Fixed-charge labels for simplified reaction analysis: 5-hydroxy-1,2,3-triazoles as byproducts of a copper(I)-catalyzed click reaction

High-resolution multistage mass spectrometric studies of isotope-labelled derivatives of a fixed-charge labelled sugar triazole assisted the identification of 5-hydroxy-1,2,3-triazoles as byproducts of the copper(I)-catalyzed cycloaddition of azides and terminal alkynes. Reaction optimization with inclusion of the auxiliary ligand, tris(benzyltriazolylmethyl)amine furnished an improved ligation protocol in which formation of the 5-hydroxytriazole is mitigated.     

Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic oxidative coupling reaction of alkynes and azicles

In this paper, an efficient synthesis of 5-alkynyl-1,2,3-triazoles through a one-pot aerobic oxidative coupling reaction of various alkynes and azides has been developed. Further derivatization of 5-alkynyl-1,2,3-triazoles readily yielded 5-carbonyl-1,2,3-triazoles, 5-carboxylic-1,2,3-triazole, 5-hydroxyalkyl-1,2,3-triazoles and 5-quinoxaline-1,2,3-triazole, which provided an entry into structurally diverse 5-functionalized-1,2,3-triazoles.     

Synthesis of 5-functionalized-1,2,3-triazoles via a one-pot aerobic oxidative coupling reaction of alkynes and azides

In this paper, an efficient synthesis of 5-alkynyl-1,2,3-triazoles through a one-pot aerobic oxidative coupling reaction of various alkynes and azides has been developed. Further derivatization of 5-alkynyl-1,2,3-triazoles readily yielded 5-carbonyl-1,2,3-triazoles, 5-carboxylic-1,2,3-triazole, 5-hydroxyalkyl-1,2,3-triazoles and 5-quinoxaline-1,2,3-triazole, which provided an entry into structurally diverse 5-functionalized-1,2,3-triazoles.     

Regioselective synthesis of [1,2,3]-triazoles catalyzed by Cu(I) generated in situ from Cu(0) nanosize activated powder and amine hydrochloride salts

A straightforward and efficient method for the regioselective synthesis of functionalized 1,4-disubstituted [1,2,3]-triazoles, from terminal alkynes and azides, has been established utilizing Cu(0) as the source of the catalytic species. The presumed catalytic Cu(I) species is generated by the combination of 10 mol % copper nanosize activated powder and 1 equiv of an amine hydrochloride salt. The addition of an amine hydrochloride salt into the reaction mixture enhanced the dissolution of copper metal, and subsequently facilitated the formation of the Cu(I)-acetylide intermediate required for the regioselective cycloaddition.     

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.     

Alkylation of 1,2,3-benzotriazole with iodomethyl ketones

Solvent-free reactions of 1,2,3-benzotriazole with 1-iodopropan-2-one and 1,3-diiodopropan-2-one in the absence of a catalyst involved alkylation of the heteroring at the N¹ atom and subsequent quaternization at the N³ atom with formation of 1,3-bis(2-oxopropyl)-1H-1,2,3-benzotriazolium triiodide which is a new conducting ionic liquid. The reaction of 1,2,3-benzotriazole with 1,3-diiodopropan-2-one was accompanied by reductive deiodination of the iodomethyl groups in the initial ketone with hydrogen iodide liberated by N¹-alkylation. Triiodide ion readily exchanges for nitrate ion by the action of AgNO₃ to produce 1,3-bis(2-oxopropyl)-1H-1,2,3-benzotriazolium nitrate. The reaction of 1,2,3-benzotriazole with 2-iodo-1-phenylethan-1-one in melt resulted in the formation of 1,3-bis(2-oxo-2-phenylethyl)-1H-1,2,3-benzotriazolium triiodide.     

