Dipolar cycloaddition, of acetylenic

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). 

Katritzky AR, Zhang Y, Yuming S, Sandeep K (2003) 1,2,3-triazole formation under mild conditions via 1,3-dipolar cycloaddition of acetylenes with azides. Heterocycles 60 1225-1239... 

A review on the 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published <03H(60)1225>. The synthesis of a benzotriazole azo dye phosphoramidite and the subsequent use in solid phase synthesis of oligonucleotides has been reported <03TL1339>. The chemical reactivity of [l,2,3]triazolo[l,5-a]- and [l,5-c]-pyrimidinium salts has been published <03T4297>. A review on the use of benzotriazole as an ideal synthetic auxiliary has been disclosed <03CEJ4586>. 

Triazole formation under mild conditions via 1,3-dipolar cycloaddition of acetylenes with azides 03H(60)1225. 

However, 1,3-dipolar cycloaddition of acetylenic dipolarophiles such as dimethylacetylenedicarboxylate (DMAD) have been reported. Thus, thiazole and its alkyl derivatives undergo condensation with dimethyl acetylenedicarboxylate, giving 1 2 adducts. For example, Potts et al. reported that thiazole when quartemized as an ylide with alkylators such as bromoacetophenone (BrCH2COPh), undergoes 1,3-dipolar cycloaddition... 

Scheme 6.27. Dipolar cycloadditions of acetylenic sulfones toward the synthesis of pyrazoles.

The 1,3-dipolar cycloaddition of acetylenes and alkenes with oxazolones is widely used for the construction of the pyrrole ring. The presence of a CFs-group in the 1,3-dipolar component opens a pathway to 2-CF3-pyrroles, while the application of trifluoromethylated dipolarophiles provides 3-CF3-pyiroles. For example, the dimethyl pyrroledicarboxylate 120 was synthesized in 78 % yield by the reaction of the CFs-containing oxazolone 118, prepared from proline 117 and trifluoroacetic anhydride (TFAA), with dimethyl acetylene dicarboxylate (DMAD) [53]. 

The reaction of alkynyl sulfoximines with in situ-prepared organic azides in water-dichloromethane under reflux has been reported to afford 1,4,5-triazoles in a fully selective manner (Scheme 54) [132]. In addition, an instructive paper on the 1,3-dipolar cycloadditions of acetylenic sulfones in solution and on solid supports has been published by Back et al. [137]. 

Structure (74), with strong S—N interaction, is not entirely ruled out. On treatment with sodium ethoxide, (70) forms l,3-bis(arylamino)-l,2,4-thiadiazoles (71). The thermal decomposition of (69 Ar = Ar = Ph or p-MeCjHJ likewise produces (70) (ca. 50%), together with (71), as a by-product. Similarly, the 1,3-dipolar cycloaddition of acetylenes to Hector s bases (69) gives 2-aryl-amino-thiazoles (73), probably by way of the intermediate 1,2,4-thiadiazolo-[5,l-fl][l,3]thiazoles (72). ... 

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... 

Heating of bis(trimethylsilylmethyl)sulfoxide 1166 generates HMDSO 7 and, via 1167, the reactive intermediate thioformaldehyde-S-methyhde 1168, which can be trapped in situ, e.g. by N-methylmaleimide, to give 81% of the l,3-dipolar cycloaddition product 1169 [14] (Scheme 8.3). Further analogous 1,3-dipolar cycloadditions with acetylenes are discussed elsewhere [15]. 

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,... 

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)... 

Scheme 6.220 1,3-Dipolar cycloaddition of benzyl azides with acetylenic amides.

The 1,3-dipolar cycloaddition of azidofurazans to acetylenes afforded 1,2,3-triazoles linked with furazan cycle <2000CHE91>. Treatment of 3-azido-2-amino-l,2,5-oxadiazole 194 with ethyl 4-chloroacetoacetate gives access to the functionalized [l,2,3]-triazoles 195, which are good precursors for GSK-3 inhibitors with favorable water solubility (Equation 38) <2003JME3333>. 

Dimethyl-3,5-dimethyl-l//,3//-pyrrolo[l,2-r ][l,3]thiazole-6,7-dicarboxylate 399 (R = H) was prepared from cysteine 396 using the method developed of Padwa et al. <1989JOC644>. The thiazolidine carboxylic acid 397 (R = H), obtained by reaction of the cysteine with formaldehyde, was heated in the presence of acetic anhydride and DMAD to give the sulfide 399 by dipolar cycloaddition of the acetylene to the intermediate dipole 398 (Scheme 59) <2002J(P1)1795>. 

