Click fleximers: a modular approach to purine base-expanded ribonucleoside analogues

The synthesis of nucleoside analogues incorporating 4-(5-pyrimidinyl)-1,2,3-triazole aglycons as expanded purine nucleobase mimics were accessed using the copper-catalyzed azide-alkyne Huisgen cycloaddition between a ribosyl azide and 5-alkynylpyrimidines. Depending on the nature of the alkyne employed, other nucleoside analogues that possess fluorescence or potential metal-binding properties were prepared. Computational studies were undertaken on the purine analogues and indicate that the heterocycles of the unfused nucleobase prefer a coplanar arrangement and the anti-glycosidic conformer is favoured in most instances.     

Some reactions of diazomethane with polyfluoroazaolefins

The reactons of some polyfluoroazaolefins with diazomethane are described. Thus 5-H-decafluoro-2-aza-hex-2-(Z)-ene yields 1-trifluoro-methyl-2-fluoro-2-(1,1,2,3,3,3-hexafluoropropyl)-aziridine as the sole isolable product. However, undecafluoro-2-azahex-2(Z)-ene yields not only the corresponding aziridine, 1-trifluoromethyl-2-fluoro-2-(heptafluoropropyl) aziridine, but also 1-trifluoromethyl-5-(heptafluoropropyl)-1,2,3-triazole, and 1-trifluoromethyl-2-fluoromethyl-2-(heptafluoropropyl) aziridine. 5-H-octafluoro-2-azahexa-2(Z)4(Z)-diene yielded the expected aziridine and 1-trifluoromethyl-2-fluoromethyl-2-(1,1,3,3,-tetra-fluoroprop-2-enyl)aziridine. No products were observed as a result of reactions at the C = C bond and no triazole was isolated in this case. Nonafluoroazacyclohex-1-ene gave the corresponding aziridine and a small amount of a compound believed to be 2,2,3,3,4,4,5,5-octafluoro-1,8,9-triazabicyclo [4,3,0] nonadiene i.e. the triazole product.     

Synthesis of isomerically pure 3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acid derivatives via the reaction of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide

Treatment of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide in DMSO afforded the corresponding (Z)-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in good yields. Similarly, 4-aryl-3-carbethoxy-6-trifluoromethyl-2-pyrones smoothly reacted with sodium azide in acetonitrile to produce (E)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in high yields, whereas their reactions in ethanol, accompanied by a configurational change, gave the thermodynamically more stable (Z)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids.     

Synthesis of novel 1,4-disubstituted-1,2,3-triazole semi synthetic analogues of forskolin by click reaction

New 1,4-disubstituted-1,2,3-triazole analogues of forskolin (5a-g, 6a-g) have been prepared by regioselective propargylation at 1-position followed by Cu(I) catalysed cycloaddition of different alkyl azides under the click reaction conditions. An interesting acyl shift in the base catalysed propargylation afforded a new series of 1,4-disubstituted-1,2,3-triazole analogues of forskolin (6a-g). These analogues have potential selective therapeutic applications as antihypertensive, antiglaucoma, antiasthma and antiobesity agents.     

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87–92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl₃ was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82–92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky’s rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-β-lactamase.     

Easy preparation of 1,4,5-trisubstituted 5-(2-alkoxy-1,2-dioxoethyl)-1,2,3-triazoles by chemoselective trapping of copper(I)–carbon bond with alkoxalyl chloride

We found that alkoxalyl chloride (ClCOCO₂R) did not carry out an acylation on 1-copper(I) alkyne in solvent without additives, but chemoselectively on 5-copper(I) 1,2,3-triazole (an intermediate in cycloaddition of 1-copper(I) alkyne and azide). Thus, a one-pot preparation of 1,4,5-trisubstituted 5-(2-alkoxy-1,2-dioxoethyl)-1,2,3-triazole was achieved by simply stirring the mixture of 1-copper(I) alkyne, azide, and alkoxalyl chloride at room temperature for 4 h.     

Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO₃ to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a–p in high yields via 1,3-dipolar cycloaddition reaction.     

