Homogeneous and Gas-Liquid Catellani-Type Reaction Enabled by Continuous-Flow Chemistry.

A practical homogeneous and gas-liquid palladium-catalyzed Catellani-type reaction using a continuous-flow platform is described. The implementation of continuous-flow technology allowed the acceleration of the transformation and, for the first time, expansion of the chemical space to gaseous olefins (i.e., ethylene, propylene and 3,3,3-trifluoropropene), thus providing a safe and practical approach to sterically hindered ortho-disubstituted styrenes and vinyl arenes. The complete control over the stoichiometry of gaseous reagents through flow technology proved essential for directing the selectivity of the Catellani reaction to the desired products.

Flow Synthesis of Diaryliodonium Triflates.

A safe and scalable synthesis of diaryliodonium triflates was achieved using a practical continuous-flow design. A wide array of electron-rich to electron-deficient arenes could readily be transformed to their respective diaryliodonium salts on a gram scale, with residence times varying from 2 to 60 s (44 examples).

Liquid phase oxidation chemistry in continuous-flow microreactors.

Continuous-flow liquid phase oxidation chemistry in microreactors receives a lot of attention as the reactor provides enhanced heat and mass transfer characteristics, safe use of hazardous oxidants, high interfacial areas, and scale-up potential. In this review, an up-to-date overview of both technological and chemical aspects of liquid phase oxidation chemistry in continuous-flow microreactors is given. A description of mass and heat transfer phenomena is provided and fundamental principles are deduced which can be used to make a judicious choice for a suitable reactor. In addition, the safety aspects of continuous-flow technology are discussed. Next, oxidation chemistry in flow is discussed, including the use of oxygen, hydrogen peroxide, ozone and other oxidants in flow. Finally, the scale-up potential for continuous-flow reactors is described.

A Modular Flow Design for the meta-Selective C-H Arylation of Anilines.

Described herein is an effective and practical modular flow design for the meta-selective C-H arylation of anilines. The design consists of four continuous-flow modules (i.e., diaryliodonium salt synthesis, meta-selective C-H arylation, inline copper extraction, and aniline deprotection) which can be operated either individually or consecutively to provide direct access to meta-arylated anilines. With a total residence time of 1 hour, the desired product could be obtained in high yield and excellent purity without the need for column chromatography, and the residual copper content meets the standards for parenterally administered pharmaceutical substances.

Optimization of a Decatungstate-Catalyzed C(sp3)-H Alkylation Using a Continuous Oscillatory Millistructured Photoreactor.

Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C-H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp3)-H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.

Mild and selective base-free C-H arylation of heteroarenes: experiment and computation.

A mild and selective C-H arylation strategy for indoles, benzofurans and benzothiophenes is described. The arylation method engages aryldiazonium salts as arylating reagents in equimolar amounts. The protocol is operationally simple, base free, moisture tolerant and air tolerant. It utilizes low palladium loadings (0.5 to 2.0 mol% Pd), short reaction times, green solvents (EtOAc/2-MeTHF or MeOH) and is carried out at room temperature, providing a broad substrate scope (47 examples) and excellent selectivity (C-2 arylation for indoles and benzofurans, C-3 arylation for benzothiophenes). Mechanistic experiments and DFT calculations support a Heck-Matsuda type coupling mechanism.

Aerobic C-H olefination of indoles via a cross-dehydrogenative coupling in continuous flow.

Herein, we report the first site-selective, Pd(II)-catalyzed, cross-dehydrogenative Heck reaction of indoles in micro flow. By use of a capillary microreactor, we were able to boost the intrinsic kinetics to accelerate former hour-scale reaction conditions in batch to the minute range in flow. The synergistic use of microreactor technology and oxygen, as both terminal oxidant and mixing motif, highlights the sustainable aspect of this process.

Rapid trifluoromethylation and perfluoroalkylation of five-membered heterocycles by photoredox catalysis in continuous flow.

Trifluoromethylated and perfluoroalkylated heterocycles are important building blocks for the synthesis of numerous pharmaceutical products, agrochemicals and are widely applied in material sciences. To date, trifluoromethylated and perfluoroalkylated hetero-aromatic systems can be prepared utilizing visible light photoredox catalysis methodologies in batch. While several limitations are associated with these batch protocols, the application of microflow technology could greatly enhance and intensify these reactions. A simple and straightforward photocatalytic trifluoromethylation and perfluoroalkylation method has been developed in continuous microflow, using commercially available photocatalysts and microflow components. A selection of five-membered hetero-aromatics were successfully trifluoromethylated (12 examples) and perfluoroalkylated (5 examples) within several minutes (8-20 min).