Visible Light Induced Radical Fluoroalkylations and Oxidation Reactions

Abstract

Recently, visible light photocatalysis has attracted substantial attention due to its environmental compatibility and versatility in promoting a large number of synthetically important reactions. A variety of radical transformations using Ru- and Ir-based photocatalysts under visible light irradiation, including fluoroalkylations and oxidation reactions of carbonyl compounds have been developed. Fluoroalkylated organic compounds play significant roles in the pharmaceuticals and agrochemicals owing to superior metabolic stability, binding selectivity, bioavailability, and lipophilicity compared to those of their non-Fluoroalkylated analogues. First, electron-rich heterocycles such as indoles, pyrroles, thiophenes, and furans were transformed into trifluoromethylated products by using CF3I as the trifluoromethyl radical source and Ru(bpy)3Cl2 as the photocatalyst under mild reaction conditions. We have also developed a method to access trifluoromethylated alkenes without prefunctionalization with CF3I, Ru(Phen)3Cl2, and DBU. This process works especially well for terminal alkenes to give alkenyl-CF3 over allyl-CF3 products with E-stereochemistry. Next, a controlled method was established for the preparation of a set of highly valuable CF3-containing molecules, trifluoromethylated-alkenyl iodides [Ru(bpy)3Cl2, TMEDA, CH3CN], alkenes [fac-Ir(ppy)3, DBU, CH3CN/THF] and alkynes [fac-Ir(ppy)3, tBuOK, DMF], from alkynes and CF3I by visible light photocatalysis. Subtle differences in the combination of catalyst, base, and solvent enabled the control of reactivity and selectivity of the reaction. The incorporation of various difluoroalkyl groups (-CF2R) into organic compounds is particularly interesting not only because these groups alter molecular properties, but also because it introduces the possibility of functional group modification of the appended alkyl groups. A process for selective hydro-difluoroalkylation of unactivated alkenes has been developed by using fac-Ir(ppy)3 and BrCF2CO2Et. The choice of base was crucial in governing the chemo-selectivity of the process. In the second part of investigation, we studied several visible light-induced oxidation methods. An effort was made to oxidize aldehydes to carboxylic acids. Singlet oxygen, generated by visible light in the presence of Ir(dFppy)3 photocatalyst, reacted with aldehydes to give the corresponding carboxylic acids in excellent yields. The method is an example of an ideal green chemical reaction in the sense that molecular oxygen and visible light are key sources for the transformation. Later on, this oxidation ability of aldehydes under visible light conditions was exploited to develop one-pot amide synthesis method; visible-light irradiation of a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide using Ru(bpy)3Cl2 photocatalyst afforded an acid chloride, which subsequently reacted with amine to yield the corresponding amide. The reaction was used to synthesize moclobemide and a D3 receptor intermediate. During the course of development of oxidation reactions, α-CH oxidation of amines under visible light was exploited for C-N bond cleavage to synthesize carbonyls from amines. The process, which utilizes 1 mol% Ru(bpy)3Cl2 complex as the photocatalyst, potassium persulfate (K2S2O8) as the oxidant and water/acetonitrile (H2O/CH3CN) as the solvent, transforms a variety of primary, secondary and tertiary amines to corresponding carbonyl compounds. In addition, the method was applied to the removal of a p-methoxylbenzyl (PMB) group from N-PMB protected amides.