Photo-Catalyzed Fluoroalkylation Of Coumarins By The Recyclable Ru(?) Or Ir(?) Photosensitizers In Continuous Flow

The introduction of trifluoromethyl and perfluoroalkyl into the organic molecules is a key strategy that the chemists develop new drugs and new functional molecules,since F-containing group could significantly improve the lipophilicity,polarity and solubility.Coumarin derivatives represent a vast family of compounds which are mostly extracted and isolated from traditional Chinese herbs,and have emerged as promising and valuable natural products with high biological activities and luminescence properties.Fluoroalkylated modification of coumarin is an effective method for the development of new drugs and luminescence materials.Togni's reagent is commonly used for the reported trifluoromethylation of coumarin,leading to be hard to apply on the indusrial production of trifluoromethylation of coumarin due to the high price of Togni's reagent.Continuous flow chemistry has advantages of the efficient mass-transfer,heat-transfer and easy scale-up reaction with the characteristics of the micro-channel and big specific surface area.A mild,efficient and cheap trifluoromethylation of coumarin in continuous flow could be developed through the application of continuous flow to the trifluoromethylation.In recent years,photocatalysis involving visible light to trigger reaction has drawn much attention from global chemists as an efficient and new synthetic method.However,despite Ru(bpy)3Cl2 and fac-Ir(ppy)3 as the efficient and common photocatalysts for a wide application,the relatively high cost and pollution still limit their practical uses in large scale.The recyclable photocatalysts have been reported with a polymer-bound ligand,and the problem of the molecular weight distribution occurre.In this paper,the hydrocarbon phase selectively soluble Ru and Ir complex photocatalysts with the known carbon chain-bound ligands were designed and synthesized based on the principle that the substances with the similar polarity could easily dissolve by each other,aiming to efficiently,easily and fast recovery the photocatalysts after completement of the reaction.The recyclability and catalytic activity of the recyclable Ru and Ir complex photocatalysts were evaluated through the fluoroalkylation of coumarin as model reactions,the detailes as following:(1)A continuous flow trifluoromethylation of coumarin was developed using CF3SO2Na as a cheap trifluoromethylated reagent.The trifluoromethylation in continuous flow yielded 3-trifluoromethyl coumarin in 68%with 2 equiv.of CF3SO2Na at 60? in 100 ?L/min flow rate(40 min)after the optimization reaction condition,showing more significant advantages of trifluoromethylation in continuous flow than in batch.The scale-up flow process was run continuously to obtain product in 68%yield when the concentration was increased five-fold.A mild,efficient,cheap and easily up-scaled trifluoromethylation of the coumarin in continuous flow has been successfully developed.(2)A n-heptadecanyl-bound,selectively soluble in hydrocarbon solvent phase and recyclable fac-Ir(hdppy)3 photocatalyst was designed and synthesized,and which could be fast,efficiently,conveniently recovered through the auto phase-separation in TMS system.The average yield of the recovered fac-Ir(hdppy)3 was 96%after the 1st run for the trifluoromethylation,difluoroacetylation of phenyl 3-phenylpropiolate and trifluoromethylation of 2-isocyanide.And then the average yield of the recovered fac-Ir(hdppy)3 was 79%after the 5th run,and the yield of products decreased in a slight,showing the excellent recyclability and catalytic activity of fac-Ir(hdppy)3.Meanwhile,a new visible light-photocatalyzed synthetic method of 3-trifluoromethyl-4-phenyl coumarin and 6-trifluoromethyl phenantridine using the recyclable fac-Ir(hdppy)3 has been developed.(3)A 1-nonyldecanyl-bound,hydrocarbon solvent phase selectively soluble and recyclable Ru[(ND)2bpy]3Cl2 photocatalyst was designed and synthesized,and which could be recovered repeatedly by extraction with hexane after the solvent of reaction was removed.The yield of the recovered Ru[(ND)2bpy]3Cl2 was 93%and 53%after the 1st and 5th run,respectively,and the moderate yield of the trifluoromethylation of coumarin using TFAA and pyridine N-oxide as reagents catalyzed by visible light was obtained.Meanwhile,the 6th run gave the product in a slight decreased yields,showing excellent recyclability and catalytic activity of Ru[(ND)2bpy]3Cl2.The results in batch for up-scale and in continuous flow make this approach attractive for large-scale application in industry.