Mild Catalyst- and Additive-Free Three-Component Synthesis of 3-Thioisoindolinones and Tricyclic γ-Lactams Accelerated by Microdroplet Chemistry.

Isoindolinones, bearing both γ-lactam and aromatic rings, draw extensive interest in organic, pharmaceutical, and medicinal communities as they are important structural motifs in many natural products, bioactive compounds, and pharmaceuticals. As the main contributor to isoindolinone synthesis, metal catalysis is associated with many drawbacks including essential use of toxic/precious metals and excessive additives, high reaction temperatures, specially predesigned starting materials, and long reaction times (typically 8-30 h). In this study, we developed a catalyst- and additive-free, minute-scale, and high-yield microdroplet method for tricomponent isoindolinone synthesis at mild temperatures. By taking advantage of the astonishing reaction acceleration (1.9 × 10-9.4 × 10 acceleration factor range with a typical rate acceleration factor of 1.51 × 10 for the prototype reaction as the ratio of rate constants by microdroplet and bulk phase), 12 3-thioisoindolinones and two tricyclic γ-lactams were synthesized using various 2-acylbenzaldehydes, amines, and thiols with satisfactory yields ranging from 85% to 97% as well as a scale-up rate of 3.49 g h. Because of the advantages (no use of any catalysts or additives, mild temperature, rapid and satisfactory conversion, broad substrate scope, and gram scalability), the microdroplet method represents an attractive alternative to metal catalysis for laboratory synthesis of isoindolinones and their derivatives.