Microwave 1,3-dipolar cycloaddition

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

Kappe and co-workers proposed an application of a microwave-assisted Huisgen 1,3-dipolar cycloaddition of terminal acetylenes and azides 70, imder Cu(I) catalysis, as an example of click chemistry to obtain a collection of... 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

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,... 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

A family of interesting polycychc systems 106 related to pyrrolidines was obtained in a one-pot double intermolecular 1,3-dipolar cycloaddition, irradiating derivatives of o-allyl-sahcylaldehydes with microwaves in toluene for 10 min in presence of the TEA salt of glycine esters [71]. A very similar approach was previously proposed by Bashiardes and co-workers to obtain a one-pot multicomponent synthesis of benzopyrano-pyrrolidines 107 and pyrrole products 108 (Scheme 37). The latter cycloadducts were obtained when o-propargylic benzaldehydes were utihzed instead of o-allyhc benzalde-hydes, followed by in situ oxidation [72]. 

The authors have also elaborated a microwave-enhanced one-pot procedure [90] for the Huisgen 1,3-dipolar cycloaddition reaction. In a typical procedure, a pyrazinone with a triple bond connected to the core via C - O linkage, was reacted with a suitable benzylic bromide and NaNs in presence of the Cu(I) catalyst in a t Bu0H/H20 system under microwave irradiation (Scheme 26). The cycloaddition was found to proceed cleanly and with full regioselectivity. As the azide is generated in situ, this procedure avoids the isolation and purification of hazardous azides, which is especially important when handling the ahphatic ones, which are known to be toxic and explosive in nature. 

The microwave-assisted dipolar cycloaddition of pyridazinyl quaternary salts such as 20 was shown to be substantially better than the reaction using conventional heating. Novel regioselective reactions using monosubstituted dipolarophiles were also included <06SL804>. 

The concept of performing microwave synthesis in room temperature ionic liquids (RTIL) as reaction media has been applied to several different organic transformations (Scheme 4.18), such as 1,3-dipolar cycloaddition reactions [54], catalytic transfer hydrogenations [55], ring-closing metathesis [56], the conversion of alcohols to alkyl halides [57, 58], and several others [59-61],... 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

Previous work [111] by our group has demonstrated that RTIL-catalyzed 1,3-dipolar cycloaddition under the action of microwave irradiation leads to dramatically shorter reaction times with better yields of isolated products. We have recently investigated the reactivity of the formyl group covalently grafted on the ionic liquid phase 75 in the Knoevenagel reaction with malonic derivatives 76 [112], as shown in Scheme 8.76. 

The 1,3-dipole is often very unstable, its formation requires high temperatures and the subsequent cycloadditions require often long reaction times. Both of these conditions result in a decrease in yields and purity of products. The rapid heating induced by microwave irradiation avoids the harsh reaction conditions associated with classical heating and facilitates 1,3-dipolar cycloadditions that are very difficult (or impossible) to achieve with classical energy sources. 

In the nineteen-nineties, numerous examples of 1,3-dipolar cycloadditions under microwave heating were reported with a wide variety of dipoles. In many cases the product yields and/or reaction times were improved and the method was used to prepare valuable compounds that could not be obtained by classical heating and, in some instances, the regioselectivity of the reaction was modified. Most of these processes were performed in the absence of solvent. 

In the following section the main 1,3-dipolar cycloadditions under microwaves will be reviewed according to the nature of the dipole. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

A general method for the functionalization of C60 (4) is the 1,3-dipolar cycloaddition of azomethine ylides. This process was first described by Prato [94] and leads to fulleropyrrolidines. Several fulleropyrrolidines (143a-c) have been prepared under microwave irradiation by Langa et al. [72]. These authors observed that microwave irradiation again competes favorably with thermal heating and, in this way, 143 a was... 

Inter- and intramolecular 1,3-dipolar cycloadditions of nitrones under microwave irradiation have been reported to give heterocyclic derivatives. 

Likewise, Loupy showed the utility of focused microwaves as an energy source in the 1,3-dipolar cycloaddition of N-methyl-a-phenylnitrone (152) with fluorinated di-polarophiles in solvent-free conditions (Scheme 9.47) [98],... 

Microwave irradiation induces 1,3-dipolar cycloadditions of nitrones, such as 152, with aliphatic and aromatic nitriles in the absence of solvent. The products of these reactions are the corresponding 2,3-dihydro-l,2,4-oxadiazoles 156 (Scheme 9.48). The use of microwaves led to yields that were always higher than those obtained with classical heating, with the differences being more significant with the less reactive nitriles [99]. 

Microwave irradiation has been extensively employed to generate nitrile oxides and to promote 1,3-dipolar cycloadditions of the previously prepared dipole. 

Diaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of the me-sitonitrile oxide 10 with aliphatic and aromatic nitriles in solvent-free conditions [99]. The procedure allowed the corresponding heterocyclic adducts, the 1,2,4-oxadia-zoles 187, to be obtained in a domestic oven. The reaction times were shorter and the yields better than those seen with the classical homogeneous reactions (Scheme 9.57). 

Triazole derivatives are very interesting compounds that can be prepared by 1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction conditions associated with thermal cycloadditions (toluene under reflux) and the very long reaction times. 

A significant acceleration of 1,3-dipolar cycloaddition of nitriles with nitrile oxides is shown, in the absence of solvent, at microwave irradiation (395). The reactions are finished within 2 to 10 min, to give 1,2,4-oxadiazoles in good yields. 

Electroactive 3-(N-phenylpyrazolyl)fullereno[l,2-r/]isoxazolines have been synthesized by using 1,3-dipolar cycloaddition of pyrazole nitrile oxides, generated in situ, to Cgo at elevated temperature or microwave irradiation. The cyclic voltammetry measurements show a strong donor pyrazole ring, and a better acceptor ability of the fullerene moiety than the parent C60 (538). Treating fullerene Cgo with mesitonitrile oxide in toluene gives fullerene-nitrile oxide adduct, which is supposed to be useful for electrical and optical components (539). 

Improvements in 1,3-dipolar cycloaddition were achieved at high pressures (15kbar) (74), and by solvent-free microwave activation (739). 

Isoxazolines are partially unsaturated isoxazoles. In most cases these compounds are precursors to the isoxazoles, and as a result, the synthesis can also be found in Sect. 3.2.1b. Kaffy et al., used a 1,3-dipolar cycloaddition of a nitrile oxide (186) with the respective styrene (201a or b) to generate isoxazolines (202a or b, respectively). Depending on the substitution of the vinyl portion of the styrene molecule, either 3- or 4-substituted isoxazolines could be formed (Scheme 55) [94], Simoni et al. employed similar chemistry to produce isoxazolines [60]. Kidwai and Misra emplyed microwave technology to treat chalcones with hydroxylamine and basic alumina [99]. The isoxazoles synthesized by Simoni et al. possess anti-proliferative and apoptotic activity in the micromolar range [60]. 

The microwave-assisted preparation of aryl tetrazoles 179 was reported using the intermolecular 1,3-dipolar cycloaddition of aryl nitriles 178 with sodium azide (38) (Scheme 9.38). 

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