Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition

The solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of polymer-bound azides to various alkynes is reported. Polymer-bound azides were synthesized from polymer-bound halides and sodium azide and reacted with alkynes to produce polymer-bound 1,2,3-triazoles. Cleavage of the triazoles was performed with trifluoroacetic acid. A traceless synthesis of 1,2,3-triazoles was developed using 2-methoxy-substituted resin (polymer-bound 4-hydroxy-2-methoxybenzyl alcohol). In addition, a synthesis of 4-hydroxybenzyl-substituted 1,2,3-triazoles from the bromo-Wang resin (4-(bromomethyl)phenoxymethyl polystyrene) was achieved.     

Regiospecific synthesis of 2-allyl-1,2,3-triazoles by palladium-catalyzed 1,3-dipolar cycloaddition

2-Allyl-1,2,3-triazoles were prepared by the palladium-catalyzed three component coupling (TCC) reaction of alkynes, allyl methyl carbonate and trimethylsilyl azide. A π-allylpalladium azide complex, which undergoes the 1,3-dipolar cycloaddition with alkynes, is proposed as a key intermediate in the TCC reaction.     

Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles

[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.     

Synthesis of functionalized organotrifluoroborates via the 1,3-dipolar cycloaddition of azides

[reaction: see text] We have successfully prepared potassium azidoalkyltrifluoroborates from the corresponding halogen compounds in 94-98% yields through a nucleophilic substitution reaction with NaN(3). In the presence of various alkynes and Cu(I) as a catalyst, these azidotrifluoroborates easily formed 1,4-disubstituted organo-[1,2,3]-triazol-1-yl-trifluoroborates in 85-98% yields. This method was then developed into a facile one-pot synthesis for the preparation of various organo-[1,2,3]-triazol-1-yl-trifluoroborates using haloalkyltrifluoroborates as the starting materials.     

Scope and regioselectivity of the 1,3-dipolar cycloaddition of azides with methyl 2-perfluoroalkynoates for an easy,metal-free route to perfluoroalkylated 1,2,3-triazoles

1,3-Dipolar cycloadditions of methyl 2-perfluoroalkynoates with various azides have been examined, leading to a simple metal-free synthetic protocol for the synthesis of perfluoroalkylated 1,2,3-triazoles. The regiochemical results demonstrated that the cycloaddition was controlled by FMO (the frontier molecular obitals) interaction and steric hindrance in transition states.     

Unusual Cu(I)-catalyzed 1,3-dipolar cycloaddition of acetylenic amides: formation of bistriazoles

C-carbamoyl-1,2,3-triazoles have recently attracted much interest due to their potent biological activity. While synthesizing C-carbamoyl-1,2,3-triazoles by the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides 1 and acetylenic amides 2, we found that the expected 1,2,3-triazole products 3 were obtained as the only products in excellent yields when CuSO₄ and sodium ascorbate were used as the Cu(I)-catalyst. Surprisingly, the unexpected bistriazole products 4 were one of the major products obtained along with the 1,2,3-triazoles 3 when using a direct Cu(I)-catalyst such as CuI or CuBr.     

Ruthenium-catalyzed 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols with azides

The 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols 1 with azides in the presence of catalytic [Cp*RuCl₂]_n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles 2 in high yields.     

Synthesis of bis-spirofused thiapyrrolizidinooxindoles by 1,3-dipolar cycloaddition

The 1,3-dipolar cycloaddition of unstabilized azomethine ylide, which is generated in situ from isatin and thiaproline, to arylidene derivatives of rhodanine affords bis-spirofused thiapyrrolizidinooxindoles. The 1,3-dipolar addition reactions under consideration are fully regio- and diastereoselective.     

Dipolar cycloaddition reactions of organic azides with some acetylenic compounds

Phenyl azide 1 and several substituted benzyl azides 2a-o underwent 1,3-dipolar cycloaddition reactions with dimethyl acetylenedicarboxylate 3, phenylacetylene 4 and ethyl propiolate 5 to afford the triazoles 6-13. The reactions of these azides with ethyl propiolate were found to be completely regiospecific.     

Synthesis of 3,4-fused cycloalkanopyrroles by 1,3-dipolar cycloaddition

The synthesis of a number of 3,4-fused cycloalkanopyrroles bearing substituents on the cycloalkane ring was accomplished by 1,3-dipolar cycloaddition. The yield of the cyclization appeared to depend on the base-sensitivity of the Michael acceptor, but the method is applicable across a broad range of cyclic α,β-unsaturated ketone esters. Functional group transformations can be undertaken following pyrrole synthesis to increase the diversity of cycloalkanopyrroles accessible by this method. One pyrrole thus made is a diester of a conformationally-constrained analogue of porphobilinogen, the precursor of the natural tetrapyrroles.     

