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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2024 , Vol. 36 >Issue 7: 1014 - 1025

DOI: https://doi.org/10.7536/PC231017

Review

Synthesis of 4-Monosubstituted 1,2,3-Triazoles

  • Liguo Teng ,
  • Shuitao Zhang ,
  • Tiebo Xiao ,
  • Baomin Yang , * ,
  • Yubo Jiang , *
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  • Faculty of Science, Kunming University of Science and Technology, Kunming 650500, China
* e-mail: (Baomin Yang);
(Yubo Jiang)

Received date: 2023-10-30

  Revised date: 2024-03-10

  Online published: 2024-07-01

Supported by

National Natural Science Foundation of China(21662020)

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Abstract

1,2,3-Triazoles are a kind of five-membered N-heterocycles featured with unique properties in biology and material science.They have played more and more important roles in the fields of medicine,pesticide,and materials since the Cu-catalyzed diploar cycloaddition reaction of azide and alkyne was founded by Sharpless and Medal groups,respectively.4-Monosubstituted 1,2,3-triazole is considerably important in its family,especially because of its structural merits of widely facile modifications.The synthesis of 4-monosubstituted 1,2,3-triazoles based on different reaction types and substrates,including cycloaddition of alkyne with azide,cycloaddition of nitroolefin with azide,cyclization of hydrazone with amino derivatives,and N1-substituent removal of 1,4-disubstituted 1,2,3-triazoles are reviewed.The substrate scope,limitation,and representative mechanism are also discussed 。

Contents

1 Introduction

2 Progress in the synthesis of 4-monosubstituted 1,2,3-triazoles

2.1 1,3-Dipolar cycloaddition of alkyne and azide

2.2[3+2]Cycloaddition of nitroolefin and azide

2.3 Cyclization of hydrazone with amino derivative

2.4 Removal of N1-substituent from 1,4-disubstituted 1,2,3-triazole

2.5 Reaction of alkenyl bromide with sodium azide

2.6 Other methods

3 Conclusion and outlook

Key words： 4-monosubstituted 1,2,3-triazoles; synthesis; cycloaddition; cyclization; substituent removal

Cite this article

Liguo Teng , Shuitao Zhang , Tiebo Xiao , Baomin Yang , Yubo Jiang . Synthesis of 4-Monosubstituted 1,2,3-Triazoles[J]. Progress in Chemistry, 2024 , 36(7) : 1014 -1025 . DOI: 10.7536/PC231017

1 Introduction

1,2,3-triazole is a kind of unique five-membered nitrogen heterocyclic structure,which is a bioisostere of amide bond and shows strong stability in metabolic transformation,redox,acid-base environment and thermal conditions,and has been widely used in medicine,pesticides,materials and other fields[1][2⇓~4][5,6][7,8]。 Since the"copper-catalyzed azide-alkyne cycloaddition reaction"(CuAAC,the classic"click Chemistry")developed by Sharpless and Meldal in 2002,1,2,3-triazole compounds have been rapidly and widely used in the field of biology,for which they have won the Nobel Prize in chemistry in 2022[9,10][11,12]。
4-monosubstituted-1,2,3-triazole is one of the important members of this heterocyclic family,and many molecules have important physiological activities[13,14]。 As shown in Fig.1,compound A is an hMetAP2 inhibitor,compound B is an IDO1 inhibitor,compound C is an anti-infective(ceftriaxone),and compound D is an angiogenesis inhibitor[15][16][17][18]。
图1 具有生物活性的4-单取代-1,2,3-三氮唑衍生物[15⇓⇓~18]

Fig. 1 Biologically active 4-monosubstituted 1,2,3-triazole derivatives[15⇓⇓-18]

At the same time,4-monosubstituted-1,2,3-triazole has many reaction sites such as N—H and C—H bonds,which is easy to modify and transform,and can be efficiently transformed into various functionalized triazole derivatives,which is widely used[19⇓⇓⇓⇓⇓~25]。 Therefore,the synthesis of these compounds is of great significance.Although the synthesis of 4-monosubstituted-1,2,3-triazoles has been concerned in the early review literature,new methods have emerged in recent years,which have important reference value[26⇓~28]。 in this paper,the synthesis of these compounds is reviewed,especially the representative new methods in recent years are introduced in detail。

