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Tetrahedron report 1120 Advances of azide-alkyne cycloaddition-click chemistry over the recent decade Maya Shankar Singh * , Sushobhan Chowdhury, Suvajit Koley Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi 221005, India article info Article history: Received 5 September 2015 Available online 14 July 2016 Keywords: Azide-alkyne Click chemistry CuAAC 1,2,3-Triazoles Copper catalysis Organic synthesis Contents 1. Introduction ......................................................................................................................5257 2. Mechanistic overview ............................................................................................................. 5258 3. Copper-catalyzed reactions ........................................................................................................ 5258 3.1. Copper halide catalysis ...................................................... ............................................... 5259 3.2. Copper sulfate catalysis ...................................................................................................... 5264 3.3. Copper acetate catalysis ..................................................................................................... 5268 3.4. Copper triflate catalysis ...................................................................................................... 5270 3.5. Use of other copper catalysts ................................................... ............................................ 5271 4. Use of other non-copper catalysts ................................................................................................... 5274 5. Photoclick chemistry ........................................................... ...................................................5277 6. Advances of click methods in chemical biology ....................................................................................... 5279 7. Summary and outlook ............................................................................................................ 5280 Acknowledgements ........................................................... ................................................... 5280 References and notes .............................................................................................................. 5280 Biographical sketch ........................................................... ................................................... 5283 1. Introduction During the past years, a variety of scientic and methodological developments have been achieved, which urge chemists to increase the tools of their arsenal to improve the ease and practicality of synthesis and related separation/purication processes. Huisgen 1,3-dipolar cycloaddition between organic azides and alkynes is one among many synthetic tools that became quite well-known over the recent decade, mainly due to its key improvement in terms of rate and regioselectivity. The revolutionary idea was in- dependently introduced by Sharpless and Meldal groups in 2002 through the introduction of Cu(I) catalysis termed as Click * Corresponding author. Fax: þ 91 542 236 8127; e-mail address: [email protected] (M.S. Singh). Contents lists available at ScienceDirect Tetrahedron journal homepage: Tetrahedron 72 (2016) 5257e5283 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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    Tetrahedron report 1120

    Advances of azide-alkyne cycloaddition-click chemistry over therecent decade

    Maya Shankar Singh *, Sushobhan Chowdhury, Suvajit KoleyDepartment of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi 221005, India

    a r t i c l e i n f o

    Article history:Received 5 September 2015Available online 14 July 2016

    Keywords:Azide-alkyneClick chemistryCuAAC1,2,3-TriazolesCopper catalysisOrganic synthesis

    * Corresponding author. Fax: 91542 236 8127; (M.S. Singh). 2016 Elsevier Ltd. All rights reserved.


    1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52572. Mechanistic overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52583. Copper-catalyzed reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5258

    3.1. Copper halide catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52593.2. Copper sulfate catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52643.3. Copper acetate catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52683.4. Copper triflate catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52703.5. Use of other copper catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5271

    4. Use of other non-copper catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52745. Photoclick chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52776. Advances of click methods in chemical biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52797. Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5280

    Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5280References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5280Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5283

    1. Introduction

    During the past years, a variety of scientific and methodologicaldevelopments have been achieved, which urge chemists to increase

    il address: [email protected]

    the tools of their arsenal to improve the ease and practicality ofsynthesis and related separation/purification processes. Huisgen1,3-dipolar cycloaddition between organic azides and alkynes isone among many synthetic tools that became quite well-knownover the recent decade, mainly due to its key improvement interms of rate and regioselectivity. The revolutionary idea was in-dependently introduced by Sharpless and Meldal groups in 2002through the introduction of Cu(I) catalysis termed as Click

    mailto:[email protected]:[email protected]://

  • Fig. 1. Proposed mechanism for copper-catalyzed azide-alkyne cycloaddition (CuAAC).

    Fig. 2. Proposed mechanism for ruthenium catalyzed azide-alkyne cycloaddition(RuAAC).

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835258

    Chemistry.1 Copper-catalyzed azide-alkyne cycloaddition (CuAAC)is a type of Huisgen 1,3-dipolar cycloaddition based on the for-mation of 1,4-disubstituted 1,2,3-triazoles between a terminal al-kyne and an aliphatic azide in the presence of copper, and isclassified as a click reaction. Click chemistry promotes the use oforganic reactions that allow the connection of two molecularbuilding blocks in a facile, selective, high-yielding reaction undermild reaction conditions with few or no byproducts. Furthermore,this chemistry has the capacity to promote bioconjugation andpeptide ligation, stemming from the properties of the triazolelinkage as a peptide mimetic.

    The tremendous synthetic potential of initial protocols forHuisgen 1,3-dipolar cycloaddition reaction between organic azidesand alkynes was limited by the markable disadvantages like heat-ing requirement, prolonged reaction time and formation of struc-tural isomers due to the lack of selectivity. The wonderful Cu(I)-catalyzed modification introduced at the dawn of last decade,allowed the cycloaddition to occur at room temperature or withmoderate heating leading to the exclusive formation of 1,4-disubstituted triazole with shortest workup and purificationsteps. In 2005, another analogous RuAAC was reported by Fokingroup, which led to the selective formation of 1,5-disubstitutedtriazole.2 Therefore, these remarkable modifications turned azide-alkyne click method a practically quantitative, robust, insensitiveand general orthogonal ligation reaction that is suitable in all as-pects of drug discovery, combinatorial chemistry, target-templatedin situ chemistry, material chemistry, proteomics and DNA researchusing bio-conjugation reactions.1

    Since the introduction of Cu(I) catalysis, azide-dipolarophile 1,3-dipolar cycloaddition has been advanced remarkably over the lastdecade, and now has engulfed almost every section of chemistryand applied sciences. Realizing the importance and practical ap-plicability of the method, a number of reviews describing its vari-ous aspects in different scientific fields like carbohydrate chemistry,polymer, drug discovery, materials etc. are already reported andemerging frequently in the literature.3 However, no well-directeddatabase describing the azide-dipolarophile cycloaddition meth-odologies developed over the recent years is yet reported. There-fore, this is a significant topic for all the sectors of chemistry andapplied sciences. To fulfill the demand and in continuation of ourprevious report on 1,3-dipolar cycloaddition chemistry,4 herein wepresent an overview of the open literature focussed on the de-velopment of azide-dipolarophile 1,3-dipolar cycloaddition chem-istry over the recent years (2006 onwards). Starting witha preliminary discussion on the mechanistic aspects, the report iscategorized based on different dipolarophiles to couple with azidedipole leading to the formation of diverse 1,2,3-triazoles and re-lated systems. The azide-alkyne cycloaddition section is furthersub-categorized based on the use of different copper catalysts (i.e.,click chemistry) as well as non-copper catalysts. Additionally,a sub-section based upon the short discussion on photoclickchemistry under click methods on chemical biology has also beenincluded. In this review, we use the terms CuAAC and click chem-istry interchangeably.

