A metallaphotoredox C−O coupling reaction was optimized through the use of High Throughput Experimentation (HTE) and Design of Experiment (DoE) techniques. The resulting methodology utilizes more sustainable and cost effective materials than previously reported conditions, and has been demonstrated on a range of substrates from 300 μL up to 500 mL scales.

Abstract

Using High-Throughput Experimentation (HTE), a visible light-mediated etherification method was developed, employing the organic photocatalyst thioxanthen-9-one (TXO) and a commercially available, air-stable nickel source. Design of Experiments (DoE) techniques were utilized in conjunction with HTE to identify optimal reaction conditions which are mild, cost-effective, robust and therefore suitable for use in an industrial setting. A diverse substrate scope was prepared via parallel synthesis and selected examples were demonstrated on a 4.2 mmol scale in batch. Furthermore, the reaction was successfully performed on an 83 mmol scale, utilizing a standard jacketed reactor and Kessil PR160 L lamps.