Because of their unique properties and high biological activities, organophosphorus compounds have been used worldwide in agricultural, industrial, medicinal, and veterinary applications. Conventional strategies for direct phosphonylation suffer from the usage of stoichiometric or excessive metallic or nonmetallic catalysts and long reaction times under harsh conditions, leading to a strong desire for environment-friendly protocols for phosphonylation. A protocol for the accelerated phosphonylation of N-phenyltetrahydroisoquinolines in minutes was developed without the use of any catalyst in microdroplets. The phosphonylation process was completed (>85% yields) in 10 min at 40 °C using 0.8 equiv 2,3-dicyano-5,6-dichlorobenzoquinone as the oxidant and acetonitrile as the solvent. The microdroplet phosphonylation strategy showed good suitability to alkyl phosphites and N-phenyltetrahydroisoquinolines bearing electron-withdrawing and electron-donating substitutes, and the yields of the microdroplet reaction were much greater than those of the bulk (accelerated by two orders of magnitude from the ratio of the rate constants using the microdroplet and the bulk method). Furthermore, microdroplet phosphonylation can be scaled up to a 1-phenyl-2-dimethylphosphonite-1,2,3,4-tetrahydroisoquinoline amount of 510 mg h–1 by spraying 0.1 mol L–1 N-phenyltetrahydroisoquinoline at 300 μL min–1. These figures of merit make it a promising alternative to classic organic methodologies for the synthesis of organophosphorus compounds.

Due to their important roles in medicine and asymmetric metal catalysis, the formation of Betti bases has attracted wide interest in organic chemical community. Traditional multicomponent reaction methods for synthesizing Betti bases normally require long reaction times under harsh conditions (high temperature, microwave or ultrasonic irradiation, etc.) in the presence of various catalysts. In this study, we developed a mild, highly efficient and environmentally friendly method to synthesize Betti bases without the use of any catalysts in microdroplets. The Betti reaction was accelerated by 6.53×103 in microdroplets by comparing the measured rate constant in bulk. Fifteen Betti bases were synthesized by the microdroplet method using a variety of aldehydes, naphthols and amines with 68–98 % yields at a scaled‐up amount of 1.9 g h−1. Overall it is an attractive alternative to classic organic synthesis for the construction of Betti bases and derivatives.

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