    2. Mechanistic overview

    The classical Huisgen 1,3-dipolar cycloaddition of organic azidewith dipolarophiles is a one-step process,4 whereas its copper(I)-catalyzed variant is considered to be a step-wise process in-volving copper in the intermediate steps.5 In the initial step, copperforms acetylide via coordinationwith alkyne. In the next step, azidebinds to the copper followed by the formation of an unconventionalcopper(III)metallacycle. The energy calculation showed a consider-able low energy barrier for the step justifying the higher rate of thereaction than its uncatalyzed version. The intermediate then

    undergoes ring contraction to give copper triazolyl derivative,which upon protonolysis gives the desired 1,2,3-triazole product(Fig. 1).

    The analogous RuAAC does not involve a ruthenium acetylideintermediate like copper, since it applies to both terminal as well asnon-terminal alkynes. In the first step, the spectator ligands getdisplaced to form activated complex. This is followed by oxidativecoupling between terminal nitrogen of azide and more electro-negative less sterically demanding carbon of the alkyne to forma Ruthenacycle. The Ruthenacycle then undergoes reductive elim-ination to release 1,2,3-triazole compound regenerating the activecomplex for the next cycle (Fig. 2).6

    3. Copper-catalyzed reactions

    The copper either as metal or in salt form (ionic or complex) hasbeen employed as a most effective catalyst to promote the 1,3-dipolar addition reaction-click chemistry. In this section, the clickreactions, which are catalyzed by different copper catalysts, arehighlighted. This section has been further sub-divided into fiveclasses depending on the type of copper catalysts used either inzero, mono or divalent form.

  • M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5259

    3.1. Copper halide catalysis

    Among copper halide catalysts, copper iodide is being fre-quently used in various transformations. Few reports of copperbromide catalysis are also available. Cu(I) combined with Cu(II)salts, other metal complexes or ionic liquids are also used as ef-fective catalytic systems. Most of the reactions proceed smoothly atroom temperature. However, there aremany reports, which requiretraditional heating and some are facile upon application of un-conventional energy sources like microwave (MW) irradiation andultrasound/sonication conditions. Use of co-solvent systems alsopromotes the reactions efficiently. In this part, we categorized thefeatures as systematically as possible so that it would help thereader to find the required portion at one stroke.

    Alkyne is one of the indispensable component in click re-actions.7 Yang et al.8 used calcium carbide 14 as a source of acety-lene in copper-catalyzed 1,3-dipolar cycloaddition reaction for thesynthesis of 1-aryl-1,2,3-triazoles 15 in 72e95% yields (Scheme 1).

    Scheme 1. CaC2 as a source of acetylene in 1,3-dipolar cycloaddition.

    Scheme 4. Sonogashira coupling followed by Cu-catalyzed click reaction.

    Novak and co-workers9a treated acetylene with aliphatic/aro-matic azides in Et3N followed by the addition of H2O or D2O in thepresence of CuI, which afforded diverse monosubstituted 1,2,3-triazoles 17 or deuterated triazoles 18 (Scheme 2). Here, Et3Nplayed dual role of base and solvent.

    Scheme 2. Synthesis of simple and deuterated triazoles.

    The copper(I)-catalyzed three-component reaction of N-tosyl-hydrazones, terminal alkynes, and azides has been realized in anefficient and regioselective manner for the synthesis of 1,4,5-trisubstituted 1,2,3-triazole derivatives. Mechanistically, the re-action involves the trapping of the copper(I) triazolide intermediateto form a copper carbene and subsequent migratory insertion and

    Scheme 3. Synthesis of benzofuran- and indole-substituted 1,2,3-triazoles.

    protonation.57 Trialkylsilyl-protected alkynes such as 2-silylalkynylsubstituted benzofuran 19 and indole 20 have been utilized asa source of alkyne for click method to access benzofuran- andindole-substituted 1,2,3-triazoles 22 and 23, respectively (Scheme3).10 Here, in situ deprotection of silyl group followed by final cy-clization involving click approach afforded the desired triazoles.

    Aryl iodides 24 are transformed into 4-aryl-1,2,3-triazoles 27 viapalladium-catalyzed Sonogashira coupling followed by copper-catalyzed click reaction using trimethylsilyl acetylene 25 as acety-lene surrogate.11 In the first step, there occurs the formation ofTMS-protected phenyl acetylenes 26 through Sonogashira reaction.The fact was also confirmed by the isolation of TMS-protectedphenyl acetylenes in presence of electron-donating functionalgroups such as amino and methoxy, which underwent subsequentdeprotection and cycloaddition with azide to afford the substitutedtriazoles (Scheme 4).

    Another method for the direct use of trimethylsilyl-protectedalkynes via copper(I)-mediated alkyne-azide cycloaddition re-action was developed by Pericas and co-workers.12 This method-ology is particularly useful for selective addition of thetrimethylsilyl in front of other silicon-based C(speH protectinggroups. Ionic liquids as environmentally benign solvents have beenemployed in click reactions due to their low vapor pressure, effi-ciency to dissolve metal salts in metal-catalyzed reactions, goodmicrowave absorbing capacity and recyclability. Liang and co-workers13 performed a three-component click reaction involvingalkynes 28, alkyl/aryl halides 29, and sodium azide to form 1,4-disubstituted 1,2,3-triazoles 31 in presence of CuI in a mixture ofionic liquid [bmim][BF4] and water (Scheme 5).

    Scheme 5. Synthesis of 1,2,3-triazoles in ionic liquid.

    Hagiwara et al.14 developed another heterogeneous catalyst byimmobilizing cuprous bromide as a Cu-SILC in the pores ofamorphous mercaptopropyl silica gel with the aid of an ionicliquid, [bmim][PF6]. Further, they used it to catalyze Huisgen[32] cycloadditions regioselectively at room temperature inaqueous ethanol. The catalyst can be reused at least six timeswithout losing its activity. In another reaction, various structurallydiverse organic azides and terminal alkynes were combined in

  • Scheme 9. Synthesis of 1,4-disubstitutred triazoles via light induced click method.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835260

    a polyoxygenated ionic liquid (AMMOENG 100) in the presenceof CuI to construct 1,4-disubstituted triazole derivativesexclusively.15

    Use of non-conventional energy sources like microwave heat-ing, ultrasound and light-induced click reactions have emerged aspowerful technique to enhance reaction rate of various chemicaltransformations. Recently, a few microwave-Cu(I)-coupled click-chemical methods have been reported.16aed,69,152c Microwave ac-tivation was applied with Cu(I) catalysis to enhance the 1,3-dipolarcycloaddition between azido-20-deoxyribose 32 and terminal al-kynes 33 under solvent-free conditions to afford corresponding 4-substituted 1,2,3-triazolyl-nucleosides 34 (Scheme 6). Furtherdeprotection of the obtained nucleosides was made on their 30- and50-positions to give the corresponding free analogs.16d

    Scheme 6. Microwave-Cu(I) coupled click reaction to access 1,2,3-triazoles.

