A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

Metal‐Free CN‐ and NN‐Bond Formation: Synthesis of 1,2,3‐Triazoles from Ketones,N‐Tosylhydrazines,and Amines in One Pot

A novel synthetic approach toward 1,4‐disubstituted 1,2,3‐triazoles by C?N‐ and N?N‐bond formation has been established under transition‐metal‐free conditions. Complete control of the regioselectivity was successfully achieved. Commercially available anilines, ketones, and N‐tosylhydrazine were treated with molecular iodine in one pot to allow the regioselective generation of 1,4‐disubstituted 1,2,3‐triazoles in high yields without the use of azides.     

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.     

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.     

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.     

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.     

1,3‐Dipolar Cycloaddition Reactions of Organic Azides with Morpholinobuta‐1,3‐dienes and with an α‐Ethynyl‐enamine

The cycloaddition of organic azides with some conjugated enamines of the 2‐amino‐1,3‐diene, 1‐amino‐1,3‐diene, and 2‐aminobut‐1‐en‐3‐yne type is investigated. The 2‐morpholinobuta‐1,3‐diene 1 undergoes regioselective [3+2] cycloaddition with several electrophilic azides RN₃ 2 ( a , R=4‐nitrophenyl; b , R=ethoxycarbonyl; c , R=tosyl; d , R=phenyl) to form 5‐alkenyl‐4,5‐dihydro‐5‐morpholino‐1H‐1,2,3‐triazoles 3 which are transformed into 1,5‐disubstituted 1H‐triazoles 4a , d or α,β‐unsaturated carboximidamide 5 (Scheme 1). The cycloaddition reaction of 4‐[(1E,3Z)‐3‐morpholino‐4‐phenylbuta‐1,3‐dienyl]morpholine ( 7 ) with azide 2a occurs at the less‐substituted enamine function and yields the 4‐(1‐morpholino‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 8 (Scheme 2). The 1,3‐dipolar cycloaddition reaction of azides 2a – d with 4‐(1‐methylene‐3‐phenylprop‐2‐ynyl)morpholine ( 9 ) is accelerated at high pressure (ca. 7–10 kbar) and gives 1,5‐disubstituted dihydro‐1H‐triazoles 10a , b and 1‐phenyl‐5‐(phenylethynyl)‐1H‐1,2,3‐triazole ( 11d ) in significantly improved yields (Schemes 3 and 4). The formation of 11d is also facilitated in the presence of an equimolar quantity of tBuOH. The three‐component reaction between enamine 9 , phenyl azide, and phenol affords the 5‐(2‐phenoxy‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 14d .     

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.     

The structures of 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles related to J147, a drug for treating Alzheimer's disease

J147 [N‐(2,4‐dimethylphenyl)‐2,2,2‐trifluoro‐N′‐(3‐methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X‐ray structures of seven new 1,4‐diaryl‐5‐trifluoromethyl‐1H‐1,2,3‐triazoles, namely 1‐(3,4‐dimethylphenyl)‐4‐phenyl‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₇H₁₄F₃N₃, 1 ), 1‐(3,4‐dimethylphenyl)‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 2 ), 1‐(3,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 3 ), 1‐(2,4‐dimethylphenyl)‐4‐(4‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₆F₃N₃O, 4 ), 1‐[2,4‐bis(trifluoromethyl)phenyl]‐4‐(3‐methoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₈H₁₀F₉N₃O, 5 ), 1‐(3,4‐dimethoxyphenyl)‐4‐(3,4‐dimethoxyphenyl)‐5‐trifluoromethyl‐1H‐1,2,3‐triazole (C₁₉H₁₈F₃N₃O₄, 6 ) and 3‐[4‐(3,4‐dimethoxyphenyl)‐5‐(trifluoromethyl)‐1H‐1,2,3‐triazol‐1‐yl]phenol (C₁₇H₁₄F₃N₃O₃, 7 ), have been determined and compared to that of J147 . B3LYP/6‐311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147 , and to examine the correlation between hydrazone J147 and the 1,2,3‐triazoles, both bearing a CF₃ substituent. Using MEPs, it was found that the minimum‐energy conformation of 4 , which is nearly identical to its X‐ray structure, is closely related to one of the J147 seven minima.     

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.     

