Water Microdroplet Chemistry for Accelerating Green Thiocyanation and Discovering Water-Controlled Divergence

As an important class of five-membered N-heterocyclic compounds, pyrazolin-5-one derivatives play an extremely important role in the construction of fine chemicals and bioactive molecules. Traditional synthetic methods for functionalization (i.e., thiocyanation) used organic solvents to undergo slow reactions, which poses problems such as environmental pollution, low efficiency, and high cost. Herein, we develop a green, efficient, and gram-scale pyrazolinone thiocyanation method by water microdroplet chemistry. Using water as the solvent, this microdroplet method reduced the equivalent of oxidant and completed the thiocyanation reaction (>90% yields) within milliseconds (reaction time for a single microdroplet, although the actual collection time for detectable amounts of products is on the order of minutes to hours). The water microdroplet method was suitable for various pyrazolinone derivatives, and the yields of the aqueous microdroplet reactions were much higher than those of bulk reactions. In addition, we efficiently discovered a unique role of water in driving different reaction pathways by aqueous microdroplet chemistry. In the presence of water, pyrazolinone incubated with ammonium thiocyanate afforded tandem thiocyanation/ammonium cross-coupling products, compared to only thiocyanated products in pure organic solvents, leading to a possible water-controlled divergence.