Rapid and Mild One-Flow Synthetic Approach to Unsymmetrical Sulfamides Guided by Bayesian Optimization

Bayesian optimization (BO) is regarded as an efficient approach that can identify optimal conditions using a restricted number of experiments. Despite demonstrated potential of BO, applications of BO-based approaches in synthetic organic chemistry remain limited. Herein, we achieved the first rapid and mild (5.1s, 20 degrees C) one-flow synthesis of unsymmetrical sulfamides from inexpensive sulfuryl chloride. Undesired reactions were successfully suppressed and the risk in handling sulfuryl chloride was minimized by the use of micro-flow technology. The reaction conditions producing >= 75% yield were identified by a machine learning approach based on BO. It was demonstrated that BO produced the desired reaction conditions with a small number of experiments (19 and 10 experiments) in the entire search space (10,500 combinations of reaction conditions). Gaussian process (GP) models produced by BO provided the relationships between combinations of reaction parameters and outputs (RCRPO).

Automated summary

This study demonstrates a rapid and mild continuous synthesis of unsymmetrical sulfamides from sulfuryl chloride. By using a machine learning approach based on BO, high-yield reaction conditions were successfully identified.