2 Synthesis of 4-monosubstituted-1,2,3-triazole

2.1 1,3-dipolar cycloaddition of alkynes and azides

The method mainly uses the cycloaddition reaction of terminal alkyne or its precursor with azide,and the azide mainly includes HN3,NaN3and TMSN3,while HN3is difficult to be used directly due to its high toxicity and explosiveness 。

2.1.1 Terminal alkyne and NaN3.

In 2018,Banerjee's group prepared graphene polymer-supported nano-copper Cu@g-C3N4,and used it as a catalyst and water as a solvent to realize the 1,3-dipolar cycloaddition reaction between terminal alkyne 1 and sodium azide 2,and efficiently prepared 4-monosubstituted-1,2,3-triazole derivatives 3(Scheme 1 )[29]。 the method has the advantages of wide substrate range,short reaction time,green solvent,recyclable catalyst and the like。
图式1 Cu@g-C3N4催化的1,3-偶极环加成反应[29]

Scheme 1 Cu@g-C3N4 Catalyzed 1,3-dipolar cycloaddition reaction[29]

In 2019,Myznikov's group found that the“ZnCl2-NaN3”system could significantly reduce the temperature of the cycloaddition reaction between azide ion and nitrile or thiocyanate in organic solvents,and could shorten the reaction time,so it was applied to the cycloaddition reaction of terminal alkyne 1 to prepare a series of 4-monosubstituted-1,2,3-triazoles 3(Scheme 2 )[30]。 The mechanistic study showed that ZnCl2not only acted as a phase transfer catalyst during the reaction,but also reduced the energy barrier for the nucleophilic addition reaction between azide ion and substrate 。
图式2 ZnCl2促进的亲核加成反应[30]

Scheme 2 ZnCl2 promoted nucleophilic addition[30]

in 2022,Gazvoda's group reported the efficient preparation of 4-monosubstituted-1,2,3-triazole derivatives 3(Scheme 3)by copper-catalyzed cycloaddition of hydrazoic acid(formed In situ from sodium azide)with terminal alkynes[31]。 It is worth noting that formic acid has a dual effect,not only promoting the formation of hydrazoic acid,but also reducing Cu(Ⅱ)to regenerate Cu(Ⅰ).the method has the advantages of high atom economy,high functional group tolerance,and the like,and the amino acid and the unprotected polypeptide can be well compatible。
图式3 铜催化叠氮酸与炔烃环加成反应[31]

Scheme 3 Copper catalyzed cycloaddition of hydrazoic acid and alkyne[31]

2.1.2 Terminal alkyne and TMSN3.

In 2004,Yamamoto's group synthesized 4-monosubstituted-1,2,3-triazole derivatives 3(Fig.4)by CuAAC reaction of unactivated terminal alkyne 1 with TMSN34[32]。 They proposed a possible reaction mechanism in which CuI first reacted with alkyne 1 to form alkyne-Cu intermediate 4-A,followed by cycloaddition with in situ generated hydrazoic acid 4-B to give intermediate 4-C,followed by protonolysis to give 4-monosubstituted-1,2,3-triazole 3 and regeneration of catalyst CuI。
图式4 铜催化端炔与TMSN3环加成反应[32]

Scheme 4 Copper catalyzed cycloaddition of terminal alkyne with TMSN3[32]

Although CuAAC reaction is widely used in chemistry and biology,trace metal residue is an unavoidable problem.Therefore,in 2018,Young's group developed a 1,3-dipolar cycloaddition strategy with short reaction time,green solvent and microwave assistance,and constructed 4-monosubstituted-1H-1,2,3-triazole derivatives,which solved the problem of metal residue and was suitable for amino acid substrates[33]。 in the same year,Prakash's group developed a catalyst-free and solvent-free microwave-assisted strategy to synthesize 4-monosubstituted-2H-1,2,3-triazole derivative 5 In high yield(Scheme 5)[34]。
图式5 微波辅助的1,3-偶极环加成反应[34]

Scheme 5 Microwave assisted 1,3-dipolar cycloaddition[34]

2.1.3 Alkynoic acid and sodium azide

In 2012,Choi's group prepared novel,efficient,easily separable and reusable silver modified graphene oxide catalyst(GOSH-Ag)by depositing nano-Ag particles on the surface of GOSH for decarboxylation/cycloaddition reaction to construct a series of 4-monosubstituted-1,2,3-triazole derivatives 7(Fig.6)[35]。
图式6 GOSH-Ag催化脱羧环加成反应[35]

