Versatile Synthetic Platform for 1,2,3-Triazole Chemistry

Disha P Vala; Ruturajsinh M Vala; Hitendra M Patel

doi:10.1021/acsomega.2c04883

. 2022 Oct 10;7(42):36945–36987. doi: 10.1021/acsomega.2c04883

Versatile Synthetic Platform for 1,2,3-Triazole Chemistry

Disha P Vala ¹, Ruturajsinh M Vala ¹, Hitendra M Patel ^1,^*

PMCID: PMC9608397 PMID: 36312377

Abstract

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1,2,3-Triazole scaffolds are not obtained in nature, but they are still intensely investigated by synthetic chemists in various fields due to their excellent properties and green synthetic routes. This review will provide a library of all synthetic routes used in the past 21 years to synthesize 1,2,3-triazoles and their derivatives using various metal catalysts (such as Cu, Ni, Ru, Ir, Rh, Pd, Au, Ag, Zn, and Sm), organocatalysts, metal-free as well as solvent- and catalyst-free neat syntheses, along with their mechanistic cycles, recyclability studies, solvent systems, and reaction condition effects on regioselectivity. Constant developments indicate that 1,2,3-triazoles will help lead to future organic synthesis and are useful for creating molecular libraries of various functionalized 1,2,3-triazoles.

1. Introduction

Heterocyclic chemistry is wide, important and most studied discipline of medicinal chemistry. Heterocyclic bioactive molecules have various heteroatoms such as nitrogen,^1,2 oxygen,^3,4 sulfur,⁵⁻⁸ and other⁹ atoms which have significant biological applications. The study of heterocyclic bioactive molecules containing nitrogen atoms is one of the most important disciplines of medicinal chemistry.^10,11 Among nitrogen-containing heterocycles, azoles are five-membered heterocyclic moieties which are essential structural parts in diverse biologically active natural products.¹² Azoles and their derivatives display various biological effects including capable antibacterial activity.¹³ A 1,2,3-triazole scaffold is a potent nitrogen-bearing heterocyclic scaffold which has found wide applications.^14,15 1,2,3-triazole is an unsaturated, π-excessive, five-membered heterocycle with a 6π delocalized electron ring system which gives it an aromatic character. 1,2,3-triazole is made up of three nitrogens and two carbons. All five atoms are sp²-hybridized. One N atom is pyrrole kind, and the other two atoms are pyridine kind. Monocyclic 1,2,3-triazole, 1,2,3-triazolium salt, and benzotriazoles are primary classes of 1,2,3-triazoles. Depending on the location of the NH proton, monocyclic 1,2,3-triazoles are further categorized into three subclasses (Figure 1).

The 1H- and 2H-1,2,3-triazoles are aromatic and in equilibrium with each other in solution as well as a gas phase, while 4H-1,2,3-triazole is nonaromatic in nature.¹⁶ Among all possible isomers of monocyclic 1,2,3-triazoles, 1H-1,2,3-triazole is a powerful scaffold and widely present in therapeutic agents and has gained more interest due to its medicinal chemistry applications, agrochemicals and material science.¹⁷⁻²¹ Some synthetic biologically active drugs are mentioned below (Figure 2).

Synthetic bioactive compound containing a 1,2,3-triazole ring.

Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) IV is a novel 1,2,3-triazole bearing antiepileptic drug known by the trade name Inovelon and Xilep, which was discovered by Novartis Pharmaceutical.²² 1,2,3-Triazole thioether V (IC₅₀: 10 nM) is more potent than the original lead molecule RN-18 (IC₅₀: 6 μM) against HIV-1 strain.^23,24 1,2,3-Triazole-tethered sulfonamide–berberine hybrid compounds VI showed an antimalarial activity with IC₅₀ = 0.142–28.006 μM in which the R = p-chlorophenylamino substituent was the most potent (IC₅₀ = 0.142 μM).²⁵ Imidazole-bearing triazole VII showed antibacterial activity comparable to or better than that of linezolid and vancomycin against Enterococcus faecium (MIC = 0.5 μg/mL).²⁶ Cefatrizine showed β-lactam antibiotic activity against Serratia marcescens (MIC: >400 μg/mL).²⁷ Cyclotetrapeptide analogues IX showed a 3-fold increase in tyrosinase activity (IC₅₀ = 0.5 mM) compared to that of naturally occurring cyclo-[Pro-Tyr-Pro-Val] (IC₅₀ = 1.5 mM).²⁸ Macrotriazoles (analogous to Migrastatin) X are active against the MDA-MB-361 cell line.²⁹ Tazobactam is also a 1,2,3-triazole-containing β-lactam antibiotic that shows MIC values of 1.56, 0.1, and 3.13 mg/L against Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae, respectively.³⁰ 1,2,3-Triazole is used as an isostere of carboxylic acid, amide, and ester in the synthesis of many drugs.³¹ Several review articles covered the synthetic strategy of 1,2,3-triazole derivatives using only transition-metal-catalyzed cycloaddition. Ding and co-workers³² covered the literature on metal-catalyzed cycloaddition of azide and internal alkyne only, whereas da Silva Júnior and co-workers³³ presented a review beyond the use of copper-based catalysts due to selective access to 1,5-disubstituted triazole, which involves other transition metal scopes except for copper. In 2020, Ramachary and co-workers³⁴ reviewed the synthesis of vinyl-functionalized 1,2,3-triazole molecules. Sahu and co-workers³⁵ reported an advanced synthetic approach for synthesizing a 1,2,3-triazole scaffold. In 2013, Schubert and co-workers³⁶ reported the coordination and supramolecular chemistry of triazole. Moses and Moorhouse³⁷ gave a detailed application of the click approach. Kappe and Van der Eycken³⁸ discussed nonclassical methods (such as microwave, heating, or continuous flow processing) for the click reaction. Jozwiak and co-workers³⁹ reviewed the role of click reaction in drug development. As copper is cytotoxic, Koo and co-workers⁴⁰ reported a copper-free click approach as a valuable tool in the biomedical field. So, there are relatively few systematic and recent reviews on 1,2,3-triazole and its derivatives. The present review focuses on the systematic, readable, and researched synthesis of monocyclic 1,2,3-triazoles and their derivatives with their mechanism. The main goal of this review is to present and analyze various methodologies for the synthesis of titled compounds via metal catalysts, organocatalysts, solvent-promoted, catalyst- and solvent-free neat routes which are useful in the future advancement in the synthesis of heterocyclic compounds incorporated with 1,2,3-triazoles (triazole) and their derivatives. Some privileged triazole-bearing scaffolds are shown in Figure 3.

Some privileged triazole-bearing scaffolds covered in this review.

2. Synthesis of 1,2,3-Triazole via Metal-Catalyzed Azide–Alkyne Cycloaddition

1,2,3-Triazole derivatives were first synthesized in 1960 through a Huisgen 1,3-dipolar cycloaddition (Scheme 1) using azide 2 and alkyne 1 under thermal conditions to produce a mixture of 1,4- and 1,5-disubstituted triazoles 3 and 4.⁴¹

The regioselectivity of the approach is controlled by the electronic as well as steric factors of substrates. This approach has not been widely used in synthetic chemistry due to its elevated temperature, low yield, and generation of two regioisomers when using asymmetric alkynes. Later, various strategies were developed to control regioselectivity. With the introduction of a click reaction, traditional 1,3-dipolar cycloaddition failed. Sharpless and co-workers⁴² gave criteria for “click chemistry” in 2001. Using a copper catalyst, the click approach generates only 1,4-disubstituted 1,2,3-triazole 3 at ambient temperature in an aqueous medium.⁴³ It was later found that the ruthenium catalyst produced only 1,5-disubstituted products 4.^44,45 Metal-catalyzed azide–alkyne cycloaddition (MAAC) reactions are discussed below.

2.1. Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC)

The CuAAC reaction was discovered independently by two research groups of Sharpless–Folkin⁴⁶ and Meldal and co-workers⁴⁷ in 2002. The CuAAC reaction is often quite slow because of the kinetic stability of starting materials, azide 2 and alkynes 1. In addition, the CuAAC reaction required high pressure or temperature, as well as a long time to complete. The Huisgen reaction produces a combination of 1,4- and 1,5-products 3 and 4, whereas with a CuI catalyst or precursors of the CuI catalyst, the reaction of terminal alkynes is selective in the synthesis of 1,4-disubstituted triazoles 3(47,48) (Scheme 2). Using this catalyst, the reaction rate increased up to 10⁷ times in comparison to the catalyst-free reaction. The CuAAC reaction becomes an excellent reaction for organic synthesis. Many click reactions have been reported recently, but none of them can meet all of the standards of the ideal click reaction given by Sharpless and co-workers.⁴⁸

However, the CuAAC reaction has been regarded as the most suitable reaction for click reactions since it fits with the majority of the criteria for a perfect click reaction. Copper-catalyzed reaction of alkynes with organic azides represents the classic example of click chemistry.⁴⁹

Fokin and co-workers proposed the mononuclear mechanism of the CuAAC catalytical cycle first. The generation of the alkynes Cu(I) complex A initiates the reaction process, and the formation of copper(I) acetylide B occurs. The formation of Cu(I) with a terminal alkyne reduces the pK_a of the acetylene proton up to pH 9.8,^46,51 providing deprotonation in the aqueous system without the use of the strong base. By coordinating to the metal center, azide is activated. This results in an intermediate between two species—azide and acetylene. The next stage is the generation of the C–N bond, which goes through a strained six-membered copper-containing intermediate. Second, C–N bond formation along with reductive elimination results in the formation of the desired 1,4-disubstituted 1,2,3-triazole 3 byproduct isolation, and catalyst regeneration takes place⁵¹ (Figure 4). Fokin and co-workers⁵² presented a common binuclear mechanism for the CuAAC reaction in which copper(I) acetylide is activated through a second copper center via a fragile interaction to form the binuclear copper intermediate D.⁵⁰

Fokin and co-workers proposed a catalytic cycle for the CuAAC reaction. Reprinted from ref (50). Copyright 2005 American Chemical Society.

2.1.1. Cu(I)-Catalyzed Azide–Alkyne Cycloaddition

2.1.1.1. CuI-Catalyzed Synthesis

Orita and co-workers⁵³ reported a process-controlled regiodivergent copper-catalyzed process for the synthesis of 4-bromo- and 5-bromotriazoles 6 and 7 through cycloaddition between bromo(phosphoryl)ethyne 5 and azide 2 using CuI as a catalyst and MeOH/H₂O as a proton source for regeneration of the copper catalyst (Scheme 3). KOH-promoted one-shot dephosphorylation of 5 with azide resulted in 4-bromo-1,2,3-triazole 6. CuAAC reaction of 5 with azide 2 formed 5-bromo-1,2,3-triazole 7 instead of 6 because the 4-position was occupied by the sterically bulky Ph₂P(O) group. Pd-catalyzed and MeOK-promoted nucleophilic substitution converted products 6 and 7 to 4- and 5-functionalized triazoles 8 and 9, respectively.

Wu and co-workers⁵⁴ reported a one-pot synthesis of 5-trifluoromethylthiotriazole 10 from 1 and 2 with sulfur powder (S₈) and trifluoromethyltrimethylsilane (TMSCF₃) using a CuI catalyst (Scheme 4). A terminal alkyne with the electron-donating group (EDG) on aryl alkyne favored this multicomponent reaction, while the electron-withdrawing group (EWG) led to poor yield. In addition, a moderate yield was obtained for alkyl alkyne. An electron-withdrawing group on azide also decreases the yield; heterocyclic azide is also a suitable substrate for this reaction.

Xu and co-workers⁵⁵ reported a CuAAC/persulfuration reaction with a wide substrate scope, complete regioselectivity, and excellent functional group tolerability for the synthesis of asymmetric triazole disulfides 12 from 1, 2, and electrophilic persulfur reagent 11 (SS-t-butyl p-toluenesulfono) in the presence of the CuI catalyst and LiO^tBu as a base (Scheme 5). They evaluated a wide range of 5-persulfur-functionalized triazoles in moderate to good yield and produced single regioisomers. The scope of the reaction was investigated with various azides and alkynes. Under the standard circumstances, all of the aliphatic azides and alkynes reacted easily, giving the appropriate disulfides in good to outstanding yields.

Under the standard conditions, functionalized alkynes obtained from various carbohydrates, vitamins, and proteins can be simply converted to the corresponding triazole disulfides in good to excellent yields. These reactions indicate that this modification has great potential for generating novel physiologically active compounds.

To access a wide range of 5-functionalized triazoles 17, Xu and co-workers⁵⁶ reported a copper-catalyzed interrupted click reaction from 1, 2, and different heteroatom electrophiles 16 using much less catalytic quantities of CuI catalyst and LiO^tBu (act as a base) under relatively mild conditions (Scheme 6). This approach has a very broad scope and no required ligands for alkynes, azide, and other heteroatom electrophiles. This intramolecular reaction can be used to construct a bicyclic triazole with various ring sizes.

Zhang and co-workers⁵⁷ developed a direct route to synthesize bifunctional trimethylsilyl-5-iodotriazoles (TMSIT) 20 from TMS-alkyne 18, 2, and iodide followed by copper/palladium-catalyzed nucleophile coupling reaction and desilylation, resulting in a novel approach for the synthesis of structurally diverse 1,5-disubstituted triazoles 21, 22, 23, and 24 via a one-pot reaction, respectively, in high to excellent yields (Scheme 7). This route gave a great alternative for the synthesis of structurally diverse 1,5-disubstituted triazoles due to its short synthetic route and stability of the key precursors 5-iodo-4-TMS-triazoles.

Renslo and co-workers⁵⁸ reported a one-pot two-step procedure of copper-catalyzed cycloaddition of terminal alkyne 1, diazide 29/30, and CuI in DMSO for the synthesis of disulfide-bearing triazole 25/26 (Scheme 8).

