Visible-light Photoredox Catalytic Trifluoromethylthiolation

Organic fluorides are used widely in drugs and materials.The introduction of fluorine-containing functional groups into target molecules often significantly changes their physical and chemical properties.Among the fluorine-containing functional groups,the strong electron-withdrawing properties of SCF₃ group can effectively reduce the electron cloud density of the target molecule,thereby improving the metabolic stability of the target molecule.Owing to the high lipophilicity,introduction of SCF₃ group can substantially improve the lipophilicity and cellmembrane permeability of parent drug molecules.Visible light photoredox catalysis relys on a very small amount of photosensitizer to absorb light energy engaging in single-electron transfer with organic substrates to start the reaction.Compared with the traditional thermal reaction,the photoreaction proceeds with low activation energy under safe and mild reaction conditions.It is one of the most ideal methods for the synthesis of alkyl trifluoromethyl sulfide.At present,the following challenges for the synthesis of alkyl trifluoromethyl sulfide are as follows:1)synthesis of tertiary alkyl trifluoromethyl sulfide with large steric hindrance;2)mild conditions,and no transition metals involved;3)synthesis of alkyl trifluoromethyl sulfide with precise and predictive regioselectivity.Therefore,we have developed a series of visible light redox catalytic strategies to synthesize alkyl trifluoromethyl sulfide.This dissertation mainly consists of the following two parts:Part ?:Methoxymethyl ethers have been firstly used as a source of alkyl radicals for trifluoromethylthiolation reactions.Through photocatalysis/organic catalysis,synthetic catalysis strategy,the reaction is well compatible with weaker benzyl C-H bonds.Based on the polarity-matching principle,the alkyl radical,generated from site-selectively cleavage of tertiary sp³ C?sp³?–O ether bonds,reacts with the trifluoromethylthio reagent Phth-SCF₃ to give various tertiary alkyl trifluoromethyl sulfides.Selective difluoromethylthiolation of C?sp³?–O bonds has also been achieved.Consecutive procedures can be successefully applied for trifluoromethylthiolation of complex tertiary alkyl alcohols.The present reaction processes under the mild conditions,and avoids the involvement of transistion-metal.It provides an efficient method for the synthesis of tertiary alkyl trifluoromethyl sulfide.Part ?:As an ongoing research of the part I work,this present work develops a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of1^o,2^o and 3^o benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes.The precise and predictive regioselectivity among various C?sp³?-H bonds originates from an inner-sphere benzylic radical initiation mechanism,and avoids the use of external oxidants or hydrogen atom abstractors.At the same time,the trifluoromethylthiolation of the benzylic C-H bond in drugs and complex molecules has been successfully completed,and the synthesis of molecules with potential insecticidal activity has been also achieved.Finally,trifluoromethylthiolation of complex molecules in 1 mmol scale can be achieved with continuous flow photoredox technology.These advantages fully illustrate the important synthetic value of this strategy.The two research works have provided an access to the gentle and efficient synthesis of various alkyl trifluoromethyl sulfide compound libraries.In addition,the photocatalytic/organic catalysis and photocatalytic the inner-electron excitation strategy for activation of benzyl C-H bond provide new means for future organic synthesis.