Synthesis methods of 1,2,3-/1,2,4-triazoles: A review

Triazole, comprising three nitrogen atoms and two carbon atoms, is divided into two isomers 1,2,3-triazole and 1,2,4-triazole. Compounds containing a triazole are one of the significant heterocycles that exhibit broad biological activities, such as antimicrobial, analgesic, anti-inflammatory, anticonvulsant, antineoplastic, antimalarial, antiviral, antiproliferative, and anticancer activities. A great quantity of drugs with a triazole structure has been developed and proved, for example, ketoconazole and fluconazole. Given the importance of the triazole scaffold, its synthesis has attracted much attention. This review summarizes the synthetic methods of triazole compounds from various nitrogen sources in the past 20 years.

Frontiers in Chemistry frontiersin.org 04 and alkynes as substrates participated in reactions, which had been successfully used in synthesis of bioactive nucleoside analogues. In this method, based on the temperature effect, copper bromide is used as a catalyst in the absence of a ligand. Between 0 o C and 70°C, the yield of bis(1,2,3-triazole) increased with the decrease of reaction temperature and reached 91% (Li et al., 2013) after stirring for 20 h at 0°C. The opposite phenomenon: the yield of 5-alkynyl-1,2,3-triazole was highest SCHEME 3 Synthesis and mechanism of triazole derivatives from TMSN 3 .
Frontiers in Chemistry frontiersin.org 05 (68%) at 60°C. As the temperature increases, the yield increases, and 60°C is the optimum temperature (Scheme 1A).
A possible mechanism of the temperature-mediated reaction is described in Scheme 1B. The triazolyl-copper complex intermediate 3 was generated by the CuAAC reaction. The tandem aerobic oxidative coupling reaction might be the key of this reaction. In addition, temperature might affect the reactivity of the triazolyl-copper complex 4 and 5. At 0°C, the aerobic oxidative coupling reaction could react preferentially by Path A to construct bis(1,2,3-triazole) 1. Meanwhile, at 60°C, the aerobic oxidative coupling reaction could react preferentially by Path B to construct 5-alkynyl-1,2,3-triazole 2.
In 2008, Kalisiak reported an efficient three-component synthetic pathway for the production of 2-hydroxymethyl-2H-1,2,3-triazoles through Cu-catalyzed cycloaddition of terminal alkyne, NaN 3 , and formaldehyde in one pot (Jarosław Kalisiak and Fokin, 2008;Tian et al., 2022). Using copper as a catalyst, acetic acid was added in equal amounts and 1,4-dioxane was used as the solvent. At room temperature, yields ranged from 67% to 95% (Jarosław Kalisiak and Fokin, 2008;Tian et al., 2022). Due to the advantages of wide range of substrates and high compatibility of functional groups, the target products could be diversified (Scheme 2A).
In 2012, the "one pot" three components preparation of N2substituted-1,2,3-triazole with chalcone, sodium azide, and halogenated aromatics as raw materials through cuprous oxide was proposed by Chen et al. (Zhang et al., 2012). The method could prepare selectively N2-substituted-1,2,3-triazoles and yield achieved was 98% (Zhang et al., 2012). It was an efficient strategy for multiple component condensation sequences about the combination of azide-chalcone oxidative cycloaddition and post-triazole arylation presented in diversity-oriented Scheme 2B. The mechanism study showed that cuprous oxide was used as an oxidant and a primer to accelerate the reaction. Corresponding products were obtained via nitrogen anion intermediates arylated with halogenated aromatics (Scheme 2C).
In 2016, another three-component reaction of alkynes, TMSN 3 , and dimethyl sulfoxide for synthesis of 1,2,3-triazole was developed (Phanindrudu et al., 2016). Kumar Tiwari et al. used nano-Cu 0 /Fe 3 O 4 as an efficient catalyst for the regioselective synthesis of 1,2,3-triazoles by one-pot tandem; the yield was up to 96% (Phanindrudu et al., 2016). The reaction could be compatible with a variety of alkynes such as aromatic, aliphatic, heteraromatic, and polyaromatic compounds. The advantages of wide range of substrates and simple operation provided an attractive and convenient route for the synthesis of thiotriazole (Scheme 3B).