They found that heating the triazoles to 60 °C during the exchange action maintained the homogeneity of the reaction mixtures. The exchange reaction gave a mixture of thermodynamic products which favored the asymmetrical disulfide products 27/28 and decreased the reversible reaction which formed the symmetrical starting material 25/26.

Imperiali and co-workers⁵⁹ suggested a synthesis of red-shifted 5(4-substituted-1H-1,2,3-triazol-1-yl)quinoline-8-ol 33 from 5-azidoquinoline-8-ol 32 and 1 in the presence of a catalytic amount of CuI, ascorbic acid, DMF/4-methylpiperidine (8:2) at RT. The intended product was obtained with 100% yield within 12 h (Scheme 9). Because of the electron-rich azido group’s quenching action, 32 displayed no fluorescence. Due to the removal of azide quenching following synthesis of the triazole, 33 showed fluorescence in the presence of 10 mM MgCl₂ (λ_ex = 371 nm and λ_em = 522 nm). Because of these derivative fluorescent properties, they employed them as chelation-sensitive fluorophores to make peptide-based probes for the MAPK-activated protein kinase-2 (MK2) and sarcoma kinase (Src), which are both MAPK-activated protein kinases.

Ley and co-workers⁶⁰ reported a flow-based process for the synthesis of 3 from 1 and 2 via the CuI catalyst and DCM as a base. The starting material is introduced into the flow stream and pumped through the column containing amberlyst A-21 (PS-NMe₂) 34, quadrapure TU (QP-TU) 35, and phosphine resin (PS-PPh₂) 36 placed in a series. The process required 3 h to give the product in 70–93% yield with >95% purity (Scheme 10).

Suresh and co-workers⁶¹ reported CuI(I)-catalyzed and Ru(II)-catalyzed 1,3-dipolar cycloaddition of aryl azide 1-azido-4-(methanesulfonyl)benzene 37 and various phenyl acetylenes 38 for the synthesis of 1,4- and 1,5-diaryl-substituted triazoles 39 and 40, respectively (Scheme 11).

Wu and co-workers⁶² reported the synthesis of 5-thio- or 5-selenotriazole 42 from 1, 2, organohalides/arylboronic acids/tosylates 41, and elemental sulfur or selenium using CuI as a catalyst and K₂CO₃ under mild conditions with good subtract scope and excellent yields (Scheme 12).

Noroozi Pesyan and co-workers⁶³ developed a mild, clean, and effective process for the synthesis of 1,4-disubstituted triazole 47 from 2-amino-6-(azidomethyl)-8-oxo-4-aryl-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile 45 and phenylacetylene 46 in the presence of copper iodide (CuI) and green solvent EtOH/H₂O (2:1) at 80 °C for 2 h (Scheme 13). 45 was synthesized from Knoevenagel adducts and 43 using NaN₃44, SOCl₂, dry DMF, and EtOH. A wide range of azides gave a reaction with phenylacetylene and gave excellent yields of 47.

Belokon and co-workers⁶⁴ reported an efficient reaction for the asymmetric synthesis of amino-acid-containing 1,4-disubstituted triazoles 51 and 52 from azides 48 and Schiff bases of (S)- or (R)-BPB chiral Ni(II) complexes 49 and 50, respectively, using copper(I) iodide catalyst, Et₃N, and DMSO at 70 °C with excellent enantioselectivities (>99% ee) (Scheme 14). Complex 50 was prepared using (S)-BPB Ni-Gly followed by propargyl bromide alkylation.⁶⁵ For the substrate scope of azides, they found that most of all azides gave good to excellent yields (68–93%) except 1-(azidomethyl)-3-fluorobenzene, 4-(azidomethyl)benzonitrile, and 9-(azidomethyl)anthracene, which gave comparatively fewer yields of 53, 38, and 42%, respectively.

Zheng and co-workers⁶⁶ reported novel, one-pot, efficient multicomponent reactions (MCRs) of OBoc-alkynes 53, azides 2, amines 54, and 2H-azirines 55 for the synthesis of fully substituted 1,2,3-triazole 56 using copper iodide, DIPEA, and MeOH (Scheme 15). Here, 2H-azirines are readily disclosed for the C–N bond formation. Electron-donating and electron-withdrawing alkynes had a good transformation, but alkyl-substituted OBoc-alkyne does not transform into the desired product. For 55, alkyl 2H-azirines did not provide the desired product. This approach is very useful for polyfunctionalized triazole with a wide substrate scope, mild conditions, and good yield.

2.1.1.2. CuCl-Catalyzed Synthesis

Xu and co-workers⁶⁷ reported a three-component interrupted click approach for a bench-stable 5-stannyl triazole 58 from easily available 1, 2, and Bu₃SnOMe using CuCl as a catalyst (Scheme 16). Through a Sn/Cu transmetalation, 5-stanyl triazole 58 was produced which can be used as a potent nucleophilic reagent. This mutual Sn/Cu transmetalation is crucial for future progress in tin chemistry and useful for the synthesis of fully functionalized triazole 59, trifluoromethylthiolated triazole 10, and trifluoromethylated triazole 60.

Zhou and co-workers in 2013⁶⁸ reported the first highly enantioselective asymmetric desymmetrization for the synthesis of quaternary oxindoles bearing 1,2,3-triazole 64 from oxindole-based 1,6-heptadiynes 61 and azide 2 using CuCl (18 mol %), PyBOX ligand (15 mol %) 63, and 2,5-hexanedione at 0 °C for 96 h (Scheme 17a). The N-protecting group of oxindole favors most of the alkyl and acetyl groups but is less favorable for the electron-withdrawing acetyl protecting group, which leads to the formation of undesired ditriazole 65.

Here, 64 with the alkyne group uses as a versatile synthetic tool for further modification such as [3 + 2] cycloaddition (a), full or partial hydrogenation (b,d), and Sonogashira reaction (c) (Scheme 17b).

Zhou and co-workers⁶⁹ first reported a highly enantioselective desymmetric CuCl-catalyzed reaction of terminal alkynes 1 or 1-iodoalkynes 71 with diazides 70 using PyBOX ligands 72 and DCM at −50 to −40 °C for the synthesis of tertiary alcohols containing 1,2,3-triazoles 73 and 74 with excellent yield (Scheme 18). For the PyBOX ligand study, they found that different C4 shielding groups showed a different result. The OBn group increased the % ee ratio of 73 but led to poor yield. Increasing the steric hindrance of the shielding group using −1-naphthyl and −2-MeO-3,5-^tBu₂-C₆H₂ also gave poor results. When the phenyl group (−Ar) group was replaced by the 4-fluorophenyl group, the reaction led to a higher % ee ratio and good yield with DCM solvent. Irrespective of the electronic effect of substituents meta-substituted diazo alcohol gave a slightly higher % ee in comparison to that at the para-position. Based on the study of the reaction mechanism, this approach showed that % ee increased with time and decreased the chiral/achiral ratio, which indicates that enantioselectivity increased by the formation of an achiral ditriazole.

Zhou and co-workers in 2021⁷⁰ reported a highly enantioselective asymmetric CuAAC synthesis of a tertiary alcohol functional group bearing 1,2,3-triazole 78 from azides 2 and highly functionalized tertiary alcohol containing ethynyl 75 using CuCl, 3-pentyl-containing PyBOX-phosphonate ligand L79, AgTFA additive, and ^tBuOAc at °0 C for 3–4 days (Scheme 19a). The 3-pentyl group at the C4 position increase the s-factor. Kinetic resolution (KR) of racemic α-ethynyl alcohol 75 gave a good yield with 87–99% ee and 39–50% yield of 77. α-Alkyl alcohol such as α-isopropyl alcohol did not give good results (60% ee and 34% yield). The E-CuAAC reaction of this tertiary alcohol containing ethynyl 75 with azide 2 gave chiral α-1,2,3-triazole bearing tertiary alcohol 79 in 70–99% yield with 48–96% ee. This approach is useful for the synthesis of bioactive compounds such as indomethacin, fenbufen, and celecobix.

This approach is also suitable for the kinetic resolution of α-monofluorinated α-ethynyl alcohol 80 and benzyl azide 76 for the synthesis of monofluorinated α-triazole-substituted alcohol 82 in 40–50% yield with 20–96% ee and gave chiral alcohol 81 (Scheme 19b).

2.1.1.3. Cu(MeCN)₄PF₆-Catalyzed Synthesis

Song and co-workers⁷¹ reported an efficient synthesis of 4-heterofunctionalized triazolyl–organosulfur 84 with high regioselectivity and wide substrate scope (33 examples) such as 85–88 from internal thiocynatoalkynes 83 and 2; they used (CuOTf)₂PhMe and Cu(MeCN)₄PF₆ (tetrakisacetonitrile)copper(I)hexafluorophosphate) as a catalyst (Scheme 20). The electronic effect was not influenced by electron-rich and electron-deficient substituents as they gave the same yield, but for the azide scope of the reaction, the yield for electron-rich azide was slightly lower than that of the electron-deficient azide. The reaction could also occur for a secondary azide.

Goldup and co-workers⁷² reported an active template Cu-catalyzed alkyne–azide cycloaddition (AT-CuAAC) reaction of propargyl cytosine 89 and azido thymine 90 for the preparation of rotaxane 92 in the presence of macrocycle 91 using [Cu(MeCN)₄]PF₆ as a catalyst, NⁱPr₂Et, and THF at 50 °C for 18 h (Scheme 21). At 32 °C, no amplification was observed when oligonucleotide rotaxane was utilized as the forward primer in PCR amplification. According to the findings, the mechanical link in rotaxanes efficiently limits the interlocked oligonucleotide’s capacity to act as a primer for the T7 polymerase. This method utilized in click DNA ligation may be easily extended to the active template manifold for the synthesis of biocompatible triazole-linked oligonucleotides based on rotaxanes.

Zheng and co-workers⁷³ reported a 3-CAP (three-component asymmetric polymerization) synthesis of chiral polytriazole-methanamines 96 and 97 from OBoc-alkynes 93, azides 2, and various types of amines 94 and 95 using Cu(CH₃CN)₄PF₆, ligand (L) 63, and DIPEA at room temperature (Scheme 22a). For 3-CAP, the secondary and primary amine gave good yield and gave M_n up to 46 700 g/mol.

This approach is also useful for the synthesis of structurally diverse polymers 101 and 102. With diazide 98, secondary amines 54 and 100 and OBoc-alkynes 93 and 99 were used as a substrate and yielded excellent M_n up to 10 200 g/mol (Scheme 22b).

Zheng and co-workers⁷⁴ reported MCP (multicomponent polymerization) and interrupted click synthesis of 1,4,5-polytriazoles (1,4,5-PTAs) 106 from diynes 103, diazides 104, and electrophile 105 using Cu(MeCN)₄BF₄ catalyst, DIPEA (N,N-diisopropylethylamine) base, and DMF as a solvent at room temperature with high yields, M_n values, and excellent modification efficiency (Scheme 23). Poor solubility of inorganic CuI does not catalyze this polymerization.

2.1.1.4. CuOTf-Catalyzed Synthesis

Fokin and co-workers⁷⁵ reported the first asymmetric CuAAC reaction via kinetic resolution of α-chiral azide and desymmetrization of gem-diazide. They also discussed the importance and the role of this new PyBOX ligand in the enantioselective synthesis of 1,2,3-triazole.

Uozumi and co-workers⁷⁶ reported a highly enantioposition-selective CuAAC approach for the synthesis of axially chiral biaryl groups bearing 1,2,3-triazoles 108 and 109 from prochiral biaryl-bearing dialkynes 107 and benzyl azide 76 using CuOTf·(C₆H₆)_0.5 (10 mol %), a tert-butyl(dimethyl)silyl (TBS) group containing PyBOX ligand L (20 mol %) 110, and 1,2-DCE at 60 °C for 24 h (Scheme 24). Increasing the load of azide up to 1.5 equiv enhanced the % ee to 91% with 64% yield. X-ray crystallographic analysis proved that the absolute configuration of triazole was R.

Fokin and co-workers⁷⁷ reported the synthesis of 5-bismuth(III) triazolides 113 from a bench-stable, readily available, as well as a nontoxic group of σ-acetylides, 1-bismuth(III) acetylides 111 and 2, in the presence of CuOTf (Tf = trifluoromethanesulfonyl) and THF as a solvent for 3 h at RT (Scheme 25a).

Further reaction of 113 with various electrophiles enabled the synthesis of fully substituted 1,2,3-triazoles 59, and 114–117 (Scheme 25b).

2.1.1.5. β-Cyclodextrin-TSC@Cu-Catalyzed Synthesis

Naimi-Jamal and co-workers⁷⁸ reported a synthesis of 1,4-disubstituted triazoles 120 and 121 from 1, azides 44/119, and alkyl halides 118 using novel, stable, water-soluble, as well as homogeneous catalyst β-CD-TSC@Cu (copper(I) ions supported on functionalized β-cyclodextrin) as a supramolecular moiety in an aqueous medium with excellent regioselectivity and high yield (Scheme 26). The catalyst was utilized up to 7 times without a remarkable loss of its activity. After the third cycle, very low (≤2 ppm) copper leaching was observed by ICP-OES.

The substrate scope of this reaction reported that 2-bromoacetophenone derivatives minutely decreased the product yield and expanded the reaction time. The hydrophobic internal cavity of β-CD provided a favorable environment for copper ions and organic substrates to interact more effectively.

2.1.1.6. Phenylethynylcopper(I)-Catalyzed Synthesis

Varela-Palma and co-workers⁷⁹ developed a synthesis of 1-(1-benzyl-1,2,3-triazol-4-yl)cyclohexanol 124 from 1-ethynylcyclohexanol 123 and benzyl azide 76 using phenylethynylcopper(I) 122 catalyst and CH₂Cl₂ as a solvent at RT for 24 h. Adding a Fehling A and B solution to the glucose–phenylacetylene 46 mixture resulted in yellow particles such as phenylethynylcopper(I). The 1,3-bis(1,2,3-triazol-1-yl)-propan-2-ol core containing a triazole (10 examples) was synthesized by this protocol with 80–92% yields (Scheme 27).

