Four‐Component,One‐Pot Synthesis of 1,4‐Disubstituted 1,2,3‐Triazoles Bearing 1‐(2‐Phenylselenocyclohexyl) Group

An efficient, one‐pot, three‐step, regioselective synthesis of 4‐substituted 1‐(2‐phenylselenocyclohexyl)‐1,2,3‐triazoles, involving in situ generation of l‐azido‐2‐phenylselenocyclohexane has been developed via four‐component reaction of phenylselenenyl bromide, cyclohexene, sodium azide and terminal alkynes catalyzed by copper iodide in a mixture of DMF/THF (1:1) at room temperature under mild conditions with simple workup and good yields.     

Pd‐NHC‐Catalyzed Direct Arylation of 1,4‐Disubstituted 1,2,3‐Triazoles with Aryl Halides

A highly efficient method for the synthesis of unsymmetrical multi‐substituted 1,2,3‐triazoles via a direct Pd‐NHC system catalyzed C(5)‐arylation of 1,4‐disubstituted triazoles, which are readily accessible via "click" chemistry has been developed. It is important to note that C? H bond functionalizations of 1,2,3‐triazoles with a variety of differently substituted aryl iodides and bromides as electrophiles can be conveniently achieved through this catalytic system at significantly milder reaction temperatures of 100°C under air.     

Efficient Atropodiastereoselective Access to 5,5′‐Bis‐1,2,3‐triazoles: Studies on 1‐Glucosylated 5‐Halogeno 1,2,3‐Triazoles and Their 5‐Substituted Derivatives as Glycogen Phosphorylase Inhibitors

Whereas copper‐catalyzed azide–alkyne cycloaddition (CuAAC) between acetylated β‐D ‐glucosyl azide and alkyl or phenyl acetylenes led to the corresponding 4‐substituted 1‐glucosyl‐1,2,3‐triazoles in good yields, use of similar conditions but with 2 equiv CuI or CuBr led to the 5‐halogeno analogues (>71 %). In contrast, with 2 equiv CuCl and either propargyl acetate or phenyl acetylene, the major products (>56 %) displayed two 5,5′‐linked triazole rings resulting from homocoupling of the 1‐glucosyl‐4‐substituted 1,2,3‐triazoles. The 4‐phenyl substituted compounds (acetylated, O‐unprotected) and the acetylated 4‐acetoxymethyl derivative existed in solution as a single form (d.r.>95:5), as shown by NMR spectroscopic analysis. The two 4‐phenyl substituted structures were unambiguously identified for the first time by X‐ray diffraction analysis, as atropisomers with aR stereochemistry. This represents one of the first efficient and highly atropodiastereoselective approaches to glucose‐based bis‐triazoles as single atropisomers. The products were purified by standard silica gel chromatography. Through Sonogashira or Suzuki cross‐couplings, the 1‐glucosyl‐5‐halogeno‐1,2,3‐triazoles were efficiently converted into a library of 1,2,3‐triazoles of the 1‐glucosyl‐5‐substituted (alkynyl, aryl) type. Attempts to achieve Heck coupling to methyl acrylate failed, but a stable palladium‐associated triazole was isolated and analyzed by ¹H NMR and MS. O‐Unprotected derivatives were tested as inhibitors of glycogen phosphorylase. The modest inhibition activities measured showed that 4,5‐disubstituted 1‐glucosyl‐1,2,3‐triazoles bind weakly to the enzyme. This suggests that such ligands do not fit the catalytic site or any other binding site of the enzyme.     

Metal‐Free Synthesis of Functional 1‐Substituted‐1,2,3‐Triazoles from Ethenesulfonyl Fluoride and Organic Azides

The boom in growth of 1,4‐disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu^I‐catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1‐substituted‐1,2,3‐triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click‐inspired protocol for the synthesis of 1‐substituted‐1,2,3‐triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal‐free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1‐substituted‐1,2,3‐triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1‐substituted triazolium sulfonyl fluoride salts.     

