Synthesis Of Monofluoromethoxy Compounds

Fluorine-containing compounds have been widely used in the fields of pharmaceuticals,agrochemicals and functional materials,mainly due to the well-known“fluorine effect”of the fluoroalkyl groups on the physical,chemical and biological properties of molecules.Tri-and difluoromethyl ethers play an important role in many medicinally compounds.Among various fluorinated moieties,OR_f-containing groups have attracted much more attention very recently owing to the impressive conformational changes and maximal shifts in electron distribution brought by fluorine.The?-fluorine substitution of ethers shortens and strengthens the C-O bond and thus improves the in vivo oxidative stability of the ether moiety of a drug.In the past few decades,there have been many reports on the synthesis methods of trifluoromethoxy compounds and difluoromethoxy compounds,but relatively few reports on monofluoromethoxy compounds.Considering the importance of synthesizing monofluoromethoxy compounds and the limitations of substrates in current research,this paper describes a one-pot synthesis method that uses aryl halides,aryl boronic acids,and aromatic hydrocarbons as substrates.Its monofluoromethoxylation is achieved to obtain monofluoromethyl ether.(1)In the experimental process of using aryl halides as substrates to synthesize monofluoromethoxy compounds,palladium catalyzed aryl halides were used to achieve the conversion of arylphenols,and the resulting monofluoro was converted in situ with a monofluoromethylation reagent Methoxy compounds.The conversion of aryl halides to monofluoromethoxy compounds is a one-pot two-step process,which is also suitable for some drug molecules.For example,loratadine can be converted into the corresponding product in a yield of 53%,and fenofibrate forms the target monofluoromethoxy compound in a yield of 81%.(2)Monofluoromethoxy compounds are obtained from arylboronic acid by a one-pot method,in this process,the hydrogenation of arylboronic acid with hydrogen peroxide as an oxidant has a high efficiency,and further monofluoromethylation to obtain a monofluoromethoxy compound.(3)For the monofluoromethoxylation of aromatics,the C-H bond on the aromatics needs to be borated,hydroxylated,and monofluoromethylated using an iridium catalyst system,and finally a monofluoromethoxy compound is obtained.In the course of the experiment,it was found that the di-substituted compound having a substituent at the 3and 5 positions can obtain a good reaction,and further hydroxylated the monofluoromethyl group to obtain a monofluoromethoxy compound.