2.1.1.7. Miscellaneous CuAAC-Catalyzed Reaction

Fossey and co-workers⁸⁰ reported a short review on asymmetric CuAAC′ (chiral Click) reaction (Scheme 28). Taking advantage of the difference in the rate of reaction kinetic resolution through CuAAC gave the formation of new enantioenriched material or product. A racemic mixture (50:50) also converts into either R or S and becomes enantioenriched. Using this approach, kinetically resolved triazoles 131 and 132 are produced from an α-benzylic azide and phenylacetylene.⁷⁵ Desymmetrization leads to the loss of one or more symmetry elements and results in a prochiral molecule from the chiral molecule. This approach is useful for producing a single enantiomer from a nonchiral reactant.⁸¹ Desymmetrization is very useful for the synthesis of some biologically active chiral compounds⁸² such as (−)-podophyllotoxin and (−)-picropodophyllin.⁸³

Zhou and co-workers⁸⁴ reported the synthesis of 1,2,3-triazoles 137 and 138 using desymmetrization and an enantioselective CuAAC approach. The newly synthesized chiral PyBOX ligand shows excellent enantioselectivity in 1,2,3-triazole. Enantioselective CuBr-catalyzed cycloaddition of azide 2 and alkynylphosphine oxide (P-chiral and P-substituted) 135 using 1-naphthyl-bearing PyBOX ligand L139 and MeCN at −20 °C for 4 days yielded P-chiral phosphine oxides bearing a 1,2,3-triazole scaffold 137 in excellent yield and high enantioselectivity (Scheme 29a). Desymmetrization of dialkynylphosphine 136 with azide 2 under the CuAAC approach yielded monotriazole 138 with excellent results. This ethynyl-containing triazole is useful for further functionalization.

For the desymmetric CuAAC approach for phosphole diynes 140, the reaction of 140 with azide 2 yielded chiral monotriazole 141 with good enantioselectivity (Scheme 29b). This versatility of monoethynylphosphine oxide 141 was used as a chiral building block for various reactions.

2.1.2. Cu(II)-Catalyzed Azide–Alkyne Cycloaddition

2.1.2.1. CuCl₂-Catalyzed Synthesis

Xu and co-workers⁸⁵ reported a copper-catalyzed synthesis of indole–triazole 146 from 1-(prop-2-ynyl)-1H-indole 146 and 2 using CuCl₂/Zn powder in water at RT. At RT, the H atom linked to the N atom of indole 143 was replaced by pro-2-ynyl 144 using Bu₄N⁺·Br^–, NaOH, and toluene, resulting in 145 (Scheme 30).

Most compounds show moderate to good antifungal activity against Colletotrichum capsica and cotton Physalospora pathogens, using flutriafol and hexaconazole as positive controls. The activity of compounds XII and XIII was unaffected by the distance between the phenyl ring and the triazole moiety.

The findings revealed that the ortho-substituents of the phenyl ring are helpful toward the activity; however, when R is an electron-withdrawing group or hydrogen at the meta-position is replaced, the impact is unfavorable. Compound XIV has no substituted phenyl ring and was shown to be the most efficient against Colletotrichum capsica, with an inhibition ratio of up to 83.33% (Figure 5).

Typical triazole derivatives that show antifungal activity.

2.1.2.2. CuSO₄-Catalyzed Synthesis

Cunha Lima and co-workers⁸⁶ described a synthesis of 1,4-disubstituted triazoles 151 from ethyl 2-azidoacetate 149 and terminal alkyne 150 in the presence of CuSO₄·5H₂O, sodium ascorbate (NaASc), and EtOH/H₂O (1:1) at RT (Scheme 31). 149 was synthesized by azidation of ethyl 2-bromoacetates 147 and 150 synthesized from a natural product by a propargylation reaction. All synthesized compounds showed moderate antioxidant activity with an EC₅₀ value above 75.5 μg/mL in the DPPH assay and 101.1 μg/mL in the ABTS assay. In the CuAAC reaction, the formation of copper(I)acetylide is an important step from the deprotonation of a terminal alkyne. Electron-withdrawing groups raised the reactivity and acidity of the terminal alkyne hydrogen, so reaction times were decreased and yields were increased.

Huang and co-workers⁸⁷ developed a step-growth polymerization of diazide 153 and phthalimide dialkyne 152 using the copper catalyst for the synthesis of polytriazoleimide 154 under mild conditions (Scheme 32). IR, NMR, wide-angle XRD, differential scanning calorimetry, thermogravimetric analysis, and intrinsic viscosity are used for characterization. The polytriazoleimides have high solubility in polar solvents and could be readily cast into clear, robust, and flexible films with intrinsic viscosities of 0.39–0.58 dL g^–1. The thermal stability and mechanical qualities of these new polytriazoleimide films were impressive.

Cuevas-Yañez and co-workers⁸⁸ reported a copper-catalyzed synthesis of 2-aryl-1-(1,2,4-triazolyl)-3-(1,2,3-triazolyl)propan-2-ol derivatives 157 and 158 from 2-(2,4-difluorophenyl)-1-[1,2,4]triazol-1-yl-pent-4-yn-2-ol 155 with various azides 2 and 1-azido-2-(2,4-difluorophenyl)-3-[1,2,4]triazol-1-yl-propan-2-ol 156 with different alkynes 1 using CuSO₄ and sodium ascorbate, respectively (Scheme 33). These fluconazole analogues showed good antifungal activity.

Joshi and co-workers⁸⁹ reported a facile, greener, and ultrasound-promoted synthesis of triazole 163 in the presence of CuSO₄, sodium ascorbate, and DMF/t-BuOH/H₂O (1:1:1) by reaction between 2-(azidomethyl)-1H-benzo[d]imidazole 162 and 1 with good yields. The enhanced product formation was observed due to the greater solubility of copper sulfate in this aqueous medium (Scheme 34). O-Phenylenediamine 160 reacted with chloroacetic acid in HCl and resulted in 2-(chloromethyl)-1H-benzo[d]imidazole 161, which was treated with sodium azide 44 in DMF at RT to yield 162. An in vitro antimicrobial study reported that all of the synthesized molecules showed moderate activity compared to that of standard drugs. According to the findings, all synthesized molecules were more active against Gram –ve bacteria in comparison to Gram +ve bacteria.

Crowley and co-workers⁹⁰ performed a safe, one-pot CuAAC approach of an exofunctionalized pyridyl-triazole 166 from dialkyne 164, dibromide 165, and sodium azide 44 using CuSO₄·5H₂O and DMF/H₂O (4:1) for 48 h, resultin in a 44% isolated yield (Scheme 35).

Weinreb and co-workers⁹¹ reported a synthesis of N-protected 4-substituted triazole 169 from β-tosylethylazide 168 and 1 using sodium ascorbate/CuSO₄ as a catalyst in aqueous tert-butanol at RT. With a further reaction of 169 with KOt-Bu in THF at −78 °C, the mixture was gently warmed to 0 °C to produce unprotected 4-substituted 1,2,3-triazole 170. 168 was synthesized from p-tolyl vinyl sulfone 167, sodium azide 44, and sulfuric acid in MeOH at 0 °C to RT with good yield (Scheme 36). This cycloaddition was also favored for acetylene dicarboxylic acid and dimethyl acetylenecarboxylate with azide. They also reported an efficient ruthenium-catalyzed cycloaddition of alkyl azide with terminal and asymmetric internal alkynes using Cp*Ru(PPh₃)₂ and PhH to produce 1,2,3-triazole.

Crowley and co-workers⁹² reported a synthesis of various bi- and tridentate pyridyl-triazole ligands with Cu(II) and Ag(I) 173 and 174 from halides (2-(bromomethyl)pyridine 171 and 2,6-(bis-9-bromomethyl)pyridine 172) with sodium azide 44 and 1 using CuSO₄·5H₂O, ascorbic acid, DMF/H₂O at RT for 20 h, respectively (Scheme 37).

Thibonnet and co-workers⁹³ performed the one-pot method of 1,2,3-triazole-containing morpholine scaffold 176 in the presence of 18-crown-6, NaASc, CuSO₄·5H₂O, and CHCl₃/H₂O from 1, iodomorpholinone 175, and sodium azide 44 at RT for 24 h using the CuAAC approach (Scheme 38). This synthetic approach was carried out under an argon atmosphere.

Tan and co-workers⁹⁴ reported a synthesis of novel hybrid phthalimide analogues containing a triazole 181 and 182 via CuAAC reaction of 2-ethynylisoindoline-1,3-dione 178 with various organic azides (2-azido-N,N-disubstituted acetamide 179 and 2-azido-N-substituted acetamide 180) in the presence of CuSO₄·5H₂O, sodium l-ascorbate, and MeOH/H₂O (1:1) at RT (Scheme 39). Compound 178 was synthesized from phthalimide 177 and propargyl bromide using K₂CO₃ in acetonitrile at 75 °C.

The molecular docking of compounds XV, XVI, and XVII (Figure 6) with molecular dynamic simulation studies showed interaction of PPI with ACE2-S1, the best binding energy of XV with a value of −9.70 kcal/mol, and the best approximated K_i value of XV (0.077 μM). In the interaction with the Mpro protein, compound XVI exhibited the best binding energy (−8.76 kcal/mol) and approximate K_i value (0.315 μM), while in the interaction with the PLpro, compound XVII showed the best binding energy (−8.87 kcal/mol) and estimated K_i value (0.315 μM). Based on an in silico study, these derivatives may block the entry of SARS-CoV-2 into the host cell.

Sierra and co-workers⁹⁵ developed a synthesis for 1,2,3-triazole-BODIPY scaffold 186 from anilines 184 and alkynyl sulfoxides 183 using NfN₃185, NaHCO₃, and CuSO₄·5H₂O/sodium ascorbate in MeOH/H₂O/Et₂O with 41–80% yield (Scheme 40). Further substitution on this moiety led to chiral-at-metal BODIPY-based iridium(III) complexes 194–196, which showed excellent luminescence properties.

Thordarson and co-workers⁹⁶ reported a step process for the synthesis of iridium(III)azides 199 and further reaction of 199 with 1-(prop-2-ynyl)-1H-pyrrole-2,5-dione 198 using DMF, CuSO₄, and NaASc for the synthesis of Ir(III)-containing triazole-bisterpyridine 199 for 3 days (Scheme 41). This complex showed photophysical activity which is important for the modification of the polymer and the surface.

2.1.3. Heterogeneous Cu-Catalyzed Azide–Alkyne Cycloaddition

2.1.3.1. Cu₂O/HTNT-7-Nanocatalyzed Synthesis

Peddiahgari and co-workers⁹⁷ developed a novel approach for the CuAAC reaction from organic halides 118, sodium azide 44, and 1 using Cu₂O/HTNT-7 nanoparticles (Cu₂O nanoparticles supported on hydrogen trititanate nanotubes) as a catalyst and 4-MeO-C₆H₅I/4-MeO-C₆H₅NH₂ as an azide precursor in water mediated at RT with excellent yield for the synthesis of 1,4-disubstituted triazole 120 (Scheme 42). Using different halides and alkynes, they investigated the extent of the CuAAC reaction, in which they found 3-(bromomethyl)thiophene, 2-(bromomethyl)thiophene, and 2-(bromomethyl)pyridine immediately produced a complex mixture of byproducts, turning the reaction mass dark and viscous. The reusability of the catalyst was tested under optimal conditions and recovered using centrifugation. The retrieved catalyst was reused seven times with no discernible difference in yield. ICP-MS investigation revealed that very low (≤1 ppm) copper leaching was observed.

2.1.3.2. Cu@N–C-Catalyzed Synthesis

Xie and co-workers⁹⁸ reported a one-pot synthesis of 3 from 1, aryl halides 41, and sodium azide 44 using a novel, efficient, recyclable heterogeneous catalyst Cu@N–C (copper supported on nitrogen-doped carbon) and t-BuOH/H₂O (3:1) at 50 °C with high yield and broad substrate scope (Scheme 43). Under an argon flow, the powder Cu(im)₂ (copper(II) bisimidazolate) was deposited in a tube furnace and calcined to 600 °C at a heating rate of 5 °C·min^–1 for 5 h. The resultant solid was cooled to RT to afford the Cu@N–C(600). The retrieved catalyst was used up to 4 times without a discernible change under the standard conditions. Benzyl chloride required a longer time for completion because of its low activity for nucleophilic substitution reaction with sodium azide. Aliphatic alkynes required high temperatures and long reaction times due to their lower reactivity compared to aryl alkynes. The para-substituted compounds containing electron-deficient groups resulted in lower yield compared to that with ortho- and meta-substituted compounds. This approach was also used for the synthesis of ethisterone and zidovudine.

2.1.3.3. CuI Nanoparticle Synthesis

Maurya and co-workers⁹⁹ developed an effective copper-catalyzed protocol using heterogeneous CuI nanoparticles to synthesize 1,4,5-trisubstituted triazole 202 derivatives by reacting alkynes 200 and benzyl azides 201 in a water medium at 70 °C for 3 h (Scheme 44). CuI NPs displayed a significant activity and recyclability (up to 6 cycles) for this reaction, and the intended product was formed in 81–96% yields.

2.2. Nickel-Catalyzed Azide–Alkyne Cycloaddition (NiAAC)

A possible catalytic path for NiAAC reaction is shown in Figure 7. First, intermediate A is produced from Ni(0) and internal alkyne. In the following cycloaddition process, intermediate A acts as a Nu, which allows electron-rich C to attack the terminal N of azide, resulting in nickelacycle intermediate B, which further leads to intermediate C. After removal of a metal atom, the desired triazole product is obtained and regeneration of the catalyst occurs.

