1.3- Dipolar cycloaddition of azides

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). 

Dipolar cycloaddition of azides with olefins provides a convenient access to triazolines, cyclic imines, and aziridines and hence is a valuable technique in heterocyclic synthesis. For instance, tricyclic -lactams 273 - 276 have been synthesized using the intramolecular azide-olefin cycloaddition (lAOC) methodology (Scheme 30) [71]. 

Recently, Li et al. have reported an efficient 1,3-dipolar cycloaddition of azides with electron-deficient alkynes without any catalysts at room temperature in water.128 The reaction has been applied successfully to the coupling of an azido-DNA molecule with electron-deficient alkynes for the formation of [l,2,3]-triazole heterocycle (Eq. 4.66). 

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)... 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

The synthesis of the 2-triazolylpyrimido[l,2,3-cti]purine-8,10-diones 172 and 173 was achieved using the 1,3-dipolar cycloaddition of azides with the terminal... 

SYNTHESIS OF NATURAL PRODUCTS, INTERMEDIATES, AND THEIR ANALOGUES VIA 1,3-DIPOLAR CYCLOADDITION OF AZIDES... 

The 1,3-dipolar cycloaddition of azides combined with further synthetic transformations is a highly useful reaction for the synthesis of heterocycles and natural products. Even though the chemistry of azide cycloadditions has been known for... 

Fleet and co-workers (75a) synthesized various tetrazoles from manno- and rhamnopyranoses, as well as furanoses, based on the intramolecular 1,3-dipolar cycloadditions of azides with nitriles (Scheme 9.75). All of these tetrazoles were tested for their inhibitory activities toward both glycosidases and other sugarprocessing enzymes. D-Mannopyranotetrazole (397) was prepared from L-gluono-lactone (393). Azide 394 on ring opening with ammonia followed by dehydration with trifluoroacetic anhydride gave the azido nitrile 395. Intramolecular 1,3-dipolar cycloaddition of 395 in refluxing toluene followed by deprotection produced the D-mannopyranotetrazole 397 in 86% overall yield. 

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. 

Table 9 1,3-Dipolar cycloaddition of azide 110 with various alkynes a-j ...

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