Microwaves thermal reactions

The description of the association of heterocychc chemistry and microwave irradiation has also shown that performing microwave-assisted reactions should be considered with special attention. A few of these considerations can be applied generally for conducting microwave-assisted reactions and include the following (a) the ratio between the quantity of the material and the support (e.g., graphite) or the solvent is very important (b) for solid starting materials, the use of solid supports can offer operational, economical and environmental benefits over conventional methods. However, association of liquid/solid reactants on solid supports may lead to uncontrolled reactions which may result in worse results than the comparative conventional thermal reactions. In these cases, simple fusion of the products or addition of an appropriate solvent may lead to more convenient mixtures or solutions for microwave-assisted reactions. 

From the studies covered in this chapter, it can be concluded that a completely green chemical process in the synthesis of this kind of material is still a challenge. Some protocols, despite using non-toxic precursors, are time- and/or energy-consuming processes or require the use of non-friendly and non-recyclable solvents. Reaction times in microwave-assisted reaction processes have shown to be shorter. On the other hand, the substitution of conventional solvents for chemical and thermally stable I Ls allowed the reutilization of the solvent and also provided control of the size and shape of NPs. 

Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. Regioselective N4-aminoethylation of the l,4-benzodiazepin-2-one 94 was observed under microwave conditions in DMF/K2C03 to afford, for example, 96a and 96b in 64% and 67% yield respectively (Table 4). In contrast, the thermal reaction at 80 °C in DMF with K.2CC)3 as base gave the Nl-aminoethylation products (95a, 65%) and (95b, 76%). These results were... 

Microwave heating is often applied to already known conventional thermal reactions in order to accelerate the reaction and therefore to reduce the overall process time. When developing completely new reactions, the initial experiments should preferably be performed only on a small scale applying moderately enhanced temperatures to avoid exceeding the operational limits of the instrument (temperature, pressure). Thus, single-mode reactors are highly applicable for method development and reaction optimization. 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

In a recent study, classical heating, microwave radiation and gamma radiation have been compared as energy sources to perform 1,3-dipolar reactions between unsaturated oximes and conventional dipolarophiles. On using gamma radiation the reactions were clean and yields obtained were similar to those for the thermal reactions. However, microwave radiation reactions were extremely clean, occurred more rapidly and gave higher yields [102],... 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

The aim of this chapter is to describe some advances in catalysis achieved by use of microwave heating. The aspects of microwave catalytic reactions which differ from traditional thermal methods are emphasized. The input of microwave energy into a reaction mixture is quite different from conventional (thermal) heating and it is the task of synthetic chemists to exploit this special situation as fully as possible. 

We chose the microwave-enhanced Raney Nickel catalyzed hydrogen isotope exchange of indole and N-methylindole as our substrates and D20, CD3COCD3, CD3OD and CDC13 as the solvents. The thermal reaction had already been the subject of a recent study [44], The microwave-enhanced method was some 500-fold faster than the corresponding thermal reaction (at 40 °C). Furthermore the pattern of labeling (Scheme 13.3) varied with the choice of solvent. Thus in the case of indole it-... 

Neither tritium or deuterium gas, with zero dipole moments, can be expected to interact positively with microwave radiation. Their low solubilities are seen as a further disadvantage. Our thoughts therefore turned towards an alternative procedure, of using solid tritium donors and the one that has found most favor with us is formate, usually as the potassium, sodium or ammonium salt. Catalytic hydrogen transfer of this kind is remarkably efficient as the results for a-methylcinnamic acid show [50]. The thermal reaction, when performed at a temperature of 50 °C, takes over 2 h to come to equilibrium whereas the microwave-enhanced reaction is complete within 5 min. A further advantage is that more sterically hindered al-kenes such as a-phenylcinnamic acid which are reduced with extreme difficulty when using H2 gas and Wilkinson s catalyst are easily reduced under microwave-enhanced conditions. 

As of now no details of the synthesis of optically active tritiated compounds produced under microwave-enhanced conditions have been published. Another area of considerable interest would be the study of solvent effects on the hydrogenation of aromatic compounds using noble-metal catalysts as considerable data on the thermal reactions is available [52]. Comparison between the microwave and thermal results could then provide useful information on the role of the solvent, not readily available by other means. 