Conceivable mechanism for NiAAC. Reprinted with permission from ref (32). Copyright 2020 John Wiley and Sons.

2.2.1. Ni(COD)₂-Catalyzed Synthesis

Topczewski and Liu¹⁰⁰ reported the synthesis of N-chiral triazole derivative 205 that proceeds via the NiAAC reaction by dynamic kinetic resolution (DKR) between allylic azide 203 and alkynes 204 using Ni(COD)₂ as a catalyst and (R)-1-(2-(diphenylphosphanyl)phenyl)ethan-1-amine 206 as a ligand in PhMe at 50 °C for 24 h (Scheme 45). This DKR is enabled by a spontaneous [3,3]-sigmatropic rearrangement of the allylic azide. For the alkyne scope of E-NiAAC (enantioselective NiAAC), the reaction with a neutral and electron-deficient substituent on the aryl group had less effect on enantioselectivity, while a strong EWG decreased regioselectivity. The azide scope of the E-NiAAC reaction reported that the scope of allylic azide was not much affected by electron-rich and electron-deficient groups, but when the cyclohexyl part was changed by acyclic allylic azide, both (E)- and (Z)-alkene isomers were observed (7:1 E/Z). However, the desired derivative was separated as a single isomer.

2.2.2. Cp₂Ni/Xantphos-Catalyzed Synthesis

Hong and co-workers¹⁰¹ reported an efficient and simple nickel-catalyzed cycloaddition reaction of 1 with 2 in water or organic solvent (toluene) using Cp₂Ni/xantphos as a catalyst. Product 4 was obtained in 42–95% yield with broad substrate scope and high regioselectivity (Scheme 46). They also reported that ortho-OMe-substituted alkyne gave no reaction due to a steric effect, whereas meta- and para-OMe-substituted alkynes gave 93 and 91% yield, respectively. So, a lower steric hindrance of substituted alkynes strongly favored the NiAAC reaction. This approach was further explored for biomolecules such as carbohydrates and amino acids. The xantphos ligand and Cp₂Ni precatalyst were essential in achieving the catalytic manifold, which was insensitive to molecular oxygen and water.

Bosc and co-workers¹⁰² reported an effective synthesis of various 1,5-disubstituted-triazole 207 via nickel catalyzed (nickelocene) cycloaddition reaction of 1, bromide 118 and sodium azide 44 using xantphos, Cs₂CO₃ and DMF. They heated the reaction mixture for 4 h at 50 °C in a microwave which showed excellent yield and regioselectivity (Scheme 47). This approach is very useful when the low-molecular-weight azide is added as a reactant for the synthesis of triazoles. Due to steric hindrance, the ortho-substituted phenyl ring containing bromide provided less yield compared to that with the meta-/para-substituted bromide.

Hong and co-workers¹⁰³ reported a synthesis of various fully substituted triazoles 42, 211, and 212 from 2 and various alkynes 209, 208, and 210, respectively. They used Cp₂Ni as a catalyst, Xanthos 213/dppbz 214 as a ligand, and Cs₂CO₃ and DCM or toluene as a solvent at RT (Scheme 48).

2.2.3. Raney-Nickel-Catalyzed Synthesis

Surya Prakash Rao and co-workers¹⁰⁴ developed a regioselective method of 1,4-disubstituted triazole 216 at 45 °C using a Raney nickel catalyst and toluene solvent from 2 and propargylic ether 215 with excellent yield (Scheme 49). An additional reducing agent was not needed in this reaction with Raney nickel. Here, alkyl and aryl acetylene gave a good yield. However, the NiAAC reaction of propargyl alcohol and phenyl azide yielded the 1,4- and 1,5-regioisomers in a 3:2 ratio with a 93% yield. Without any catalyst, this reaction also produced the 1,4- and 1,5-regioisomeric adducts in a 3:2 ratio; however, it needed 2 min of microwave heating to 140 °C in PEG-200 (polyethylene glycol-200). Per the mechanistic study, Raney Ni serves as a coordinating species in azide and alkyne cycloaddition reactions, and the method does not proceed through Ni acetylides.

2.2.4. Ni-rGO-Zeolite Nanocatalyzed Synthesis

Basu and co-workers¹⁰⁵ performed a one-pot method of 1,4-disubstituted triazole 120 with good regioselectivity in water from 1, halides 118, and NaN₃44 in the presence of the stable catalyst ternary nanocomposite substance, Ni-rGO-zeolite, for 4–6 h at 90 °C (Scheme 50). For the synthesis of the nanocatalyst, they prepared hybrid GO-zeolite from 2D GO (graphene oxide) and NaY zeolite. Synthesis of the GO-zeolite complex involved the addition of NaY zeolite to an aqueous suspension of GO and increasing its pH near 7 due to protonation. The negative charge on zeolite balanced due to protonation, resulting in Al–OH–Si bridging. The reaction mass was heated at 60 °C for 16 h under gentle stirring with subsequent evaporation of H₂O and drying under vacuum. This GO-zeolite was then treated with Ni(OAc)₂·4H₂O in the presence of NaBH₄ under hydrothermal conditions, and the ternary nanocomposite material, Ni-rGO-zeolite, resulted. The catalyst performed up to four cycles without loss of activity.

2.3. Ruthenium-Catalyzed Azide–Alkyne Cycloaddition (RuAAC)

Based on density functional theory (DFT), Boren, Lin, and Fokin described the RuAAC cycle (Figure 8) based on the computational study.¹⁰⁶

Proposed catalytic cycle of the RuAAC reaction.^106−108 Reprinted from ref (106). Copyright 2008 American Chemical Society.

2.3.1. Cp*Ru(COD)Cl-Catalyzed Synthesis

Goswami and co-workers¹⁰⁹ reported a one-pot [3 + 2]/[2 + 2 + 2], facile, and atom-economical approach for the synthesis of 2-triazolyl thio-/selenopyridines 218 and 219 from 1-alkynyl thio-/selenocyanates 217 and alkyl/aryl azides 2 using Cp*Ru(COD)Cl catalyst in THF/toluene as a solvent at 70 °C/RT conditions. Further reaction of 218 with diyne 220 in the presence of Cp*Ru(COD)Cl in EtOH yielded 222 with 26–91% yield, whereas the reaction of 217 and 2 with tetraynes 221 using Cp*Ru(COD)Cl in ethanol gave 223 with moderate to good yield (Scheme 51).

Song and co-workers¹¹⁰ reported a regioselective synthesis of fully substituted 5-thiocyanatotriazoles 225 from thiocyanato alkynes 224 and 2 using Cp*Ru(COD)Cl catalyst in THF at RT for 12–24 h (Scheme 52). Further functionalization of 225 using TFAA (trifluoroacetic acid) and H₂O₂ at 80 °C for 24 h yielded 226. The AAC/nucleophilic substitution cascade three-component reaction of 224 and 2 and alkyl/aryl magnesium bromide using Ru(Cp*)(COD)Cl gave 42 with moderate to good yield. This route is also fit for the synthesis of non-natural carbohydrates.

Mascareñas and co-workers⁴⁵ reported an orthogonal reaction for the synthesis of thio-functionalized triazole 42 using thioalkynes 209 and 2 using (Cp*)Ru(COD)Cl as a catalyst in water at RT (Scheme 53). Aliphatic azides are also suitable for this approach and gave a good yield. Also, water is replaced by some biomolecular additives, which also gave good results with this methodology.

Guo and co-workers⁴⁴ reported a mild and convenient method for the synthesis of CF₃CH₂- and CF₃S-containing 1,4,5-trisubstituted triazoles 230–232 from (trifluoromethyl)thiolated alkynes 227 and 228 and trifluoromethylated alkynes 229 with various alkyl 2 and aryl azides 119 and 76 using (Cp*)Ru(COD)Cl catalyst at RT in benzene or toluene (Scheme 54). Also, this methodology is suitable for aryl halides, hydroxyl groups, ester, and N-, S-, and O-containing heterocyclic molecules. Regioselectivity of the reaction affords CF₃CH₂ or CF₃S at the 5-position of triazole.

Blixt and co-workers¹¹¹ developed solid-phase peptide synthesis (SPPS) of triazole peptide 234 from peptide-terminated (S)-(−)-4-tert-butyl 2-azidopeptide 233 and internal alkynes 200 using (Cp*)Ru(COD)Cl and HFIP (1,1,1,3,3,3-hexafluoroisopropanol)-DCM (1:4) at RT for 15 min. For the alkyne scope, dimethyl acetylene dicarboxylate gave <2% yield (Scheme 55).

2.3.2. [Cp*RuCl]₄-Catalyzed Synthesis

Liskamp and co-workers¹¹² reported a first Ru-catalyzed macrocyclization for the production of a bicyclic 1,5-triazole-bridged vancomycin CDE ring 242 from amino-acid-containing azides 235 and pentapeptide-containing alkynes 237 using [RuCl(Cp*)]₄ catalysts (Scheme 56). In this method, the two ether bridges of bicyclic vancomycin CDE ring were replaced by 1,5-disubstituted triazole.

2.3.3. [RuClCp*(PPh₃)₂]-Catalyzed Synthesis

Johansson and co-workers¹¹³ developed a one-pot two-step methodology for the synthesis of 1,5-disubstituted-1H-1,2,3-triazole 207 from 1, alkyl halide 118, and NaN₃44 using [RhClCp*(PPh₃)₂] under MW heating at 100 °C for 30 min (Scheme 57). The secondary alkyl halide did not give any reaction even at a high temperature. An acidic-group-containing alkyl halide is not a suitable substrate for this methodology.

2.4. Iridium-Catalyzed Azide–Alkyne Cycloaddition (IrAAC)

A proposed mechanism for IrAAC reaction of alkyne 196 and azide 2 shown in Figure 9. First, Ir(I) complex A triggered the alkyne, which led to the generation of the alkynyl complex B as the CuAAC mechanism.¹¹⁵ Then the terminal nitrogen of azide had an electrophilic center after coordination with metal, which led to the formation of stabilized Ir carbenoids C and C′. Subsequent Ir [3 + 2] cycloaddition underwent “Cope-like” cyclization, and D and E yielded metallacycle F,¹¹⁴ which finally led to the production of the titled product 197.

Postulated mechanism of IrAAC. Reprinted from ref (114). Copyright 2013 American Chemical Society.

2.4.1. [Ir(COD)Cl]₂-Catalyzed Synthesis

Ding and co-workers¹¹⁶ reported a novel, simple, efficient, and sequence-defined polytriazole 246. First, 1 converted into internal thoialkynes 244 by reacting with 243. 244 reacted with 2 in the presence of an Ir catalyst to give 5-thio-functionalized 1,2,3-triazole 245. 245 further underwent an iterative sequential growth (ISG) method for the formation of polytriazole 246 (Scheme 58). Various functional groups were incorporated at the C4 position of the triazole scaffold. The C–S bond is easily detected by tandem mass spectrometry analysis due to the cleavage of a relatively weak C–S bond.^117−119

Gao and co-workers¹²⁰ reported a synthesis of fully substituted 5-thiotriazoles 248 from alkynyl thioether 247 and benzyl azide 76 using [Ir(COD)Cl]₂ catalyst and CH₂Cl₂ overnight in a N₂ atmosphere at RT to give 81% yield (Scheme 59). 247 can be easily synthesized from bench-stable, rapidly prepared, and easily activated N-alkynylthiophthalimide and 4-methoxyphenylmagnesium bromide via thioester, which under subsequent acid hydrolysis yielded the desired compound 247.

Sun and co-workers¹²¹ reported a first electron-rich internal alkyne for the synthesis of 5-thiotriazole 42 and fully substituted triazoles 59 using 2 and internal thoialkynes 209 as well as internal alkynes 200 using [Ir(COD)Cl]₂ catalysts and dichloromethane at RT, respectively (Scheme 60). Diverse aryl and alkyl azides are suitable for the approach as well as for enhancing steric hindrance on internal thoialkynes 209, which also did not affect the reaction efficiency. Due to mild reaction conditions, alcohol, ester, aryl halides, ethers, THP-, and silyl-protected alcohols and phthalimide- and Boc-protected amines were also tolerated in this approach. For internal alkynes, they reported that electron-donating and neutral alkynes gave poor yield with greater regioselectivity. Also, prop-1-yn-1-ylbenzene, 1,2-diphenylethyne, and 1,2-diphenylethyne gave a trace amount of yield (<5%), whereas hex-3-yne showed very low conversion.

Song and co-workers¹²² developed a highly regioselective, mild, bioorthogonal strategy for the synthesis of fully substituted 5-amidotriazole 250 from ynamides 249 and 2 using [Ir(COD)Cl]₂ catalysts with DCM or aqueous conditions at RT (Scheme 61). Cyclic and acyclic ynamide work well with the approach; the electron-rich cyclic ynamide gave a slightly higher yield, while the electron-deficient group gave a slightly low yield. If the adjacent position of ynamide (−R²) was substituted by a bulky group, the reaction yield decreases.

Cui and co-workers¹²³ reported a mild, efficient, and hydroxyl group synthesis of fully substituted triazole 252 from alkynes 251 and 2 using [Ir(COD)Cl]₂ catalysts in DCM at RT (Scheme 62). With the achievement of the cycloaddition of 252 with 2, they predicted that a hydroxyl group of internal alkynes would work as a directing group.^124−128 For the substrate scope of alkynes, they found that alkyl alkynes gave a yield comparatively less than that of aryl alkynes. Aliphatic alcohol-containing alkynes did not give any reaction,¹²⁸ whereas the meta-substituted phenolic group gave a very low yield.

Song and co-workers¹²⁹ reported excellent regio- and chemoselective synthesis of 5-ether triazoles 254 and 256 from internal alkynes 253 and 255 with azides 2 and 76 using [Ir(COD)Cl₂]₂ catalysts in chloroform at 60 °C for 12–24 h (Scheme 63). Upon further investigation, they found that the yield dramatically decreases with an increase in the steric hindrance.

