Multimode reactors, microwave-assisted

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

Other microwave-assisted parallel processes, for example those involving solid-phase organic synthesis, are discussed in Section 7.1. In the majority of the cases described so far, domestic multimode microwave ovens were used as heating devices, without utilizing specialized reactor equipment. Since reactions in household multimode ovens are notoriously difficult to reproduce due to the lack of temperature and pressure control, pulsed irradiation, uneven electromagnetic field distribution, and the unpredictable formation of hotspots (Section 3.2), in most contemporary published methods dedicated commercially available multimode reactor systems for parallel processing are used. These multivessel rotor systems are described in detail in Section 3.4. 

Consequently, we consider that the industrial scale technological management of microwave assisted chemical reaction is no compatible with batch reactors coupled with multimode applicators. Some typical processes with a systematic decrease of the dielectric losses of the concerned reactant, such as filtration and drying of mineral or pharmaceutical powders are compatible with multimode applicators. To our knowledge, the only industrial batch microwave device is the microwave variant of the Turbosphere ( all in one solution mixer/granulator/dryer designed by Moritz... 

Stadler, A., Yousefi, B.H., Dallinger, D., Walla, P., VanderEycken, E., Kaval, N. and Kappe, C.O., Scalability of microwave-assisted organic synthesis from single-mode to multimode parallel batch reactors, Org. Process Res. Dev., 2003,7, 707. 

In the literature, first microwave-assisted experiments on organic synthesis employed multimode household microwave ovens [12,13]. More recently, the use of microwave reactors for chemical syntheses has become more advanced, and, at the moment, some chemical journals specializing in organic chemistry intend to refuse manuscripts in which experiments were carried out in a domestic microwave oven (even including ovens with... 

The integration of microwave heating and fluorous technologies has generated a powerful solution to address both the reaction and separation issues in parallel and combinatorial synthesis. With the further development of multimode microwave reactors for plate reactions and F-SPE for plate-to-plate separations, microwave-assisted fluorous synthesis will play an even more important role in compound library synthesis. 

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