Scheme 6 GOSH-Ag-Catalyzed decarboxylative cycloaddition reaction[35]

2.2 [3 + 2] cycloaddition of nitroalkene derivative and sodium azide

In addition to alkynes,nitroalkene derivatives can also undergo[3+2]cycloaddition with sodium azide for the construction of 4-monosubstituted-1,2,3-triazole derivatives。

2.2.1 [3 + 2] cycloaddition of nitroalkene with sodium azide

In 2014,Guan Zhenghui's group found that 0.5 equiv of p-toluenesulfonic acid(p-TsOH)as an additive could effectively promote the 1,3-dipolar cycloaddition reaction of nitroalkene derivative 8 and NaN32,and efficiently synthesized 4-monosubstituted-1,2,3-triazole 7 derivatives under mild conditions(Fig.7 )[36]。
图式7 p-TsOH促进的硝基烯烃−叠氮化钠1,3-偶极环加成[36]

Scheme 7 p-TsOH-mediated 1,3-dipolar cycloaddition of nitroolefins with NaN3[36]

In 2016,Wang Zuli's research group used the polymer solid acid catalyst of vinylbenzene sulfonic acid and divinylbenzene(Amberlyst-15)to realize the efficient construction of 4-monosubstituted-1,2,3-triazole derivative 7(Fig.8),and the efficiency of the catalyst was not reduced after 8 times of recycling[37]。
图式8 Amberlyst-15催化硝基烯烃-叠氮化钠偶极环加成[37]

Scheme 8 Amberlyst-15 Catalyzed 1,3-dipolar cycloaddition of nitroolefins with NaN3[37]

In 2017,Shankaraiah's group selected the stable,cheap,non-corrosive and efficient green sulfamic acid（NH2SO3H）as an additive to efficiently synthesize 21 4-aryl-1,2,3-triazole compounds 7 in a short time(Fig.9 )[38]。 Mechanistic studies showed that NH2SO3H not only helped to inhibit the formation of the by-product triarylbenzene,but also could significantly activate the nitroalkene,favoring the formation of intermediate 9-B,followed by immediate cyclization to form intermediate 9-C,followed by elimination to 9-D,and finally protonation to give the final product 7 。
图式9 NH2SO3H促进的硝基烯烃-叠氮化钠1,3-偶极环加成反应[38]

Scheme 9 NH2SO3H mediated 1,3-dipolar cycloaddition of nitroolefins with NaN3[38]

In 2017,the research group of Mingyang He reported that acidic ion exchange resin(Amberlite IR-120)was used to catalyze the 1,3-dipolar cycloaddition reaction of nitroalkenes and sodium azide,and 4-aryl-1H-1,2,3-triazole derivatives were efficiently constructed,and the catalyst could be reused by simple filtration recovery[39]。
In 2018,Chen Zhangpei's team developed a magnetic recovery and high activity magnetic silica sphere grafted sulfonic acid（MSS-SO3H）for the catalytic cycloaddition reaction of nitroalkenes and sodium azide,which is in line with the concept of environmental friendliness[40]。 In the same year,Zhong Linxin's research group used xylan hemicellulose as raw material to synthesize heterogeneous carbon-based solid acid（CXH-SO3H）,which is easy to prepare,simple in post-treatment and recyclable,and can efficiently catalyze such reactions[41]。
In 2018,Banerjee's group prepared the nanocatalyst Cu@g-C3N4,which can be used not only for the cycloaddition reaction of terminal alkyne with sodium azide,but also for the 1,3-dipolar cycloaddition reaction of nitroalkene with sodium azide(Fig.10 )[19]。 The possible reaction mechanism is as follows:firstly,nitroalkene 9 coordinates with the active sites on the surface of the catalyst to form 10-A,followed by nucleophilic addition with sodium azide to give 10-B,followed by cyclization to give 10-C,followed by elimination of HNO2and catalyst to give 10-D,and finally protonation to give the final product 3.From the reaction results,steric effect and electronic effect will not affect the reaction,and the substrate with active hydrogen(-OH)can also be well compatible in the reaction.In this system,water is used as solvent,the reaction time is short,and the catalyst can be reused,which is in line with the concept of green chemistry 。
图式10 Cu@g-C3N4催化的1,3-偶极环加成反应[19]