Xu and co-workers¹³⁰ reported a first atroposelective approach for the synthesis of axially chiral aryl triazole 258 from internal alkynes 257 and azides 2 using Ir(I)/squaramide (O) 259 and DCE/EtOH (5:1) at 25 °C (Scheme 64). The optimum asymmetric induction was achieved with quinidine squaramide (O) and Ir(I). Other metals such as Cu(I) and Pd(II) are not suitable metal catalysts for this reaction, and organocatalysts (O) by themselves did not generate any product. The result suggested that both organocatalysts and metal catalysts are a necessity for the reaction. When the epimer of O (quinine-derived squaramide O′) was applied with the Ir(I)/squaramide (O) catalyst, the configuration-reversed product (aR) was formed in excellent yield with 3:97 er in standard conditions. Sterically hindered mesityl azide is also a suitable substrate for this approach that results in great enantioselectivity. The reaction was completely stopped when the −OH group of alkynes was protected, suggesting that the VQM (vinylidene ortho-quinone methide) intermediate was probably formed by the organocatalyst. Here, the VQM bifunctional ligands provide hydrogen bonding interactions with ketone. Therefore, the C–N bond determines the stereoselectivity of the approach.¹³¹

2.4.2. [Ir(COD)OMe]₂-Catalyzed Synthesis

Taran and co-workers¹¹⁴ reported a synthesis of 4-bromo-1,5-substituted triazoles 261 using bromoalkynes 260 and 2 using [Ir(COD)OMe]₂ catalysts in dichloromethane at −25 °C for 15 h (Scheme 65). For the substrate scope of the reaction, they found that electron-donating aryl alkynes gave a good yield compared to that with an electron-withdrawing group, and this approach is also suitable for sulfur-containing scaffolds but is affected by the steric effect.

2.5. Rhodium-Catalyzed Azide–Alkyne Cycloaddition (RhAAC)

2.5.1. [Rh(CO)₂Cl]₂-Catalyzed Synthesis

Zheng and co-workers¹³² reported a one-pot and regiodivergent synthesis of fully substituted 4-sulfonyl-1,2,3-triazole 263 and 5-sulfonyl-1,2,3-triazole 116 using the RhAAC reaction. Here, the regioselectivity of the reaction is controlled by nonmetallic sulfur(II) and sulfur(VI), giving 4- and 5-sulfonyl-functionalized products, respectively (Scheme 66).¹⁰⁶ For the synthesis of 263, internal thoialkynes 209 oxidized using m-CPBA gave internal sulfonyl alkyne 262, which further reacts with azide using [Rh(CO)₂Cl]₂ and DCE at 40 °C for 12–24 h. The electronic effect of aryl substituents does not affect the regioselectivity and yield, but p-nitrophenyl-substituted derivatives gave a slightly lower yield (73%). For the synthesis of 116, the first internal thoialkyne 116 undergoes the RhAAC reaction to yield 5-sulfur-1,2,3-triazole 42, which further oxidized into 5-sulfonyl-1,2,3-triazole 116. Here, 263 followed the nonchelation path, while 116 followed the chelation path (Figure 10).

Mechanistic cycle of the Rh catalyst.^32,132 Reprinted with permission from ref (32). Copyright 2020 John Wiley and Sons.

Song and co-workers¹³³ reported a regioselective approach for the synthesis of fully substituted 5-thiotriazoles 266 and fully substituted 5-trifluoromethylthiotriazoles 10 from internal thoialkynes 265 and internal alkynyl trifluoromethyl sulfides 264 with 2 at 40 °C and RT, respectively (Scheme 67). They used [Rh(CO)₂Cl]₂ as a catalyst and CHCl₃ as a solvent. They investigated the substrate scope of the reaction between 264 and 2 in which they found that various fully substituted 5-trifluoromethylthiotriazoles 10 were synthesized at RT without an inert gas medium in good yield and excellent regioselectivity. Yields were similar, and no significant electronic effects were observed. However, the yield of the corresponding compound was lower when p-nitrophenylethynyl(trifluoromethyl)sulfane was used as the reactant, but the regioselectivity was excellent. The RhAAC reaction could also be carried out with good yields using ortho- and meta-substituted phenylacetylenes. Due to a combination of unfavorable electronic as well as steric effects with a prolonged reaction time and higher temperature, the reaction for alkyl-substituted 264 did not occur. The expected compound could be produced with good yield and high regioselectivities when alkyl or aryl azides were used as substrates. This approach tolerated a broad range of functional groups, including halogen, ester, and carbonyl groups. The yield was drastically reduced when aryl azides were employed instead of alkyl azides.

Li and co-workers¹³⁴ reported the first rhodium(I)-catalyzed open flask approach for the synthesis of 5-aminotriazoles 268 from internal ynamides 267 and 2 using [Rh(CO)₂Cl]₂ catalysts and MeCN as a solvent at RT for 0.5–22 h (Scheme 68). They also reported that exclusion of air and moisture was not necessary because the reaction maintains similar efficiency with an open flask. This approach was also carried out with a variety of solvents without any discernible change in the reaction yield. The reaction outcomes were unaffected by ynamides with different protective groups. Interestingly, the reaction of ynamides with the nosyl group proceeded successfully, producing a triazole with an 84% isolated yield. The prolonged reaction time is most likely due to the nosyl group’s strong electron-withdrawing group properties. Regardless of the electronic nature, the reaction of para-methyl, methoxy, trifluoromethyl, and chloro-substituted ynamides produced the appropriate triazoles in excellent yields when compared to those with the standard ynamide. The meta- and ortho-substitution on the phenyl ring was also tolerated. The ynamides with a heteroaromatic ring or an extra alkenyl moiety were found to be good substrates for the RhAAC reaction.

Moses and co-workers¹³⁵ reported 2-substituted alkynyl-1-sulfonyl fluorides (SASFs) 269 as a new class of connective hubs. Stereoselective DOC (diversity-oriented clicking) of SASFs 269 with azide 270 showed various 1,5-substituted 1H-1,2,3-triazole-4-sulfonyl fluorides 271 in the presence of [Rh(CO)₂Cl]₂ catalysts and DCE solvent for 16 h at 40 °C (Scheme 69). Method A was effective with the electron-poor substrate but ineffective for electron-rich substrate caused by separation problems, while method B is effective for electron-rich reactants.

2.5.2. [Rh(COD)Cl]₂-Catalyzed Synthesis

Li and co-workers¹³⁶ reported an unprecedented and challenging approach for five-membered atropisomerism of 1,2,3-triazole 272 as chiral units. Axially chiral 1,4,5-substituted 1,2,3-triazole 272 was synthesized from internal alkyne 257 and azides 270 using enantioselective Rh catalyst, ligand (L) 273, and 4 Å MS (molecular sieves) in toluene at 10 °C for 10 h (Scheme 70). Here, employment of 4 Å MS enhanced the enantioselectivity and efficiency of E-RhAAC. This approach showed excellent functional group tolerance, as well as electronic properties of the substituent of the aryl rings, but does not affect the enantioselectivity and efficiency of E-RhAAC. Based on a DFT study and experimental observation, it was found that the hydroxy group plays an important role in regioselectivity.

2.6. Palladium-Catalyzed Azide–Alkyne Cycloaddition (PdAAC)

Mechanistically, there are two paths A and B for this PdAAC reaction. Both paths A and B are expected to lead to the title product. Surface-bound Pd-alkyne complex A collapses to produce complex B, which might lead through either pathway A or pathway B. These pathways are characterized by the earlier (path A) and later (path B) substitution reaction step using organohalide. Meanwhile, treatment of commercially available 4-phenyl-1H-1,2,3-triazole with 1,2-dichloroethane under the same condition did not yield 1-(2-chloroethyl)-4-phenyl-1H-1,2,3-triazole, ruling out pathway A (Figure 11).^137,138

Mechanistic cycle for the Pd catalyst.^137,138 Reprinted with permission from ref (137). Copyright 2015 Royal Society of Chemistry.

2.6.1. Pd(PPh₃)₄-Catalyzed Synthesis

Kar and co-workers¹³⁹ reported the synthesis of 1,2,3-triazolopolyhydroarenes/cycloalkenes 203 class using tandem Sonogashira coupling–CuAAC reaction. 275 was synthesized by Pd(0)–Cu(I)-catalyzed intramolecular heteroannulation of 2-/1-azidomethyl-1-/2-bromodihydronaphthalenes/arene/cycloalkenes 274 and 1 using catalyst Pd(PPh₃)₄, cocatalyst CuI, and Et₃N as the base at 60 °C using DMF as a solvent in an inert atmosphere (Scheme 71). This efficient method gave moderate to good yields of up to 59% and required 8–10 h for completion. This approach is very helpful for the synthesis of potential bioactive fused triazoloarenes.

2.6.2. Pd@PR Nanocatalyzed Synthesis

Das and co-workers¹³⁷ developed an efficient method for synthesizing 4-aryl-1-alkyl-1H-1,2,3-triazoles 280, 281 and 282 from selective monoazidation of 1,2-dihaloethane 278/279, 2-bromoethanol 277 and benzyl bromide 276 with sodium azide 44 and terminal aryl alkynes 46 using Pd@PR (polystyrene resin-supported palladium[0]) nanocomposite and DMF as a solvent for 8–12 h at 100 °C, respectively. 282 further reacted with K₂CO₃ and DMF at 110 °C for 3 h, giving the corresponding N-vinyl derivatives 283. Pd@PR-catalyzed Heck coupling reaction of 283 with aryl iodide 284 in the presence of K₂CO₃ and DMF at 120 °C for 20 h gave 4-aryl-1-(2-arylalkenyl)-1H-1,2,3-triazoles 285. In addition, Pd@PR-catalyzed MW-assisted dehydrohalogenative Heck coupling expanded the scope of N-vinyl-1H-1,2,3-triazole 283 (Scheme 72). The aryl alkynes with electron-releasing and electron-withdrawing functional groups produced the same yields comparatively. Both heteroaromatic and polyaromatic alkynes were suitable for this phenomenon. Under identical reaction conditions, 1-bromo-2-chloroethane in place of DCE generated an indivisible mixture of corresponding Cl and Br derivatives in moderate yield. Due to more prevalent SN² at the C–Br center, a higher percentage of chloro derivatives was produced. This novel phenomenon can provide outstanding examples of Pd@PR nanocomposite catalytic efficiency and selectivity as well as industrial interest.

2.7. Gold-Catalyzed Azide–Alkyne Cycloaddition (AuAAC)

Au cycloaddition followed a stepwise mechanism as in the previous report¹⁴¹ in which due to Au(I) active metal ion A, the electron density of alkynes is decreased. So, azide undergoes nucleophilic attack on B,^142,143 which leads to the formation of six-membered intermediate C. Finally, 3 was derived by the removal of gold from D (Figure 12).¹⁴¹

Au/TiO₂-catalyzed cycloaddition.^140,141 Reprinted from ref (140). Copyright 2013 American Chemical Society.

2.7.1. Au/TiO₂ Nanocatalyzed Synthesis

Muthusubramanian and co-workers¹⁴⁰ reported the green, efficient, and regioselective synthesis of 1,4-disubstituted triazoles 287 and 288 from substituted phenacyl azide 286 with terminal/internal alkynes 1/200 using porous Au/TiO₂ nanoparticles in water at RT for 20–30/45 min, respectively (Scheme 73). They also reported that solvents such as THF, DMSO, and ethanol showed moderate yields, and water or ^tBuOH/water resulted in remarkable yields as a single regioisomer, whereas p-xylene, 1,2-dichloroethane, acetonitrile, and toluene offered poor yields. Researchers further investigated that a stepwise technique for the synthesis of triazoles performed better than a one-pot MCR using azide 286, phenacyl/alkyl bromide, and 1 in 75% yield for 30 min. The catalyst was synthesized using the deposition–precipitation method and used up to five cycles without remarkable loss in the yield. For the substrate scope of alkynes, they found that aliphatic and aromatic alkynes with electron-withdrawing and electron-donating groups were suitable for this approach.

2.8. Silver-Catalyzed Azide–Alkyne Cycloaddition (AgAAC)

A mechanistic cycle of the AgAAC reaction is discussed below (Figure 13). The active catalyst A is formed by losing electrons from 18e^– molecules, which generates ligated silver(I) acetylide B. Nucleophilic interaction of azide 2 with B produces intermediate C, which is indicated as a 16e^– system, in which nitrogen migrates to carbon, carrying both electrons to produce metalated triazole D,¹⁴⁵ which leads to targeted molecule 3 on protonation and regenerates the active catalyst.

Mechanistic cycle of AgAAC. Reprinted with permission from ref (144). Copyright 2011 John Wiley and Sons.

2.8.1. Ag(I)-Complex-Catalyzed Synthesis

McNulty and co-workers¹⁴⁴ reported a novel, mild, regioselective, and the first purely silver-catalyzed azide–alkynes cycloaddition (AgAAC) reaction for the synthesis of 1,4-disubstituted triazoles 292 from azides 291 and alkynes 41 using a 2-diphenylphosphino-N,N-diisopropylcarboxamide-ligated silver(I)acetate complex as catalyst 290, caprylic acid, and PhMe at RT for 48 h (Scheme 74). Catalyst 290 was synthesized using silver(I)acetate with the amide of the tunable 2-diphenylphosphinobenzoic acid ligand 289 and CH₂Cl₂. They found that the hemilabile nature of the P,O-type ligand may play an important role in cycloaddition because Ag(I) salts alone did not give cyclization products. This hemilabile nature of the ligand may contribute to opening coordination sites for azide complex formation and provide electron density to the alkyl bond via metal to achieve cyclization.

McNulty and co-workers¹⁴⁵ developed a well-defined, chemically stable, highly effective homogeneous silver(I) 293 catalyst for the regioselective synthesis of 1,4-disubstituted triazole 3 from 2 and 1 using caprylic acid and PhMe at 90 °C. The reaction required 24 h for completion (Scheme 75). This approach provides a broad substrate scope as well as a catalyst that can be reused three times without noteworthy loss in product.

