An Efficient Copper‐Catalyzed One‐Pot Synthesis of 1‐Aryl‐1,2,3‐triazoles from Arylboronic Acids in Water under Mild Conditions

A convenient method for one‐pot two‐step 1,3‐dipolar cycloadditon reaction of arylboronic acid, sodium azide followed with terminal alkynes in the presence of 2‐pyrrolecarbaldiminato‐Cu(II) complexes catalyst is reported. Various 1‐aryl‐1,2,3‐triazoles were prepared in 63%–97% yields in water at 30°C without any additives and avoiding the isolation of unstable aryl azides.     

A reusable polymer‐supported copper(I) catalyst for triazole click reaction on water: An experimental and computational study

In the search for establishing a clickable copper‐catalysed (3 + 2) Huisgen azide–alkyne cycloaddition (CuAAC) reaction under strict conditions, in particular in terms of preventing the presence of copper particles/traces in reaction products and using an environmentally benign medium such as water, we describe here the synthesis of an aminomethyl polystyrene‐supported copper(I) catalyst (Cu(I)‐AMPS) and its characterization by means of Fourier transform infrared and energy‐dispersive X‐ray spectroscopies and scanning electron microscopy. Cu(I)‐AMPS was found to be highly active in the CuAAC reaction of various organic azides with alkynes affording the corresponding 1,4‐disubstituted 1,2,3‐triazoles in a regioselective manner in air at room temperature and using water as solvent. The insolubility and/or partial solubility of the organic azide and alkyne precursors as well as the heterogeneous Cu(I)‐AMPS catalytic system points to the occurrence of the cycloaddition at the organic–water interface ‘on water’ affording quantitative yields of water‐insoluble 1,2,3‐triazoles. A mechanistic study was performed using density functional theory aiming at explaining the observed reactivity and selectivity of the Cu (I)‐AMPS catalyst in CuAAC reactions.     

Copper Salt of 12‐Tungstophosphoric Acid: An Efficient and Reusable Heteropoly Acid for the Click Chemistry

Three components coupling of alkyl bromide, sodium azide and alkyne has been achieved using a catalytic amount of copper‐exchanged phosphotungstic acid (Cu‐TPA) in the presence of triethyl amine in DMF to afford substituted triazoles in good yields with high selectivity. Interestingly, the coupling of alkyl azide with alkyne proceeds readily at room temperature to furnish 1,2,3‐triazoles in excellent yields. The catalyst can be recovered and reused for three to four subsequent runs with a minimal decrease of activity. The use of copper modified heteropolyacids makes this procedure simple, convenient and environmentally friendly.     

NMR and mass spectral analysis of step-growth polymers from azide alkyne cycloaddition and regioselectivity afforded by copper(I) and ruthenium(II) catalysts

Azide alkyne cycloaddition was applied to step growth polymerization of the diazido monomer, di(3-azido-2-hydroxypropyl) ether of bisphenol-A (DAHP-BPA) with either tetraethyleneglycol dipropargyl ether (TEGDPE) or tetraethyleneglycol dipropiolate (TEGDP). Polymerizations were conducted without catalyst and in the presence of Cu(I) or Ru(II) complex. The resulting oligomers and polymers were characterized using ¹H- and ¹³C-NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), with an emphasis on the relative abundance of 1,4- vs. 1,5-disubstituted regioisomeric 1,2,3-triazoles. Uncatalyzed reaction of DAHP-BPA/TEGDPE at 70°C yielded a 55/45 mixture of 1,4/1,5-disubstituted triazoles; reaction was slow and residual alkyne end groups were observed, suggesting attritional loss of azide. Catalyzed with Cu(PPh₃)₃Br, the same system yielded 93/7, 1,4/1,5-disubstituted triazoles, and few residual end groups were detected, consistent with higher molecular weight and controlled 1:1 depletion of azide and alkyne. Cp*RuCl(COD) catalyst was not soluble in the bulk system, necessitating solution polymerization in THF. Ru(II) yielded 6/94, 1,4/1,5-disubstituted triazoles, and MALDI-TOF-MS showed an end group composition similar to that observed with Cu(I). Uncatalyzed reaction of the DAHP-BPA/TEGDP system, involving the more reactive propiolate, yielded a high proportion (85%) of 1,4-disubstituted triazole linkages, and MALDI-TOF-MS revealed a controlled 1:1 depletion of azide and alkyne groups.     