The possible reaction mechanism of these reactions is shown in Scheme 3E. AgN 3 was prepared based on anion interchange of TMSN 3 with Ag 2 SO 4 and AgOH in the wake of the liberation of (TMS) 2 SO 4 and TMSOH in a basic solution. Then vinyl azide 2 was obtained because of AgN 3 insertion into the C-C triple bond via protodemetalation of vinylsilver 1 with H 2 O. Then SCHEME 4 Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles.
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Frontiers in Chemistry frontiersin.org 07 2 underwent 1,3-dipolar cycloaddition with the tautomerization of 1,3-dicarbonyl compound in basic conditions, which generated the coupling adduct 3. Finally, the triazole products were passed through the dehydration-driven aromatization process.
In 2015, Ning Jiao described an effective Cu-catalyzed nitrogenation of alkynes and alkenes for the rapid synthesis of sulfur-containing triazoles (Shen et al., 2015). Available sulfoxides and azides were employed as the S-and N-source to readily prepare highly value N-and S-containing 1,2,3-trizoles. A direct and practical solution was provided to gain sulfurcontaining triazoles in this method (Scheme 4).
In the following year, Zhenghu Xu further developed the method to construct N-alkyl-5-sulfur/selenium/amino-1,2,3triazoles via using Cu-catalyzed alkyne, alkyl azide, and thiosulfonate or selenesulfonic ester (Wang et al., 2016). The reaction was reacted under mild conditions, with a broad scope of substrates, and various fatty mercaptols and aromatic thiophenols were well compatible with the conditions (Scheme 5C).
Frontiers in Chemistry frontiersin.org 08 A possible mechanism is described in Scheme 6B. First, 1,10phenanthroline reacted with Cu(OAc) 2 ·H 2 O to form the active Cu(II) intermediate 1 that then reacted with phenylacetic acid, further underwent decarboxylation, and CO 2 was released to form 3. Subsequently, 4 reacting with diphenyl diselenide following reductive elimination to generate phenyl(phenylethynyl)selane 5, as well as copper(I) species. The complexation of copper intermediate with phenyl(phenylethynyl)-selane and -azide, which underwent oxidative cyclization, turned into products under air atmosphere to finish the reaction.
A probable mechanism of copper-catalyzed [3+2] cycloaddition or oxidative reaction is proposed in Scheme 7B. The regioselective 1,3-dipolar cycloaddition took place between nitro-olefin and azide to form the triazole intermediate 1; transition metal complexes could promote this process. Then 2 is obtained through Cu(II) catalyst, which could be stabilized with the help of an Ar group. The cation intermediate 3 was given because of this the radical lost another electron; then, 4-NO2-1,5trisubstituted-1,2,3-triazoles would be formed via cation intermediate 3 losing a proton. In this reaction, The Cu(II) as a catalyst play an important role, which could be regenerated in acidic condition from Cu(I) species with O 2 .
Frontiers in Chemistry frontiersin.org as a catalyst and ascorbic acid/DMF as a solvent, 1,5disubstituted-1,2,3-triazoles were obtained in good yield (80%) (Kumar et al., 2018) at 115°C. The adaptability of various arylsubstituted azides and cinnamic acid substrates was investigated, and it was found that various functional groups including halogen, nitro group, and cyanide group could be applied under the reaction conditions (Scheme 8A). The proposed mechanistic pathway is shown in Scheme 8B: First, the regioselective 1,3-dipolar cycloaddition arose with azides and cinnamic acid to form the cation intermediate 1.

