MW irradiation

French researchers [38c] have investigated the /zetero-Diels-Alder reaction of methylglyoxylate and glyoxal monoacetal with 2-methyl-1,3-pentadiene in a microwave oven under various reaction conditions (Table 4.9). The microwave (MW) irradiation does not affect the diastereoisomeric ratio of adducts trans/cis = 70 30) but dramatically reduces the reaction time. The glyoxal monoacetal, for instance, gives 82 % adducts after 5 minutes when submitted to irradiation with an incident power (IP) of 600 W in PhH and in the presence of ZnCL (Table 4.9, entry 1), while no reaction occurs if carried out for 4h at 140 °C in sole PhH. Similarly, methylgloxylate in water at 140 °C gives 82% adducts after 3h, whereas microwave irradiation reduces the reaction time to 8 minutes (Table 4.9, entry 5). 

A great acceleration was also observed in the cycloadditions of alkylidene derivatives of 5-iminopyrazoles with nitroalkenes, as electron-poor dienophiles, under MW-irradiation in solvent-free conditions [40c]. Some results are illustrated in Scheme 4.10. All the reactions took place with loss of HNO2 and/or NHMei after the cycloaddition, inducing aromatization of the final product. 

Diels-Alder reactions of vinylpyrazoles 45 and 46 only occur with highly reactive dienophiles under severe conditions (8-10 atm, 120-140 °C, several days). MW irradiation in solvent-free conditions also has a beneficial effect [40b] on the reaction time (Scheme 4.11). The indazole 48, present in large amounts in the cycloaddition of 45 with dimethylacetylenedicarboxylate, is the result of an ene reaction of primary Diels-Alder adduct with a second molecule of dienophile followed by two [l,3]-sigmatropic hydrogen shifts [42]. The MW-assisted cycloaddition of 46 with the poorly reactive dienophile ethylphenyl-propiolate (Scheme 4.11) is significant under the classical thermal reaction conditions (140 °C, 6d) only polymerization or decomposition products were detected. 

The results of reactions with and without MW irradiation are reported in Table 4.11. The reaction yields are comparable, but the reaction times of the irradiated reactions are considerably reduced. The alumina does not give acceptable results. The same reactions were carried out in nitrobenzene as solvent and under free-solvent conditions with and without MW irradiation. The results are reported in Table 4.12. In this case too, the only significant difference is the reaction time, so that the authors [41] concluded that MW-promoted reactions proceed like the thermal reactions except for a much higher reaction rate. 

The hemiacetal 54 adsorbed on water-saturated silica gel gives, by MW irradiation, a 1 1 mixture of cycloadducts isolated as silyl derivatives 55 and 56. The water is probably necessary for the success of the reaction because (i) it is an efficient generator of heat in the MW process, (ii) it accelerates the cycloaddition by hydrophobic effect, and (iii) it facilitates the hemiacetal-hydroxyketone equilibrium which furnishes the dienophile moiety for the cycloaddition [42]. 

Tab. 3.1 Boiling points (°C) of some polar solvents under the action of MW irradiation in the absence or presence of a nucleation regulator.

Using MW irradiation under solvent-free conditions, it was possible to obtain regio-specific benzylation in position 1 of 1,2,4-triazole whereas only the 1,4-dialkylated product was obtained in poor yields under the action of conventional heating [114] (Eq. 64). 

Most of these reactions occurred much faster using MW irradiation (at increased pressure and temperature) than under conventional heating (ambient pressure, reflux), with rate enhancements ranging from 5 to 1200 times. 

Dimethyl formamide (DMF) has been found to be a particularly useful solvent in these reactions because it absorbs MW irradiation strongly, has a relatively high boil-... 

Sun et al. [34] reported that the rate of hydrolysis of the biomolecule ATP under MW irradiation was 25 times faster than under classical heating at similar temperatures. However, the same research group [35] later observed that, with more accurate temperature control, the hydrolysis rates were in fact almost identical. 

The isomer ratio E Z (33 32) was 1.2-1.6 over the course of the reaction and was not affected by the heating method, so it was concluded that MW irradiation did not affect the stereochemical outcome of this reaction, presumably due to the reaction being under thermodynamic control. 