    Scheme 10. Cu(I)-catalyzed click reaction in the presence of UV light.

    Reddy and co-workers17 employed CuI as an efficient catalyst inan ultrasound-accelerated three-component reaction involving al-kyl halides 35, terminal alkynes 36, and sodium azide for theregioselective synthesis of l,4-disubstituted 1,2,3-triazoles 37(Scheme 7).

    Scheme 7. Ultrasound-accelerated synthesis of 1,2,3-triazoles.Scheme 11. Polymer supported Cu(I)-catalyzed 1,3-dipolar cycloaddition.

    Applying click chemistry Chen and co-workers18 synthesized4,5-disubstituted-1,2,3-(NH)-triazoles 40 catalyzed by palladiumvia Sonogashira coupling/1,3-dipolar cycloaddition involving acidchlorides 39, terminal acetylenes 38, and sodium azide in one-pot (Scheme 8). Further from 4,5-disubstituted-1,2,3-(NH)-tri-azoles 1,4,5-trisubstituted-1,2,3-(NH)-triazoles could be madeeasily.

    Scheme 8. Palladium-catalyzed synthesis of 4,5-disubstituted-1,2,3-(NH)-triazoles. Scheme 12. Cu(I)-catalyzed reaction of diaryliodonium salts, sodium azide andalkynes.

    Diverse triazoles have been prepared in moderate to good yieldsvia click reactions using a combination of Cu(II) and Cu(0) salts andsodium ascorbate as a reducing agent. Recently, 1,4-disubstitutred1,2,3-triazoles 43 have been synthesized by the reaction of

    appropriate azides 41 and alkynes 42 via light induced click re-actions (Scheme 9).19

    UV light is used as an activator for the in situ generatedcopper(I)-catalyzed click reaction between azides 44 and alkynes45 in the presence of air without reducing agent (Scheme 10).20

    Heterogeneous catalysts are being frequently used in clickchemistry. Chi and co-workers21 used ionic polymer supportedcopper(I) as a reusable catalyst for Huisgens 1,3-dipolar cycload-dition to produce 1,4-disubstituted 1,2,3-triazoles 49 in high yields(Scheme 11).

    A regioselective synthesis of 1,4-diaryl-1H-1,2,3-triazoles 52have been developed by copper(I)-catalyzed reaction of diary-liodonium salts 50, sodium azide and terminal alkynes (Scheme12).22 Here aryl azides 51 have been generated in situ via the re-action of diaryliodonium salts and sodium azide in polyethyleneglycol 400 (PEG-400)-water (1:1, v/v) mixture followed by couplingwith terminal alkyne at room temperature. Girard et al.23 haveelaborated a new catalytic system based on copper(I)-dopedWyomings montmorillonite in click reaction.

    Dipolar addition reactions are being utilized extensively in bi-ology and related fields with small biosurrogates. Zhang and co-workers24 synthesized several 1,2,3-triazole-linked glyco-conjugates 55 in high yields via Cu(I)-mediated 1,3-dipolar

  • M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5261

    cycloaddition. Treatment of 2-azidoethyl 2,3,4,6-tetra-O-acetyl-b-D-galactopyranoside 53 with aryl acetylenes 54 in the presence ofCuI afforded glycoconjugates 55 in good yields (Scheme 13). Fur-ther, the treatment of azides with glycosyl alkyne in the presence ofCuI afforded the desired glycoconjugates 57 in good yields (Scheme14).

    Scheme 13. Synthesis of 1,2,3-triazole-linked glyco-conjugates 55.

    Scheme 14. CuI-mediated synthesis of glycoconjugates 57.

    Scheme 16. Intramolecular 1,3-dipolar cycloaddition to form spirocyclic compound 67.

    Muller et al.25 studied the scope of metal-mediated base pairingby developing a new family of 1,2,3-triazole-based click nucleo-sides. The utilization of 2-deoxy-b-D-glycosyl azide 58 as a commonprecursor permitted the modular synthesis of 1,2,3-triazole nu-cleosides (60e63) through CuI-catalyzed Huisgen 1,3-dipolar cy-cloaddition (Scheme 15).

    Scheme 15. CuI-catalyzed Huisgen 1,3-dipolar cycloaddition.

    Scheme 17. Thermal cycloaddition of internal alkynes with azides.

    Cobb and co-workers26a devised a proficient synthesis of spi-rocyclic triazolooxazine nucleosides 67 by the renovation of b-D-psicofuranose to the corresponding azido-derivative 64 followed byalkylation of the primary alcohol with a range of propargyl bro-mides 65. The products 66 of these reactions went through 1,3-dipolar addition to produce the protected spirocyclic adducts 67(Scheme 16).

    Taourirte and co-workers26b reported synthesis of 1,2,3-triazoleand bis(1,2,3-triazoles) acyclonucleoside analogs of Acyclovir. Theyprepared a series of novel 1,2,3-triazole acyclonucleosides linked tonucleobases via copper(I)-catalyzed 1,3-dipolar cycloaddition of N-9 propargylpurine, N-1-propargylpyrimidines or N-1-propargylindazoles with the azido-pseudo-sugar by applying mi-crowave radiation followed by treatment with K2CO3/MeOH.

    Alternatively, thermal cycloaddition of internal alkynes withazideswere reportedbyAnandet al.27 Reactionof1,4-O-bis(4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranos-1-yloxy) -but-2-yne 68 with the above two glycosyl azides 69 and 70 separately in

    refluxing toluene led to the formation of corresponding triglycosy-lated triazoles 71 and 72 (Scheme 17).

    Click methods have also been applied toward the synthesis of D-()-1,4-disubstituted triazolo-carbanucleosides.28 Benhida and co-workers29 described one-pot azideealkyne 1,3-cycloaddition/electrophilic addition tandem reaction approach leading to a newfamily of 4,5-difunctionalized triazolyl nucleosides. Two click sys-tems, azido-precursor from regioselective chlorination of thymi-dine and propargyl derivative from selective 30-O-alkylation ofthymidine were compiled for 1,3-dipolar cycloaddition to obtainthe desired triazole-linked 30e50 thymidine dimer under MW ir-radiation by Zerrouki et al.30

    A green approach has been devised to synthesize (1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines 76through copper(I)-catalyzed three-component reaction based onthe Huisgen cycloaddition using amine 73, propargyl halide 74 andazide 75 in water (Scheme 18).31 Various copper salts such asCuSO4, CuCl2 and Cu(OAc)2 without any reducing agent, non-copper catalysts like ZnCl2, InCl3, AgCl, AgI, and silver metal werealso investigated but could not provide the desired triazoles.