Cu(I)‐Catalyzed Regioselective and Highly Efficient One‐Pot Synthesis of Novel 1,2,3‐Triazoles Decorated with Pyridine and Heterocyclic Amines

An efficient one‐pot synthesis of 1,2,3‐triazoles via the three‐component coupling reaction between propargyl bromide, secondary amines, and 3‐azidopyridine in the presence of CuI as catalyst has been presented. The reaction is highly regioselective and afforded novel 1,4‐disubstituted‐1,2,3‐triazoles in excellent yields by the [3 + 2] Huisgen cycloaddition reaction. This method avoids isolation and handling of terminal acetylenes. The ease of purification has made this methodology clean and safe for the synthesis of 1,2,3‐triazoles with a broad scope.     

Benedict's solution/ vitamin C: An alternative catalytic protocol for the synthesis of regioselective‐1,4‐disubstituted‐1H‐1,2,3‐triazoles at room temperature

A novel and highly efficient method for the synthesis of 1,4‐disubstituted‐1H‐1,2,3‐triazoles by copper‐catalyzed azide‐alkyne cycloaddition has been developed. This economic and sustainable protocol uses a readily available Benedict's solution/Vitamin C catalyst system affording a wide range of 1,4‐disubstituted‐1H‐1,2,3‐triazoles under mild conditions.     

An Efficient and Convenient Synthesis of Ethyl 1‐(4‐Methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate

The “click chemistry” of using organic azides and terminal alkynes is arguably the most efficient and straightforward route to the synthesis of 1,2,3‐triazoles. In this paper, an alternative and direct access to ethyl 1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate is described. Treatment of ethyl diazoacetate with 4‐methoxyaniline derived aryl imines in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene provided fully substituted 1,2,3‐triazoles in good to high chemical yields. The base‐mediated reaction tolerates various substituted phenyl imines as well as ethyl diazoacetate or the more bulky diazoacetamide. A reasonable mechanism is proposed that involves the addition of an imine nitrogen atom to the terminal nitrogen atom of the diazo compound, followed by aromatization to give the 1,2,3‐triazole. The presence of the 4‐carboxy group is advantageous as it can be easily transformed into other functional groups.     

Concise Stereoselective Synthesis of Oxaspirocycles with 1‐Tosyl‐1,2,3‐triazoles: Application to the Total Syntheses of (±)‐Tuberostemospiroline and (±)‐Stemona‐lactam R

A 4‐substituted‐1‐tosyl‐1,2,3‐triazole‐based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh‐catalyzed loss of nitrogen from 4‐substituted‐1‐tosyl‐1,2,3‐triazoles, Grignard reaction, and a ring‐closing metathesis reaction as key steps. By employing readily available and stable 4‐substituted‐1‐tosyl‐1,2,3‐triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (±)‐tuberostemospiroline and (±)‐stemona‐lactam R.     

Synthesis of 4‐Vinyl‐1H‐1,2,3‐triazoles on Solid Supports via Polystyrene‐Bound But‐3‐ynyl Selenide

A facile method for solid‐phase organic synthesis of 1‐substituted‐4‐vinyl‐1,2,3‐triazoles from polystyrene‐supported but‐3‐ynyl selenide has been developed. This sequential [3+2] cycloaddition and oxidation–elimination reactions could be carried out under mild reaction conditions with straightforward operation and good yield and purity of the products, and broad scope of substrates, and could be applied in this reaction system in generation of a small library of title compounds.     

Synthesis of Purine‐based Triazoles by Copper (I)‐catalyzed Huisgen Azide–Alkyne Cycloaddition Reaction

An efficient protocol for the synthesis of substituted 1,2,3‐triazol‐9H‐purines via copper (I)‐catalyzed click chemistry of 2,6‐dichloropurine with aromatic azide has been reported. A wide range of 1,4‐disubstituted triazoles ( N‐9 substituted purines) was accessible in good‐to‐excellent yields with remarkable functional group tolerance. The base‐catalyst ratio was tuned to achieve optimum reaction condition (>95% conversion and purity in most cases). Furthermore, the structure of 4i has been unambiguously assigned by X‐ray crystallographic study to yield structural information on the 1,3‐dipoles entering the reaction.     