Synthesis and reactivity ratios of regioisomeric vinyl‐1,2,3‐triazoles with styrene

The free radical reactivity ratios between styrene and different vinyl‐1,2,3‐triazole regioisomeric monomers in 1,4‐dioxane at 65 °C have been established using nonlinear least square method. The results obtained for the reactivity ratio between regioisomers show exceptionally different polymerization behavior, highlighting the effects of the electronic and steric factors of these regioisomeric monomers. The experimental results highlight the effects of the electronic and sterics on the copolymerization behavior. In case of 1,4‐vinyl‐triazoles, it was found that without the steric effects, the reactivity is very similar to that of styrene and forms random copolymers. However, it was found that 1,5‐vinyl‐triazoles are more reactive than 1,4‐vinyl triazoles. In the case of styrene‐co‐1,4‐vinyl‐1,2,3‐triazoles, the reactivity ratios were calculated to be r_styrene: r_{1‐octyl‐4‐vinyl‐triazole} = 1.97:0.54, r_styrene : r_{1‐benzyl‐4‐vinyl‐triazole} = 1.62:0.50, and r_styrene: r_{1‐methyl‐4‐vinyl‐triazole} = 0.90:0.87. On the other hand, reactivity ratios for styrene‐co‐1,5‐vinyl‐1,2,3‐triazoles were found to be r_styrene: r_{1‐octyl‐5‐vinyl‐triazole} = 0.13:0.66 and r_styrene: r_{1‐benzyl‐5‐vinyl‐triazole} = 0.34:0.49. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3359–3364     

Facile One‐Pot Synthesis of Monosubstituted 1‐Aryl‐1H‐1,2,3‐triazoles from Arylboronic Acids and Prop‐2‐ynoic Acid (=Propiolic Acid) or Calcium Acetylide (=Calcium Carbide) as Acetylene Source

The synthesis of monosubstituted 1‐aryl‐1H‐1,2,3‐triazoles was achieved in a one‐pot reaction from arylboronic acids and prop‐2‐ynoic acid or calcium acetylide (=calcium carbide), respectively, as a source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction conditions were successfully applied to arylboronic acids, including analogs with various functionalities. Unexpectedly, the 1,2,3‐triazole moiety promoted a regioselective hydrodebromination (Scheme 2).     

Cu+‐catalyzed 1,3‐Dipolar Intramolecular Click Opposite Cross Cyclization Reaction of Polyoxyethylene Bis(azido‐terminal alkynes): Synthesis of New 1,2,3‐Triazolo‐crown Ethers

The Cu⁺ catalyzed, 1,3‐dipolar cycloaddition of polyoxyethylene di(azidoalkynes), yields a mixture of the polyoxyethylene 1,5‐disubstituted fused di(1,2,3‐triazole‐1,4‐oxazines) as the major product, and the 1,4‐disubstituted mono‐(1,2,3‐triazolo) azidoalkyne crown ether.     

CuFeO2/tetrabutylammonium bromide catalyzes selective synthesis of 1,4‐disubstituted 1,2,3‐triazoles in neat water at room temperature

A completely green medium including water as a solvent and antiviral CuFeO₂ as a catalyst is described for the synthesis of 1,4‐disubstituted 1,2,3‐triazoles. Excellent yields of products are obtained at room temperature. Cost effectiveness, high stability and high recyclability of CuFeO₂ along with antiviral properties of the catalyst make it a unique catalyst for cycloadditions of phenylacetylene with a wide variety of aryl halides. Copyright © 2016 John Wiley & Sons, Ltd.     

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.     

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.     

Heterocyclic Systems Containing Bridged Nitrogen Atom: Synthesis and Antibacterial Activity of 3‐(2‐Phenylquinolin‐4‐yl)/3‐(1‐p‐Chlorophenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazine Derivatives

The condensation of 4‐amino‐5‐mercapto‐3‐(2‐phenylquinolin‐4‐yl)/3‐(1‐p‐chlorophenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazoles 1a‐b with chloroacetaldehyde 2a‐b , ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone 3a‐b , chloranil 4a‐b , 2‐bromocyclohexanone 5a‐b , 2,4′‐dibromoacetophenone 6a‐b and 2‐bromo‐6′‐methoxy‐2′‐acetonaphthone 7a‐b are described. The structures of the compounds synthesized were confirmed by elemental analyses, IR, 1H NMR and mass spectra. The antibacterial activities were also evaluated.     

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.