1,3-Dipolar cycloaddition of organic azides to alkynes by a dicopper-substituted silicotungstate

The dicopper-substituted gamma-Keggin silicotungstate TBA 4[gamma-H2SiW10O36Cu2(mu-1,1-N3)2] (I, TBA = tetra- n-butylammonium) could act as an efficient precatalyst for the regioselective 1,3-dipolar cycloaddition of organic azides to alkynes. Various combinations of substrates (four azides and eight alkynes) were efficiently converted to the corresponding 1,2,3-triazole derivatives in excellent yields without any additives. The present system was applicable to a larger-scale cycloaddition of benzyl azide to phenylacetylene under solvent-free conditions (100 mmol scale) in which 21.5 g of the analytically pure corresponding triazole could be isolated. In this case, the turnover frequency and the turnover number reached up to 14,800 h(-1) and 91,500, respectively, and these values were the highest among those reported for the copper-mediated systems so far. In addition, I could be applied to the one-pot synthesis of 1-benzyl-4-phenyl-1H-1,2,3-triazole from benzyl chloride, sodium azide, and phenylacetylene. The catalyst effect, kinetic, mechanistic, and computational studies show that the reduced dicopper core plays an important role in the present 1,3-dipolar cycloaddition.     

Synthesis of celecoxib via 1,3-dipolar cycloaddition

A regioselective 1,3-dipolar cycloaddition reaction between a nitrile imine and an enamine is described for the preparation of celecoxib. Nitrile imines are generated in situ from the corresponding hydrazonoyl benzenesulfonates.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

Cu(I)-catalyzed one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles via nucleophilic displacement and 1,3-dipolar cycloaddition

An efficient method is described for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in high yields from a variety of Baylis-Hillman acetates and terminal alkynes with sodium azide using CuI as a catalyst, in either water or polyethylene glycol (PEG). This procedure is operationally simple and environmentally benign. Polyethylene glycol (PEG) serves as an efficient reusable solvent with higher efficiency.     

Synthesis of isoxazolidines by 1,3-dipolar cycloaddition and their bioactivity

A series of new isoxazolidines was prepared by 1,3-dipolar cycloaddition of different mono-substituted styrenes with 1,3-dipolar compounds that were prepared by the reaction of N-methylhydroxylamine sulfate with aromatic carbonyl substances. This synthetic pathway for the preparation of isoxazolidines was an ideal process of green chemistry. The synthetic products were 5-substituted isoxazolidines and their structures were characterized by mass and NMR (¹H-, ¹³C-, COSY, HSQC, and DEPT) spectrometry, and their bioactivity was investigated indicating that some new compounds inhibited Botrytis cinerea effectively. __________ Translated from Chinese Journal of Organic Chemistry, 2005, 25(11) (in Chinese)     

Sulfated tungstate a heterogeneous acid catalyst for synthesis of 4-aryl-NH-1,2,3-triazoles by 1,3-dipolar cycloaddition of nitroolefins with NaN3

A facile and new method for the synthesis of 4-aryl-NH-1,2,3-triazoles from nitroolefins and NaN₃ by 1,3-dipolar cycloaddition reaction, employing a mild solid inorganic acid sulfated tungstate as a heterogeneous catalyst, has been developed. The protocol emphasizes broad substrate scope with many functionalities, less reaction time, stability to open air, easy work-up, and with good to excellent yields.     

Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole-fused glycosides and nucleosides by an intramolecular 1,3-dipolar cycloaddition reaction

Various 1,2,3-triazole and 1,2,3,4-tetrazole fused multi-cyclic compounds were synthesized from carbohydrate derived azido-alkyne and azido-cyanide substrates. The acid sensitive 1,2-O-isopropylidene group of the furanosyl sugar was utilized for diversification to glycosides and nucleosides under Fischer glycosidation and Vorbruggen's conditions, respectively.     

Kinetics and mechanism of the 1,3-dipolar cycloaddition of phenyl azides to methyl 3-pyrrolidinoacrylate

Kinetics of cycloadditions of phenyl azides to methyl 3-pyrrolidinoacrylate (2) produced Hammett ? = 2.2. An E_a of 13.5 kcal mole ^?1 and Δ S^* of ?37.4 cal.K^?l mole^?1 were calculated for the cycloaddition of p-O₂NC₆H₄N₃ to 2. The cycloadditions are concerted, non-synchronous, and are controlled by LUMO (azide) - HOMO (dipolarophile) interactions.     

Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition

An efficient method was developed for the asymmetric synthesis of 2′-alkyl-4′aryl-1H-spiro[indole-3,3′-pyrrolidin]-2-ones, which are potential inhibitors of the p53-MDM2 interaction. Our X-ray crystallographic analysis revealed that this 1,3-dipolar cycloaddition proceeds with high stereoselectivity but differently from previously published results.     

Synthesis of 1,3-dioxacyclan-2-yl-substituted 1,2,3-triazoles

A new method for preparing 4-(1,3-dioxacyclan-2-yl)-5-phenyl-1,2,3-triazoles in 30–75% yields has been developed on the basis of azide–alkyne cycloaddition to 2-phenylethinyl-1,3-dioxacyclanes. It has been shown that the best results are achieved when the reaction is carried out at 150–155°C in DMSO.