The reactions were performed in an open beaker using a domestic MW oven, and reaction times were reduced from 2-24 h of conventional reflux to 3-11 min under MW irradiation. 

There have been a few reports recently of substantial MW rate enhancements of reactions of polar reactants in nonpolar solvents [53, 54], Soufiaoui et al. [53] have synthesized a series of l,5-aryldiazepin-2-ones 36 in high yield in only 10 min by the condensation of o-aryldiamines 34 with /J-ketoesters 35 in xylene under MW irradiation in open vessels (Scheme 4.18). The temperature at the end of these reactions was shown to be 136-139 °C. Surprisingly, they observed that no reaction occurred when the same reactions were heated conventionally for 10 min at the same temperature. These results could be taken as evidence for a specific MW effect. 

Under MW irradiation (980 W) in xylene yields of 73-93% were obtained in 10-20 min, whereas under conventional conditions a complex mixture of products was obtained, which was unsuitable for preparative work. Thus it would appear that these reactions not only occur much faster under microwaves but also give cleaner products, indicating greater selectivity. Loupy [44, 45] has speculated that these reactions, among others performed in nonpolar solvents or in the absence of solvent, might be accelerated under MW irradiation due to the involvement of relatively polar... 

Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhancements when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide supra, Scheme 4.15) was performed in toluene than when ethanol was used as the solvent. The calculated rate constants in toluene solution were more than three times higher under MW irradiation than under conventional conditions, whereas the rate constants of the reaction in ethanol were the same, within experimental error, under both heating methods. 

Because observed rate enhancements are usually small, or zero, nonthermal effects do not seem to be important in MW heated reactions in homogeneous media, except possibly in some reactions of polymers and reactions in nonpolar solvents. Relatively few studies have been conducted on MW-assisted reactions of polar reactants in nonpolar solvents. Also, since there is some disagreement as to whether or not these reactions are accelerated significantly by MW, in comparison with conventionally heated reactions at the same temperature, more research on the effect of MW irradiation on the rates of these reactions is required. Nonthermal effects may, however, explain the more substantial MW rate enhancements in solvent-free reactions on solid supports [44] (see Chapt. 5) and solid state reactions [68, 69]. 

Another interesting question is whether MW heating can result in changes in selectivity, leading to different product compositions than those obtained using conventional heating. The effect of MW irradiation on selectivity was discussed in a review by Langa et al. in 1997 [9] and more recently by Loupy et al. [44, 70]... 

However, more significant modifications in selectivity, which have useful applications in synthesis, have been reported in a number of other reactions performed under the action of MW irradiation [9, 44, 70]. Many of these reactions were performed under heterogeneous and/or solvent-free conditions, and only those performed under homogeneous conditions will be discussed here. 

Bose et al. [77] compared a similar reaction of the acid chloride of tetrachlor-ophthaloyl glycine 57 with a Schiff base under MW irradiation and conventional... 

In contrast with the results of Langa et al. on the cydoaddition reaction to C70, MW irradiation had no effect on the regioselectivity of the reactions in polar solvents, but a substantial effect was observed both in the nonpolar solvent, xylene and under solvent-free conditions. In polar solvents (pentanol and DMF) the ratio of products 64, 65, and 66 was 95 5 0 under both MW and conventional heating. In xylene and in the absence of solvent the ratio of isomers changed from 32 28 40 (xylene) and 36 27 27 (no solvent) under conventional heating to 100 0 0, i. e. totally regioselec-tive, under MW activation. 

As discussed earlier, careful comparisons of the rates of MW irradiated reactions in homogeneous media, particularly in polar solvents, at atmospheric pressure show that these rates are the same or only slightly higher than similar reactions under... 

There have also been a number of reports of accelerations of reactions in the liquid and gaseous phase in the presence of a solid catalyst which absorbs MW irradiation [81]. 

Recently, Hajek and Radoiu observed that MW not only increase the rate of heterogeneous catalytic reactions, but also affect the product selectivity [85], The results were explained in terms of MW-induced polarization, involving the absorption of MW by highly polarized reagent molecules on the active site of the catalyst. On the other hand there is little, if any, activation of homogeneous catalytic reactions in polar solvents [86], presumably due to the high absorbent power of MW irradiation by the solvent. 