Hydrazone as nitrogen source
In recent years, a method of synthesis N-substituted-1,2,3triazoles from hydrazones instead of azides had been developed. In addition, 30 years ago, Sakai developed a fascinating scheme SCHEME 9 Synthesis of N-substituted-1,2,3-triazole framework and the mechanism of N-substituted-1,2,3-triazole framework.
Frontiers in Chemistry frontiersin.org for the production of 1,2,3-triazole via the condensation of an amine and α, α-dichlorotosyl hydrazone in mild reaction conditions. The approach does not need a metal catalyst and azide, but this pathway had not been used adopted widely for a long period (Sakai et al., 1986).
In 2010, Hanselmann further applied the cyclization reaction of α, α-dichlorotoluene sulfonyl-substituted hydrazone with primary amine mediated by DIPEA to synthesize N1-substituted-1,2, 3triazoles (Roger Hanselmann et al., 2010). N-substituted-1,2,3triazoles with antibacterial activity can be synthesized in an ethanol solvent by this method. The key 1,2,3-triazole skeletons could be easy obtained under the presence of DIPEA on a large scale with the yield of 80% (Roger Hanselmann et  In 2013, Zhang showed the method to synthesis 1,4,5trisubstituted-1,2,3-triazoles by copper-mediated reaction of N-tosylhydrazones and aniline with the yield of 82% (Chen et al., 2013). Significant features of this scheme involved the unique constituent of 1,4-or 1,4,5-substituted regioisomers, the advantages of wide scope with regard to low cost of reagents, and the convenient operating conditions for the N-tosylhydrazones and the aniline substrates (Scheme 9C).
In 2014, an efficient method for the synthesis of 1,4-diaryl-1,2,3triazoles from N-tosylhydrazones with anilines under the mediation of I 2 /TBPB (terbutyl benzoate peroxide) system was reported by Cai et al. (2014). The method used I 2 as a catalyst and TBPB as an oxidant without any metal catalyst. A variety of 1,4-diaryl-1,2,3triazoles could be produced with moderate to good yields (89%) (Chen et al., 2013) The general mechanism of Scheme 9A,B was depicted as Scheme 9E. First, α, α-dichlorotosyl hydrazone was converted into vinyldiazine 1 that passed the process of elimination of HCl; intermediate 2 was formed via the amine addition and toluenesulfinate ion elimination. Finally, 1,2,3-triazoles were produced through deprotonation and cyclization.
The preliminary mechanism of Scheme 9C,D was depicted as Scheme 9F. The N-tosylhydrazone might isomerize to 1.
Subsequently, 1-tosyl-2-vinyldiazene 2 was given via N-tosylhydrazone oxidation and then the intermediate 3 was produced by an aza-Michael addition with aniline. Finally, the 1,2,3-triazole derivatives were prepared through the Cu/I-catalyzed cyclization of 3 with the formation of a N-N bond and subsequent aromatization. A radical process occurred in the reaction.
In 2012, Guru developed a copper-catalyzed production of 2,4,5-triaryl-1,2,3-triazoles from bis(arylhydrazones) under a mild condition (Guru and Punniyamurthy, 2012). In this method, a variety of N 2 -aryl-1,2,3-triazoles were produced by continuous C-H functionalization and C-C, N-N, and C-N bond formation reactions with Cu(OAc) 2 as a catalyst. This scheme took place under mild reaction conditions, could be utilized in large synthesis range, and possessed wide functional compatibility with easily available substrates (Scheme 10).