    In some 1,3-dipolar cycloaddition reactions, mixture of Cu(I) andCu(II) systems have been extensively used for the synthesis of tri-azole nucleus. Chen and co-workers32 used terminal alkynes,phenylboronic acids 77 and sodium azide in a 1,3-dipolar cyclo-addition/coupling to afford a series of 1,4,5-trisubstituted 1,2,3-triazoles 80 using CuI/CuSO4 as catalyst (Scheme 19). Use of onlyCuSO4 could not trigger the reaction. Various solvents along withwater such as acetone, MeCN, DMF, DMSO, EtOH, MeOH, THF, t-BuOH, and 1,4-dioxane were screened. Best result was obtained in1,4-dioxaneewater medium. Diyne byproduct was obtained in thiscase, which was assumed to form as a result of competing Glasercoupling. Therefore, the course of the reaction was assumed to beinitial Glaser coupling and subsequent 1,3-dipolar cycloaddition.But sequential treatment of 1,4-diphenyl buta-1,3-diyne with

  • Scheme 18. Synthesis of triazolylmethyl-dialkylamines.

    Scheme 19. Glaser coupling followed by 1,3-dipolar cycloaddition to give compound80.

    Scheme 21. CuI-catalyzed synthesis of compound 86.

    Scheme 22. Synthesis of 4-aryl-1H-1,2,3-triazoles 89.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835262

    sodium azide and phenylboronic acid gave no desired product.Treatment of disubstituted triazole with alkyne in the presence ofCuI and CuSO4$5H2O also could not trigger the reaction. Thus,a concerted cyclic pathway was assumed for the reaction.

    1,4-Disubstituted 1,2,3-triazoles have been prepared in highyields by one-pot one-carbon homologation of various aldehydesfollowed by CuAAC.33 A series of 2-[(4-substituted 1H-1,2,3-triazol-1-yl)-1,4-naphthoquinones 83 were prepared in excellent yieldsfrom 2-azido-1,4-naphthoquinone 81 with terminal alkynes 82 inthe presence of a catalytic amount of copper(I) iodide in acetonitrile(Scheme 20).34

    Scheme 20. CuAAC to generate triazolyl naphthoquinones.

    Scheme 23. Synthesis of triazolo fused macrocycles 93 via click method.

    Kuang and co-workers35 synthesized 1-substituted 1,2,3-triazoles by the reaction of azides with propiolic acid via copper-catalyzed click cycloaddition/decarboxylation sequence. Variousaryl and vinyl azide derivatives are well tolerated in this protocol.Nguyen and Miles36 employed copper iodide as an efficient catalystfor the synthesis of compound 86 (1,2,3-triazole derivatives ofpodocarpic acid) at room temperature through click cycloadditionreaction of methyl O-propargylpodocarpate and propargyl O-propargylpodocarpate 84 with different substituted aliphatic andaromatic azides 85 (Scheme 21).

    Grtli et al.37 synthesized 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines viaclick method. 1,4-Disubstituted 1,2,3-triazoles 89 have been syn-thesized from anti-3-aryl-2,3-dibromopropanoic acids 87 and or-ganic azides in dimethyl sulfoxide using CuI as a catalyst (Scheme22).38 Yang and co-workers39 synthesized 4-aryl-1H-1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids employingCuI as a catalyst in DMSO.

    CuBr-NCS-mediated multicomponent azideealkyne cycloaddi-tion to synthesize 5-bromo-1,4-disubstituted-1,2,3-triazoles hasbeen developed by Li et al.40 Ueda and co-workers41a synthesized1,2,4-triazoles by the reaction of 2-aminopyridine and aromaticnitriles in presence of Cu(I or II) bromide/acetate as catalyst andzinc bromide as additive. Diez-Gonzalez and Lal138 used[CuBr(PPh3)3] system for the synthesis of triazoles under neatconditions at room temperature.

    Tron and co-workers42 synthesized complex macrocycles inmoderate to good yields via click chemistry (Scheme 23). Theycombined three appropriately designed substrates with a pro-grammed sequence involving acetamide-based three-componentreaction followed by copper-catalyzed intramolecular [32] cy-cloaddition of alkyne 92 and azide 91 to give the desired macro-cycle 93.

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    Brimble and co-workers43 generated the novel spiroacetal-triazole hybrid structures via cycloaddition of a spiroacetal azidewith a series of alkynes. Conte et al.44 synthesized nonlinear 1,4-diaryl-1,2,3-triazoles 98 in a regioselective manner via Cu(I)-catalyzed 1,3-dipolar cycloaddition of aryl azides 95 to terminalaryl acetylenes 94. If the cycloaddition is thermally conduced, a 1:1mixture of 1,4- and 1,5-disubstituted triazole derivative 96 and 97,respectively is usually obtained (Scheme 24). The 1,4-regioselectivity of the reactions were improved by carrying outthem with a catalytic amount of Cu(I) or Cu(II) salts and sodiumascorbate in water or still in encapsulated systems.

    Scheme 24. Cu-catalyzed regeoselective synthesis of 1,4 disubstituted 1,2,3-triazoles.

    Scheme 27. Palladium-copper catalyzed synthesis of fused triazoles.

    Scheme 26. Synthesis of oxepan-2-one substituted triazoles.

    Copper catalysts have been used in modular one-pot multi-component syntheses of fully substituted 1,2,3-triazoles 102through a chemo- and regio-selective sustainable click reaction/direct arylation sequence (Scheme 25).45 Frost and co-workers46

    displayed the utility of the azido-boronate motif as a modularbuilding block in the rapid synthesis of drug-like structuresemploying sequential catalytic azideealkyne cycloaddition undermild conditions.

    Scheme 25. Copper-catalyzed syntheses of 1,2,3-triazoles.

    Scheme 28. Use of SiO2-NHC-Cu(I) in [32] cycloaddition.

    Numerous functionalized oxepan-2-ones have been synthesizedvia Huisgens [32] cycloaddition. Since 5-substituted lactones 104are less sensitive to ring-opening than 3-substituted lactones 103under the experimental conditions, the click reactions occur only incase of 5-substituted lactones 104 (Scheme 26).47

    Chowdhury and co-workers48a synthesized isoindoline fusedtriazoles 109 from ortho-iodobenzyl azide 107 and acetylenes 108through palladiumecopper catalysis. The reaction was equally ap-plicable to both aromatic and aliphatic acetylenes. Chiral sugaracetylene derivative shows parallel compatibility with the protocol(Scheme 27).

    Shao et al.55 selected a combination of acid and base system topromote azide-alkyne cycloaddition in presence of CuI as catalyst.They selected CuI/DIPEA/HOAc system. Here, HOAc acts as the

    accelerator for the conversions of the CeCu bond-containing in-termediates and buffer the basicity of DIPEA. Thus, it minimizes thedrawbacks of CuI/NR3 catalytic system. Dzyuba and co-workers49

    studied effects of the product distribution pattern upon switchingbase and concentration of reaction bulk in a copper-promoted al-kyne-azide cycloaddition reaction leading to the formation of 5-iodo-triazoles. Generally in base promoted Cu-catalyzed azide-al-kyne cycloadduct iodo-triazoles are valuable synthon for a varietyof cross-coupling reactions. Further they are important in modu-lating various recognition processes relevant to supramolecular andbiological chemistry.

