1.3- Dipolar cycloaddition reactions alkyl azides

Further examples of multifunctional isothiocyanates include aryl for-mamidinoyl-isothiocyanates RiNC(=NR )NCS, which may be isomerized into 3H-quinazoline-4-thiones and which undergo well-known amine addition and cycloaddition reactions associated with simpler isothiocyanates ° and sulphonyl isothiocyanates, for which 1,3-dipolar cycloaddition to alkyl azides has been demonstrated,thermolysis of the resulting thiatriazolines giving sulphonyl carbodi-imides ArS02N=O=NR. 

Treatment of meso-ionic l,2,3,4-oxatriazole-5-thiones (286) (Section VII, I, 3) with boiling ethanoUc ammonia yields the isomers 297. These belong to a new class of meso-ionic heterocycle, which by O-alkylation with triethyloxonium tetrafluoroborate 3rield the salts 298, These are useful intermediates for the sjmthesis of a number of novel types of meso-ionic 1,2,3,4-thiatriazoles (299, 300, and 301). The l,2,3,4-thiatriazol-5-ones (297) have dipole moments in accord with their meso-ionic formulation. They are remarkably stable to acidic hydrolysis, and 1,3-dipolar cycloaddition reactions have not been observed alkaline hydrolysis yields aryl azides. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

Sharpless and coworkers pubhshed a paper in 2002 (Rostovtsev et al., 2002) where the formation of 1,23-triazoles by the Cu(l)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction between alkyl/aryl azides and non-activated alkynes was described as a chck reaction in contrast to the purely thermal (imcatalyzed) azide-alkyne chck reaction which refers to the 13-dipolar cycloaddition reaction between alkyl/aryl azides and strongly activated alkynes. The Cu(l)-catalyzed... 

A range of indolo(triazolo)-l,4-diazepine derivatives 104 were obtained by a microwave-heated three-component reaction involving tandem N-alkylation of indole 101 with epichlorohydrin 102, ring-opening of the epoxide with azide 103, and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions (13BJO401). Fused triazolodiazepinones were obtained via azide-alkyne 1,3-dipolar cycloaddition followed by lactamization (13JHC430). 

Among the chemical procedures listed above, click chemistry can be considered an efficient method that covers a wide range of different, requested functionalizations. The key reaction, called Sharpless-type click reaction , is a variant of the Huisgen 1,3-dipolar cycloaddition reaction between C—C triple bonds, C—N triple bonds, and alkyl-, aryl-, and sulfony 1-azides. 

General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis, " and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids and o-aryl carboxylic acids direct preparation of thiol esters from carboxylic acids and thiols the stereospecific preparation of alkyl azides and the phosphorylation of alcohols and amines The application of DPPA in a modified Curtius reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source, and can undergo 1,3-dipolar cycloaddition reactions. The Curtius degradation of carboxylic acids in the presence of f-butanol gives the Boc-protected amine directly (eq 1). 

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). 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Reactions of salts of 1,2,3-triazole with electrophiles provide an easy access to 1,2,3-triazol-jV-yl derivatives although, usually mixtures of N-l and N-2 substituted triazoles are obtained that have to be separated (see Section 5.01.5). Another simple method for synthesis of such derivatives is addition of 1,2,3-triazole to carbon-carbon multiple bonds (Section 5.01.5). N-l Substituted 1,2,3-triazoles can be selectively prepared by 1,3-dipolar cycloaddition of acetylene or (trimethylsilyl)acetylene to alkyl or aryl azides (Section 5.01.9). 

The 1,3-dipolar cycloaddition of azidoalkylphosphonates to enamines afforded A2-1,2,3-triazoles which are further converted to the 1,2,3-triazoles [95H(40)543] fused triazoles are similarly obtained when a cyclic enamine was employed. Fused 1,2,3-triazole (88), a xanthine oxidase inhibitor, was prepared by the reaction of an alkyl azide with cyanoacetamide with further elaboration of intermediate (87) by treatment with HMDS in xylene [95FES257]. The fused 4H-l,2,3-triazolo[l,5- ][l,4]benzodiazepin-6(5H)-one (90) was obtained from propargylamide (89) via an intermediate azide [95S647]. 

Alkyl azides readily undergo 1,3-dipolar cycloaddition to arylsulfonyl isothiocyanates (375) to yield thiatriazolines (376). Thermolysis of (376) in the presence of isocyanates or carbodiimides produces 1,2,4-thiadiazole derivatives (378) and (379), respectively. The intermediate formation of a thiaziridinimine (377) has been postulated as indicated in Scheme 137 (75JOC1728, 75S52). The use of isothiocyanates as dipolarophiles produces dithiazolidines (380) instead of the thiadiazole derivatives. In these reactions the intermediate thiazirine (377) functions as a 1,3-dipole with the positive charge primarily localized on sulfur. It was recently proposed that the reaction of oxaziridines (381) with isothiocyanates produces a similar thiazirine intermediate (382) which reacts in a different regiospecific manner with isothiocyanates to produce 1,2,4-thiadiazole derivatives (383) and (384 Scheme 138) (74JOC957). 

The difficulty in trying to forecast which way round a 1,3-dipolar cycloaddition will go is well illustrated when a substituted azide adds to an alkyne in the synthesis of 1,2,3-triazolcs. Reaction of an alkyl azide with an unsymmetrical alkyne, having an electron-withdrawing group at one end and an alkyl group at the other, gives mostly a single triazole. 

---