Sarma and co-workers¹⁴⁶ reported a highly efficient, robust, as well as novel approach for the regioselective synthesis of 3 from 2 and 1 catalyzed by highly efficient silver dicyanamide/DIPEA using H₂O/ethylene glycol at RT for 2–6 h (Scheme 76). For the substrate scope of alkynes, they found that aromatic alkyne gave slightly more yield (90–97%) compared to aliphatic alkyne (90–94%). Various functional groups containing alkynes such as alcohol and ester are also suitable substrates for this approach.

2.9. Zinc-Catalyzed Azide–Alkyne Cycloaddition (ZnAAC)

Based on a deuterated study¹⁴⁸ and according to the proposed mechanistic study of the ZnAAC reaction, transformation initially metalizes the alkyne C–H due to amine base, and formation of zinc acetylide B occurs.^149,150 Azide 2 attack on acetylide accelerated the generation of a six-membered intermediate C. After a subsequent reaction of D with an electrophile, desired product 4 was obtained (Figure 14).¹⁴⁷

Proposed mechanistic for ZnAAC. Reprinted from ref (147). Copyright 2013 American Chemical Society.

2.9.1. ZnEt₂-Catalyzed Synthesis

Greaney and co-workers¹⁴⁷ reported a regioselective synthesis of 4 from 1 and 2 using ZnEt₂ as a catalyst and NH₄Cl at RT for 72 h (Scheme 77). At high temperatures, the reaction gave less yield due to the decomposition of the reactant. For the alkyne substrate scope, they found that ester, thioether, propargylic ether, 1,2-diphenyl acetylene, and (iodoethynyl)benzene were suitable, whereas for the azide scope, tosyl azide and alkyl azide were not suitable for this approach. However, substitution at the 4-position was also observed by replacing NH₄Cl with D₂O/D₃CCO₂D through a 3-MCR coupling reaction to afford 1,4,5-trisubstituted triazole. The above approach takes 18 h for completion at ambient temperature.

2.9.2. Zn/C-Catalyzed Synthesis

To overcome the problem of separation of homogeneous catalysts from products and relatively few advancements done on heterogeneous solid catalysts, Chen and co-workers¹⁵¹ develop a novel, mild, and heterogeneous Zn/C (zinc on charcoal)-catalyzed approach for the synthesis of 4 and 59 from 2 with aryl alkynes 1 and 200, respectively (Scheme 78). They also found that aprotic and polar solvent DMF was a suitable solvent, and 50 °C was the suitable temperature for this approach. Zn dust typically contains Cu(II) impurities, whereas charcoal might be reduced from Cu(II) to Cu(I). They thought that a trace amount of CuI produced in situ catalyzed cycloaddition instead of Zn/C, but no cycloaddition products were observed. It is suggested that Zn/C could catalyze the reaction. They also reported that electron-deficient aryl alkynes gave less yield than electron-rich substituents, and that aliphatic alkynes did not cause a reaction. This approach was also performed under a one-pot, three-component reaction that produced less yield. The reaction required 15–20 h, and the efficiency of the catalyst decreased after the fifth cycle.

2.9.3. Zn(OTf)₂-Catalyzed Synthesis

Eppakayala and co-workers¹⁵² developed a simple and efficient synthesis of novel benzimidazole-linked triazoles 298 from 2-(4-azidophenyl)1H-benzo[d]imidazole 297 and alkynes 1 using t-BuOH/H₂O, Zn(OTf)₂, and NaASc at RT. For the synthesis of compound 297, o-phenylenediamine 159 and 4-aminobenzoic acid were reacted in the presence of PPA at 250 °C for 4 h, yielding compound 296, which further reacted with sodium azide 44 to obtain desired 297 azides (Scheme 79).

2.10. Lanthanide-Catalyzed Azide–Alkyne Cycloaddition (LnAAC)

A possible chemical path for the Ln[N(SiMe₃)₂]₃-catalyzed cycloaddition of 1 with azide is shown in Figure 15.¹⁵³ Activation of the C–H bond of 1 proceeds through the generation of lanthanide acetylide A and release of HN(SiMe₃)₂. The important intermediates (C and C′) are formed by the coordination and subsequent 1,1-insertion of azide into the Ln–C bond of A.¹⁵⁵ Following that, the distant N atom’s intramolecular anti-nucleophilic interaction on a p-coordinated alkyne moiety would result in the generation of triazole complex (D). Then protonation of D with another alkyne results in triazole 4 and the regeneration of lanthanide acetylide A. On the other hand, path b might be used to complete the catalytic cycle.

Proposed mechanism for SmAAC reaction^153,154 Reprinted with permission from ref (153). Copyright 2013 Royal Society of Chemistry.

2.10.1. Sm[N(SiMe₃)₂]₃-Catalyzed Synthesis

Zhou and co-workers¹⁵³ reported a first organolanthanide-/rare-earth-metal-catalyzed cycloaddition with broad substrate scope, mild conditions, and easily available catalyst. They synthesized 4 from 2 and 1 using Sm[N(SiMe₃)₂]₃, ⁿBuNH₂, and toluene at 50 °C for 24 h with good to excellent yield (Scheme 80). This catalytic approach differentiates internal and terminal alkynes. It also exhibits novel mechanistic characteristics such as a tandem anionic cascade cyclization reaction and antiaddition across the C≡C triple bond. For the substrate scope, they found that aryl azides are more reactive than alkyl azides because the aryl ring promotes the delocalization of negative charge to its neighboring N atom via conjugation, leading to an increased nucleophilicity of the N atom during the cyclization process. Noncoordinated substituents at the para-position of aromatic azides had little effect on the reaction. o-Methoxyphenyl azide formed in moderate yield, which might be due to the chelating coordination capable of increasing the bond between the Ln–N kinetic inertness and thermodynamic stability. Furthermore, the competitive coordination of nitro to the metal caused a decrease in yield. Moreover, the reactivity of alkyne is lowered by the strong chelating coordination of the pyridyl group. They also observed that 1-azido-4-(azidomethyl)benzene formed mono- and dicyclized compounds, depending on the stoichiometric amount of alkyne, while hexa-1,5-diyne gave only monocyclization product.

3. Organocatalytic Synthesis of 1,2,3-Triazole

Heavy metals in biological systems have been linked to cellular toxicity, oxidative damage, and metabolic instability.¹⁵⁶ To date, several metal-free (3 + 2) cycloaddition methods have been reported to synthesize numerous functionalized 1,2,3-triazoles. As a result, considerable scientific efforts have been put toward the evolution of a metal-free approach for the synthesis of triazoles in mild conditions. Organocatalysts have recently received a lot of interest in comparison with metal catalysts.^157,158 To accelerate the chemical reaction, organocatalysis employs a small organic moiety mostly consisting of C, P, N, O, H, and S. So, if we compared it with transition metal catalysts, the benefits of organocatalysis include their lack of sensitivity toward moisture and oxygen, their inexpensive, lower toxicity, and ready availability.¹⁵⁹ In 2008, Ramachary and co-workers¹⁶⁷ reported the first organo-catalyzed method for the synthesis of triazole. Later on, Bressy and co-workers¹⁶⁰ reported a synthesis of triazole using unactivated ketones, which becomes a solution for avoiding even trace amounts of metal residues in the final product. Here, we covered DBU, l-proline, diethylamine, pyrrolidine, and prolinamide-catalyzed approaches for the synthesis of 1,2,3-triazole.

Organocatalyzed synthesis is useful for metal-free as well as a one-pot combination of MCRs. Here, ketones are used as a surrogate of alkyne for enamine formation and various fully functionalized 1,2,3-triazoles, which are only obtained intermediately (Figure 16).^160,162,163 According to the catalyst screening done by Wang and co-workers,¹⁶¹ in addition to a secondary amine, primary and tertiary amines do not show significant catalytic activity and gave very low yields of 26 and <5%, respectively.

Organocatalytic synthesis of 1,2,3-triazole.^160,161 Reprinted with permission from ref (160). Copyright 2011 John Wiley and Sons.

3.1. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-Catalyzed Synthesis

Dehaen and co-workers¹⁶⁴ describe a novel approach for the synthesis of nonsymmetrical 5,5′-C,C-linked bi-1,2,3-triazoles 305 and 306 from 5-formyl-1,2,3-triazole 302. 5-Methoxybenzyl analogue 301 was easily synthesized from methyl 4-methoxyacetoacetate 299 and phenyl azide 300 using DBU and DMSO at ambient temperature for 3 h (Scheme 81). A subsequent photochemical conversion of 301 with bromine yielded 302 with a 65% yield. Aldehyde 302 was further transformed into nitroalkene derivatives 304 via oxidative [3 + 2] cycloaddition reaction. This aldehyde 302 and nitroalkene 304 are used as a reactant for the synthesis of axially chiral unsymmetrical tetra-ortho-substituted 5,5′-bi-1,2,3-triazoles 305 and 306, respectively. More steric hindered ortho-substituents prevent atropisomerism. Both approaches showed a broad scope for alkyl and aryl azide with various functional groups.

Mandal and co-workers¹⁶⁵ developed a regioselective, efficient, straightforward, as well as environmentally friendly protocol for the synthesis of sulfonyl-1,2,3-triazolyl glycoconjugates 311 and completely substituted 1,2,3-triazolyl glycoconjugates 312 from glycosyl azides 307, β-keto sulfone 308, and substituted phenyl aldehyde 309 using DMSO in an open flask at 50 °C for 1 h and DBU and DMSO for 1 h at RT, respectively (Scheme 82). For the DBU-promoted reaction, they found that aprotic polar solvents such as DMSO and DMF gave a good result compared to that with MeOH and CH₃CN (30% yield). They also reported that DMF with DBU gave 85% yield, whereas DMSO with DBU resulted in 92% yield. These results clearly showed that the formation of reactive enolates occurs, and DABCO, benzylamine-like less basic tertiary amine, gave moderate yield compared to that with DBU, while Et₃N in DMSO did not have a reaction after 24 h at RT.

Ramachary and co-workers¹⁶⁶ reported a regiospecific and mild DBU-catalyzed synthesis of 314 and its derivative 315. Ketones 313 and azides 2 reacted with DBU and DMSO at RT for 0.75–1.5 h to synthesize 314, which further reacted with Raney Ni and EtOH at RT for 1–3 h to obtain 315 (Scheme 83).

3.2. l-Proline-Catalyzed Synthesis

Bressy and co-workers¹⁶⁰ reported a highly substituted triazole 318 from unactivated ketone 316 and aryl azides 119 using l-proline 317 as an organocatalyst and dichloromethane at 80 °C under thermal conditions (Scheme 84). All cyclic ketones gave good yields. Among all the cyclic ketones cyclooctane gave a higher yield, and the dissymmetrical cyclic ketone showed excellent regioselectivity. They also reported that 4-(NO₂)PhN₃ as well as acetophenone did not react through this approach. Here, the reaction’s regioselectivity depends on a combination of two factors. First, regioselectivity results from the preferred form from two enamine intermediates, and second, the regioselectivity is caused by the addition of azide to the enamine.

Ramachary and co-workers¹⁶⁷ reported the first NH-1,2,3-triazoles 321 and 322 from Hagemann’s ester 319 and p-toluenesulfonyl azide 320 using amino acid (l-proline) catalyst 317 and DMSO as a solvent at RT for 0.75–24 h (Scheme 85). This approach gave 322 as a major product. If the reaction proceeds with BnNH₂ and DMSO, it yields diazo compound 323 as a major product.

3.3. Diethylamine-Catalyzed Synthesis

Wang and co-workers¹⁶² reported the first metal-free, regioselective, and organocatalyst-promoted enamide–azide cycloaddition reaction using diethylamine 325 as a catalyst. 1,4,5-Trisubstituted 1,2,3-triazole 59 was synthesized from β-ketoester 324 and azides 2 using DMSO as a solvent at 70 °C with 80–96% yields (Scheme 86). Also, this approach is useful for various functional groups like ester, ketone, and nitrile for further synthetic applications. Without affecting the yields, the electron-donating group required a longer time compared to the electron-withdrawing group. However, alkyl azide is also a suitable substrate for this approach but required 10 mol % catalyst loading.

Alves and co-workers¹⁶⁸ reported a mild, efficient, and novel approach for a wide range syntheses of (arylselanyl)-phenyl-1H-1,2,3-triazole-4-carboxamides 328 from β-oxo-amides 326 and aryl azidophenyl selenides 327 using diethylamine 325 catalyst and DMSO at RT for 2–5 h (Scheme 87). For the substrate scope of β-oxo-amides, they reported that the electron-deficient group nearer to the oxo position (−R) decreased the yield, while the EWG or EDG group on the amide aromatic ring (−R¹) gave a good isolated product. However, when they performed a reaction with a strong electron-withdrawing group such as R¹ = −NO₂, only 59% desired product was obtained. For the aryl azidophenyl selenide scope of this reaction, they found that the electron-EWG-containing aromatic ring (−R³) gave good yields compared to those with the EDG. This approach may be useful in the future for the synthesis of novel selenium-containing triazole scaffolds.

3.4. Miscellaneous Organocatalysts

3.4.1. Pyrrolidine-Catalyzed Synthesis

Wang and co-workers¹⁶¹ reported a Huisgen [3 + 2] cycloaddition-promoted enamine-catalyzed method for the synthesis of highly substituted triazoles 59/330 using 2 and acyclic/cyclic carbonyl compounds 324/329 using pyrrolidine 310 as a catalyst and DMSO at up to 80 °C with complete regioselectivity (Scheme 88). This approach gave moderate to good yield with a very vast substrate scope (28 examples) and was useful for further sophisticated heterocyclic scaffolds. Both cyclic and acyclic ketone compounds gave a good yield with this approach; however, the acyclic ketone gave a good yield compared to that with the cyclic ketone. They also reported that the reaction of TsN₃ with cyclohexanone in the presence of l-proline did not react, while the pyrrolidine-catalyzed reaction gave an 85% yield.