    Wang et al.50 developed a highly efficient novel catalyst SiO2-NHC-Cu(I) for [32] cycloaddition of organic azides 110 and ter-minal alkynes 111. 1 mol % of SiO2-NHC-Cu(I) drives the reactionsmoothly to generate the corresponding regiospecific 1,4-disubstituted 1,2,3-triazoles 112 in excellent yields under solvent-free conditions at room temperature (Scheme 28). Further thecatalyst can be reused for 10 cycles without any loss of its activity.

    Brimble and co-workers51 synthesized a series of 1,2,3-triazoleanalogs of the nanaomycin family of antibiotics. Treatment ofnaphthalene azide to various alkynes employing click dipolar

  • Scheme 32. Three-component click synthesis of 1,2,3-triazoles involving copper(I)triazolide intermediate.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835264

    cycloaddition followed by oxidation furnished the desired triazoleanalogs. Click chemistry was also applied in the synthesis of fer-rocene complexes.52

    Qian et al. developed a click and activate strategy in a four-component, stepwise condensation leading to the synthesis ofa library of trisubstituted triazolylpyridazinones 116. The one-potprocess comprises of regioselective azide substitution at 2-substituted-4,5-dichloropyridazinones, followed by a Cu(I) cata-lyzed 1,2,3-triazole formation that triggered subsequent nucleo-philic substitution at the neighboring position to achieve threepoints of diversity (Scheme 29).53

    Scheme 29. Tandem process including click step to synthesize trisubstitutedtriazolylpyridazinones.

    Kumar et al. developed a ligand-free copper-catalyzed tandemazide-alkyne cycloaddition (CuAAC), Ullmann-type CeN coupling,and intramolecular direct arylation leading to the synthesis of 1,2,3-triazole-fused imidazo[1,2-a]pyridines 120 in a single step inmoderate to good yields (Scheme 30).54

    Scheme 30. Ligand-free copper-catalyzed tandem CuAAC leading to 1,2,3-triazole-fused imidazo[1,2-a]pyridines 120.

    Scheme 33. Synthesis of coumarin complexed 1,2,3-triazoles.

    Hu et al. developed a novel acid-base promoted CuAAC wherea combination of CuI/DIPEA/HOAcwas used. HOAcwas identified toaccelerate the conversions of the CeCu bond-containing in-termediates, thus buffer the basicity of DIPEA which in turn over-comes the drawbacks of the popular catalytic system CuI/NR3.55

    Sun et al. developed a sequential one-pot azide-alkyne click re-action followed by tandem aerobic intramolecular CeH amidationleading to the synthesis of triazoloquinazolinones 124 (Scheme31).56

    Scheme 31. Click step in tandem process to synthesize triazoloquinazolinones 124.

    Scheme 34. Cu(I)-catalyzed synthesis of triazole 134 from aromatic amines.

    Wang et al. developed CuI catalyzed regioselective synthesis of1,4,5-trisubstituted 1,2,3-triazoles 128 via three-component re-action of N-tosylhydrazones 125, terminal alkynes 126 and azides127. The reaction involves a copper(I) triazolide intermediate thatforms copper carbene which suffers subsequent migratory in-sertion and protonation leading to the desired triazole product(Scheme 32).57

    3.2. Copper sulfate catalysis

    CuSO4 is usually used in two forms either with sodium ascorbateorwith Cu(0) system. Trialkylsilyl protected alkynes are also used inpresence of CuSO4. Many biological models containing azide oralkyne components have been used successfully under the cyclo-addition methodology. The pioneer Sharpless and co-workers58a

    performed one ideal example of click method catalyzed by CuSO4in presence of sodium ascorbate in water and tert-butanol mixturein 2:1 ratio at room temperature. Himo et al.58b performed DFTstudies and revealed the stepwise mechanism for the cycloaddi-tion. 1,4-Disubstituted 1,2,3-triazoles and 3,4-disubstituted iso-xazoles were achieved by the reaction of azides and nitrile oxides inthe presence of copper(I) acetylides via an unprecedented metal-lacycle intermediates for non-concerted Huisgens 1,3-dipolarcycloaddition.

    Wang and co-workers58c performed copper(I)-catalyzed 1,3-dipolar cycloaddition reaction of nonfluorescent 3-azidocoumarins 129 with terminal alkynes 130 to afford intensefluorescent 1,2,3-triazoles 131 (Scheme 33). A library of pure fluo-rescent coumarin dyes have been synthesized applying the aboveprotocol.

    Moses et al.59 developed an efficient and improved pro-cedure for the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cyclo-addition of substituted alkynes with in situ generated aromaticazides from aromatic amines 132. Thus, they obtained 1,4-disubstituted 1,2,3-triazoles 134 in excellent yields from a vari-ety of aromatic amines without isolating the azide in-termediates (Scheme 34).

    Wittmann and co-workers60 reported the synthesis of 1,4-disubstituted 1,2,3-triazoles 137 in excellent yields from a varietyof readily available amines 135 via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition without the isolation of the azide in-termediates (Scheme 35).

    Kumar and co-workers61 synthesized two classes of 1,4-disubstituted 1,2,3-triazoles 141 from a-tosyloxy ketones/a-haloketones 138, sodium azide, and terminal alkynes 139 in the pres-ence of aqueous PEG via one-pot click approach (Scheme 36).

  • Scheme 35. Synthesis of 1,2,3-triazoles 137 via diazo transfer followed by azide-alkyne1,3-dipolar cycloaddition.

    Scheme 36. Synthesis of 1,2,3-triazoles 141 from a-tosyloxy ketones/a-halo ketones.

    Scheme 39. Synthesis of triazolyl substituted alkyl phosphonates.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5265

    Shingare et al.62 synthesized 2-chloro-3-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)quinoline derivatives 144 via 1,3-dipolar cy-cloaddition reaction of 3-(azidomethyl)-2-chloro-quinoline de-rivatives 142with phenyl acetylene in the presence of Cu(I) catalystin excellent yield (Scheme 37).

    Scheme 37. Synthesis of triazolylmethyl substituted quinolines.

    Scheme 40. Synthesis of 1,2,3-triazole-containing phosphono carboxylates.

    Botta and co-workers63 applied a microwave-assisted Cu(I)-catalyzed click chemistry to generate a small library of enantio-merically pure a-[4-(1-substituted)-1,2,3-triazol-4-yl]benzylaceta-mides 147 from racemic propargyl amines 145 (Scheme 38).

    Scheme 38. MW-assisted Cu(I)-catalyzed click reaction.

    Scheme 41. Synthesis of 1,2,3-triazoles by decarboxylative coupling of alkynoic acids.

    Scheme 42. Synthesis of TSE-protected 1,2,3-triazoles.

