The creation of carbon-phosphorus bonds is crucial due to the extensive use of organophosphorus compounds in various fields, including chemistry, materials science, and biology. Existing C-H phosphorylation methods often rely on directing groups, transition metal catalysts, or chemical oxidants, limiting their scope and sustainability. Current methods, whether electrochemical or not, often necessitate directing groups, transition metal catalysts, or chemical oxidants, thus restricting the range of applicable substrates. This study aims to address these limitations by developing a more efficient and sustainable method for C-H phosphorylation. The researchers hypothesize that utilizing electrochemistry in a continuous flow reactor will allow for the generation and subsequent reaction of highly reactive P-radical cations with a wide range of arenes, including electron-deficient ones, without the need for catalysts or external oxidants. This approach offers a potential solution for the challenges associated with traditional C-H phosphorylation methods. The importance of this research lies in providing a more versatile and environmentally friendly approach to synthesizing aryl phosphorus compounds, which have broad applications in various fields, as exemplified by the commercial success of brigatinib, an ALK inhibitor containing a phenylphosphine oxide motif. This green and scalable synthesis strategy is expected to significantly impact the production of valuable organophosphorus compounds.

The literature review covers existing methods for C-H phosphorylation, highlighting their limitations. Transition-metal-catalyzed reactions, while effective, often require directing groups, thereby limiting substrate scope. Radical-based methods, typically employing photochemical or transition-metal-catalyzed oxidation, are often restricted to electron-rich arenes. Electrochemical approaches have shown promise but often necessitate metal catalysts or are limited to electron-rich substrates. The authors discuss the concept of using P-radical cations, a largely unexplored class of reactive intermediates, to overcome these limitations, inspired by the observation that protonation of aminyl radicals enhances their reactivity. This review sets the stage for the proposed electrochemical method using a continuous-flow reactor to facilitate P-radical cation formation and its subsequent reaction with arenes.

The researchers employed a continuous flow electrochemical cell with a graphite anode and a platinum cathode. The reaction was optimized using benzoate 1 and triethyl phosphite as model substrates. The electrolysis conditions, including the amounts of reagents (triethyl phosphite, HBF4, H2O), solvent (MeCN), flow rate (0.2 mL/min), current (45-55 mA), and residence time (75s) were systematically investigated. The optimal conditions were then applied to a wide range of arenes with various electronic properties (electron-rich and electron-deficient) to evaluate substrate scope. The reaction was also tested with trialkyl phosphites containing different alkyl chains. Moreover, the method’s applicability to late-stage functionalization of complex molecules (natural products and bioactive compounds) was demonstrated. To assess scalability, a continuous production of mesitylphosphonate was performed for 231 hours using a system of two parallel electrochemical flow cells, producing 55.0 grams of the product. Post-synthetic transformations including hydrolysis, chlorination, and reactions with various nucleophiles were performed on the obtained aryl phosphonates to further extend their synthetic utility. Mechanistic studies involved cyclic voltammetry to determine oxidation potentials, 31P-NMR spectroscopy to analyze reaction mixtures and identify phosphorus species, and isotopic labeling experiments (using H218O) to elucidate the reaction mechanism. Kinetic isotope effect (KIE) experiments were conducted to probe the rate-determining step. The experimental details including reagents, concentrations, electrolysis parameters and workup procedures, as well as the characterization of the synthesized compounds are provided in the Supplementary Methods.

The study successfully developed a catalyst- and external oxidant-free electrochemical method for the C-H phosphorylation of arenes. The method uses a continuous-flow electrochemical cell that is effective for arenes with diverse electronic properties, including both electron-rich and electron-deficient substrates. The high reactivity of the electrochemically generated P-radical cations enables efficient reactions under mild conditions. The method demonstrated excellent functional group tolerance and was successfully applied to late-stage functionalization of complex natural products and bioactive molecules. The scalability of this approach was demonstrated by the continuous production of 55.0 g of mesitylphosphonate (83% yield) over 231 hours using a parallel flow reactor system, which is significantly higher than the yield obtained on a smaller scale (70%). Mechanistic studies suggest that the reaction proceeds through the oxidation of trialkyl phosphite to generate P-radical cations, which react with arenes. The presence of water and acid (HBF4) was found to be crucial for the reaction's success. Water aids in the hydrolysis of trialkyl phosphite to produce HPO(OEt)2, which likely reduces the decomposition of the P-radical cation. The absence of a significant kinetic isotope effect indicates that C(aryl)-H bond cleavage is not involved in the rate-limiting step. This electrochemical method offers an efficient, sustainable, and scalable approach for C-P bond formation.

The results address the limitations of existing C-H phosphorylation methods by providing a catalyst- and oxidant-free electrochemical approach applicable to a broad range of substrates. The use of continuous flow enhances the efficiency and scalability, addressing challenges associated with batch processes. The reaction's tolerance for diverse functionalities including electron-deficient arenes, and its compatibility with complex molecules represents a significant advancement in the field. The mechanistic insights gained provide a clearer understanding of the process and pave the way for future optimization efforts. The high yield and scalability achieved in the continuous flow system show considerable promise for industrial applications, reducing reliance on traditional transition metal catalyzed methods and contributing to sustainable synthesis. The findings enhance the toolbox for synthesizing arylphosphonates, significantly impacting medicinal chemistry, materials science, and catalysis.

This research successfully demonstrates a novel electrochemical method for direct C-H phosphorylation of arenes. The method is catalyst- and oxidant-free, highly efficient, scalable (as shown by the continuous flow production of 55g of product), and tolerates a broad range of functional groups. The mechanistic studies shed light on the reaction pathway, involving P-radical cations. Future work could explore the application of this technology to other C-heteroatom bond formations and investigate different electrochemical cell designs for further improvements in efficiency and scalability.

While this method demonstrates broad applicability, the scope might still be limited by certain functional groups that could interfere with the electrochemical process. Further optimization of the reaction conditions could improve the yields for some substrates. The mechanistic understanding, although advanced, might benefit from more detailed studies to fully elucidate the roles of all components, particularly HPO(OR)2, and the exact nature of the deprotonation steps. Additionally, exploring the long-term stability of the electrochemical system for even larger scale applications would be beneficial.