Scheme 10 Cu@g-C3N4 Catalyzed 1,3-dipolar cycloaddition reaction[19]

In 2019,following the previous research,Banerjee's research group developed a mesoporous material Pd-MCM-41 with high stability,high activity and reusability,and realized the rapid 1,3-dipolar cycloaddition reaction between nitroalkenes and TMSN3to synthesize 4-aryl-1H-1,2,3-triazole derivatives with high yields of 93%–99%[42]。 In addition,tungstate sulfate,hypercrosslinked porous organic polymer MeBP@H,and magnetic nanocomposite Fe3O4@g-C3N4-SO3H were used as recyclable catalysts for the efficient construction of 4-monosubstituted-1,2,3-triazoles[43][44][45]。
In 2021,Ferreira's group used green PEG-400 as a solvent to synthesize 4-monosubstituted-1,2,3-triazole derivative 7(Figure 11)under acid-promoted and microwave-assisted conditions.the reaction efficiency was high,but The yield was generally moderate to low[46]。
图式11 微波辅助的1,3-偶极环加成反应[46]

Scheme 11 Microwave assisted 1,3-dipolar cycloaddition[46]

In 2021,Gu Yanlong's research group designed and prepared N-methyl-N-(3-phenylpropyl)formamide hypercrosslinked polymer HCP-DMF and HCP-DMF-SO3H rich in dimethylformamide(DMF)and SO3H fragments,which can efficiently promote the conversion of NaN3into 4-monosubstituted-1,2,3-triazole derivatives 7(Fig.12)in green and pollution-free Et OH,and is easy to recycle,avoiding the direct use of harmful solvent DMF[47]。 the DMF fragment introduced into the polymer plays a key role in the reaction,providing a"solvated microenvironment"。
图式12 HCP-DMF-SO3H催化的1,3-偶极环加成反应[47]

Scheme 12 HCP-DMF-SO3H Catalyzed 1,3-dipolar cycloaddition reaction[47]

2.2.2 In situ [3 + 2] cycloaddition of nitroalkenes with sodium azide

Nitroalkenes can be generated in situ from aromatic aldehydes and nitromethane.This method is easy to operate,efficient and economical。
In 2015,Lin Qiang's group developed a one-pot three-component reaction of aryl aldehyde,nitromethane and sodium azide(Fig.13)[48]。 In this reaction,the acidity of the system was adjusted by NaHSO3-Na2SO3,and the cycloaddition effect was improved by controlling the addition rate of nitromethane.The reaction can be completed at 110℃without the participation of transition metals,and the raw materials are easily available 。
图式13 NaHSO3-Na2SO3促进芳基醛、硝基甲烷和叠氮化钠的一锅三组分反应[48]

Scheme 13 NaHSO3-Na2SO3 promoted three components one-pot reaction of aryl aldehyde, CH3NO2 and NaN3[48]

In 2016,Chen Yunfeng's group developed an aluminum chloride catalytic method to realize the three-component reaction of aromatic aldehyde 10,nitromethane 11 and sodium azide(Fig.14),and obtained the corresponding 4-aryl-2H-1,2,3-triazole derivatives 5 with good to excellent yields,which has the advantages of simple system and wide range of substrates[49]。
图式14 AlCl3催化的原位硝基烯烃和叠氮化钠的反应[49]

Scheme 14 AlCl3-Catalyzed reaction of in situ-formed nitroolefin with sodium azide[49]

In 2017,Guan Zhenghui's team used the NH4OAc/HOAc system to realize the"one-pot"three-component reaction of aryl aldehyde 10,nitromethane 11 and sodium azide(Fig.15),which is safe and easy to obtain[50]。 They proposed a possible reaction mechanism:aryl aldehyde 10 first condenses with nitromethane 11 to form nitroalkene 15-A,and ammonium azide,which is produced by the reaction of ammonium acetate with sodium azide,undergoes nucleophilic addition to nitroalkene 15-A to give intermediate 15-B.This is followed by an intramolecular nucleophilic cyclization reaction to give intermediate 15-C,followed by an intramolecular elimination NH4NO2to give intermediate 15-D under heating conditions,and finally isomerization to give 4-aryl-NH-1,2,3-triazole 7 。
图式15 NH4OAc/HOAc促进原位硝基烯烃和叠氮化钠的反应[50]