    Delain-Bioton and co-workers64 reported the copper-catalyzedsynthesis of 1,2,3-triazolyl-alkyl phosphonates 150 and 153through Huisgen 1,3-dipolar cycloaddition. Here, alkynyl phos-phonate 148 or azido phosphonate 151 is used as starting materialfollowed by cycloaddition with an azidoalkane 149 or substitutedalkyne 152, respectively. High yields of regiospecific products wereobtained (Scheme 39).

    A practical and selective method for the preparation ofmonopropargyl-substituted phosphonocarboxylate (PC) has beendeveloped by the addition of sodium acetylenide to ethylidenephosphonate and corresponding ethyl(propargyl)-, tri-fluoromethyl(propargyl)- and dipropargyl-substituted derivatives

    154, which were synthesized by direct alkylation of either the corre-sponding substituted phosphono carboxylates or methylene phos-phonocarboxylate with excess of propargyl bromide.65 Furthermore,compounds 154were transformed to a series of novel potentially bi-ologically active 1,2,3-triazole-containing phosphono carboxylates156 by copper(I)-catalyzed 1,3-dipolar cycloaddition (Scheme 40).

    Kolarovic et al.66 developed a tandem practical protocol for thesynthesis of 1,4-disubstituted triazoles 160 from aryl halides 157and alkynoic acids 158 via 1,3-dipolar cycloaddition involvingdecarboxylative coupling (Scheme 41).

    Weinreb and co-workers67 prepared TSE-N3 162 in one stepfrom p-tolyl-vinyl sulfone 161 and sodium azide/H2SO4 followed bymetal-catalyzed 1,3-dipolar cycloadditions with alkynes 163 toproduce TSE-protected 1,2,3-triazoles 164 (Scheme 42).

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    Ramana et al.68 utilized activated fluorobenzenes 166 to reactwith azide nucleophile to form aryl azides, which upon treatmentwith alkynes 165 afforded 1,4-substituted triazoles 167. Cu(I) cat-alyst was used to catalyze the SNAr reaction followed by [32]cycloaddition (Scheme 43).

    Scheme 43. Cu(I)-catalyzed SNAr followed by [32] cycloaddition reaction.

    Scheme 46. Reaction of propargylated diazenes with 2-(azidomethyl) pyridine.

    Microwave-assisted three-component one-pot reaction hasbeen developed to prepare a series of 1,4-disubstituted-1,2,3-triazoles from corresponding alkyl halides 168, sodium azide, andalkynes 169. The azides are generated in situ from correspondinghalides, followed by click cycloaddition to give the corresponding1,4-disubstituted-1,2,3-triazoles 171 (Scheme 44).69

    Scheme 44. Microwave-assisted synthesis of 1,4-disubstituted-1,2,3-triazoles.

    Scheme 47. Copper(I)-catalyzed click reaction.

    Chandrasekhar et al.70 devised a three-component couplingprotocol for the synthesis of a series of 1,4-disubstituted-1,2,3-triazoles 175 from the corresponding acetylated BayliseHillmanadducts 172, sodium azide and terminal alkynes 173 (Scheme 45).

    Kosmrlj et al.71 prepared propargyl functionalized diazenes 176and utilized as alkyne click component in copper-catalyzed azide-alkyne cycloadditions (CuAAC) with 2-(azidomethyl) pyridine 177to give the substituted triazoles 178. Reaction with azidoalkyl-amines 179 completedwithin fewminutes by copper(II)sulfate, anddoes not require any reducing agent. Whereas 2-(azidomethyl)pyridine takes nearly 2e24 h to complete the reaction in thepresence of metallic copper (Scheme 46).

    Scheme 45. Synthesis of 1,2,3-triazoles from acetylated BayliseHillman adducts.

    Fratila et al.72 developed a new strategy for the synthesis ofunsymmetrically 1,10-disubstituted 4,40-bis-1H-1,2,3-triazoles from4-ethynyl-1,2,3-triazoles and azides via double-click strategy. One

    is stepwise Swern oxidation/OhiraeBestman alkynylation of read-ily available 4-hydroxymethyl-1,2,3-triazoles and the second one isthe stepwise cycloaddition of TMS-1,4-butadiyne. The protocol iscompatible with orthogonally protected and functionalizedsaccharide-peptide hybrids. 1-N-Alkyl-4-aryl-1,2,3-triazoles 182have been prepared from in situ generated alkyl azide and alkyne181 followed by copper(I)-catalyzed click cycloaddition. The un-desired 1,5-disubstituted cycloadduct 183 was formed in minoramount (Scheme 47).73

    Simpson et al.74 developed one-pot three-step procedure for thesynthesis of 1,10-disubstituted-4,40-linked unsymmetrical bis(1,2,3-triazoles), which act as good coordinating ligand for transitionmetals. Here, they have employed sequential copper-catalyzedazide-alkyne cycloaddition and deprotection steps on a monosilylbutadiyne. Fletcher and co-workers75 developed two-step one-potreaction conditions for the synthesis of 1-substituted-1,2,3-triazoles 186 up to 90% yields. It involves potassium carbonate-catalyzed deprotection of trimethylsilyl acetylene 184 followed byCu-catalyzed Huisgen 1,3-dipolar cycloaddition under aqueousconditions withmethanol as the alcoholic aqueous co-solvent. Bothalkyl and aryl azide reactants 185, including analogs with electron-donating and electron-withdrawing functionalities were toleratedsuccessfully in this protocol (Scheme 48).

    Yao et al.76 developed an assembly of small molecule-basedMMP inhibitors containing rhodanine 190 warheads using one-pot click chemistry (Scheme 49). Aucagne and co-workers madean in-depth study and systematic comparison of five classical silylalkyne protective groups to examine their potential in multiplesuccessive copper(I)-catalyzed alkyne-azide cycloaddition(CuAAC).77

  • Scheme 48. Synthesis of 1-substituted-1,2,3-triazoles.

    Scheme 49. Synthesis of Rhodanine containing 1,2,3-triazoles.Scheme 51. Synthesis of 1,2,3-triazole-containing b-D-glucopyranosides 196 via Cu(I)-catalyzed CuAAC.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5267

    Substituted 1,2,3-triazoles has been synthesized by involvingone-pot direct azidation of allylic/benzylic alcohols or their methylethers followed by the click reaction (Scheme 50). Two methodswere successfully developed for synthesizing various substituted1,2,3-triazole derivatives 193 directly from various allylic/benzylicalcohols without isolating the corresponding azides. The firstmethod (method A) involved magnetic nano Fe3O4-catalylzed di-rect azidation of various allylic/benzylic alcohols with TMSN3 as thefirst step followed by the Cu-catalyzed click reaction of the corre-sponding azides with alkynes as the second step. The secondmethod (method B) involved the Cu(OTf)2-catalyzed direct azida-tion of various allylic/benzylic alcohols 191 and methyl ethers ofallylic/benzylic alcohols with TMSN3 192 as the first step followedby the click reaction of the corresponding azides with alkynes asthe second step.78

    Scheme 50. One-pot tandem azidation/click reaction leading to the synthesis ofsubstituted 1,2,3-triazoles 193.

