Solvent-free conditions 1.3-dipolar cycloadditions

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

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)... 

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). 

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],... 

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. 

Triazoles are generally prepared by the 1,3-dipolar cycloaddition of an alkyne with an azide at elevated temperatures. Thus, reaction of organic azides with acetylenic amides was significant only after 12 h refluxing in toluene. As a contrast, microwave dielectric heating at 55-85 °C under solvent-free conditions furnished the corresponding disubstituted... 

Diaz-Ortiz et al. (1996) extended the procedure for accessing to 2,3-dihydro-l,2,4-oxadiazoles (15) by 1,3-dipolar cycloaddition of nitriles with nitrone under solvent-free conditions. The use of microwave led to yields that were always higher than those obtained with classical heating, the differences being more signihcant with the less reactive nitriles. Baruah et al. (1997a,b) reported that the regiospecihc 1,3-dipolar... 

Diaz-Ortiz, A., Diez-Barra, E., De la Hoz, A., Moreno, M., Goomez-Escalonilla, M.J., and Loupy, A. 1996. 1,3-Dipolar cycloaddition of nitriles under microwave irradiation in solvent-free conditions. Heterocycles, 43 1021-30. 

Lerestif, J.M., Perrocheau, J., Tonnard, F., Bazureau, J.P., and Hamelin, J. 1995. 1,3-Dipolar cycloaddition of imidate ylides on imino-alcohols Synthesis of new imidazolones using solvent free conditions. Tetrahedron, 51 6757-74. 

SPS of isoxazolidines through 1,3-dipolar cycloaddition and their transformations have been reviewed <2005CSR507>. Isoxazolidines were also prepared by nitrone 1,3-dipolar cycloaddition on silica gel in solvent-free conditions under microwave irradiation <2001J(P1)452>. Fused polycyclic isoxazolidines were prepared via a multi-component palladium-catalyzed allene insertion-intramolecular 1,3-dipolar cycloaddition cascade <2002CC1754, 2005AGE7570>. 

Diaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of mesi-tonitrile oxide to aliphatic and aromatic nitriles under solvent-free conditions. The adducts were obtained in shorter reaction times and better yields than with classical methods [84]. By the same approach, Corsaro reported the successful cycloaddition of arylnitrile oxides to naphthalene or aromatic polycyclic dipolaro-philes under solvent-free microwave activation [85]. In the same report, the yields of bis-cycloadducts were also improved by microwave exposure [85]. 

An interesting report from Loupy et al. described the use of solvent-free conditions and microwaves for the synthesis of regioisomeric 1,2,3-triazoles 188 and 189 with substantial reduction for reaction times - down to 5-30 min compared with 30-40 h under reflux in toluene under thermal conditions for the 1,3-dipolar cycloaddition between phosphonate azides 186 and acetylenic esters 187 (Scheme 11.48) [31c]. 

Methylene-1,3-dioxepane (28) has also found application in 1,3-dipolar and hetero-Diels-Alder cycloadditions in solvent-free conditions under microwave irradiation to give products (47), (48), and (49) (Scheme 7) <94JCS(Pl)3595>. Treatment with phenyl isocyanate gives Spiro compound (46)... 

Isoxazolidines is another class of heterocycles that are very useful in medicinal chemistry. DABCO has been used for the synthesis of these compounds by using activated nitrocompounds in the presence of dipolar-ophiles. Pyrazolines could also be obtained by means of DABCO in the [3 + 2] cycloaddition reaction of ethyl diazoacetate with various activated olefins, under solvent-free conditions. ... 

Alkylidene-lH-imidazol-5(4H)-ones are obtained in good to excellent yields by 1,3-dipolar cycloaddition, in solvent-free condition under focussed microwaves from an activated imidate and aldehydes in the presence of catalytic amounts of anhydrous acetic acid (Scheme 63). ... 

Sc(OTf) 3-catalyzed 1,3-dipolar cycloaddition reactions of phenyl aziridines with olefins such as cyclic enol ethers and allyltrimethylsilane also proceeded well [36]. Sc(OTf)3 could also be used as a catalyst for [3 + 2] cycloaddition of aziridines with various nitriles to give the corresponding imidizalines in good to excellent yields under solvent-free conditions (Scheme 12.20) [37]. Although a relatively large amount of Sc (OTf) 3 was used in this reaction, the fast reaction rate, mild conditions and experimental operational ease are the features of this system. 

A homogeneous Ag(I)-catalyst (65) has been developed for the 3 -I- 2-cycloaddition reaction of azides to terminal alkynes to form the corresponding 1,4-triazoles. A simple metal-free synthesis of pentafluoroalkylated 1,2,3-triazoles has been developed from the 1,3-dipolar cycloaddition reaction of azides with methyl 2-perfluoroalkynoates. Again, the intramolecular alkyne-azide Huisgen 3 -I- 2-cycloaddition reaction in water is an example of Click reaction in the absence of a metal catalyst. The Cu(I)-catalysed azide-alkyne 3-1-2-cycloaddition reaction yielded 1,4-disubstimted 1,2,3-triazoles in excellent yields in 2-25 min under solvent-free conditions. The use of 16-electron... 

The 1,3-dipolar cycloaddition of azido-2 -deoxyribose with terminal alkynes in presence of Cu (I) catalyst was dramatically enhanced under solvent-free condition and microwave irradiation, where 4-substituted-l,2,3-triazalyl nucleosides was formed as product rapidly and efficiently with high yield (91-98%) (Guezgueg et al., 2006). 

Using microwave irradiation under solvent-free condition, hexahydrochromeno [4,3-b] pyrroles have been synthesized by intramolecular 1,3-dipolar cycloaddition reactions by Pospisil and Potacek (2007). The yields range between 16-84% in 15-40 min microwave irradiation. 

The 1,3-dipolar cycloaddition of azides to acetylenic amides is particularly difficult under conventional thermal conditions and extended reaction times of 14 h to 1 week have been reported32,33. Katritzky reported a microwave-mediated solvent-free variant ofthis procedure to give N-substituted C-carbamoyl- 1,2,3-triazoles in good to excellent yields in only 30 min (Scheme 3.19)34. 

Touaux, B., Texier-Boullet, F., and Hamelin, 1.1998. Synthesis of oximes, conversion to nitrile oxides and their subsequent 1,3-dipolar cycloaddition reactions under microwave irradiation and solvent-free reaction conditions. Heteroatom Chemistry, 9 351-54. 

According to Nishida ° the [27t-l-27r] cycloadditions proceed via dipolar intermediates, whereas the [2n + 2(7] cycloadditions start with a single-electron-transfer process. In [27i-l-27t] additions a deeply colored charge-transfer complex is initially formed and the reaction is favored by polar solvents (as is usually the case with [2jt-l-2jt] additions of TCNE to electron-rich alkenes). Vinylcyclopropanes with a very low ionization potential afford the [2 t-f 2(t] product they do not form a charge-transfer complex with TCNE and the reactions have to be performed under oxygen-free conditions (Table 5). 

Microwave-induced 1,3-dipolar cydoaddition reactions involving azomethine ylides have been widely reported in the literature. In 2002 many examples were described in a book chapter by de la Hoz [3j], which provides extensive coverage of the subject. The objective of this section is to highlight some of the most recent applications and trends in microwave synthesis, and to discuss the impact of this technology. Highly stereoselective intramolecular cycloadditions of azomethine ylides have been performed under solvent-free microwave conditions. 

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