Due to its stability and water-solubility sodium tetraphenylborate is a particularly convenient starting material for such reactions. Several halogenated heterocycles were phenylated with NaBPlu in aqueous solution with [Pd(OAc)2] catalyst under microwave irradiation (Scheme 6.13) [36]. All reactions were mn under argon in Teflon-closed pressure tubes. It is not easy to compare these results to those of thermal reactions, since the temperature of the irradiated samples is not known precisely. Nevertheless, the microwave method is certainly very effective since 8-12 min irradiation at 100-160 W power allowed the isolation of 60-85 % phenylated products. 

Alkylthio derivatives are normally prepared by alkylation of thiones, but they can also be prepared by alkanethiolysis reactions, and selective reaction can be achieved. Aromatic sulfides are commonly prepared by arenethiolysis reactions with halopyrimidines <1994HC(52)1>. In addition to halide displacement at the electrophilic 2-, 4-, and 6-positions, displacement can also occur at the unactivated 5-position when microwave irradiation is used. Thus, 5-bromopyrimidine 197 gave 5-phenylthiopyrimidine 198 in 96% yield after 40 h of microwave irradiation, whereas the thermal reaction only gave a 7% yield in the same time period <2002T887>. 

The microwave-assisted iV-alkylation of 2-chloropyridines proceeds more rapidly and in better yields compared to the corresponding thermal reactions <9912317>. 

Besson and co-workers have investigated the microwave-assisted multi-step (seven steps) synthesis of thiazoloquinazolinone derivatives, utilising commercially available nitroanthranilic acids as the initial precursors69. Comparison of the conventional thermal heating and microwave heating approaches demonstrated that the overall time for the multi-step synthesis could be considerably reduced (by a factor of 8) by adopting the microwave-heated reaction methods (Scheme 3.44). In addition, the reactions were cleaner and the products could be purified rapidly. For the microwave-heated multi-step synthesis, the overall yield of the final product was increased by a factor of 2, which enabled the scale of the overall synthesis to be increased from 0.2 to 1 g. 

The copper-catalysed hydrosilylation of vinylpyridines was significantly improved by microwave irradiation (Scheme 4.8). With 2-vinylpyridine, the reaction times were decreased by a factor of 360, and the yield of the product was enhanced from 5% under thermal conditions to 75% in the microwave-assisted reaction. Due to the much cleaner reaction under microwave conditions, the work-up procedure was considerably simplified30. 

Carbonyl)chlorohydridotris(triphenylphosphine)ruthenium(II) was used as a catalyst in the transfer hydrogenation of benzaldehyde with formic acid as a hydrogen source. Under these conditions, the reduction ofbenzaldehyde to benzyl alcohol is accompanied by esterification of the alcohol with the excess of formic acid to provide benzyl formate (Scheme 4.16). In this microwave-assisted reaction, the catalyst displayed improved turnover rates compared to the thermal reaction (280 vs. 6700 turnovers/h), thus leading to shorter reaction times36. 

Aromatic aldehydes can also be converted selectively into the corresponding benzylic alcohols in a crossed Cannizzaro reaction, if NaOH is used as a base. Similarly, the reaction is performed under solvent-free conditions by mixing the aldehyde with the base and an excess of paraformaldehyde and irradiating with microwave for 20—25 s. An alternative protocol uses 40% formalin solution and basic alumina to obtain comparable yields. The thermal reaction in refluxing methanol was found to require 12 h, providing considerably lower yields of the benzylic alcohols (Scheme 4.22)42. 

To avoid strongly basic conditions that might lead to the formation of by-products with sensitive substrates, a more recent report quotes the use of KF-A12C>3 in combination with paraformaldehyde for the crossed Cannizzaro reaction of aromatic aldehydes. Similarly, microwave irradiation completed the solvent-free reaction within a few minutes, whereas the thermal reaction in dioxane required reaction times of up to 3 h (Scheme 4.23)43. 

---