Catalyst‐Free Three‐Component Petasis Reactions Accelerated in Microdroplets: Reaction Optimization and Senstive Detection by Mass Spectrometry

Abstract

Due to their important roles in medicine, the product of the Petasis reaction has attracted extensive interest in pharmaceutical, medical and chemical communities. Traditional three‐component Petasis methods normally use various catalysts under harsh conditions (high temperature, microwave, etc.) for long reaction times. In this study, we developed a green and highly efficient microdroplet method for accelerating the Petasis reaction, which obtain good yields without the need of any catalysts under mild reaction conditions. The Petasis reaction in microdroplets was suitable for a variety of salicylaldehydes, arylboronic acids and amines. The Petasis reaction in microdroplets was accelerated by approximately 4 orders of magnitude by comparing the measured rate constants in bulk. Further, a scaled‐up amount of 0.8 g h−1 was achieved for the Petasis reaction in microdroplets. This study supplies not only a high‐efficiency and environment‐friendly methodology to constructing aryl amines in organic community but also a useful derivatization strategy for highly sensitive mass spectrometric detection of arylboronic acids and aryl aldehydes.

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

“…Our previous studies demonstrated a moderate correlation of Betti and Petasis reactions in microdroplets to reaction temperature (controlled by the heated chamber through which microdroplets flew) and collection temperature (controlled by placing the collection flask in a water/ice bath). The temperature effect of the Passerini microdroplet reaction was hence investigated.…”

“…Until now, three-component Biginelli, Hantzsch, Mannich, , Betti, Povarov, and Petasis reactions and a five-component spiro-pyrrolidine construction have been unlocked by microdroplet chemistry, where the three-component Passerini reaction has not yet been uncovered. Additionally, the above MCR examples were limited to milligram-scale synthesis except the Betti reaction and Petasis reaction, restricting the applicability of microdroplet chemistry in MCRs. A gram-scale microdroplet Passerini methodology is highly desirable to the construction of α-acyloxy carboxamides considering their bioactive importance.…”

“…63 The above-mentioned features of microdroplet chemistry have encouraged preliminary explorations of multicomponent reactions in microdroplets. Until now, threecomponent Biginelli, 64 Hantzsch, 65 Mannich, 41,66 Betti, 67 Povarov, 68 and Petasis reactions 69 and a five-component spiro-pyrrolidine construction 38 have been unlocked by microdroplet chemistry, where the three-component Passerini reaction has not yet been uncovered. Additionally, the above MCR examples were limited to milligram-scale synthesis except the Betti reaction 67 and Petasis reaction, 69 restricting the applicability of microdroplet chemistry in MCRs.…”

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

“…For instance, organic applications of microdroplet chemistry were classified into five major classes including addition/elimination (Schiff base reactions, Katritzky transamination, Claisen–Schmidt condensation, Michael addition, etc. ), oxidation/reduction, ,,,,,− biphasic reactions (gas–liquid, ,,, liquid–liquid, − and liquid–solid , reactions), multicomponent reactions (Hantzsch, Biginelli, Betti, Petasis and Passerini reaction, N-alkylation, five-component spiro-pyrrolidine construction, etc. ), and others (Pinacol and Beckmann rearrangement, metal catalysis, etc.).…”