    C(2)-Propargylsubstituted pentacyclic triterpenoids 194 weresuccessfully transformed to conjugates with 1,2,3-triazole-con-taining b-D-glucopyranosides 196 via Cu(I)-catalyzed 1,3-dipolarcycloaddition reaction (Scheme 51).79 1,2,3-Triazole-containing b-D-glucopyranosides generated by 1,3-dipolar addition of pentacyclictriterpenoids and azide-sugars may act as antitumor agents.

    Song and co-workers80 synthesized a series of triazole-linkedester-type glycolipids in excellent yields via two-step sequenceinvolving microwave accelerated click strategy and debenzylation.Numerous O-alkynyl fatty esters and 1-azido-tetra-O-benzyl-b-D-glucosides are well tolerated to 1,3-dipolar cycloaddition reaction.Vitamin D ring system synthons with triazole rings in their sidechains has been prepared. Triazole ring was formed via a [32]cycloaddition of a vitamin D side chain terminal azide with a ter-minal acetylene.81 Wang et al.82 developed a one-pot synthesis of1,2,3-triazole-linked glycoconjugates via Cu(I)-catalyzed 1,3-dipolar cycloaddition as the key step. A number of neo-glycoconjugates derived from unprotected saccharides or per-acetylated saccharides have been prepared by this method.

    Several applications of click chemistry in biological and relatedfields have already been reported. Here some more examples arediscussed. Agrofoglio et al.83developed the synthesis of 1,2,3-triazolo-30-deoxy-4-hydroxymethyl carbanucleosides under different re-actionconditionsanddiversemodulationsontheheterocycle residuesby the application of click chemistry. Brunet and co-workers84 syn-thesized a new ligand bearing the bis-triazolylpyridine motif andpendant phosphonate groups by means of click chemistry. A newTTFePDI conjugate has been synthesized from an azide-functionalized TTF and an acetylenic PDI employing a Cu(I)-catalyzedHuisgen-Meldal-Sharplessreactionakindof clickmethod.85

    Hughes et al.86 have prepared a series of orthogonally protected1,4-disubstituted-1,2,3-triazoles from the corresponding alkynolsand trialkylsilyl-propargyl azides via 1,3-dipolar cycloaddition.Further they have selectively deprotected the cycloadducts andextended in a stepwise manner to form oligomeric peptidomimeticcompounds via further click reactions. A diverse novel set of P,N-type ligand family (Click Phine) 199 have been furnished usingthe Cu(I)-catalyzed azide-alkyne click cycloaddition (Scheme 52).87

    Hackenberger et al.88 reported the synthesis of borane-protected triazole phosphonites 202 in the presence of CuSO4tris(3-hydroxypropyltriazolylmethyl)amine and sodium ascorbatein H2O/tBuOH at room temperature (Scheme 53).

    Shreeve and co-workers89,90 disclosed that 1-pentafluorosulfanyl acetylene and its derivatives react with azideor diazomethane giving rise to SF5-substituted 1,2,3-triazoles orpyrazoles through click chemistry. Pore and co-workers91 designed

  • Scheme 52. Synthesis of P,N-type ligand family having 1,2,3-triazole unit.

    Scheme 53. Synthesis of borane-protected 1,2,3-triazole phosphonites.

    Scheme 55. Microwave assisted CuAAC to access conformationally restricted pyrimi-dine derivatives.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835268

    novel fluconazole/bile acid conjugates and carried out their regio-selective synthesis in very high yield via Cu(I)-catalyzed in-termolecular 1,3-dipolar cycloaddition. Voelcker et al.92

    investigated the catalytic activity of various copper (Cu)-loadedPAMAM dendrimers towards click chemistry and found fasterconversion upon using PAMAM dendrimers as macromolecularCu(I) ligands compared to traditional small molecular ligand sys-tems. Another method for the preparation of 1,4-disubstituted1,2,3-triazoles from aldehyde and amine has been developed byMaisonneuve and Xie.93 During the course of the reaction in situtransformation of aldehyde into alkyne occurs followed by diazotransfer of amine into azide and subsequent cycloaddition.

    Bahulayan et al. have demonstrated a two-step synthesis of 12-and 14-membered cyclic peptidotriazoles (peptidomimetics) bycombining a one pot four-component reaction and an intra-molecular [32] azideealkyne click cycloaddition reaction strategy(Scheme 54).94 Structural features as well as the preliminary as-sessment of drug-likeness contributing parameters indicate that,the macrocycles can be used in the search for drug leads. Synthesis

    Scheme 54. MCR and click methods for the synthesis of 14 and 12-memberedmacrocycles.

    of 12- and 14-membered cyclic peptidotriazoles (209 and 214 re-spectively) differs slightly in the substrate variation.

    Moses and co-workers95 performed one-pot azidation of ani-lines with t-BuONO and TMSN3. Thus, in situ generated azidesunder microwave irradiation afforded 1,4-disubstituted 1,2,3-triazoles. Fletcher and co-workers96 described the synthesis ofa series of 1-allylated and 1-benzylated 1,2,3-triazoles in 74e98%yields with various substituents at the 4-position. The reactioncourse follows a tandem process involving the nucleophilic sub-stitution of allyl chloride and benzyl bromide with sodium azide toform organic azide intermediates followed by Cu-catalyzed Huis-gen 1,3-dipolar cycloaddition with alkyne in one pot. OrthogonallyN-protected (Boc and Cbz) 4-(1,2,3-triazol-4-yl)-substituted 3-aminopiperidines were prepared from piperidine building blockby using copper-catalyzed Huisgen 1,3-dipolar cycloaddition asa key step.97a In a study, Shao et al. have shown remarkable pro-moting efficiency of carboxylic acids in all three key steps in thecatalytic cycle of CuAAC. Among different carboxylic acids benzoicacid showed the best promotion activity. On the other side, theacids that can form strong chelate to Cu(I) ion could not serve forthis purpose.97b

    Raic-Malic and co-workers applied microwave assisted Cu(I)-catalyzed click chemistry to prepare novel conformationally re-stricted pyrimidine derivatives 219 with a 1,2,3-triazolyl scaffoldbound via Z- and E-2-butenyl spacers (Scheme 55).98

    Allard and co-workers have revealed that a mono-adduct ful-lerene building block bearing an alkyne moiety as well as a mal-eimide unit can be orthogonally clicked through stepwise or onepot processes using benzyl azide and 1-octanethiol under simpleand mild conditions (Scheme 56).99 This new strategy exposed theway for the synthesis of a wide range of fullerene derivatives de-veloping a set of orthogonal reactions.