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.     

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.     

Recent Developments in Azide‐Free Synthesis of 1,2,3‐Triazoles

1,2,3‐Triazoles, as one of the most significant nitrogen‐containing heterocycles due to their extensive use in biology, material science and organic synthesis, have aroused great interest. 1,2,3‐Triazoles are commonly synthesized by metal‐catalyzed azide–alkyne cycloaddition and organocatalytic azide–carbonyl cycloaddition, which indispensably employ the toxic and potentially explosive azides. The azide‐free synthetic approaches provide a powerful and straightforward alternative to the assembly of diverse 1,2,3‐triazoles without the use of azides. In this review, we summarize the recent development of the construction of 1,2,3‐triazoles under azide‐free conditions.     

CuII‐Catalyzed Oxidative Formation of 5‐Alkynyltriazoles

In an alcoholic solvent under the catalysis of Cu(OAc)₂?H₂O, organic azide and terminal alkyne could oxidatively couple to afford 5‐alkynyl‐1,2,3‐triazole (alkynyltriazole) at room temperature under an atmosphere of O₂ in a few hours. The involvement of 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) is essential, without which the redox neutral coupling instead proceeds to produce 5‐H‐1,2,3‐triazole (protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between terminal alkyne and organic azide, the copper‐catalyzed “click” reaction to afford protiotriazole, to an oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the copper(II)‐catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity between alkynyl‐ and protiotriazole, and other acetylide or triazolide oxidation products is determined by the competition between copper(I)‐catalyzed redox neutral cycloaddition and copper(II)/O₂‐mediated acetylide oxidation after the formation of copper(I) acetylide.     

Easy One‐Pot Synthesis of 1‐Monosubstituted Aliphatic 1,2,3‐Triazoles from Aliphatic Halides,Sodium Azide and Propiolic Acid by a Click Cycloaddition/Decarboxylation Process

1‐Monosubstituted aliphatic 1,2,3‐triazoles were synthesized by a one‐pot reaction from aliphatic halides (Cl and Br), sodium azide and propiolic acid. The yields ranged from moderate to good. The reaction was easily carried out in DMF with Cs₂CO₃ at 100°C by copper‐catalyzed click cycloaddition/decarboxylation.     

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.     

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.     

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.     

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.     

3‐miktoarm star terpolymers using triple click reactions: Diels–Alder,copper‐catalyzed azide‐alkyne cycloaddition,and nitroxide radical coupling reactions

Well‐defined linear furan‐protected maleimide‐terminated poly(ethylene glycol) (PEG‐MI), tetramethylpiperidine‐1‐oxyl‐terminated poly(ε‐caprolactone) (PCL‐TEMPO), and azide‐terminated polystyrene (PS‐N₃) or ‐poly(N‐butyl oxanorbornene imide) (PONB‐N₃) were ligated to an orthogonally functionalized core ( 1 ) in a two‐step reaction mode through triple click reactions. In a first step, Diels–Alder click reaction of PEG‐MI with 1 was performed in toluene at 110 °C for 24 h to afford α‐alkyne‐α‐bromide‐terminated PEG (PEG‐alkyne/Br). As a second step, this precursor was subsequently ligated with the PCL‐TEMPO and PS‐N₃ or PONB‐N₃ in N,N‐dimethylformamide at room temperature for 12 h catalyzed by Cu(0)/Cu(I) through copper‐catalyzed azide‐alkyne cycloaddition and nitroxide radical coupling click reactions, yield resulting ABC miktoarm star polymers in a one‐pot mode. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

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.     

Synthesis of 1,2,3‐Triazole Analogues of Lincomycin

In search for new antibiotics we replaced the amide moiety of lincomycin 1 by a 1,2,3‐triazole ring. The 1,2,3‐triazoles 10a – 10k were obtained as single regioisomers by ‘click reaction’ of azide 5 with the alkyne 9k , derived from propyl hygric acid, and the alkyl, aryl, or cycloalkyl alkynes ribosomes 9a – 9j . The new analogues proved inactive towards wild‐type and A2058G mutant.     