PM3 calculations of the 2 + 3-cycloaddition of t-butylphosphaacetylene with 2,4,6-triazidopyridine are consistent with the dipole-LUMO-controlled reaction type. An FTIR spectroscopic study of the 1,3-dipolar cycloaddition of aryl azides with acetylenes shows that the rate of reaction increases logarithmically with pressure (below 1 GPa). The 3 -I- 2-cycloaddition between an azide (69) and a maleimide (70) has been greatly accelerated by utilizing molecular recognition between an amidopyridine and a carboxylic acid [see (71)] (Scheme 24). ... 

The thiazofurin acyclic analog 925 was prepared from 924 as shown in the scheme (87H947). 1,3-Dipolar cycloaddition of the acetylenic derivative 927 to the diazo derivative 926 gave the pyrazole 928, whose amidation and debenzylation gave 929 (93MI11). 

Fluoride ion catalyzed 1,3-dipolar cycloaddition of bromo nitrile oxide, obtained in situ from dibromoformaldehyde oxime 184, to nonactivated alkynes provides a new approach to the synthesis of neuroactive isoxazoles. However, the regioselectivity of cycloaddition in this case is not high—products 185 and 186 are obtained in a 1 1 to 1 1.4 ratio (equation 80). Cycloaddition reaction of hydroximoyl chlorides and acetylene was snc-cessfully carried out also in the presence of NaHCOs as a base. For instance, a-keto oximes 187 were reacted with acetylene and NaHCOs to give isoxazoles 188 in good yields (equation 81). 

The meso-ionic l,3-oxathiol-4-ones (498) are a new class of meso-ionic heterocycle which appear to be too unstable to be isolated at room temperature. They can be generated by cyclodehydration of the acids 499, R = NR2 R — Ph, using acetic aiihydride, and trapped in situ by 1,3-dipolar cycloaddition with acetylenes the product is a furan (500) formed via the bicyclic adduct (501). ... 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

Palacios et al. (31) reported the synthesis of the isomeric 4,5-disubstituted l-(diethoxyphosphorylmethyl)-l,2,3-triazoles 156 and 157 via thermal intermole-cular 1,3-dipolar cycloadditions of the azidoalkylphosphonates 154 with the disubstimted acetylenes 155 (Scheme 9.31). 

Brillante and co-workers (33) conducted an intermolecular 1,3-dipolar cycloaddition of the aryl azide 162 with (trimethylsilyl)acetylene under high-pressure conditions (Scheme 9.33). The rate of cycloaddition increased logarithmically with pressure, and the yield of cycloadduct 163 was almost quantitative. 

Freeze and Norris (34) reported the 1,3-dipolar cycloaddition of 5-azido-5-deoxy-l,2-0-isopropylidene-D-xylofiiranose (164) with acetylenic dipolarophiles to give the triazoles 165 (Scheme 9.34). This process was subsequently extended using the soluble polymer-supported azide (166) to produce the corresponding triazoles 167 in 50-95% yield. Dipolarophiles present in large excess facilitated the cycloaddition of the polymer-supported azide 166. Purification of the triazole 167 was achieved by filtration. 

An efficient synthesis of the l-aUyl-6-(l, 2, 3 -triazolyl) analogue 170 of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (KEPT), an anti-human immunodeficiency virus (HIV) reverse transcriptase inhibitor, was reported using an intermolecular 1,3-dipolar cycloaddition of the azide 169 with acetylenes (35) (Scheme 9.35). Azidouracil (169), when refluxed with an acetylene in equimolar proportions in toluene, gave the corresponding triazoles (170) in excellent yield. 

Hlasta and Ackerman (72) reported a synthesis of the triazoles 379, related to the human leuokocyte elastase inhibitor WIN 62225 (380), based on an inter-molecular 1,3-dipolar cycloaddition of the azide 378 with alkynes (Scheme 9.72). They also investigated in detail the effect of steric and electronic factors on the regioselectivity of the cycloaddition reaction. (Azidomethyl)benzisothiazolone (378) underwent smooth 1,3-dipolar cycloaddition with various disubstituted acetylenes to give the corresponding triazoles (379) in 37-84% yields. Electron-deficient acetylenic dipolarophiles reacted more rapidly with the azide to give the respective triazoles. 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

---