Scheme 15 NH4OAc/HOAc promoted reaction of in situ-formed nitroolefin with sodium azide[50]

In 2017,Morales-Serna's group reported a multi-component reaction promoted by solid acid catalysts MCM-41,Al-MCM-41 and sulfated zirconia(SZ)to synthesize a variety of 4-aryl-NH-1,2,3-triazole derivatives 7(Fig.16)[51]。 the possible reaction mechanism is as follows:firstly,the catalyst interacts with aldehyde 10 to obtain active intermediate 16-A,which is located at the solid-liquid interface,and then condenses with piperidine to obtain intermediate 16-B,which undergoes nucleophilic addition with activated nitromethane 16-C to obtain intermediate 16-D,and then eliminates a molecule of piperidine to form nitroolefin 16-E,which finally undergoes cycloaddition with sodium azide to obtain the final product.the results showed that the acidity of the catalyst was positively correlated with its activity and reaction yield,and the catalyst could be reused more than twice.When used too many times,the catalyst will lose its initial structure,thus affecting the catalytic activity。
图式16 固体酸催化法[51]

Scheme 16 Solid acid-catalyzed method[51]

In 2018,the tandem process was realized by Saikia's group using arylaldehyde,sodium azide and nitromethane as raw materials and magnetic CuFe2O4catalyst under microwave-assisted conditions[52]。 the method has The advantages of short reaction time(5~10 min),simple operation,and reusable catalyst。
In 2019,the magnetic nanomaterials Fe3O4@SiO2@Propyl-HMTA and Fe3O4@Folic designed by Sarmast group and Heydari group respectively can effectively catalyze the tandem reaction of aromatic aldehydes,nitromethane and azide to obtain 4-aryl-NH-1,2,3-triazole derivatives with high efficiency,and the catalysts can be recycled[53][54]。
In 2021,Sarma's group synthesized 4-monosubstituted-1,2,3-triazole derivative 7(Fig.17)using ZnFe2O4magnetic nanoparticle catalyst,which is efficient,stable and easy to recycle and reuse[55]。 They proposed a possible reaction mechanism,in which aromatic aldehyde 10 first condenses with nitromethane 11 to form nitroolefin 17-A,and then Zn in the catalyst ZnFe2O4combines with nitrooxygen atom to form intermediate 17-B due to Lewis acidity.Sodium azide then attacks the electrophilic double bond of intermediate 17-B to give intermediate 17-C,which is then immediately cyclized to give intermediate 17-D,followed by the successive removal of catalyst ZnFe2O4and NO2to give the intermediate 17-E,which is finally protonated to give the final product 7 。
图式17 ZnFe2O4催化合成4-取代-NH-1,2,3-三氮唑[55]

Scheme 17 ZnFe2O4 catalyzed synthesis of 4-substituted NH-1,2,3-triazoles[55]

in 2021,the Sreekumar project assembled polyepichlorohydrin core dendrimer(TMP-PECH-Amin-G1),and found that it could efficiently catalyze the three-component condensation reaction of aromatic aldehyde,nitromethane and sodium azide In water to obtain 4-aryl-1H-1,2,3-triazole derivatives[56]。 in the same year,Sarma's research group selected whey(the aqueous component left after the removal of curd In milk,a biological waste)as a catalyst to successfully realize the three-component reaction of aryl aldehyde,nitromethane and sodium azide,and synthesized 4-aryl-1H-1,2,3-triazole derivatives with high yield,and the catalytic system can be reused[57]。
In 2021,the group of Sarma achieved the synthesis of 4-aryl-NH-1,2,3-triazole 7 derivatives using silicon-supported copper N-heterocyclic carbene（Cu-NHC@SiO2）and green solvent PEG-400(Fig.18),and the catalyst could be reused at least five times[58]。
图式18 Cu-NHC@SiO2催化法[58]

Scheme 18 Cu-NHC@SiO2 Catalyzed method[58]

In the same year,Sarma's group designed and synthesized a heterogeneous nanocomposite catalyst PPy/Cu with low copper loading(0.01 mol%)for the synthesis of 4-aryl-NH-triazole derivative 7(Fig.19),which has the advantages of excellent yield,simple operation,and easy recycling of catalyst and solvent PEG-400[59]。
图式19 PPy/Cu纳米复合材料催化法[59]

