Rapid Optimization of Reaction Conditions Based on Comprehensive Reaction Analysis Using a Continuous Flow Microwave Reactor

Abstract

Generally, the flow method has the advantage of a precise control over the reaction parameters and a facile modification of the reaction conditions, while a continuous flow microwave reactor allows for the quick optimization of reaction conditions owing to the rapid uniform heating. In this study, we developed a "9+4+1 method" to optimize reaction conditions based on comprehensive reaction analysis using a flow microwave reactor. The proposed method is expected to contribute to the synthesis of various fine and bulk chemicals by reducing cost and wastage, and by conserving time.

A continuous-flow resonator-type microwave reactor for high-efficiency organic synthesis and Claisen rearrangement as a model reaction

“…The current system was envisaged to efficiently heat the reaction solution to a high temperature in a short time by using direct MW heating. The benefits of this machine towards rapid screening and identification of optimal reaction conditions have been highlighted by recent studies [45,46,50,51].…”

“…Ley et al have used it in the syntheses of β-lactams [47]. Very recently, further applications of this device to other classes of reactions have been disclosed [48][49][50][51][52]. These reactions all required elevated conditions of temperature and pressure and were ideally suited to scale-up in the aforementioned MW flow reactor.…”

Application of reactor engineering concepts in continuous flow chemistry: a review

“…To validate the function of the MW insert they studied both a Fischer indole reaction and a Diels-Alder reaction. The Fischer indole synthesis involved cyclohexanone 35 and phenylhydrazine 36 treated under MW irradiation to form carbazole 37 on a 100 g scale in 75% yield, with a residence time of 24 s. 36 The microwave applicator has since been commercialised by SAIDA FDS Inc., and several reactions including ammonium salt-accelerated hydrazinolysis of unactivated amides, 37 Fischer esterification, 36 alcohol acetylation reactions, 38 Suzuki-Miyaura couplings, dehydrogenative aromatizations, 30 Wolff-Staudinger cascade reaction, 39 Williamson esterification, 40 C-alkylations of N-alkylamides 41 and a Johnson-Claisen rearrangement 42 have all been tested and demonstrated utilizing this insert. One of the more notable reactions performed was the scalable and selective Scheme 4 U-tube microwave insert for the application of Suzuki-Miyaura couplings under continuous flow conditions.…”

High Efficiency Microwave Flow Chemistry Towards Synthesis of Functional Materials and Pharmaceutical Cores

“…6). 14 In order to achieve the optimal conditions, they fitted the MW CF reactor with a flowIR cell, monitored the yield in-line and fed the data to a 9+4+1 optimization method (Fig. 7).…”