Microwave-enhanced conditions

Many ionic liquids are based on N,N-dialkylimidazolium cations (BMI) which form salts that exist as liquids at, or below, room temperature. Their properties are also influenced by the nature of the anion e. g. BF T PFg. The C-2(H) in imidazole is fairly labile but the C-4(H) and the C-5(H) are less so. Under microwave-enhanced conditions it is therefore possible to introduce three deuterium atoms (Scheme 13.4). As hydrogen isotope exchange is a reversible reaction this means that the three deuterium atoms can be readily exchanged under microwave irradiation. For storage purpose it might be best to back-exchange the C-2(D) so that the 4,5-[2H2] isotopomer can be safely stored as the solid without any dangers of deuterium loss. The recently... 

Ease of separation of tritiated products from a reaction medium is an important feature in the choice of labeling procedure. Sometime ago we used polymer-sup-ported acid and base catalysts [12, 13] to good effect and with the current interest in Green Chemistry one can expect to see more studies where the rate accelerations observed under microwave-enhanced conditions are combined with the use of solid catalysts such as Nafion, or zeolites. 

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. 

The methylation of secondary amines works better than for primary amines because there is no competition between the formation of mono- or dimethylated products. The best results for the microwave-enhanced conditions were obtained when the molar ratios of substrate/formaldehyde/formic acid were 1 1 1, so that the amount of radioactive waste produced is minimal. The reaction can be carried out in neat form if the substrate is reasonably miscible with formic acid/aldehyde or in DM SO solution if not. Again the reaction is rapid - it is complete within 2 min at 120 W microwave irradiation compared to longer than 4 h under reflux. The reaction mechanism and source of label is ascertained by alternatively labeling the formaldehyde and formic acid with deuterium. The results indicate that formaldehyde contri-... 

In our own preliminary studies [86] on parallel procedures under microwave-enhanced conditions, we have used the Radley s RDT 24 place PTFE carousel reaction station on the turntable of the Matsui M 169BT microwave oven. In this way, we have studied the catalytic activity of RhCl3 and Pd(OAc)2 towards the reduction or dehalo-genation of 4-bromocinnamic acid and structurally similar compounds. A nine-reaction matrix was used under microwave-enhanced conditions as illustrated in Scheme 13.9 - greatly reduced reaction times and easy optimization of reaction conditions are immediate benefits. As robotics come to play an increasingly important role in chemistry, one can immediately see more sophisticated labeling experiments being undertaken. 

Scheme 13.9 A 9-reaction parallel matrix under microwave-enhanced conditions and schematic representation of carousel arrangement.

In their study Roeda and Crouzel shower that the LAH reduction of nC02 produced 34% H11CHO plus 59% H11COOH. Our experience in using a mixture of DCHO and DCOOH for the N-methylation of both primary and secondary amines suggests that the corresponding [11C]-mixture would be ideal for the 11C-labeling of amines under microwave-enhanced conditions. 

In a series of comparative studies Dolle et al. examined the nucleophilic aromatic substitution of a number of nitropyridine derivatives [104—106], The results, as summarized in Scheme 13.14, show that under microwave-enhanced conditions the 2-N02 and 2-+NMe3 groups led to excellent fluorine incorporation whilst the 2-iodo compound was virtually unreactive. Under thermal conditions no fluorination was observed for the 2-chloro and 2-bromo compounds. In a separate study Banks et al. [107] again observed the beneficial effects of nitro and trimethylamino substitution (Scheme 13.15). The authors also developed a novel microwave-enhanced method of producing [18F]-fluoromethane [108]. 

One of the most attractive features of borohydride reductions is that under microwave-enhanced conditions they can be performed in the solid state, and rapidly. We were attracted by the work of Loupy et al. [71], and in particular Varma and Saini [72, 73] who have shown that irradiation of a number of aldehydes and ketones in a microwave oven in the presence of alumina doped NaBH4 for short periods of time, led to rapid reduction (0.5-2 min) in good yields (62-93%). In our study [74], seven aldehydes and four ketones were reduced (Table 18.3). Again reduction was complete within 1 min, the products were of high purity (>95%) and of high isotopic incorporation (95%, same as the NaBD4), and the reactions completely selective. 

With the development of new instrumentation and understanding of reaction behavior under microwave conditions more PET radioligands and PET radiopharmaceutical research are now carried out under microwave enhanced conditions. Two important reviews [8, 9] are available for an up-to-date picture whilst here we discuss some noteworthy, and more recent examples. The benefits of microwaves to PET radiochemistry are also highlighted in other general review articles [111-114]. 

Reactions of no-carrier-added [ F]y8-fluoroethyl tosylate with amine, phenol or carboxylic acid to form the corresponding [ F]N-(j8-fluoroethyl)amine, [ F]y8-fluoroethyl ether or [ F]yS-fluoroethyl ester, were found to be rapid and efficient under microwave-enhanced conditions (Scheme 18.24) [159]. The preparation of [ F]yS-fluoroethyl tosylate did not require microwaves. The subsequent O- and N-alkylation allow reactants to be heated rapidly to 150 °C in a low boiling point solvent, such as acetonitrile, and avoid the need to use high boiling point solvents, such as DM SO and DMF, to promote reaction. The microwave-enhanced reactions gave about 20% greater radiochemical yields than thermal reactions performed at similar temperatures and over similar reaction times. 

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