Efficient Synthesis of 1,2,3‐Triazoles by Copper‐Mediated CN and NN Bond Formation Starting From N‐Tosylhydrazones and Amines

An effective copper‐mediated synthesis of 1,5‐dialkyl‐4‐aryl‐1,2,3‐triazoles and 1,4‐dialkyl‐5‐aryl‐1,2,3‐triazoles has been achieved by the use of different N‐tosylhydrazones and alkyl amines. The scope of the substrates could be extended from anilines to aliphatic amines when 30 mol % amino acid is added into the reaction mixture. This methodology exhibits many notable features, such as broad substrates scope, high efficiency, and good regioselectivity. Preliminary mechanistic studies indicated that the reaction probably proceeded through a 1‐tosyl‐2‐vinyldiazene intermediate and subsequent aza‐Michael addition and N?N bond formation process.     

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.     

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.     

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.     

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.     

Regioselective Conversion of Arenes to N‐aryl‐1,2,3‐triazoles Using CH Borylation

A one‐pot protocol for the synthesis of N‐aryl 1,2,3‐triazoles from arenes by an iridium‐catalyzed C?H borylation/copper catalyzed azidation/click sequence is described. 1 mol % of Cu(OTf)₂ was found to efficiently catalyze both the azidation and the click reaction. The applicability of this method is demonstrated by the late‐stage chemoselective installation of 1,2,3‐triazole moiety into unactivated molecules of pharmaceutical importance.     

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).     

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.     

Highly N2‐Selective Coupling of 1,2,3‐Triazoles with Indole and Pyrrole

Hydrogen‐bond mediated coupling of 1,2,3‐triazoles to indoles and pyrroles results in N2 selective functionalization of the triazole moiety in moderate to excellent yields. The reaction was tolerant of un‐, mono‐ and disubstituted triazoles and was applied to synthesize tryptophan derived fluorescent amino acids.     

Microwave‐Assisted Palladium‐Catalyzed Direct Arylation of 1,4‐Disubstituted 1,2,3‐Triazoles with Aryl Chlorides

Treatment of 1,4‐disubstituted 1,2,3‐triazoles with aryl chlorides in the presence of potassium carbonate under palladium catalysis and microwave irradiation at 250 °C for 15 min leads to arylation of the triazole at the 5‐position. A variety of functional groups, including ester and hydroxy groups, are compatible. The procedure is suitable for the regioselective preparation of trisubstituted triazoles. Microwave irradiation accelerates the reaction, thus allowing the rapid synthesis of trisubstituted triazoles, which are difficult to synthesize selectively.     

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.     

Weak O‐Assistance Outcompeting Strong N,N‐Bidentate Directing Groups in Copper‐Catalyzed C−H Chalcogenation

A copper‐mediated C?H chalcogenation of triazoles has been achieved by weak coordination. The user‐friendly protocol showed high functional‐group tolerance and ample substrate scope, yielding fully substituted 1,2,3‐triazoles with complete positional site‐selectivity. The C?H selenylation could likewise be achieved by means of copper catalysis. Our findings highlight for the first time that weak O‐coordination can outcompete the strong N,N‐bidentate coordination mode in C?H functionalization technology.     

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.     

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.     

Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

Acidic 4‐hydroxy‐1,2,3‐triazole is a proven bioisostere of acidic functions that has recently been used to replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis of the three possible N‐alkylated 4‐hydroxy‐1,2,3‐triazole regioisomers have been designed and reported herein, by identifying the optimal conditions under which the alkylation of ethyl 4‐benzyloxy‐1,2,3‐triazolecarboxylate (compound 19 ) can be regiodirected to the triazole N(b) position and thus produce the only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform for parallel synthesis, called Arachno and which has been patented by the authors' group, has been used to speed up the process, and an NMR study has been carried out to better understand the reactivity of compound 19 towards the N(b) position. A library of benzyloxy protected 4‐hydroxy‐1,2,3‐triazoles has been prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the N(a) isomers; the processes are described herein. The three N‐alkylated regioisomer series have been characterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4‐benzyloxy protective group on the N‐alkylated‐4‐benzyloxy‐5‐ethoxycarbonyl‐1,2,3‐triazoles provided the corresponding substituted 4‐hydroxy‐1,2,3‐triazoles.     

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.     

Use of an efficient polystyrene‐supported cerium catalyst for one‐pot multicomponent synthesis of spiro‐piperidine derivatives and click reactions in green solvent

One‐pot multicomponent reactions are very demanding in synthetic organic chemistry. Here we report a new polystyrene‐supported cerium catalyst (PS‐Ce‐amtp) obtained via an easy two‐step procedure, which was thoroughly characterized using various techniques. PS‐Ce‐amtp catalyses the environmentally benign one‐pot multicomponent synthesis of spiro‐piperidine derivatives through the reaction of substituted aniline, cyclic active methylene compound and formaldehyde at room temperature. The catalyst also exhibits excellent catalytic activity in one‐pot synthesis of 1,4‐disubstituted 1,2,3‐triazoles via click reaction between in situ generated azides (derived from anilines and amines) and terminal alkynes. The catalyst can be recovered easily after reaction and reused five times without significant loss in its catalytic activity. The advantageous features of this catalyst are atom economy, operational simplicity, short reaction times, easy handling and high recycling efficiency.     

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