Hydrazine as nitrogen source
Hydrazine, as an important chemical raw material, is often used to construct various nitrogen-containing compounds.

Diazo compounds as nitrogen source
In 2015, a series of N1-substituted-1,2,3-triazoles were prepared through Cu-catalyzed [3+2] cycloaddition reaction of secondary amines and diazo compounds by Li et al. . This reaction used oxygen as a green oxidant and had the advantages of easy availability of raw materials, mild conditions and good compatibility of functional groups. It provided a practical synthesis method for a series of N1-substituted-1,2,3-triazoles in 55%-84% yields  (Scheme 12A).
The mechanism of Scheme 12C was similar as Scheme 12(a) were described in Scheme 12D: The first step, amine was oxidized by CuBr 2 passed electron transfer process to form amine radical cations 1. Then hydrogen radicals were transferred to form imine cations 2, which performed the [3+2] cycloaddition reaction with α-diazo compounds to obtain 3. Finally, three was oxidized by CuBr 2 in the presence of oxygen to form N1-substituted-1,2,3-triazole.

Amidines as nitrogen source
Amidine was widely used as an organic catalyst and ligand for the formation of nitrogen-carbon bonds due to the reactivity of nucleophilic nitrogen atoms. In 2011, a general method had been developed via one-pot, two-step process for the production of 1,3,5-trisubstituted-1,2,4-triazole with excellent yield (up to 90%) (Castanedo et al., 2011). The sequence started with the in situ formation of amide from carboxylic acid and amidine. Aniline further reacted with monosubstituted hydrazine and cyclized to trisubstituted triazole. This method had the advantages of high regioselectivity and good tolerance of functional groups (Scheme 13A).
Frontiers in Chemistry frontiersin.org raw materials. In fact, nitrogen atoms and methyl groups from DMF were incorporated into the triazole. For amides replaced by various functional aromatic fragments (fluorine, bromine, methyl, methoxy, and trifluoromethyl), the reaction sequence appears to be highly effective (scheme 13B). In 2019, Xia developed a facile copper-catalyzed one-pot method to prepare 3,5-disubstituted-1,2,4-triazole from amide and nitrile by cascade addition oxidation cyclization (Xia et al., 2019). In this reaction, O 2 was used as an oxidant, and functionalization was catalyzed by the complex of  with high yield (91%) . The pathway was utilized to prepare a various of 1,2,4-triazole derivatives (Scheme 13C).
The possible reaction mechanism shown in Scheme 13D. As 2) showed Cu-catalyzed C (sp3)-H firing the amine to prepare imine-type intermediate 1 via a single-electron transfer (SET) procedure would be the first step of this reaction. In the following process, nucleophilic of 1 attack by the amidine to form intermediate 2. Taking the case of tertiary amine, the amine motif was delivered to get imine intermediate 3. Another molecular amidine 4 undertook the second attack of 3 with an intramolecular nucleophilic cyclization and followed oxidation to generate the final 1,3,5-triazine compounds.

Imidates as nitrogen source
Imidates are helpful precursors of triazoles, which have been extensive wielded in this field. In 2016, Guirado proposed a simplified SCHEME 13 Synthesis and mechanism of N-disubstituted-1,2,4-triazole derivatives.
Frontiers in Chemistry frontiersin.org 15 good versatility, high yield, easy access to starting materials, mild and simple experimental steps (Scheme 14A).
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Frontiers in Chemistry frontiersin.org 17 showed that the selectivity formation of 5-vinyl-1,2,4-triazoles could arrest take place potential five-member and seven-member byproducts via theoretical calculations and NMR (Scheme 14C).
Take Scheme 14B as an example, the possible reaction mechanism described in Scheme 14D. PTSA catalyzed 2,2,2trichloroethyl imidates undergone a series of oxidate and cyclization reaction to generate 1,2,4-triazole derivatives. PTSA played a significant role in this reaction. PTSA was not only a catalyst, but also a Lewis acid participated in reaction.

Amidrazones as nitrogen source
Amidine was an excellent raw material to provide nitrogen atom in the synthesis of triazole. In 2011, Siddaiah et al. reported that 1,2,4-triazole derivatives can be prepared at 80°C with moderate to high yields (55%-95%) in solvent-free conditions using HClO 4 -SiO 2 as a catalyst (Siddaiah et al., 2011). The advantages were that the substituents on amide hydrazone and anhydride had good tolerance during optimized conditions, and the HClO 4 -SiO 2 catalyst could SCHEME 20 (A) Access to 3,4,5-trisubstituted-1,2,4-triazoles from N-tosylhydrazones and aromatic amines. (B) Plausible mechanism base on experimental.
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Frontiers in Chemistry frontiersin.org 19 be recycled continuously for at least three times (Scheme 15A).
A possible mechanism was showed in Scheme 15C. Ceric ammonium nitrate reacted as both a Lewis acid and an oxidant. CAN play an irreplaceable role in promoting the occurrence of the reaction.

Aryl diazonium salts as nitrogen source
Aryl diazonium salts as intermediates, which were utilized broadly as nitrogen source for the generation of abundant heterocycles compounds due to the advantages of shortcutting available and highly reactive. In 2020, Tian et al. developed the synthesis of 1,2,4-triazole by decarboxylation and cyclization of 2-aryl-2-isocyanate with aryl diazonium salts (Tian et al., 2020).
A possible mechanism was described in Scheme 17B. Thus, bis(arylhydrazones) could be converted into the radical cation 1 via single-electron transfer (SET) to Cu(II)X2. Base on the elimination of HX, that intermediate 1 could be transformed to 2. 2 could lead to the formation of 3 pass by dimerization, which could isomerize to form the intermediate 4. The latter could afford a radical cation 5 by reductive elimination of elemental copper through SET process. The catalytic cycle might be completed via regenerate the active Cu(II) species from reduced Cu(0) species was reoxidized by air. This was conducive to promoting the process of response. Besides, DABCO is not only acting as a base but also playing a crucial role of an effective ligand for the Cu(II)-catalyzed oxidative cyclization.