Novel first-generation dendrimers on calix[4]resorcinol core equipped with multiple triazole units

Novel first-generation dendrimers on the calix[4]resorcinol core with four branches each containing multiple 1,2,3-triazole units have been synthesized in one-step by acid catalyzed condensation of resorcinols with a new aldehyde dendron, namely, 4-{3,5-bis[(1-benzyl-1H-1,2,3-triazol-4-yl)- methoxy]benzyloxy}benzaldehyde (obtained by alkyne–azide cycloaddition). The reaction proceeds stereoselectively to form rccc-diastereoisomers in high yields.     

1,3-dipolar cycloaddition reactions in the series of <Emphasis Type="Italic">N</Emphasis>-alkynyl-substituted uracils

Reactions of 1-(ω-bromoalkyl)-3,6-dimethyluracils and 1,3-bis(ω-bromoalkyl)-6-methyluracils with sodium azide gave the corresponding mono- and bis-azides. 1,3-Dipolar cycloaddition of the latter with prop-2-yn-1-ol, hex-1-yne, and dec-1-yne in the presence of copper(I) ions afforded acyclic and macrocyclic uracil derivatives containing 1,4-disubstituted 1,2,3-triazole fragments, which were subjected to quaternization with propyl iodide and methyl p-toluenesulfonate at the 1,2,3-triazole nitrogen atom.     

Synthesis of α-galactosyl ceramide analogues with an α-triazole at the anomeric carbon

The synthesis of 1,2,3-triazole containing analogues of α-GalCer and galacturonic acid containing Sphingomonous cell wall antigens is described. Anomerisation was used to provide the required α-glycosyl azide precursor. Copper azide–alkyne cycloaddition (CuAAC) generated the α-triazole linkage.     

Synthesis of novel glycolipids derived from glycopyranosyl azides and N-(β-glycopyranosyl)azidoacetamides

A general and expedient method based on a click reaction has been developed for the synthesis of novel glycolipids. The Cu(I) catalyzed [3+2] cycloaddition of several fully acetylated β- as well as α-d-glycopyranosyl azides, including the 1,6-diazide derived from d-glucose, with long chain alkyl propargyl ethers gave the respective 1,4-substituted 1,2,3-triazole derivatives in good yields. Treatment of fully acetylated N-(β-glycopyranosyl)azidoacetamides under similar conditions with alkyl propargyl ethers afforded the 1,2,3-triazolylacetamido derivatives in fairly good yields. Zemplen de-O-acetylation of all the fully acetylated derivatives furnished the free glycolipids in quantitative yields.     

Highly efficient and selective biocatalytic acylation studies on triazolylsugars

Different acid anhydrides (of C₂ to C₇ aliphatic fatty acids and benzoic acid) have been used to study the selective acylation of primary/secondary hydroxyl groups in 2-phenyl-4-(d-threo-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-erythro-1′,2′,3′-trihydroxypropyl)-2H-1,2,3-triazole, 2-phenyl-4-(d-arabino-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole and 2-phenyl-4-(d-lyxo-1′,2′,3′,4′-tetrahydroxybutyl)-2H-1,2,3-triazole in the presence of Candida antarctica lipase B in diisopropyl ether. Among the different acid anhydrides, butanoic anhydride was found to be the most efficient acylating agent (for butanoylation); for acetylation, vinyl acetate gave the best results. The reactions with both these acylating agents were highly selective and efficient yielding exclusively the monoacylated products in 95-99% yields in 1-5 h.     

Functional Acetal Methacrylates: IV. Electrophophilic Addition of Triazoles to Vinyloxyalkyl Methacrylates

Reactions of vinyloxyalkyl methacrylates with triazoles (1,2,4-triazole, 1,2,3-benzotriazole, 5-methyl-1,2,3-benzotriazole) under electrophilic conditions (50°C, 1-2 h, 1 wt% CF₃COOH) occur chemoselectively and afford in quantitative yield polyfunctional methacrylates with triazole and benzotriazole yields.     

Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC₅₀ values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC₅₀ values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.     