Scheme 19 PPy/Cu Nanocomposites catalyzed method[59]

2.3 Cyclization of hydrazones with ammonia derivatives

In addition to the classical[3+2]reaction of terminal alkynes and nitroalkenes with azide derivatives,4-monosubstituted-1,2,3-triazoles can also be prepared by hydrazone and amino derivatives。
In 2019,Wu Anxin's group developed an iodine molecule-promoted[4+1]cyclization reaction to construct 4-aryl-NH-1,2,3-triazole derivative 7(Scheme 20)[60]。 The possible mechanism of the reaction is that in the presence of iodine,theα-position of hydrazone 12 is first iodinated to form intermediate 20-A.Next,there are two possible pathways for the conversion of intermediate 20-a to 20-C:Path a,20-a first eliminates hydrogen iodide to give 20-B,which then adds to NaN3to give 20-C;Path B,20-A directly undergoes nucleophilic substitution with NaN3to give 20-C.Then,20-C cyclization and removal of the Ts group gave intermediate 20-D,followed by elimination of nitrogen to give intermediate 20-E,and finally 1,5-hydrogen migration to give the target product 7 。
图式20 碘促进的[4+1]环化反应[60]

Scheme 20 Iodine-mediated [4+1] cyclization reaction[60]

Similarly,in 2020,Shu Wenming's group developed a metal-free iodine reaction to prepare 4-monosubstituted-1,2,3-triazole derivatives through the condensation-cyclization process ofα-azidoketone and p-toluenesulfonyl hydrazine,which uses ketone and hydrazine to generate hydrazone in situ[61]。 in the same year,Clark's group developed a metal-free"one-pot"three-component reaction to prepare alkyl and aryl substituted NH-1,2,3-triazole derivatives using readily availableα-ketoacetals,p-toluenesulfonyl hydrazide,and ammonia(dissolved In triethylamine)[62]。
In 2021,based on the previous experience,Wu Anxin's group designed the iodine-promoted[2+2+1]cyclization of aromatic ketone 13,p-toluenesulfonyl hydrazine 14 and aminopyridinium iodonium salt 15 to prepare 4-aryl-NH-1,2,3-triazole derivative 7(Fig.21)[63]。 the possible mechanism of the reaction is as follows:first,the aromatic ketone 13 is converted to the intermediate 21-C through two possible reaction pathways.Path a,aromatic ketone 13 is iodinated to give intermediate 21-a,which is then dehydrated and condensed with p-toluenesulfonylhydrazide 14 to give intermediate 21-C;Path B,aromatic ketone 13 is dehydrated and condensed with p-toluenesulfonyl hydrazide 14 to give intermediate 21-b,which is subsequently iodinated at theαposition to give intermediate 21-c.intermediate 21-C then undergoes nucleophilic substitution with aminopyridinium iodonium salt 15 to form 21-D,followed by intramolecular cyclization,removal of pyridine to form intermediate 21-E,and elimination of TsH to give the desired product 7.This method provides a new route for the preparation of NH-1,2,3-triazole by using p-toluenesulfonyl hydrazine and aminopyridinium iodide as alternatives to azide。
图式21 碘促进的[2+2+1]环化反应[63]

Scheme 21 Iodine-mediated [2+2+1] cyclization reaction[63]

2.4 1, 4-Disubstituted-1, 2, 3-triazole desubstituent

The synthetic pathways of 1,4-disubstituted-1,2,3-triazoles are very rich,so it has broad prospects to remove the substituent at the N1position to obtain 4-monosubstituted-1,2,3-triazole derivatives 。

2.4.1 C-N bond cleavage method

In 2005,Sharpless's group successfully synthesized a series of 1,4-disubstituted-1,2,3-triazole derivatives 16,17,18 by CuAAC reaction of methyl pivalate,methyl morpholine-4-carboxylate and methyl N,N-diethylcarbamate with terminal alkynes,respectively,and then removed the substituent at the N1position in alkaline methanol-water solution to obtain the corresponding 4-monosubstituted-NH-1,2,3-triazole derivatives 3(Fig.22 )[64]。
图式22 碱促进N1位取代基去除[64]

Scheme 22 Base-promoted removal of substituent on N1[64]