Ramachary and co-workers¹⁶³ developed a one-pot combination of MCR pyrrolidine 310 catalyzed functionalized bicyclic N-aryltriazole 332 from activated cyclic enone 319 and aryl azides 119 using DMSO as a solvent at RT for 1–6 h (Scheme 89). For the azide scope of the method, they found that the electron-withdrawing group and neutral azides resulted in good to excellent yields. However, 4-MeOC₆H₄N₃ did not react even at a higher temperature. The predicted bicyclic N-aryltriazole was obtained in good to excellent yields from aliphatic and aromatic unmodified cyclic enones. The aryl substitution at the C6 position of cyclic enone enhanced the yield, while aliphatic substitution lowered the yield and increased the reaction time.

3.4.2. Prolinamide-Catalyzed Synthesis

Wang and co-workers¹⁶⁹ reported a green, enamine-catalyzed, and more feasible method for the synthesis of triazole 59 from cycloaddition of ketones 324 and 2 using water as a solvent. To access a vast library of 1,2,3-triazoles, a longer aliphatic chain-tolerated prolinamide 333 was used as an effective organocatalyst to fully drive the Huisgen 1,3-dipolar cycloaddition (Scheme 90a). This catalyst is effective as a broad substrate scope for the reaction.

Cyclic ketones with six- to eight-membered rings are suitable substrates for this approach, and naphthalene is a suitable substrate for the azide scope of this reaction.

They also reported that dissymmetrical cyclic ketone has a high level of regioselectivity (Scheme 90b). For example, 3,3-dimethylcyclohexanone 335 resulted in a single regioisomer 337 because the heterocycle is sterically separated from the gem-dimethyl group, while the isomer of 335, which is 4,4-dimethylcyclohexanone 336, yielded 338, which is also an isomer of 337 because cycloaddition occurs with the most stable enamine to explain the regioselectivity.

4. Metal-Free Synthesis of 1,2,3-Triazole

Apart from this organocatalysis method, some simple, green, general, efficient, and convenient metal-free approaches are developed for the various types of functionalized triazole derivatives. Some of the reactions are important for the synthesis of thiolated and sulfone-functionalized-1,2,3-triazoles. For example, Wan and co-workers¹⁷⁰ reported a metal-free, organic solvent-free, and easy synthesis of 5-thiolated 1,2,3-triazole. Mohanan and co-workers¹⁷¹ reported mild as well as metal-free synthesis of a sulfone-functionalized triazole scaffold. These methods involve some base, solvent, ionic liquid, and molecular iodine.

Harmata and co-workers¹⁷² reported an experimentally convenient synthesis of N-TBS-S-alkynyl sulfoximines 341 from sulfoximines 339 and methyl ester (RCO₂Me) using LDA as a base, THF, Tf₂O, and pyridine with good to excellent yield. Further utilization of 341 with 334 in H₂O at reflux for 18 h gave a mixture of regioisomers of 1,4,5-trisubstituted triazoles 342 and 343 with a good yield (Scheme 91). They also reported that the steric influence controls the regioselectivity of the reaction.

Wan and co-workers¹⁷⁰ reported a metal-free synthesis of sulfur-containing triazole 272 from easily available tosyl azide 320 and β-thiolated enaminones 344 using TMEDA as a base and water in a sealed tube at 120 °C (Scheme 92). This approach has broad substrate scope with excellent yield. The use of water as the only medium^173−176 provided a greener route without interfering with any trace amount of metal toxicity.

Mohanan and co-workers¹⁷¹ reported a metal-free, mild reaction for the synthesis of fully substituted sulfonyl triazole 349 from benzaldehyde 346, primary amine 347, and α-diazo-β-keto sulfone 348 using K₂CO₃, I₂, and EtOH at RT for 48 h (Scheme 93). For the substrate scope of the approach, they determined that aryl aldehyde containing and electron-deficient group did not react because of rapid hydrolysis of imine, and heteroaryl and bi- and trisubstituted aryl aldehyde were also suitable for this approach. Aliphatic, aromatic, as well as sterically crowded primary amine are suitable for this reaction and gave moderate to good yield.

Pokhodylo and co-workers¹⁷⁷ reported a base-catalyzed cycloaddition of β-keto sulfone/β-nitrile sulfones 350 and aryl azides 119 using MeONa and MeOH at RT to synthesize 1H-1,2,3-triazol-4-yl sulfones 351 with moderate to good yield for 2–5 h (Scheme 94). These molecular libraries are very useful for biological activity testing. The internal electrophile in β-keto sulfone or β-nitrile sulfone might be a carbonyl or cyano group. Also, sulfonyl azides were employed for diazo transfer to the CH-acid moiety, specifically for activated β-keto ester and β-keto sulfones.^178,179 In this approach, enolate or enol attacks the 119, and the formation of triazene occurs, which combines with the diazo moiety and sulfonamide after tautomerization.

Back and co-workers¹⁸⁰ reported a cycloaddition reaction of acetylenic sulfones 352 and benzyl azide 76 using toluene, LiOH, and THF for 3–7 days for the synthesis of 1,4,5-trisubstituted triazole isomers 353 and 354 (Scheme 95).

Shafii and co-workers¹⁸¹ reported the synthesis of 1-(4-aminosulfonylphenyl)-5-aryltriazoles and 1-(4-methylsulfonylphenyl)-5-aryltriazoles 359 as COX-2 inhibitors. First, they prepared an imino compound 357 by the reported method,¹⁸² but it did not work. So they performed this reaction in a mixture of ethanol/THF from 4-methylsulfonylaniline 355 and substituted benzaldehyde 356 to afford compound 357 with a good yield (Scheme 96). According to the literature, subsequent 1,3-cycloaddition of 357 with diazomethane in ether also did not provide a cyclization product.¹⁸³ Ultimately, cycloaddition was achieved with diazomethane in dioxane/water¹⁸⁴ to obtain 1-(4-methylsulfonylphenyl)-5-aryl-4,5-dihydro-1H-1,2,3-triazoles 358. Subsequent oxidation of 358 with potassium permanganate in acetone gave a low yield¹⁸⁵ of product of 359 but achieved moderate yield (40–52%) with a phase transfer catalyst (tetrabutylammonium chloride).¹⁸⁶ For the synthesis of 1-(4-aminosulfonylphenyl)-5-aryltriazoles, the −NH₂ bearing imino compound did not undergo cycloaddition with diazomethane in dioxane. Therefore, 4-acetamidobenzenesulfonyl chloride was reacted with dibenzyl amine in THF followed by acid hydrolysis to obtain compound 362, which further reacted with substituted benzaldehyde in p-toluenesulfonic acid to give imino compound 363. Further reaction of 363 gave 364, which further oxidized in the presence of KMnO₄ to give compound 365. Deprotonation of compound 365 yielded the desired product 1-(4-aminosulfonylphenyl)-5-aryltriazoles 366 with 20–49% yield.

Fokin and co-workers¹⁸⁷ reported a mild, transition-metal-free approach for the synthesis of 1,5-disubstituted triazole 367 from terminal aryl alkynes 41 and aryl azides 119 using tetraalkylammonium hydroxide in DMSO at RT (Scheme 97). For the substrate scope, it was found that aryl, heteroaryl, terminal alkynes, and base-labile functional groups are suitable for the reaction. Due to the low acidity, alkyl acetylene did not provide any yield under this condition.¹⁸⁸ Electron-deficient azides and alkyne both gave lower yields due to ineffective triazenide cyclization and a decrease in nucleophilicity.

The aryl acetylide A formed by reversible deprotonation of the 41 reacts as a Nu^– for an attack on the terminal nitrogen of aryl azide 119 and forms triazenide intermediate B, which undergoes 6π-electrocyclization or 5-endo-dig cyclization to generate the 1,5-disubstituted triazolyl anion C and achieves the catalytic cycle by deprotonation of DMSO, water, or a terminal alkyne to form 367.

Wan and co-workers¹⁸⁹ developed a novel, regioselective, metal- and azide-free 3-MCR approach for the synthesis of 1,5-disubstituted triazole 371 using enaminones 368, tosyl hydrazine 369, and primary amines 370 using molecular iodine and DMSO at 110 °C (Scheme 98). For enaminones, they found that the electron-donating group containing the aryl ring gave a good yield compared to that with the electron-withdrawing group, and heteroaryl-based (thiophene) enaminones are also a suitable substrate for this reaction. Primary alkyl amine is not a suitable substrate for this reaction due to the inactive key intermediate.¹⁹⁰

4.1. Strain-Promoted Azide–Alkyne Cycloaddition (SPAAC)

Bioorthogonal synthesis of such chemically modified biomolecules is an emerging field of chemistry as well as biology. Besides these, the CuAAC reaction is important for such synthesis, but the cytotoxicity of the copper catalyst is still a disadvantage for bioorthogonal chemistry. To reduce this restriction, Bertozzi and co-workers^191,192 performed the bioorthogonal, copper-free, and strain-promoted azide–alkyne cycloaddition (SPAAC).

Wills and co-workers¹⁹³ reported a catalyst-free and strain-promoted azide–alkyne cycloaddition of strained alkynes 372 with azide 2 using MeCN at room temperature to 60 °C for 1–14 days or using PhC(Cl)NOH and DMF at room temperature for 3 days for the synthesis of functionalized triazole 373 with 81–96% yield (Scheme 99). These strained alkynes 372 were synthesized from biaryl diols and 1,4-ditosylbut-2-yne.¹⁹⁴

For the versatile use of the SPAAC reaction, Kii and co-workers¹⁹⁵ reported a catalyst-free strain-promoted “double-click” (SPDC) reaction of Sondheimer (sym-dibenzo-1,5-cyclooctadiene-3,7-diyne) 374, which has two highly strained alkyne bonds with two azido molecules, 375 and 376, which gave the desired 1,2,3-triazole product 377 (Scheme 100). Here, they use these azido groups which are azido biomolecules (such as proteins, sugars, lipids, and nucleotides) 375 and small azido compounds (fluorescent dyes, photoreactive group, chemical ligands) 376.

5. Solvent- and Catalyst-Free Neat Synthesis of 1,2,3-Triazole

For utilization of greener and more simple routes for the synthesis of the titled compound, some metal-/metal-additive-free, catalyst-free, and solvent-free reactions are important because these routes do not require any purification step.

Gouin and co-workers¹⁹⁶ reported a metal-free, green, and regioselective generation of 4-sulfonyl-functionalized triazoles 379 and 380 from p-toluene sulfonyl alkyne 378 and azides 2 at ambient temperature (Scheme 101). The strong withdrawing action of the sulfonyl group lowers the activation energy barrier for the [3 + 2] cycloaddition and allows for direct incorporation of a chemical group onto the aromatic ring for structuring the titled compound. First, the reaction mixture was dissolved in a minimum amount of dichloromethane, and then the mixture was evaporated at 16 °C under reduced pressure for 5 min and then took 2 h under MW conditions to complete the reaction with high regioselectivity. Steric hindrance does not affect the reaction time and product yield.

Surya Prakash and co-workers¹⁹⁷ reported a solvent- and catalyst-free microwave-assisted synthesis of 4,5-disubstituted triazoles 382 using alkynes 200 and trimethylsilyl azide (TMSN₃) 381 at a constant temperature of 200 °C for 1–7 h under inert conditions (Ar/N₂). After MW irradiation, the reaction vessels were introduced to air for 30 min (Scheme 102). For the alkyne substrate scope, they found that electron-deficient aromatic, electron-rich aromatic, halogenated, allylic, as well as symmetric and asymmetric substrates are also suitable for this approach. Because the polar moiety selectively absorbs MW irradiation, and nonpolar moieties are inert to it, the presence of polar moieties is necessary to attain more effective heating across the reaction, and as a result, a shorter reaction time can be expected as several polar moieties on the substrate increase. Because of the presence of the trimethylsilyl group, steric hindrance and electron-rich moieties also interfere with the reaction. This approach also provides a safe, atom-economical, as well as a more convenient route for the synthesis of the title compound.

6. Conclusion

This review paper analyzed the synthesis recorded in the past 21 years (2002–2022) for 1,2,3-triazole. The CuAAC reaction is the most efficient and often used bioorthogonal reaction because it possesses the majority of criteria for the click reaction and has huge applications in various fields. However, cytotoxicity is also a severe problem that has been detected in various types of cells. Ruthenium is a good choice for 1,5-regioisomers and has a broad substrate scope. This approach is influenced by the steric and electronic factors of the substrate. Zn and Sm are also suitable catalysts for the synthesis of 1,5-disubstituted triazole. IrAAC and RhAAC reactions have broad substrate scope as well as the same steric and electronic effect as that in the RuAAC reaction. Some other MAAC reactions have not been explored yet. Recently, organocatalysis synthesis is dominant for the title compound. Nowadays, some green and click-chemistry-based metal- and solvent-free reactions are developed. The majority of this research has been done using simple substances. A few efficient approaches for the manufacture of triazole-scaffold-containing pharmaceuticals have been recently discovered. A constant invention of new developments indicates that 1,2,3-triazoles will help lead to future organic synthesis and are useful for creating molecular libraries of various functionalized 1,2,3-triazoles.

Acknowledgments

We are thankful to the Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar for proving the necessary research facilities.