Synthesis of 1,4-disubstituted mono and bis-triazolocarbo-acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine by Cu(I)-catalyzed click azide-alkyne cycloaddition

A series of novel mono-1,2,3-triazole and bis-1,2,3-triazole acyclonucleoside analogues of 9-(4-hydroxybutyl)guanine was prepared via copper(I)-catalyzed 1,3-dipolar cycloaddition of N-9 propargylpurine, N-1-propargylpyrimidines/as-triazine with the azido-pseudo-sugar 4-azidobutylacetate under solvent-free microwave conditions, followed by treatment with K(2)CO(3)/MeOH, or NH(3)/MeOH. All compounds studied in this work were screened for their antiviral activities [against human rhinovirus (HRV) and hepatitis C virus (HCV)] and antibacterial activities against a series of Gram positive and negative bacteria.     

Pyrolysis and photolysis of 1-aroylamino-4,5-diaryl-1,2,3-triazoles: Generation and thermal transformations of 4,5-diaryl-1,2,3-triazolyl radicals

The pyrolysis of 1-aroylamino-4,5-diphenyl-1,2,3-triazoles 1 yields, pressumably via the 4,5-diphenyl-1,2,3-triazolyl radical ( 2a ), 2,3-diphenyl-2H-azirine ( 11a ) and 2-aryl-4,5-diphenylimidazoles 14 as the major products. Upon irradiation 1-benzoylamino-4,5-diphenyl-1,2,3-triazole ( 1a ) gives 4,5-diphenyl-1 (2)H-1,2,3-triazole ( 4a ) via the 1,2,3-triazolyl radical 2a , together with benzamide ( 5a ) and 1,2-bisbenzoylhydrazine ( 6a ). Products 5a and 6a result from the benzoylamino radical 3a by hydrogen atom abstraction and dimerization respectively.     

1,4-二取代-1,2,3-三唑衍生物的合成

在超声波辐射下,端基炔与叠氮基(3,3-二甲基-2,4-二氧戊环基)甲烷通过1,3-偶极环加成合成了1-(3,3-二甲基-2,4-二氧戊环基甲基)-4-芳基-1,2,3-三唑(5);5在酸性条件下脱保护得1-(2,3-二羟基丙基)-4-芳基-1,2,3-三唑,其结构经1H NMR,13C NMR,MS和元素分析表征。     

Controllable synthesis of bis(1,2,3-triazole)s and 5-alkynyl-triazoles via temperature effect on copper-catalyzed Huisgen cycloaddition

A facile synthetic protocol has been developed for the controllable preparation of bis(1,2,3-triazole)s and 5-alkynyl-1,2,3-triazoles from alkyne and azide under different temperatures. Various azides and alkynes were used as substrates for the reactions and the successful applications in nucleoside analogues manifested the values of this method in syntheses of bioactive molecules. Besides, a possible temperature-guided triazolyl–copper intermediate aerobic oxidative coupling mechanism was proposed for this controllable reaction procedure.     

Synthesis of 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole as novel carbon-14 anticonvulsant

Summary Two 1,2,3-triazole anticonvulsants, 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole, both labeled with carbon-14 in the 5-position were prepared from para-fluoro-benzonitrile-[cyano-¹⁴C].     

Theoretical studies on a series of 1,2,3-triazoles derivatives as potential high energy density compounds

Based on the full-optimized molecular geometric structures at B3LYP/6-31G* and B3P86/6-31G* levels, the densities (ρ), detonation velocities (D), and pressures (P) for a series of 1,2,3-triazole derivatives, as well as their thermal stabilities, were investigated to look for high energy density compounds (HEDCs). The heats of formation (HOFs) are also calculated via designed isodesmic reactions. The calculations on the bond dissociation energies (BDEs) indicate that the BDEs of the initial scission step are between 53 and 70 kcal/mol, and 4-nitro-1,2,3-triazole is the most reactive compound, while 1-(2′,4′-dinitrophenyl)-5-nitro-1,2,3-triazole is the least reactive compound for 1,2,3-triazole derivatives studied. The condensed phase heats of formation are also calculated for the title compounds. These results would provide basic information for the further studies of HEDCs. The detonation data of 1-(3′,4′-dinitrophenyl)-4-nitro-1,2,3-triazole and 1-(2′,4′-dinitrophenyl)-4-nitro-1,2,3-triazole show that they meet the requirement for HEDCs.