide reagent 3b and 2-substituted diethyl malonate: angelw Chem Int ed source of reaction mechanism: angelw Chem Int ed