Silver Catalyzed C(sp~3)-H Insertion Reaction Of Alkanes With Fluoroalkyl-N-Triftosylhydrazones

Fluorinated organic compounds show good chemical stability,high surface activity and excellent temperature resistance due to the large electronegativity of fluorine element,which promotes the widespread application of fluoride compounds in pesticides,drugs and materials chemistry,etc.Therefore,it is particularly important for synthetic chemists to selectively introduce fluorine atoms or fluorine-containing groups into organic molecules.Trifluoromethyl-modified（CF₃）bioactive molecules exhibit unique roles in affinity to receptors or metabolic processes,for example,artemisinin,astatin A,estatin A,paclitaxel,birch acid and other natural products.Therefore,it is an important research topic to explore the introduction of trifluoromethyl into organic compounds.C-H bond activation is a common strategy to introduce functional groups into compounds,which has the advantages of simplicity,rapidity and economy.At present,the research on the trifluoromethylation of aliphatic compound C（sp³）-H mainly focuses on alkanes containing guiding groups,such as carbonylα-site,nitrogen atomα-site,benzyl C-H bonds,while trifluoromethylation of non-activated alkanes is relatively rare.For a long time,the use of trifluoromethylation reagent is a common method for trifluoromethylation of C（sp³）-H bond of alkanes,but it has problems such as high cost of preparing trifluoromethylation reagent and low industrial yield.In addition,the C（sp³）-H insertion reaction of trifluoromethyldiazoethane as a carbene precursor with simple alkanes can directly obtain trifluoromethyl compounds.However,toxic and unstable diazo compounds need to be added slowly,which makes it difficult to apply this method to actual production.Therefore,there is an urgent need to develop an inexpensive and stable compound as a source of trifluoromethylation to safely and efficiently achieve the C（sp³）-H bond trifluoromethylation reaction of alkanes.Based on this,this paper designed a C（sp³）-H bond insertion reaction of simple alkanes initiated by fluoroalkyl highly electrophilic silver carbene,which successfully introduced trifluoromethyl into unactivated alkanes and constructed a series of benzyl trifluoromethyl compounds containing quaternary carbon centers.The reaction conditions are mild,the substrate range is broad（>60 examples）,and the regioselectivity is good（3°,2°,1℃（sp³）-H insertion ratio is 50:2:1）.The utility of this method in drug synthesis was demonstrated by gram scale experiments and direct C（sp³）-H trifluoromethylation of natural products and drug molecules.Density Functional Theory（DFT）calculations show that the reaction is highly selective for 3℃（sp³）-H insertion.