Weinreb's group used 1,4-disubstituted-1,2,3-triazole with a TSE（TsCH2CH2）at the N1position as a substrate to remove TSE in potassium tert-butoxide in tetrahydrofuran(THF)to obtain NH-1,2,3-triazole derivatives in good yield[65]。 In 2008,Fokin's group treated N1or N2substituted 1,2,3-triazoles with NaOH,NaBH4,or MnO2to obtain 4-monosubstituted-1,2,3-triazoles in up to 99%yield[66]。
In 2010,Nielsen's group proposed a two-step"one-pot"strategy,in which the immobilized and acid-sensitive benzylic azide 19 reacted with terminal alkyne 1 to obtain N1immobilized 1,2-disubstituted 1,2,3-triazole,and then the benzyl group was removed by trifluoroacetic acid aqueous solution to obtain the target product 3(Figure 23 )[67]。
图式23 固相合成4-单取代-1,2,3-三氮唑[67]

Scheme 23 Solid-phase synthesis of 4-monosubstituted 1,2,3-triazole[67]

In 2017,Chi's group developed a copper-catalyzed C-N bond oxidative cleavage reaction to synthesize 4-monosubstituted-NH-1,2,3-triazole derivatives 3(Fig.24)[68]。 The possible mechanism of the reaction is as follows:first,substrate 20 undergoes a single electron transfer with Cu(OAc)2to form intermediate 24-A,followed by hydrogen atom transfer(HAT)from the Cu(Ⅱ)O2radical produced by the reaction of copper(I)and oxygen to form intermediate 24-B and Cu(II)OOH,and then 24-B and Cu(II)OOH undergo another single electron transfer(SET)to form radical cation intermediate 24-C and copper(I).Then,24-C is extracted by alkali to removeα-H and hydroxyl,and then one-electron transfer with Cu(Ⅰ)occurs to form intermediate 24-D.And finally hydrolyze to obtain that 4-monosubstituted-1,2,3-triazole derivative 3.The reaction uses green oxygen as the oxidant,the reaction does not need to be carried out under anhydrous conditions,and has good functional group tolerance 。
图式24 铜催化的C—N1键断裂[68]

Scheme 24 Copper catalyzed C—N1 bond cleavage[68]

In recent years,Sekhar's group and Dash's group have obtained 4-monosubstituted-NH-1,2,3-triazole derivatives by C-N bond cleavage[69][70]。 Most of these methods have the advantages of high yields,good functional group tolerance,green solvents,and mild conditions。

2.4.2 N-S bond cleavage method

In 2018,Chandrasekaran's group proposed an efficient sulfonamide metathesis strategy under mild conditions without metal participation to synthesize 4-aryl-1H-1,2,3-triazole derivatives(Scheme 25)[71]。 The reaction proceeds in a chemoselective manner with sulfonamide exchange in high yield,short reaction time,and green conditions。
图式25 磺酰胺复分解[71]

Scheme 25 Sulfonamide metathesis[71]

Wang Feijun's research group reported similar work.They used 1,4-disubstituted-1,2,3-triazole protected by Ts at the N1position as a substrate,and obtained NH-1,2,3-triazole derivatives by removing Ts in TsOH aqueous solution.Cuevas-Ya Yañez's research group obtained 4-monosubstituted-NH-1,2,3-Triazole derivatives by N—S bond cleavage in MeOH solution[72][73]。 These methods have the advantages of high yield,good functional group tolerance,green solvents and mild conditions。

2.5 Reaction of alkenyl bromides with sodium azide

2.5.1 Alkenyl bromide and sodium azide

In 2006,Barluenga's group reported a Pd2(dba)3catalytic method for the synthesis of 4-monosubstituted-1,2,3-triazole derivatives 3 using alkenyl bromides 25 and sodium azide 2(Scheme 26 )[74]。 the possible mechanism of the reaction is as follows:the alkenyl bromide 25 first undergoes oxidative addition with palladium species to give the intermediate 26-A,followed by[3+2]cycloaddition with sodium azide to give 26-B,followed byβ-H elimination to give 26-C and 26-D,and then 26-C is protonated by the hydrogen bromide released from the reductive elimination to give the final product 3,which regenerates the palladium catalyst and realizes the cycle。
图式26 钯催化烯基溴化物和叠氮化钠反应[74]

Scheme 26 Pd-catalyzed reaction of alkenyl bromide and sodium azide[74]