C2-symmetric macrocyclic carbohydrate/amino acid hybrids through copper(I)-catalyzed formation of 1,2,3-triazoles

An efficient method was developed for the preparation of macrocyclic carbohydrate/amino acid hybrids by macrocyclization with copper(I)-catalyzed 1,2,3-triazole formation. Methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6-dideoxy-beta-D-glucopyranoside was prepared and coupled to two different N-propiolyl dipeptides (propiolyl-Tyr-Tyr-OH and propiolyl-Arg(Mtr)-Tyr-OH) to obtain bifunctional molecules carrying one azido group and one terminal alkyne. These bifunctional molecules were cyclodimerized using Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes to form macrocycles containing two 1,2,3-triazoles. Various cyclization methods were evaluated, and the most efficient conditions were found to be CuI and N,N-diisopropylethylamine in CH3CN.     

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.     

A Simple Efficient Click Synthesis of Novel Crown Ethers Containing 1,2,3-Triazole Moieties

Novel crown ether derivative containing 1,4-disubstituted-1,2,3-triazole moieties were synthesized. At the first step of the synthesis 4,13-diaza-18-crown-6 and 4-aminobenzo-15-crown-5 were converted into terminal alkynes, which were then subjected to copper(I)-catalyzed alkyne-azide coupling (CuAAC) in methylene chloride. This coupling reaction was performed according to the concept of click chemistry, using an Amberlyst A-21-supported copper(I) iodide catalyst.

     

Cu(I)-promoted one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and nitrobenzaldehydes

A series of 1,4-disubstituted 1,2,3-triazoles were synthesized through a one-pot process from easily available anti-3-aryl-2,3-dibromopropanoic acids and nitrobenzaldehydes in hexamethylphosphoric triamide. Inexpensive copper(I) iodide was the catalyst.     

An easy access to unsymmetrically substituted 4,4′-bi-1,2,3-triazoles

A convenient synthesis of 4-alkynyl-1,2,3-triazoles and novel unsymmetrically substituted 4,4′-bi-1,2,3-triazole derivatives has been devised starting from easily available 1-trimethylsilyl-1,3-butadiyne. The starting compound was reacted with several azides, leading to 4-(silylalkynyl)-1,2,3-triazoles, which were easily transformed into 4-arylalkynyl-1,2,3-triazoles by a Pd catalyzed coupling reaction with aryl halides, or into novel 4,4′-bi-1,2,3-triazole derivatives by a subsequent cyclization reaction with azides.     

Trifluoromethyl Sulfones and Perfluoroalkanesulfonamides of the Azole Series

2-Phenyl-4-trifluoromethylsulfonylmethyl-2H-1,2,3-triazole was synthesized from 4-bromo-methyl-2-phenyl-2H-1,2,3-triazole and sodium trifluoromethanesulfinate CF₃SO₂Na. 1(2)-Ethyl-4-nitro-1(2)H-1,2,3-triazoles and 4-nitro-2-phenyl-2H-1,2,3-triazole were reduced to the corresponding amines. Intermediate 1,2-bis(1-ethyl-1H-1,2,3-triazol-4-yl)diazene 1-oxide exists as a mixture of syn and anti isomers, the former being stabilized via formation of a strong intramolecular hydrogen bond. The reduction of 2-ethyl-4-nitro-2H-1,2,3-triazole in the presence of HCl afforded the target 4-amino-2-ethyl-2H-1,2,3-triazole and also 4-amino-5-chloro-2-ethyl-2H-1,2,3-triazole. Treatment of alkyl-substituted 4-amino-1,2,3-triazoles with trifluoromethanesulfonyl chloride and pentafluoroethanesulfonyl chloride gave N-triazolyl-substituted trifluoromethane- and pentafluoroethanesulfonamides and -imides.     

A facile and regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles using click chemistry

The reaction of α-tosyloxy ketones, sodium azide, and terminal alkynes in presence of copper(I) in aqueous polyethylene glycol afforded regioselectively 1,4-disubstituted 1,2,3-triazoles in good yield at ambient temperature. The one-pot exclusive formation of 1,4-disubstituted 1,2,3-triazoles involves in situ formation of α-azido ketones, followed by cycloaddition reaction with terminal alkyne. The generality of this one-pot method was demonstrated by synthesizing an array of diverse 1,4-disubstituted 1,2,3-triazoles.     

Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles

Herein we report an approach to the formation of 5-alkynyl-1,3-dioxin-4-ones using Suzuki-Miyaura cross-coupling reaction of potassium alkynyltrifluoroborate salts with 2,2,6-trimethyl-5-iodo-1,3-dioxin-4-one. The resulting 5-ethynyltrimethylsilyl-1,3-dioxin-4-ones obtained through the Sonogashira reaction were further reacted in a Cu(I)-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition to form functionalized 1,4-disubstituted-1,2,3-triazoles in good yields, using mild conditions and ultrasonic radiation to expedite the reaction.     

Silver-catalyzed three-component reaction: synthesis of N2-substituted 1,2,3-triazoles via direct benzylic amination

A novel Ag(Ⅰ)-catalyzed benzylic amination reaction with in situ generation of NH-1,2,3-triazoles for N~2-substituted 1,2,3 triazole scaffolds is described. This protocol is achieved with easily accessible substrate, broad functional group, good re gioselectivity, thus providing the efficient and practical method to diverse N~2-substituted 1,2,3-triazole rings with moderate t good yields.     

N-Alkylation of 4-nitro-1,2,3-triazole revisited. Detection and characterization of the N3-ethylation product, 1-ethyl-5-nitro-1,2,3-triazole

The products of the alkylation of sodium 4-nitro-1,2,3-triazolate with ethyl bromide were investigated using ¹H, ¹³C, and ¹⁵N NMR spectroscopy. It was found that alkylation proceeds on the triazole nitrogen atoms giving a mixture of three isomeric N-ethyl-4-nitro-1,2,3-triazoles. The molar ratio of N1, N2, and N3-alkylation products was 4:8:1. The formation of a minor N3-isomer, namely 1-ethyl-5-nitro-1,2,3-triazole was confirmed by X-ray structural analysis of single crystals of its tetranuclear copper(II) complex obtained by reaction of copper(II) chloride dihydrate with a mixture of the N2 and N3-isomers.     

Synthesis of 2(5H)-Furanone Derivatives with Symmetrical and Unsymmetrical Bis-1,2,3-triazole Structure

The interesting bioactivities of 2(5H)-furanone, 1,2,3-triazole, and amino acid derivatives have promoted their combination into one multifunctional molecule. The symmetrical bis-1,2,3-triazoles and mono-1,2,3-triazoles with one free azide group are synthesized respectively by controlling the molar ratio of reactants, N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl ester and 1,4-diazidobutane. The unsymmetrical bis-1,2,3-triazoles are afforded by the subsequent reaction of mono-1,2,3-triazoles with other terminal alkynes with good to excellent yields in a short time under the same mild “click” reaction conditions. The 32 new compounds obtained in the reactions are characterized by Fourier transform infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Because of the diversity of four or five basic units in molecule, this methodology provides easy access to different chiral 2(5H)-furanone compounds with polyheterocyclic structure, especially with unsymmetrical bis-1,2,3-triazole moiety. Importantly, a simple approach is provided for the synthesis of unsymmetrical bis-1,2,3-triazoles using common diazides.     

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.     

Pd-catalyzed regioselective C-H chlorination of disubstituted 1,2,3-triazoles

This paper mainly studied Pd-catalyzed regioselective chlorination of disubstituted 1,2,3-triazoles directed by the 1,2,3-triazole ring. A series of regioselective chlorinated products were synthesized in 47–86% yields using Pd(OAc)₂ as a catalyst and CuCl₂ as a chlorinated reagent. This method provides a new mean for the synthesis of 1,2,3-triazole halides which combines the formation of C-X bond with C-H activation.     

Modular synthesis of mono, di, and tri-1,4-disubstituted-1,2,3-triazoles through copper-mediated alkyne-azide cycloaddition

The synthesis of 1,2,3-triazoles was developed employing sequential copper azide-alkyne cycloaddition, tosylation, sodium azide, and copper azide-alkyne steps. This approach allowed the synthesis of two and three 1,2,3-triazole rings. A preliminary study to gain further insight into the reaction was performed using in situ ReactIR technology.