Hydrazones as nitrogen source
Hydrazones were popular precursors of nitrogen heterocycles in most methods for the production of fused 1,2,4-triazole. Characteristics of these compound involved highly reactive nitrogen pairs and SP-carbon atoms. Hydrazones could react with various amines to synthesize triazoles. In 2016, Chen et al. developed a synthetic method in which hydrazone could be easily converted to 1,2,4-triazole by combining amines with I 2 /TBHP in high yield (92%) (Chen et al., 2016). A wide range of functional groups were well tolerated in hydrazone and amine fragments for the synthesis of multiple compounds. The method has the characteristics of available raw materials, simple and easy operating conditions, a wide range of substrates (Scheme 19A).
A possible mechanism of the framework was presented in Scheme 19B. The Michael-type nucleophilic supplement of the terminal amino group of the benzamidrazone to form the malononitrile receptors 2. Then, the homologous spirocyclic 1,2,4-triazoles finished cyclization undergone an intramolecular nucleophilic supplement of the amino group to the imidic carbon atom to afford final 1,2,4-triazole derivatives.
In 2019, Guru et al. described a metal-free catalytic method for dehydrogenation cyclization based on B(C 6 F 5 ) 3 (Guru et al., 2019). B(C 6 F 5 ) 3 activated the hydrazine portion nucleophilic attack in progress, following in proper order amination, intramolecular cyclization and dehydrogenation steps to prepare the 3,4,5-tsubstituted-1,2,4-triazole with 85% yield (Guru et al., 2019). This reaction route was characterized by green economy, no oxidant, mild conditions and selectivity, which provided a potential platform for catalytic chemical conversion without the use of transition metal (Scheme 20A).
A predicted mechanism was described in Scheme 20B (Kojima, 2016;Cai et al., 2014). On account of recommended mechanism of the B(C6F5)3-catalyzed receptors less dehydrogenative cyclization of N-tosyl-hydrazones with anilines, investigators had carried out DFT calculations to research the sophisticated reaction mechanism and to receive deep understanding of driving force for the production of the 1,2,4-triazoles. The experimental calculations results revealed that the rate-determining step involved intra-molecular hydrogen transfer between the N-centers after aniline gets bonded to the N-tosylhydrazone unit.
The plausible mechanism was represented in Scheme 21B. Acetaldehyde was reacted with hydroxylamine hydrochloride in toluene under reflux to prepare oxime hydrochloride intermediate 1. Nitrilimine specie 2 was generated via deal with hydrazonoyl hydrochloride by a surfeit of triethylamine. The essential 1,3-dipolar cycloaddition dihydrotriazole three was constructed by disposing dipolarophile oxime with 1,3-dipole nitrilimine. When the subsequent dehydroxylation condensation was finished, the corresponding 1,3,5-trisubstituted-1,2,4triazole product was produced.
The reaction mechanism may be through oxidative addition and reductive elimination processes (Scheme 22B). Hydrazones of aromatic and aliphatic aldehydes containing electronwithdrawing and electron-donating substituents were oxidized by SeO 2 , and then through a series of electron transfer, finally removed a molecule Se(OH) 2 to give the corresponding 1,2,4triazoles.
Amidines, imidates, amidrazones, aryldiazoniums, and hydrazones are among the most correlative 1,2,4-triazole precursors. In the synthesis of 1,2,3-triazole, sodium azide is a highly toxic compound, which is not suitable for large-scale application as a nitrogen source. Compared with sodium azide, azide trimethylsilane and alkyl/aryl azide are safer and more efficient.
Hydrazone, aminohydrazine and diazo compounds are also the main materials of nitrogen sources, which were reported in a large number of literatures. The synthesis method of 1,2,4-triazole mainly uses amidine, amide, amidine hydrazone, aryl diazonium salt, and hydrazone as nitrogen sources. During the past few years, there have been excellent progress in copper-catalyzed crosscouplings in the synthesis methods of 1,2,3/1,2,4-triazole with inexpensive, low toxic, and good functional tolerance. Metal catalysis was the mainly choice at present; among them, copper-catalyzed was the most popular catalyst. With the promotion of the concept of "green chemistry", metal-free catalytic synthesis such as electrocatalysis and photocatalysis are attracting researcher' interest. It is believed that with the Frontiers in Chemistry frontiersin.org continuous efforts of researchers, more green economy and simple and mild synthesis methods will continue to develop.

Author contributions
The author JD contributed to the literature review and the writing of the review. The author ZL and ST put forward guiding opinions on the revision and writing.

Funding
This work was supported by the Taishan Scholar Project of Shandong Province, China and the Science and Technology Support Program for Youth Innovation in Universities of Shandong (2020KJM003).