Aryl fluorides are widely used in the pharmaceutical and agrochemical industries, and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon-hydrogen (C-H) fluorination. Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C-H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood-brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C-H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C-H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.

(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late‐stage aryl C−H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.

We recently reported a new method for the 18 F-difluoromethylation of N-heteroaromatics for PET imaging. The method involves the synthesis of a new 18 F-difluoromethylating reagent 2-[ 18 F]((difluoromethyl)sulfonyl)benzo[d]thiazole and a flow photoredox 18 Fdifluoromethylation. For preclinical development and human Positron Emission Tomography (PET) studies with new radiotracers, an automation of the process is mandatory, mostly to avoid radioprotection issues, due to the use of high amounts of radioactivity and to ensure a better reliability of the production. We hereby describe the automation of this 18 Fdifluoromethylation method, on a model substrate, Acyclovir, on a commercially available AllinOne (AIO) synthesizer from Trasis. The whole process is completed in 95 minutes and provides radiolabeled Acyclovir with a molar activity of 35 GBq/µmol. This automated protocol can be implemented for the 18 F-difluoromethylation of a wide range of Nheteroaromatics compounds typically found in medicinal chemistry.

Afast, scalable, and safer C sp 3 ÀHoxidation of activated andu n-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platforma llows the in situ generation of TFDO gas and its rapid reactivity toward tertiarya nd benzylic Csp 3 ÀHb onds.T he process exhibits ab road scope and good functional groupc ompatibility ( 28 examples, 8-99 %). The scalability of this methodology is demonstrated on 2.5 gs cale oxidation of adamantane.

A convenient, versatile, and regiospecific synthesis of functionalized 1,3-diarylisobenzofurans has been developed. It involves chemoselective addition of arylmagnesium reagents to the aldehyde function of o-aroylbenzaldehydes, themselves readily obtained by lead tetraacetate oxidation of N-aroylhydrazones of salicylaldehydes. Various functional groups, including nitro, iodo, or ester functionalities, have thus been positioned with complete regiospecificity on the 1,3-diphenylisobenzofuran backbone.

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C-H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.

A selective, nonchelation‐assisted methylation of arenes has been developed. The overall transformation, which combines a C−H functionalization reaction with a nickel‐catalyzed cross‐coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late‐stage methylation of small‐molecule pharmaceuticals.