Tomas Horsten

This novel platform for automated electrochemical synthesis of compound libraries in flow enabled the C−X arylation of>30 aryl halide scaffolds in the presence of diverse amines (including sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid electrode passivation.

Abstract

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure–activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C−X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across>30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C−X arylation compound libraries using flow electrochemistry.

(Z)-Enamides are important motifs, due to their prevalence in bio-active molecules. However, few strategies are known to obtain them stereoselectively. Herein we report a nickel catalyst which, combined with simultaneous photoredox and energy transfer catalysis, enables the selective formation of (Z)-enamides. Di- and tri- functionalized functionalized olefin products can be obtained in high yields and stereoselectivity, respectively, from a redox-modulated nickel intermediate. Selective and challenging nickel-catalyzed β-H abstraction is attainable through kinetic control facilitated by an external additive.

Nature Catalysis, Published online: 24 September 2024; doi:10.1038/s41929-024-01217-1

Electrifying the fragmentation of hydrocarbons is an emerging challenge in the context of decarbonizing the chemical industry. To this end, competing electrocatalytic C–C cleavage and oxidation pathways of butane were investigated.

Nature Catalysis, Published online: 19 August 2024; doi:10.1038/s41929-024-01205-5

Muconic acid is an important bio-based chemical; however its applications are limited by the lack of efficient methods to access its trans,trans-isomer. Here the authors address this problem with a catalyst based on single Ru atoms dispersed on zeolite BEA that is capable of unlocking hydride chemistries.

We developed an original method for thiocyanating C−H bonds in various phenols and their derivatives using readily available materials via electrogenerated (SCN)₂ and its Zn(II) complex. The process led to a diverse range of target products with yields of 36–97 % (include the drug riluzole and precursors for toltrazuril and ponazuril) under mild conditions.

Abstract

We developed an original method for thiocyanation of hydroxy- and alkoxy-substituted benzenes (including naturally occurring compounds) using electrogenerated thiocyanogen, (SCN)₂. The presence of zinc chloride as a Lewis acid significantly enhances reaction efficiency by activating thiocyanogen. Cyclic voltammetry of the reactants and their combinations was employed to optimize reaction conditions and investigate the proposed mechanisms. This method demonstrated broad synthetic utility, leading to mono- and bis-thiocyanated arenes and various heterocycles with yields 36–97 %. Notable products include the neuroprotective drug riluzole and precursors for the antiprotozoal drugs toltrazuril and ponazuril.

Organo-mediated electroreduction has emerged as a promising approach, in which organo-mediators can gain electrons from the electrode to form active intermediates and then efficiently activate the substrates through the electron transfer process. This review will provide a detailed description of electroreduction reactions mediated by organic molecules in recent years and elucidate the mechanism of the organo-mediators in the transformations.

Abstract

Electroreduction is an important aspect of organic electrochemistry. Its chemistry does not require the addition of additional reductants, making it an effective alternative to various traditional reduction reactions. Among them, organo-mediated electroreduction is recognized as a promising approach. Organo-mediators can be reduced directly at the cathode to form reactive radical anions that subsequently reduce the substrate via electron transfer (ET) to initiate the reaction being investigated. Organo-mediators typically have a more positive reduction potential, and their role in the whole reaction is similar to that of catalysts. Their addition transforms the ET process from the original heterogeneous process into a homogeneous one. Organo-mediated electroreduction can effectively avoid the over-electrolysis of the substrate and the product at the electrode and the intolerance of sensitive substrates or functional groups during electrolysis, thereby preventing the occurrence of side reactions. It can also prevent the excessive consumption of reagents and electrical energy while promoting the reaction to achieve higher or completely different selectivity. Considering the advantages of this type of reaction, this review will provide a detailed description of electroreduction reactions mediated by organic molecules in recent years and elucidate the mechanism of the organo-mediators in the transformations.

The combination of DoE with reaction automation using LABS was the key to the efficient optimization of the direct undivided multicomponent synthesis of alkyl arenesulfonates in flow. The transfer from the previously divided batch electrolysis protocol to undivided flow resulted in an increase in yield and productivity in scale-up.

Abstract

The necessary separation of anodic and cathodic compartments in the electrochemical multicomponent synthesis of alkyl arenesulfonates in batch was overcome by the transfer of this reaction in an undivided electrochemical flow cell. The yield was increased from an initial 23 % to 67 % by optimization using Design of Experiments (DoE). The experiments were carried out using an automated experimental flow electrolysis setup controlled by the automation software LABS (Laboratory Automation and Batch Scheduling), an open-source software that allows to plan and conduct experiments with an arbitrary, freely selectable experimental setup. The automated experimental setup turned out to be stable and provides reproducible results. In total, 6 examples are demonstrated with isolated yields up to 81 %. In addition, the robust scalability of the electrochemical reaction was demonstrated in a 10-fold scale-up.

Nature, Published online: 08 August 2024; doi:10.1038/d41586-024-02553-9

Survey of bacteria living inside household and laboratory appliances finds a robust ecosystem.