Microwave reactor

Microwave technology has now matured into an established technique in laboratory-scale organic synthesis. In addition, the application of microwave heating in microreactors is currently being investigated in organic synthesis reactions [9-11] and heterogeneous catalysis [12, 13]. However, most examples of microwave-assisted chemistry published until now have been performed on a 

There are a number of types of equipment associated with high-energy transfer to the reactants including microreactors, microwave reactors, radio frequency heating, electric pulses, ultrasonication, and spinning disc reactors. Some of these are briefly discussed later. 

Using a scaling out rather than scaling up approach, a more flexible production capacity is available with the opportunity to rapidly switch product output as market demands change, and very importantly (in the light of such disasters as Bhopal), the storage of hazardous product should become redundant. 

Microwave irradiation is a high-frequency electric field, with wavelength in the centimeter range, which places it between radio waves and infrared in the 

Microwave reactions have been successfully demonstrated for many different organic reactions including metal-mediated catalysis, cyclo-additions, heterocyclic chemistry, rearrangements, electrophilic and nucleophilic substitutions, and reduction. Many reactions work well in water, adding to the techniques green credentials [27]. 

The transformation to elements of samples containing organic material, known as mineralization, has motivated the development of many different approaches dry procedures such as oven heating, combustion, while others by wet treatment such as with mineral acids, fluxes for fusion, etc. In the absence of a universal method applicable to all inorganic elements, the mineralization must be adapted to the sample. This indispensable step of the preparation of a large number of samples, in particular for those analysed by AAS and OES, can be made easier by using of a microwave digester.  

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Another illustrative example of the application of FTIR spectroscopy to problems of interest in adhesion science is provided by the work of Taylor and Boerio on plasma polymerized silica-like films as primers for structural adhesive bonding [15]. Mostly these films have been deposited in a microwave reactor using hexamethyldisiloxane (HMDSO) as monomer and oxygen as the carrier gas. Transmission FTIR spectra of HMDSO monomer were characterized by strong... 

The synthesis of 4-unsubstituted DHPs in a focused microwave reactor has been reported using alkyl acetoacetates and hexamethylenetetramine 19 as the source of both formaldehyde and ammonia, with additional ammonium acetate to maintain the stoichiometry [57], Irradiation for 100 s under solvent-free conditions gave, for example, 1,4-DHP 20 in 63% isolated yield (Scheme 5). 

The one-pot, three-component synthesis of a 20-membered dihydrotri-azine hbrary was also dramatically accelerated through the use of microwave irradiation [79]. Heating a subset of substituted anilines, cyanoguanidine and acetone in the presence of concentrated hydrochloric acid for 35 min at 90 °C in a single-mode microwave reactor gave the corresponding 2,2-dimethyl-1,2-dihydro-s-triazine hydrochloride 51 in comparable yield to conventional conductive heating methods but in a much shorter reaction time and increased purity (Scheme 21). 

The rapid synthesis of 1,2,4-triazines has also been developed under microwave-assisted conditions [80]. Irradiation of a 1,2-diketone with acyl hydrazides and ammonium acetate for 5-10 min at 180 °C in a single-mode microwave reactor gave 3,5,6-trisubstituted 1,2,4-triazines in excellent yield and purity and reaction times that were reduced 60-300 fold over conventional conductive heating methodology (Scheme 22). 

The synthesis of functionahzed tetrahydrocarbazoles can be promoted by microwave irradiation [84], The organocatalytic four-component reaction of a solution of 2-substituted indole, aromatic aldehyde (2 equiv) and Mel-drum s acid in benzene in the presence of DL-proline proceeds when heated under Dean-Stark conditions for 5 min in a single-mode microwave reactor to give the tetrahydrocarbazole product as a mixture of diastereoisomers (Scheme 24). 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

The one-pot synthesis of thiazolo[3,4-a]benzimidazoles has been reported using a microwave-assisted condensation-cyclization (see Scheme 17) of a substituted 1,2-diamine, substituted benzaldehyde and mercaptoacetic acid [74]. Heating the mixture at reflux for 12 min using a single-mode microwave reactor for the most part gave the fused benzimidazoles in improved yield and dramatically shorter times, when compared to classical conditions of heating at reflux in benzene for 24-48 h (Scheme 29). 