In 2012,Kuang Chunxiang's group used 1,1-dibromoalkene 26 and sodium azide 2 as raw materials to synthesize 4-aryl-1H-1,2,3-triazole derivatives 7(Fig.27)under copper catalysis[75]。 the possible mechanism of the reaction is as follows:firstly,there are two ways to form the intermediate 27-C.the first way is that the alkynyl bromide intermediate 27-a is formed from 26 throughβ-elimination,and then 27-C is obtained by oxidative addition with CuI;the second is the oxidative addition of 26 to CuI to give intermediate 27-B,which undergoesβ-elimination to form 27-C,which is then replaced by sodium azide to give 27-D,which undergoes intramolecular cyclization to give 27-E,which is protonated to give the target product 7 and the copper catalyst。
图式27 1,1-二溴烯烃和叠氮化钠的反应[75]

Scheme 27 Reaction of 1,1-dibromoalkene and NaN3[75]

2.5.2 In situ alkenyl bromide and sodium azide

In 2010,Kuang Chunxiang's group designed the reaction of 3-aryl-2,3-dibromopropionic acid 27 with sodium azide 2 to synthesize 4-aryl-1H-1,2,3-triazole derivative 7 under palladium catalysis(Scheme 28)[76]。 The possible reaction mechanism is as follows:3-aryl-2,3-dibromopropionic acid is eliminated in situ in the presence of sodium azide to give(Z)-β-arylvinyl bromide 28-A,which is then added oxidatively to the catalyst to give vinyl palladium complex 28-(Z)-B.Isomerization of 28-(Z)-B to 28-(E)-B followed by[3+2]cycloaddition of the latter with HN3（produced in the debromination-decarboxylation of 3-aryl-2,3-dibromopropionic acid gave the dihydrotriazolyl palladium complex 28-C.Intermediate 28-C releases the palladium complex 28-D and the desired 4-aryl-1H-1,2,3-triazole derivative 7 viaβ-elimination.The palladium complex 28-D undergoes reductive elimination to regenerate the Pd(0)species.In the same year,the group successfully synthesized 4-aryl-1H-1,2,3-triazole derivatives by replacing the previous Pd2(dba)3catalyst with cheap CuI,and the yield was up to 95%[77]。
图式28 钯催化3-芳基-2,3-二溴丙酸与叠氮化钠反应[76]

Scheme 28 Pa-Catalyzed 3-aryl-2,3-dibromopropionic acid with NaN3 reaction[76]

2.6 Other methods

In 2014,Wu Yong's group developed a new method for the synthesis of 4-aryl-1H-1,2,3-triazole 7 from aryl ketoxime semicarbazone 28(Fig.29)[78]。 The reaction does not require azide and metal catalyst,and has the advantages of good functional group tolerance,excellent yield and short reaction time.The possible mechanism of the reaction is as follows:first,arylketoxime semicarbazone 28 isomerizes to 29-a at 110°C,and then compound 29-b is generated under oxidation–reduction conditions of O2and Na2S2O4,and its oxime hydroxyl group is further converted into an active leaving group,Promotes the cleavage of the nitrogen-oxygen bond to form the iminium ion compound 29-C,which undergoes cyclization to give the intermediate 29-D,which is hydrolyzed under alkaline conditions to give the 4-aryl-1H-1,2,3-triazole derivative 7 。
图式29 以芳基酮肟缩氨基脲为原料[78]

Scheme 29 From arylglyoxaldoxime semicarbazone[78]

3 Conclusion and prospect

4-monosubstituted-NH-1,2,3-triazole not only has a wide range of pharmaceutical activities,but also is an important intermediate in organic synthesis.Over the past decade,a large number of researchers in organic chemistry and medicinal chemistry have paid more attention to the synthesis of these compounds,and have achieved important research results.many methods have the advantages of recyclable catalyst and green conditions,but Many methods are difficult to avoid the direct use of azide.Therefore,it is still of great research significance in the future to continue to develop convenient,efficient and green methods for the synthesis of 4-monosubstituted-NH-1,2,3-triazole derivatives and to expand the diversity of 1,2,3-triazole derivatives by their structural modification and transformation.With the development of 1,2,3-triazole structure and synthesis methods,1,2,3-triazole compounds will play an increasingly important role in medicine,pesticides,materials and other fields。

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