MW heating will, of course, only be effective if the reaction mixture absorbs MW irradiation and so is limited to reactions of polar molecules, either in polar solvents or in the absence of a solvent. In some cases, reactions of polar compounds in nonpolar or slightly polar solvents can be heated with MW [19, 53], but the solutions must be must be sufficiently concentrated in order to heat effectively. Relatively high MW powers are also required. For this reason, some reactions requiring several hours of classical reflux in solvents of low polarity can be performed more rapidly in a MW oven by using a more polar solvent [17]. 

It has been shown that reaction of carboxylic acids with benzyl halides, which does not occur when heated conventionally, could be performed efficiently under the action of MW irradiation in the presence of a quaternary ammonium salt as a catalyst (Eq. 3) [15]. Typical results are given in Tab. 5.3. 

Rapid N-alkylation of title products was performed under PTC with MW irradiation (Eq. 25) [37],... 

The same reaction (R-X = n-OctBr) was studied using TBAB and several basic supports. Na2S04 and CaC03 (yields 93 and 95%, respectively, within 3 min of MW irradiation) were shown to be more efficient than K2C03 (71%) [43],... 

Functional groups were selectively introduced at the C-2 position of isophorone by epoxide ring-opening by several nucleophiles with active methylene groups. Different behavior was observed depending on the reaction conditions and the nature of the nucleophilic agents [57]. The best experimental systems involved PTC or KF-alumina under solvent-free conditions and MW irradiation (Eq. 37 and Tab. 5.15). 

A simple, rapid and efficient method has been reported for the synthesis of dibenzyl diselenides under the action of MW irradiation. Benzyl halides are reacted with selenium powder in the presence of a base and phase-transfer agent (Eq. 57 and Tab. 5.29) [80]. The reactions were performed either in THF or in C6H6-H20. 

The same authors have more recently described the synthesis of dibenzoyl diselenides by reaction of selenium with sodium hydroxide under PTC and MW irradiation conditions to afford sodium diselenides which react further with benzoyl chloride at 0 °C [81]. 

As has already been mentioned (Sect. 5.3), nitriles can be hydrolyzed to amides or acids [56]. Nitriles can be efficiently converted into the corresponding amides in the presence of PEG-400 and aqueous sodium hydroxide system under the action of MW irradiation (Eq. 58 and Tab. 5.30). 

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent Robinson annulation reactions of isophorone with chalcones were performed efficiently in a solvent-free PTC system under the action of MW irradiation. Compared with conventional heating substantial rate enhancements were observed, within very short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far better than those achieved by the classical method (NaOEt in EtOH under reflux for 24 h 40-56%). 

The synthesis of octylthiocyanate by reaction of n-octyl bromide with KSCN, and its subsequent isomerization to isothiocyanate, have been realized by use of TBAB under the action of MW irradiation. The effect of inorganic solid supports was studied (Si02, K10, graphite, NaCl) (Eq. 64). 

A related development that had profound impact on heterogeneous reactions is the use of microwave (MW) irradiation techniques for the acceleration of organic reactions. Since the appearance of initial reports on the application of microwaves for chemical synthesis in polar solvents [11], the approach has blossomed into a useful... 

A brief exposure of diacetate derivatives of aromatic aldehydes to MW irradiation on neutral alumina surface rapidly regenerates aldehydes (Scheme 6.5) [36], The selectivity in these deprotection reactions is achievable by merely adjusting the time of irradiation. As an example, for molecules bearing acetoxy functionality (R = OAc), the aldehyde diacetate is selectively removed in 30 s, whereas an extended period of 2 min is required to cleave both the diacetate and ester groups. The yields obtained are better than those possible by conventional heating methods and the procedure is applicable to compounds bearing olefmic moieties such as cinnamaldehyde diacetate [36],... 

A variety of alcohols, protected as t-butyldimethylsilyl (TBDMS) ether derivatives, can be rapidly regenerated to the corresponding hydroxy compounds on alumina surface using MW irradiation (Scheme 6.8) [42], This approach prevents the use of corrosive fluoride ions that are normally employed for cleaving the silyl protecting groups. 

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