One‐Pot Synthesis of 4‐Aryl‐NH‐1,2,3‐Triazoles through Three‐Component Reaction of Aldehydes,Nitroalkanes and NaN3

A one‐pot three‐component reaction of aldehydes, nitroalkanes and NaN₃ for the synthesis of NH ‐1,2,3‐triazoles has been developed. The reaction provides a safe, efficient and step‐economic approach for the synthesis of various NH ‐1,2,3‐triazoles in good to excellent yields.     

A General Proline‐Catalyzed Synthesis of 4,5‐Disubstituted N‐Sulfonyl‐1,2,3‐Triazoles from 1,3‐Dicarbonyl Compounds and Sulfonyl Azide

An efficient proline‐catalyzed synthesis of 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles has been accomplished from 1,3‐dicarbonyl compounds and sulfonyl azides. The developed reaction is suitable for various symmetrical and unsymmetrical 1,3‐dicarbonyl compounds, tolerates various functional groups and affords 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles in good yield with excellent regioselectivity. Rhodium‐catalyzed denitrogenative functionalization of 4,5‐disubstituted‐N‐sulfonyl‐1,2,3‐triazoles further demonstrates their utility in organic synthesis.     

One‐Pot,Three‐Component Synthesis of 1‐(2‐Hydroxyethyl)‐1H‐1,2,3‐triazole Derivatives by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of 2‐Azido Alcohols and Terminal Alkynes under Mild Conditions in Water

A safe, efficient, and improved procedure for the regioselective synthesis of 1‐(2‐hydroxyethyl)‐1H‐1,2,3‐triazole derivatives under ambient conditions is described. Terminal alkynes reacted with oxiranes and NaN₃ in the presence of a copper(I) catalyst, which is prepared by in situ reduction of the copper(II) complex 4 with ascorbic acid, in H₂O. The regioselective reactions exclusively gave the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazoles in good to excellent yields. This procedure avoids the handling of organic azides as they are generated in situ, making this already powerful click process even more user‐friendly and safe. The remarkable features of this protocol are high yields, very short reaction times, a cleaner reaction profile in an environmentally benign solvent (H₂O), its straightforwardness, and the use of nontoxic catalysts. Furthermore, the catalyst could be recovered and recycled by simple filtration of the reaction mixture and reused for ten consecutive trials without significant loss of catalytic activity. No metal‐complex leaching was observed after the consecutive catalytic reactions.     

Synthesis of 2‐Substituted 2‐Amino Ketones by Rhodium‐Catalyzed Reaction of N‐Sulfonyl‐1,2,3‐triazoles with 2‐Alkenols

A study on a rhodium(II )‐catalyzed reaction of N‐sulfonyl‐1,2,3‐triazoles with 2‐alkenols is reported. The reaction is initiated by insertion of an α‐imino carbene into the O–H linkage of alcohol, forming a 2‐alkenoxy enamide intermediate. A thermal [3,3]‐sigmatropic rearrangement follows to yield 2‐substituted 2‐amino ketone in a stereoselective manner. The successful application of this methodology to a formal synthesis of (–)‐α‐conhydrine is also described.     

Claycop/hydrazine: A new and highly efficient recyclable/reusable catalytic system for 1,4‐disubstituted‐1,2,3‐triazole synthesis under solvent‐free conditions

Clay‐supported copper(II) nitrate (claycop) has been used as an efficient catalyst for azide–alkyne cycloaddition reactions leading to 1,4‐disubstituted 1,2,3‐triazoles. The highly efficient claycop/hydrazine hydrate catalytic system affords triazoles in a few minutes (1–20 min) at room temperature, under mild and solvent‐free conditions. High regioselectivity, excellent yields, ease of claycop synthesis and recyclability/reusability of the catalyst are considered as practical merits of the protocol.     