Glossary

Abbreviations

MAAC: metal-catalyzed azide–alkyne cycloaddition
CuAAC: copper-catalyzed azide–alkyne cycloaddition
NiAAC: nickel-catalyzed azide–alkyne cycloaddition
RuAAC: ruthenium-catalyzed azide–alkyne cycloaddition
IrAAC: iridium-catalyzed azide–alkyne cycloaddition
RhAAC: rhodium-catalyzed azide–alkyne cycloaddition
PdAAC: palladium-catalyzed azide–alkyne cycloaddition
AuAAC: gold-catalyzed azide–alkyne cycloaddition
AgAAC: silver-catalyzed azide–alkyne cycloaddition
ZnAAC: zinc-catalyzed azide–alkyne cycloaddition
SmAAC: samarium-catalyzed azide–alkyne cycloaddition
SPAAC: strain-promoted azide–alkyne cycloaddition
TMSCF₃: trifluoromethyltrimethylsilane
NPs: nanoparticles
TMSIT: trimethylsilyl-5-iodo-triazoles
TMS: trimethylsilyl
DMSO: dimethyl sulfoxide
DMF: dimethylformamide
RT: room temperature
DCM: dichloromethane
BPB: N-benzyl proline benzophenone
AT-CuAAC: active template Cu-catalyzed alkyne–azide cycloaddition
PCR: polymerase chain reaction
Tf: trifluoromethanesulfonyl
THF: tetrahydrofuran
β-CD-TSC@Cu: copper(I)-ion-supported thiosemicarbazide-functionalized β-cyclodextrin
ICP-OES: inductively coupled plasma optical emission spectroscopy
PPI: protein–protein interactions
NfN₃: nonafluorobutanesulfonyl or nonaflyl azide
NaASc: sodium ascorbate
Cu₂O/HTNT-7: Cu₂O nanoparticles supported on hydrogen trititanate nanotubes
ICP-MS: inductively coupled plasma mass spectroscopy
DKR: dynamic kinetic resolution
PEG-200: polyethylene glycol-200
GO: graphene oxide
DFT: density functional theory
COD: 1,5-cyclooctadiene
TFAA: trifluoroacetic acid
SPPS: solid-phase peptide synthesis
HFIP: 1,1,1,3,3,3-hexafluoroisopropanol
MW: microwave
ISG: iterative sequential growth
THP: tetrahydropyranyl
Boc: tert-butyloxycarbonyl
SASFs: 2-substituted alkynyl-1-sulfonyl fluorides
DOC: diversity-oriented clicking
ET₃N: triethyl amine
Pd@PR: polystyrene resin supported palladium[0]
DIPEA: N,N-diisopropylethylamine
Zn(OTf)₂: bis(trifluoromethanesulfonato)zinc
PPA: polyphosphoric acid
Ln: lanthanum
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DABCO: 1,4-diazabicyclo[2.2.2]octane
TsN₃: tosyl azide
LDA: lithium diisopropylamide
N-TBS: N-tert-butyldimethylsilyl
Tf₂O: triflic anhydride
TMEDA: tetramethylethylenediamine
COX-2: cyclooxygenase-2
MCRs: multicomponent reactions
TMSN₃: trimethylsilyl azide

Author Contributions

D.P.V. and H.M.P. designed a review article collection. All authors contributed equally to the drafting.

The authors declare no competing financial interest.

This paper was published on October 10, 2022. Text related to references 160 and 167 was revised, and the corrected paper was reposted on October 13, 2022.

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PERMALINK

Versatile Synthetic Platform for 1,2,3-Triazole Chemistry

Disha P Vala

Ruturajsinh M Vala

Hitendra M Patel

Abstract

1. Introduction

Figure 1.

Figure 2.

Figure 3.

2. Synthesis of 1,2,3-Triazole via Metal-Catalyzed Azide–Alkyne Cycloaddition

Scheme 1. Synthesis of 3 and 4 through Huisgen 1,3-Dipolar Cycloaddition.

2.1. Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC)

Scheme 2. Cu Catalyzed Synthesis of 3.

Figure 4.

2.1.1. Cu(I)-Catalyzed Azide–Alkyne Cycloaddition

2.1.1.1. CuI-Catalyzed Synthesis

Scheme 3. Cu-Catalyzed Synthesis of 8 and 9 without and with the Phosphorylation Approach, Respectively.

Scheme 4. Synthesis of 10 from Alkyne, Azide, S8, and TMSCF3 Using CuI as the Catalyst.

Scheme 5. Synthesis of Derivatives of 10 Using a Persulfuration Reaction via CuI and tBuOLi.

Scheme 6. Use of Click Reaction for the Synthesis of Derivatives of 17 Using CuI as a Catalyst.

Scheme 7. Synthesis of Key Precursor 20 and Further Synthesis of Triazole Analogues.

Scheme 8. Synthesis of 27/28 via Cu-Catalyzed Cycloaddition Reaction of Terminal Alkyne and Diazide.

Scheme 9. Synthesis of Analogues of 33 Using CuI Catalyst and Ascorbic Acid at RT.

Scheme 10. Triazole 3 Synthesized from 1 and 2 in the Presence of CuI Catalyst Using a Flow Reactor.

Scheme 11. Synthesis of 39 and 40 through CuI and Ru(II) Catalysts.

Scheme 12. CuI promoted synthesis of 42 and analogous under mild reaction condition.

Scheme 13. Synthesis of 47 and Derivatives from 45 Using CuI as the Promoter.

Scheme 14. CuI-Promoted Synthesis of 51 and 52.

Scheme 15. Synthesis of Polyfunctionalized Triazole 56.

2.1.1.2. CuCl-Catalyzed Synthesis

Scheme 16. Synthesis of 59, 60, and 10 Using Divergent Routes.

Scheme 17a. Asymmetric Desymmetrization of Oxindole Derivatives 61.

Scheme 17b. Synthetic Elaboration of 64.

Scheme 18. Highly Enantioselective Synthesis of Alcohol-Containing Triazoles 73 and 74.

Scheme 19a. Synthesis of 77 and 78.

Scheme 19b. Kinetic Resolution of 80.

2.1.1.3. Cu(MeCN)4PF6-Catalyzed Synthesis

Scheme 20. Synthesis of Analogues Promoted by Cu(I) Catalyst with High Regioselectivity.

Scheme 21. [Cu(MeCN)4]PF6-Promoted Synthesis of Rotaxane 92.

Scheme 22a. Synthesis of 96 and 97 via 3-CAP.

Scheme 22b. Synthesis of Diverse Polymers.

Scheme 23. MCP Reaction of Diynes 103, Diazides 104, and Electrophiles 105.

2.1.1.4. CuOTf-Catalyzed Synthesis

Scheme 24. Synthesis of Chiral Biaryl-Bearing Triazoles 108 and 109.

Scheme 25a. CuOTf-Promoted Synthesis of 113.

Scheme 25b. Electrophilic Substitution Reactions of 113.

2.1.1.5. β-Cyclodextrin-TSC@Cu-Catalyzed Synthesis

Scheme 26. Synthesis of 120 and 121 Catalyzed by a Nanocatalyst β-CD-TSC@Cu.

2.1.1.6. Phenylethynylcopper(I)-Catalyzed Synthesis

Scheme 27. Phenylethynylcopper(I)-Promoted Synthesis of 124.

2.1.1.7. Miscellaneous CuAAC-Catalyzed Reaction

Scheme 28. CuAAC Desymmetrization and CuAAC Kinetic Resolution.

Scheme 29a. Synthesis of 137 and 138 via Kinetic Resolution and Desymmetrization.

Scheme 29b. Synthesis of Monoethynylphosphine Oxide 141.

2.1.2. Cu(II)-Catalyzed Azide–Alkyne Cycloaddition

2.1.2.1. CuCl2-Catalyzed Synthesis

Scheme 30. Synthesis of Derivatives of 146 Using CuCl2/Zn Powder in Water at RT.

Figure 5.

2.1.2.2. CuSO4-Catalyzed Synthesis

Scheme 31. CuSO4·5H2O-Promoted Synthesis of Derivative of 151.

Scheme 32. Synthesis of 154 Using Cu(I) Catalyst.

Scheme 33. Synthesis of 157 and 158 Using CuSO4·5H2O.

Scheme 34. CuSO4-Assisted Synthesis of 163 and Its Derivatives.

Scheme 35. Synthesis of 166 Using CuSO4·5H2O Catalyst in DMF/Water Solvent.

Scheme 36. Synthesis of 169 and Its Derivative 170.

Scheme 37. CuSO4·5H2O-Catalyzed Synthesis of 173 and 174 and Their Derivatives.

Scheme 38. Synthesizing 176 via Utilization of 18-Crown-6, Sodium Ascorbate, and CuSO4 in Chloroform/Water.

Scheme 39. CuSO4·5H2O and Sodium-Ascorbate-Promoted Synthesis of 181 and 182 and Their Derivatives in Aqueous Methanol.

Figure 6.

Scheme 40. Synthesis of Ir-Containing Complexes 194–196 Containing Luminescence Properties.

Scheme 41. Synthesis of 199 in the Presence of Aqueous CuSO4 with NaASc in DMF.

2.1.3. Heterogeneous Cu-Catalyzed Azide–Alkyne Cycloaddition

2.1.3.1. Cu2O/HTNT-7-Nanocatalyzed Synthesis

Scheme 42. Utilizing Cu2O/HTNT-7 as a Catalyst to Synthesize 120 at RT.

2.1.3.2. Cu@N–C-Catalyzed Synthesis

Scheme 43. Cu@N–C(600)-Promoted Synthesis of 3 in Aqueous tBuOH.

2.1.3.3. CuI Nanoparticle Synthesis

Scheme 44. CuI NP-Promoted Synthesis of 202 and Its Derivatives.

2.2. Nickel-Catalyzed Azide–Alkyne Cycloaddition (NiAAC)

Scheme 4. Synthesis of 10 from Alkyne, Azide, S₈, and TMSCF₃ Using CuI as the Catalyst.

Scheme 5. Synthesis of Derivatives of 10 Using a Persulfuration Reaction via CuI and ^tBuOLi.

2.1.1.3. Cu(MeCN)₄PF₆-Catalyzed Synthesis

Scheme 21. [Cu(MeCN)₄]PF₆-Promoted Synthesis of Rotaxane 92.

2.1.2.1. CuCl₂-Catalyzed Synthesis

Scheme 30. Synthesis of Derivatives of 146 Using CuCl₂/Zn Powder in Water at RT.

2.1.2.2. CuSO₄-Catalyzed Synthesis

Scheme 31. CuSO₄·5H₂O-Promoted Synthesis of Derivative of 151.

Scheme 33. Synthesis of 157 and 158 Using CuSO₄·5H₂O.

Scheme 34. CuSO₄-Assisted Synthesis of 163 and Its Derivatives.

Scheme 35. Synthesis of 166 Using CuSO₄·5H₂O Catalyst in DMF/Water Solvent.

Scheme 37. CuSO₄·5H₂O-Catalyzed Synthesis of 173 and 174 and Their Derivatives.

Scheme 38. Synthesizing 176 via Utilization of 18-Crown-6, Sodium Ascorbate, and CuSO₄ in Chloroform/Water.

Scheme 39. CuSO₄·5H₂O and Sodium-Ascorbate-Promoted Synthesis of 181 and 182 and Their Derivatives in Aqueous Methanol.

Scheme 41. Synthesis of 199 in the Presence of Aqueous CuSO₄ with NaASc in DMF.

2.1.3.1. Cu₂O/HTNT-7-Nanocatalyzed Synthesis

Scheme 42. Utilizing Cu₂O/HTNT-7 as a Catalyst to Synthesize 120 at RT.

Scheme 43. Cu@N–C(600)-Promoted Synthesis of 3 in Aqueous ^tBuOH.

2.2.1. Ni(COD)₂-Catalyzed Synthesis

Scheme 45. Preparation of 205 and Its Derivatives Using Ni(COD)₂ as a Promoter.

2.2.2. Cp₂Ni/Xantphos-Catalyzed Synthesis

Scheme 46. Synthesis of Derivatives of 4 at RT Using the NiCp₂/Xantphos Catalyst.

2.3.2. [Cp*RuCl]₄-Catalyzed Synthesis

Scheme 56. [RuCl(Cp*)]₄-Promoted Synthesis of 242.

2.3.3. [RuClCp*(PPh₃)₂]-Catalyzed Synthesis

Scheme 57. [RuCl(PPh₃)₂(Cp*) Impulsive Synthesis of 207.

2.4.1. [Ir(COD)Cl]₂-Catalyzed Synthesis

Scheme 58. [Ir(COD)Cl]₂-Catalyzed Synthesis of 246.

Scheme 59. Iridium-Catalyzed Synthesis of 248 in DCM at RT under a N₂ Atmosphere.

Scheme 61. Preparation of 250 and Its Derivatives Using [Ir(COD)Cl]₂ as a Catalyst.

Scheme 63. Synthesis of 254 and 256 by Utilizing [Ir(COD)Cl]₂ as a Catalyst.

2.4.2. [Ir(COD)OMe]₂-Catalyzed Synthesis

Scheme 65. Synthesis of Analogues of 261 Using [Ir(COD)OMe]₂ Catalysts in DCM.

2.5.1. [Rh(CO)₂Cl]₂-Catalyzed Synthesis

Scheme 67. [Rh(CO)₂Cl]₂-Promoted Synthesis of 10 and 266 and Their Derivatives.

Scheme 69. Use of [Rh(CO)₂Cl]₂ as a Promoted Synthesis of 271.

2.5.2. [Rh(COD)Cl]₂-Catalyzed Synthesis

2.6.1. Pd(PPh₃)₄-Catalyzed Synthesis

Scheme 71. Synthesis of 275 with Its Derivatives through Sonogashira Coupling Using Pd(PPh₃)₄.

2.7.1. Au/TiO₂ Nanocatalyzed Synthesis

Scheme 76. AgN(CN)₂, DIPEA-Catalyzed Synthesis of 3 in Aqueous Glycol at RT.

2.9.1. ZnEt₂-Catalyzed Synthesis

Scheme 77. Regioselective Synthesis of 4 and 294 Using ZnEt₂.

2.9.3. Zn(OTf)₂-Catalyzed Synthesis

Scheme 79. Synthesis of 298 Using Zn(OTf)₂ Catalyst.