Visible light promoted E-→Z isomerization of difluoroallyl compounds
Due to the unique properties of fluorine atoms,fluorinated organic compounds play significant roles in pharmaceuticals,pesticides,materials,fine chemicals,and other fields.About 25％of pharmaceuticals and 30％of pesticide molecules contain at least one fluorine atom.The fluorine atom has high electronegativity and a small atomic radius and is considered a bioisostere of the hydroxyl functional group in medicinal chemistry.Moreover,introducing fluorine atoms can significantly change lead compound's solubility,hydrophobicity,metabolic stability,and bioavailability.Introducing a difluoroallyl group is essential for drug molecules,and the difluoroallyl compounds can be used as important intermediates in synthesizing other fluorinated compounds.Therefore,the synthesis method of difluoroallyl compounds has attracted extensive attention from the synthetic community.The radical coupling reaction of reactive olefins with halogenated difluoroalkanes was developed to synthesize difluoroallyl compounds.However,the current synthesis methods always afforded(E)-allyl difluoride as a main product.The cis and trans olefins exhibit different physical and chemical properties and demonstrate different biological activities.Most of the synthesis methods of olefins mainly give the thermodynamic more stable trans olefins.Under heating conditions,trans olefins can be converted to cis olefins.In addition,trans and cis olefin mixtures are often challenging to be separated by column chromatography.Therefore,the highly selective synthesis of cis olefins is of great significance.Because the selective synthesis of thermodynamically unstable cis olefins is challenging,the conversion method from trans olefins to cis olefins has attracted much attention,which has a 100％atomic utilization rate and has been well developed in recent years.The transformation of geometric cis/trans isomerization of olefins is deeply embedded in organic photochemistry's historical background and is currently experiencing renewed interest.However,the stereospecific Z/E isomerization of difluoroallyl compounds remains underdeveloped;thus,the selective E→Z photochemical isomerization for synthesizing(Z)-allyl difluoride exemplifies this growing trend.During our study of the fluoroalkyl compound's synthesis method,we disclosed the effective activation of(E)-difluoroallyl compounds with 4CzIPN as an organic photocatalyst under visible light irradiation and selectively obtained(Z)-difluoroallyl compounds.With the optimal reaction conditions in hand,we investigated the applicability of the substrates in the current reaction.By using aromatics that contain an electron-donor substituent,the yield of cis olefin decreases with the increase of electron-donating abilities of substituents.The substrates containing substituents such as fluorine,chlorine,and bromine had little effect on the reaction outcomes.The present reaction can be well applied to various substrates with other electron-withdrawing phenyl substrates.Substrates containing substituents at the benzyl position are also suitable for the current reaction,but the reaction yield is reduced.When a substrate containing a heterocycle is used,the current reaction can proceed smoothly,and the desired product can be obtained.It is worth noting that there are no side reactions in the reaction.Therefore,the remaining(E)-difluorallyl compounds can be recovered and converted into(Z)-difluorallyl compounds again through this reaction.The developed photochemical reaction system can also suit the E→Z isomerization of trans-styrene compounds.Trans-phenylpropylene,trans-cinnamyl alcohol,and trans-cinnamate methyl ester all underwent present photocatalytic isomerization reactions,converted into corresponding cis products in good yields,demonstrating the broad application range of the current reaction.Also,the gram-scale reaction was carried out with a 78％yield,indicating that the current reaction is suitable for preparing(Z)-difluoroallyl compounds on a large scale.Further,the derivatization of cis products successfully gives the corresponding difluoroalkyl carboxylic acid and difluoroalkyl alcohol.In conclusion,a visible light-promoted photocatalytic method was established to obtain(Z)-difluorallyl compounds from(E)-difluorallyl compounds selectively.4CzIPN catalyzes this method as an organic photocatalyst suitable for the E→Z isomerization of various trans-difluoroallyl compounds and trans-styrene derivatives.This preparation method does not require a metal catalyst,is easy to operate,is mild and environmentally friendly,and could be used to prepare(Z)-difluoroallyl compounds on a large scale.
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