In‐situ Generated and Premade 1‐Copper(I) Alkynes in Cycloadditions

The copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) was discovered in 2002, which has become the most remarkable example for “click chemistry” to date. In CuAAC reaction, 1‐copper(I) alkyne has been recognized to be a key intermediate. However, many contradictory experimental results for this intermediate were reported in literature. For example, only the in‐situ generated 1‐copper(I) alkyne was used, while the premade 1‐copper(I) alkyne proved to be inefficient under the standard conditions. The kinetic studies indicated that CuAAC reaction had a strict second‐order dependence on Cu(I) and the DFT studies demonstrated that 1‐copper(I) alkyne intermediate should be a dinuclear copper(I) complex. But these results were inconsistent with the structure of the premade 1‐copper(I) alkyne. Although hundreds of structurally different ligands were reported to significantly enhance the efficiency of CuAAC reaction, their functions were assigned to prevent the oxidation and the disproportionation of Cu(I) ion. Based on the investigation of the references and our works, we proposed that the in‐situ generated 1‐copper(I) alkyne in CuAAC reaction is not identical with the premade 1‐copper(I) alkyne. The ligands may play dual roles to activate the 1‐copper(I) alkyne by blocking the polymerization of the in‐situ formed 1‐copper(I) alkynes and dissociating the polymeric structures of the premade 1‐copper(I) alkynes. As a result, we first disclosed that carboxylic acids can function as such activators and a novel carboxylic acid‐catalyzed CuAAC strategy was developed, which has been proven to be the most convenient and highly efficient CuAAC method to date. Furthermore, highly efficient and regioselective methods for the syntheses of 1,4,5‐trisubstituted 1,2,3‐triazoles were developed by using the premade 1‐copper(I) alkynes as substrates, in which the novel function of the premade 1‐copper(I) alkynes as excellent dipolarophiles was first disclosed and applied. In this article, a series of works reported by our group for the in‐situ generated and the premade 1‐copper(I) alkynes in cycloadditions are reviewed.     

An Enolate‐Mediated Organocatalytic Azide–Ketone [3+2]‐Cycloaddition Reaction: Regioselective High‐Yielding Synthesis of Fully Decorated 1,2,3‐Triazoles

An enolate‐mediated organocatalytic azide–ketone [3+2]‐cycloaddition (OrgAKC) reaction of a variety of enolizable arylacetones and deoxybenzoins with aryl azides was developed for the synthesis of fully decorated 1,4‐diaryl‐5‐methyl(alkyl)‐1,2,3‐triazoles in excellent yields with high regioselectivity at 25 °C for 0.5–6 h. This reaction has an excellent outcome with reference to reaction rate, yield, regioselectivity, operation simplicity, and availability of substrates and catalyst. This reaction has advantages over the previously known metal‐mediated reactions.     

Self‐Assembly of 3,6‐Bis(4‐triazolyl)pyridazine Ligands with Copper(I) and Silver(I) Ions: Time‐Dependant 2D‐NOESY and Ultracentrifuge Measurements

Two 3,6‐bis(R‐1H‐1,2,3‐triazol‐4‐yl)pyridazines (R=mesityl, monodisperse (CH₂ CH₂O)₁₂CH₃) were synthesized by the copper(I)‐catalyzed azide–alkyne cycloaddition and self‐assembled with tetrakis(acetonitrile)copper(I) hexafluorophosphate and silver(I) hexafluoroantimonate in dichloromethane. The obtained copper(I) complexes were characterized in detail by time‐dependent 1D [¹H, ¹³C] and 2D [¹H‐NOESY] NMR spectroscopy, elemental analysis, high‐resolution ESI‐TOF mass spectrometry, and analytical ultracentrifugation. The latter characterization methods, as well as the comparison to analog 3,6‐di(2‐pyridyl)pyridazine (dppn) systems and their corresponding copper(I) and silver(I) complexes indicated that the herein described 3,6‐bis(1H‐1,2,3‐triazol‐4‐yl)pyridazine ligands form [2×2] supramolecular grids. However, in the case of the 3,6‐bis(1‐mesityl‐1H‐1,2,3‐triazol‐4‐yl)pyridazine ligand, the resultant red‐colored copper(I) complex turned out to be metastable in an acetone solution. This behavior in solution was studied by NMR spectroscopy, and it led to the conclusion that the copper(I) complex transforms irreversibly into at least one different metal complex species.