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.     

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.     

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).     

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.     

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.     

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.     

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.     

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.     

Copper Supported on the SiO2 Nanoparticle in Click Chemistry: An Alternative Catalytic System for Regioselective and One‐Pot Synthesis of 1,2,3‐Triazoles and β‐Hydroxytriazoles

In this work, readily prepared copper supported on the SiO₂ nanoparticles has been found to effectively catalyze the 1,3‐dipolar cycloaddition of a variety of azides, alkynes, epoxides and sodium azide, furnishing the corresponding 1,2,3‐triazoles and β‐hydroxytriazoles. Click reaction proceeds in short reaction times and under mild reaction conditions, and the resulting products are obtained in good yields at ambient temperature.     

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.     

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     

Bimetal‐Catalyzed Cascade Reaction for Efficient Synthesis of N‐Isopropenyl 1,2,3‐Triazoles via In‐Situ Generated 2‐Azidopropenes

A bimetal‐catalyzed cascade reaction for the synthesis of N‐isopropenyl 1,2,3‐triazoles in high yield is reported. This reaction involves the generation of 2‐azidopropenes in situ by C(sp³)‐OAr bond cleavage for click reaction and features a broad substrate scope, good functional group tolerance and readily available substrates.     

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).     

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.     

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.     

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.     

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.     

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 .     

RhII‐Catalyzed [3+2] Cycloaddition of 2 H‐Azirines with N‐Sulfonyl‐1,2,3‐Triazoles

Rh^II‐catalyzed intermolecular [3+2] cycloaddition of 2 H‐azirines with N‐sulfonyl‐1,2,3‐triazoles is disclosed, in which a series of fully functionalized pyrroles is produced via rhodium azavinyl carbene intermediates. A distinct feature of this reaction is that the azavinyl carbene serves as a [2 C] equivalent, instead of as [1 C] or aza‐[3 C] synthons, which have been reported previously in cyclopropanations and [3+n] cycloadditions. Moreover, this methodology has also been successfully applied in the total synthesis of URB447 as well as the formal synthesis of Atorvastatin (Lipitor).