An Efficient Synthesis of Mono and Bis‐1,2,3‐triazole AZT Derivatives via Copper(I)‐catalyzed Cycloaddition

An efficient synthesis of novel mono and bis‐1,2,3‐triazoles 3′‐azido‐2′‐deoxythymidine (AZT) derivatives via copper(I)‐catalyzed 1,3‐dipolar cycloaddition reaction is described. Starting from AZT and terminal alkyne derivatives, mono and bis‐1,2,3‐triazole AZT derivatives are regioselectively obtained in good yields under mild conditions using CuSO4·5H2O and sodium ascorbate as a catalyst system, and t‐BuOH/H₂O (1:1, v/v) as a co‐solvent. The structures of these compounds were elucidated by IR, HR MS and NMR.     

A Scalable Metal‐, Azide‐, and Halogen‐Free Method for the Preparation of Triazoles

A scalable metal‐, azide‐, and halogen‐free method for the synthesis of substituted 1,2,3‐triazoles has been developed. The reaction proceeds through a 3‐component coupling of α‐ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional‐group tolerance with respect to both the α‐ketoacetal and amine coupling partners, providing access to 4‐, 1,4‐, 1,5‐, and 1,4,5‐substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3‐triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.     

Synthesis and Antimicrobial Activity of 2‐(4‐(Hydroxyalkyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐substituted propanamides

A series of 21 2‐(4‐(hydroxyalkyl)‐1H ‐1,2,3‐triazol‐1‐yl)‐N ‐substituted propanamides (1,4‐disubstituted 1,2,3‐triazoles having amide linkage and hydroxyl group) have been synthesized from click reaction between terminal alkyne and 2‐azido‐N ‐substituted propanamide (generated in situ from reaction of 2‐bromo‐N ‐substituted propanamide and sodium azide) and characterized by FTIR, ¹H NMR, ¹³C NMR spectroscopy, and HRMS. All the newly synthesized triazoles were tested in vitro for antimicrobial activity against four bacterial cultures – Escherichia coli , Enterobacter aerogenes , Klebsiella pneumoniae , and Staphylococcus aureus – and two fungal cultures – Candida albicans and Aspergillus niger . The synthesized 1,4‐disubstituted 1,2,3‐triazoles displayed moderate to good antimicrobial potential against the tested strains.     

Copper(I)‐Catalyzed Interrupted Click/Sulfenylation Cascade: One‐Pot Synthesis of Sulfur Cycle Fused 1,2,3‐Triazoles

Herein, we report a practical protocol for the synthesis of sulfur cycle fused 1,2,3‐triazoles through a copper(I)‐catalyzed tandem click/intramolecular sulfenylation reaction. The reaction proceeded via a copper‐catalyzed alkyne azide cycloaddition, followed by interception of the in situ formed cuprate‐triazole intermediate with p‐toluenesulfonothioate. This reaction shows broad substrate scope, complete regioselectivity, and excellent functional group tolerance under mild reaction conditions.     

Acid Catalyzed tert‐Butylation and Tritylation of 4‐Nitro‐1,2,3‐triazole: Selective Synthesis of 1‐Methyl‐5‐nitro‐1,2,3‐triazole via 1‐tert‐Butyl‐4‐nitro‐1,2,3‐triazole

4‐Nitro‐1,2,3‐triazole was found to react with tert‐butanol in concentrated sulfuric acid to yield 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole as the only reaction product, whereas tert‐butylation and tritylation of 4‐nitro‐1,2,3‐triazole in presence of catalytic amount of sulfuric acid in benzene was found to provide mixtures of isomeric 1‐ and 2‐alkyl‐4‐nitro‐1,2,3‐triazoles with predominance of N2‐alkylated products. A new methodology for preparation of 1‐alkyl‐5‐nitro‐1,2,3‐triazoles from 1‐tert‐butyl‐4‐nitro‐1,2,3‐triazole via exhaustive alkylation followed by removal of tert‐butyl group from intermediate triazolium salts was demonstrated by the example of preparation of 1‐methyl‐5‐nitro‐1,2,3‐triazole.