Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids

Abstract

Herein we disclose an efficient method for the conversion of carboxylic acids to trifluoromethyl groups via the combination of photoredox and copper catalysis. This transformation tolerates a wide range of functionality including heterocycles, olefins, alcohols, and strained ring systems. To demonstrate the broad potential of this new methodology for late-stage functionalization, we successfully converted a diverse array of carboxylic acid-bearing natural products and medicinal agents to the corresponding trifluoromethyl analogues.

Copper‐Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides

“…Benzylic C(sp 3 ) À Ht rifluoromethylation of pyridine and quinoline derivatives [6] with the Ruppert-Prakash reagent [7] is also known, and takes place by oxidation and subsequent nucleophilic CF 3 À addition. More recently,b ased on the trifluoromethylation of alkyl radicals, [8] copper-mediated benzylic C(sp 3 )ÀHt rifluoromethylation was also accomplished by the groups of Cook and Liu (Scheme 1a). [9] To date,o nly allylic or benzylic C À Ht rifluoromethylation is known, whereas direct trifluoromethylation of robust aliphatic C(sp 3 )ÀHb onds remains unexplored.…”

Photoredox‐Coupled F‐Nucleophilic Addition: Allylation of gem‐Difluoroalkenes

“…[3] Aside from ah andful of CF 3 -radical-based functionalizations of structurally elaborated styrene derivatives, [4] these molecules could be created either by direct trifluoromethylation of aliphatic skeletons [5] or through crosscoupling using a-CF 3 -derived precursors (Scheme 1a). [6,[12][13][14][15][16] With Lisp ioneering work on trifluoromethylation of alkyl radicals using Grushinsreagent, [7] thegroups of MacMillan, [8] Cook, [9] and Liu, [10] developed decarboxylative and benzylic C À Ht rifluoromethylation protocols,a lthough the employment of expensive CF 3 reagents,aswell as restricted substrate scope,are still concerns.…”

Photocatalysis in the Dark: Near‐Infrared Light Driven Photoredox Catalysis by an Upconversion Nanoparticle/Photocatalyst System

“…In recent years, photoredox catalysis has become a prominent field in catalysis, exploiting mild reaction conditions by using visible light as the driving force to discover new transformations . Especially late stage functionalization of drug molecules and biomolecules are prominent applications . However, photoredox catalysis is limited by the need of high photon flux and energy to run reactions efficiently and with high chemoselectivity.…”

“…[1] Especially late stage functionalization of drug molecules and biomolecules are prominent applications. [2][3][4] However, photoredox catalysis is limited by the need of high photon flux and energy to run reactions efficiently and with high chemoselectivity. Moreover, most photoredox catalysts (PC) only absorb light in the visible region, which cannot deeply penetrate tissue and other materials.…”