Pushing the boundaries of C–H bond functionalization chemistry using flow technology

Abstract

C-H functionalization chemistry is one of the most vibrant research areas within synthetic organic chemistry. While most researchers focus on the development of small-scale batch-type transformations, more recently such transformations have been carried out in flow reactors to explore new chemical space, to boost reactivity or to enable scalability of this important reaction class. Herein, an up-to-date overview of C-H bond functionalization reactions carried out in continuous-flow microreactors is presented. A comprehensive overview of reactions which establish the formal conversion of a C-H bond into carbon-carbon or carbonheteroatom bonds is provided; this includes metal-assisted C-H bond cleavages, hydrogen atom transfer reactions and C-H bond functionalizations which involve an S E-type process to aromatic or olefinic systems. Particular focus is devoted to showcase the advantages of flow processing to enhance C-H bond functionalization chemistry. Consequently, it is our hope that this review will serve as a guide to inspire researchers to push the boundaries of C-H functionalization chemistry using flow technology.

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

“…Similar results were obtained with carbonyl-containing com-pounds. Different aromatic ketones, aldehydes, esters, and carboxylic acids were transformed to the corresponding trifluoromethoxylated compounds (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) with generally good to high yields, except for 13, 16, 19 and 22 which were obtained in moderate or poor yields. Other synthetically useful substituents, including cyano, nitro, phenylsulphonyl, (pinacolato)boron, and alkyl groups could be tolerated in the reaction (24)(25)(26)(27)(28)(29)(30), leading to a yield range between 26 and 65%.…”

“…Alternative approaches were recently reported [8,9,11], for example the trifluoromethylation of hydroxyaryls [12][13][14], and the direct introduction of the -OCF 3 moiety into an organometallic species [15], a diazo compound [16,17], or an unfunctionalized C-H bond (Scheme 1B). The latter method is particularly interesting, partially due to the general interest of the community into C-H functionalization methodologies [18,19], and partially thanks to the synthetic possibilities enabled by photoredox catalysis, a field widely explored in recent years [20][21][22]. In 2018, Ngai [23,24] and Togni [25] reported simple photoredox protocols for the radical trifluoromethoxylation of unfunctionalized (hetero)arenes by using specifically designed CF 3 O radical-releasing agents (Scheme 1B).…”

“…Following our long-standing interest in the development of continuous-flow approaches for C-H functionalization [18,26] and photochemical methodologies [27][28][29][30][31], herein we report the first application of flow methods for the direct trifluoromethoxylation of arenes and heteroarenes.…”

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

“…In this context, great advances were also recently achieved in the field of direct C–H functionalization reactions under flow conditions. Persistent improvements enabled the development of innovative flow techniques, encompassing large-scale photochemical procedures, which were successfully applied to various C–H functionalization reactions [ 92 – 93 ].…”

Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides

“…Continuous-flow chemistry has rapidly established itself as a go-to technology to carry out difficult-to-handle reagents and reaction conditions [1,2]. Notable examples where flow has made an undeniable impact are photochemistry [3][4][5], electrochemistry [6][7][8], multiphase reactions [9][10][11][12] and handling of toxic, explosive or other hazardous reagents and intermediates [13-15, 16, 17].…”