Direct Phosphonylation of N-Phenyltetrahydroisoquinolines in Microdroplets

Abstract

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.

Mild Diarylmethylation of Indoles through Regioselective 1,6-Hydroarylation of para-Quinone Methides in Microdroplets/Thin Film

“…In our previous studies, ,,,,− both the reaction and collection temperature play essential roles in many microdroplet/thin film reactions, leading to a necessity to optimize the two temperatures. According to our investigation into the reaction temperature (entry 12 of Table and Table S4), high reaction temperatures were unbeneficial to the microdroplet/thin film conversion.…”

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

“…This mixture was converted into aqueous microdroplets by a homemade pneumatic nebulization device, and collected in a 25 mL beaker for 5 min (see the setup in Figure S3). , The collected product was extracted with ethyl acetate and then measured by high performance liquid chromatography for yield estimation using external calibration under the chromatographic conditions listed in Table S1 in the Supporting Information.…”

Microdroplet Chemistry Accelerating a Three-Component Passerini Reaction for α-Acyloxy Carboxamide Synthesis

“…Microdroplet chemistry is an emerging research field that attracts extensive interest in analytical, organic, and biological communities because of its amazing power in reaction acceleration. − In addition to astonishing rate acceleration, microdroplet chemistry is striking us in making conditions mild (i.e., avoiding catalysts and high temperature), − decreasing energy barrier, − facilitating spontaneous redox reactions, − stabilizing transient intermediates, − and providing novel reactivities. − The role versatility and format diversity of microdroplet chemistry open new windows for analytical derivatization, , biotic and abiotic synthesis, ,,,− and mainly organic applications (mechanistic studies, ,,, reaction screening, − rapid gram-scale organic synthesis, − etc.). Organic reactions by microdroplet chemistry and acceleration mechanisms have been comprehensively summarized in three review papers by Cooks’s group. − …”