Despite that the thiophene ring is considered as a bioisoster of the benzene ring, the synthesis and chemistry of thiophene analogs of heterocycles with therapeutic interest remain poorly studied. One of the most recent examples concerns the synthesis of new substituted thioisatoic anhydrides (6 and 7-arylthieno[3,2-d] [1,3]oxazine-2,4-diones), which were prepared on a large scale under microwave irradiation conditions. A small library of thiophene ureidoacids was easily performed using a Normatron microwave reactor (500 W) with high yields and good purity [4,5] (Scheme 4). 

One of the first published microwave-assisted synthesis of benzothiazoles is the condensation of a dinucleophile such as 2-aminothiophenol, with an ortho-ester (neat) in the presence of KSF clay in a mono-mode microwave reactor operating at 60 W under a nitrogene atmosphere [ 12] (Scheme 12). Traditional heating (oil bath, toluene as solvent and KSF clay) gave the expected products in similar yields compared to the microwave experiments but more than 12 h were required for completion. Solvent-free microwave-assisted syntheses of benzothiazoles was also described by attack of the dinucleophiles cited above on benzaldehydes and benzaldoximines [13] (Scheme 12). This methodology was performed in a dedicated monomode microwave reactor... 

Condensation of 2-aminothiophenol with the /3-chlorocinnamaldehyde in the presence ofp-toluene sulfonic acid (PISA) gave good yield of benzothia-zole (Scheme 14). The mechanism suggested in this work is beUeved to proceed via a nucleophilic attack of the sulfur atom in an addition-ehmination sequence followed by a spontaneous cyclization and ejection of acetaldehyde [15]. These investigations were performed in a domestic microwave reactor and need 1.5 min for completion (65% yield). Here again, oil bath heating seems to be inferior, providing a maximum conversion of 53% after... 

The strategies explored and defined in the various examples presented open a way for wider application of microwave chemistry in industry. The most important problem for chemists today (in particular, drug discovery chemists) is to scale-up microwave chemistry reactions for a large variety of synthetic reactions with minimal optimization of the procedures for scale-up. At the moment, there is a growing demand from industry to scale-up microwave-assisted chemical reactions, which is pushing the major suppliers of microwave reactors to develop new systems. In the next few years, these new systems will evolve to enable reproducible and routine kilogram-scale microwave-assisted synthesis. 

The biberty (Fig. 10), a monomode microwave reactor for automated SPPS, was recently introduced by the CEM Corporation [153]. Although this instrument was originally developed for SPPS, it also allows for a broader scale of solid-phase applications. The solid-phase vial is equipped with a polypropylene frit and cap at one end (the entire assembly fitting into the standard 10 mb CEM reaction vessel) to allow the processing of 0.1 to 1.0 mmol quantities of resin attached substrates. An integrated fiber optic probe provides... 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

The Bischler-Napieralski reaction has been described to proceed imder microwave irradiation to give very good yields of dihydroisoquinolines [140] and other polycyclic compounds (see below) in the presence of POCI3 and P2O5 (classical conditions) in toluene (10 cycles of 60 s each using a dedicated microwave reactor). 

Vasudevan et al. have reported a microwave-promoted hydroami-nation of alkynes. Heating a mixture of l-ethynyl-4-methoxybenzene and 4-bromoaniline in water at 200°C in a microwave reactor for 20 minutes without any catalyst gave an imine product in 87% yield (Eq. 4.45).81... 

Today, a large body of work on microwave-assisted synthesis exists in the published and patent literature. Many review articles [8-20], several books [21-23], and information on the world-wide-web [24] already provide extensive coverage of the subject. The goal of the present book is to present carefully scrutinized, useful, and practical information for both beginners and advanced practitioners of microwave-assisted organic synthesis. Special emphasis is placed on concepts and chemical transformations that are of importance to medicinal chemists, and that have been reported in the most recent literature (2002-2004). The extensive literature survey is limited to reactions that have been performed using controlled microwave heating conditions, i.e., where dedicated microwave reactors for synthetic applications with adequate... 

This chapter provides a detailed description of the various commercially available microwave reactors that are dedicated for microwave-assisted organic synthesis. A comprehensive coverage of microwave oven design, applicator theory, and a description of waveguides, magnetrons, and microwave cavities lies beyond the scope of this book. Excellent coverage of these topics can be found elsewhere [1—4]. An overview of experimental, non-commercial microwave reactors has recently been presented by Stuerga and Delmotte [4],... 

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