    3.3. Copper acetate catalysis

    Deobald et al.100 examined the use of organoselenium com-pounds in the copper catalyzed Huisgen 1,3-dipolar cycloadditionof azido arylselenides 225 with various alkynes 226. In this study,they synthesized arylseleno-1,2,3-triazoles 227 in excellent yieldsby the reaction of amino arylselenides 224 with iso-pentylnitriteand trimethylsilyl azide followed by copper-catalyzed 1,3-dipolarcycloaddition (Scheme 57).

    Reddy et al.101 synthesized b-hydroxy 1,2,3-triazoles 231 fromin situ generated 1,2-azidols 229 employing two sequential click

  • Scheme 56. Orthogonal click functionalization of compound 220 through step-wise orone-pot process.

    Scheme 57. Synthesis of arylseleno-1,2,3-triazoles.

    Scheme 59. Cu(II)-catalyzed aza-Michael addition.

    Scheme 60. Synthesis of 4-amino-1,2,3-triazoles 238.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5269

    reactions in high yields. Different Cu(I) and Cu(II) containing cat-alysts were investigated and high regioselectivity was obtainedfrom 10 mol % of Cu(OAc)2.H2O in water at room temperature(Scheme 58).

    Scheme 58. Synthesis of b-hydroxy 1,2,3-triazoles.

    Scheme 61. Reaction of gem-chloroamine CF3CH(Cl)NHAc with NaN3 to give 1,2,3-triazoles 242.

    Favi et al.102 reported a one-pot Cu(II)-catalyzed aza-Michaeladdition of trimethylsilyl azide to 1,2-diaza-1,3-dienes 232 andCu(I)-catalyzed 1,3-dipolar cycloaddition of in situ generated azi-dohydrazones with alkynes 234 to form 1,2,3-triazole derivatives235 (Scheme 59).

    Cintrat et al.103 synthesized a series of 1-substituted 4-amino1,2,3-triazoles 238 via [32] cycloaddition between azides 236and ynamides 237. The copper-catalyzed process was the example

    of a click reaction employing ynamides. Various highly function-alized azides were treated with N-benzyl/N-tosyl ynamide to givethe corresponding triazole adducts in high yields and regiose-lectivity (Scheme 60).

    Crousse and co-workers104 performed a sequential one-pot re-action of gem-chloroamine CF3CH(Cl)NHAc 239with NaN3 to affordtrifluoromethyl azido compound, which upon reaction with al-kynes 241 via Huisgen 1,3-dipolar cycloaddition provided 1,4-disubstitued 1,2,3-triazoles 242 in 74e87% yield. The reaction wascatalyzed by Cu(II) species (Cu(OAc)2, 10 mol %) without any re-ducing agent (Scheme 61).

    Use of selenium compounds, in click chemistry by copper cat-alyzed 1,3-dipolar cycloaddition of azidomethyl arylselenides withalkynes have been demonstrated by Alves and group (Scheme62).105 The selenium-triazoles 245 were selectively prepared ingood yields under mild conditions via reaction of azidomethylarylselenides 243 with a range of terminal alkynes 244. This clickprocedure minimizes the energy plea; as well the reaction timecould be reduced from several hours to few minutes using MWirradiation. By this methodology new selenium-containing tri-azoles have been efficiently synthesized with potential applicationin biological studies.

    Fiandanese et al.106 synthesized 4-alkynyl-1,2,3-triazoles 248and novel unsymmetrically substituted 4,40-bi-1,2,3-triazole de-rivatives 250 via click method. Here, 1-trimethylsilyl-1,3-butadiyne

  • Scheme 62. Synthesis of 1-(arylseleno-methyl)-1,2,3-triazoles 245.

    Scheme 65. Sequential copper-catalyzed synthesis of functionalized 1,2,3-triazolesfrom DHPMs.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835270

    246was treated with several azides 247 leading to 4-(silylalkynyl)-1,2,3-triazoles 248. Later on it was transformed into 4-arylalkynyl-1,2,3-triazoles by a Pd-catalyzed coupling reactionwith aryl halidesor into novel 4,40-bi-1,2,3-triazole derivatives 250 by a subsequentcyclization reaction with azides (Scheme 63). Kantam et al.107

    synthesized 1,2,3-triazoles in water using cheaply availableCu(OAc)2 without any additional reducing agents in a highlyregioselective manner.

    Scheme 63. Synthesis of unsymmetrically substituted 4,40-bi-1,2,3-triazoles.

    Scheme 66. Sequential synthesis of N-functionalized 1,2,3-triazoles with amide.

    Scheme 67. Copper triflate-catalyzed synthesis of 1,2,3-triazoles.

    Hu et al. synthesized 1-(pyridin-2-yl)-1,2,3-triazoles 253 from6-substituted tetrazolo-[1,5-a]pyridines 251 via copper(I)-catalyzed azideealkyne cycloaddition (CuAAC) using copper(I) ac-etate as catalyst (Scheme 64).108

    Scheme 64. Click synthesis of 1-(pyridin-2-yl)-1,2,3-triazoles from 6-substituted tet-razolo-[1,5-a]pyridines.

    Scheme 68. Synthesis of 1,2,3-triazole-linked glyco-conjugates.

    Wang et al. have reported a one-pot two-step method for gen-eration of a series of functionalized 1,2,3-triazoles derivatives (255and 257) in decent yields (Schemes 65 and 66).109 Specially, N-functionalized 1,2,3-triazoles with amide or dihydropyrimidinonewere prepared by this procedure. This technique reduces the needto handle organic halides or organic azides, as they are generated insitu, making this process more user-friendly and nontoxic.

    3.4. Copper triflate catalysis

    Gevorgyan and co-workers110 disclosed efficient use of variouspyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles 258 as

    azide components in Cu-catalyzed click reaction with alkynes 259.Thus, they synthesized a wide variety of N-heterocyclic derivativesof 1,2,3-triazoles 260 (Scheme 67).

    Glycosyl azides were prepared in situ from glucal 261 and tri-methylsilyl azide via Ferrier rearrangement. In the next step, itundergoes coupling with alkynes 262 to form 1,2,3-triazole-linkedglycoconjugates 263 or 264 in moderate stereoselectivity underneutral conditions (Scheme 68).111

    Yadav et al.112 synthesized alkoxy-1,2,3-triazoles 269 by one-potfour-component coupling of aldehyde 265, alcohol 266, trime-thylsilyl azide 268, and alkyne 267 via acetal formation, azidation,and click reaction sequence. Copper(II) triflate and copper metalcatalyzed the reaction in acetonitrile providing a wide range of

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    triazoles (Scheme 69). Mantellini and co-workers113 have demon-strated some reactions using click chemistry. Fukuzawa et al.114

    developed a method for the synthesis of 1,4-disubstituted 1,2,3-triazoles catalyzed by copper(II) triflate via substitution of ben-zylic acetates by TMSN3 followed by 1,3-dipolar addition with analkyne.

    Scheme 69. Synthesis of 1-alkoxy-1,2,3-triazoles.

    3.5. Use of other copper catalysts

    Vincent et al.115 reported that copper (I) complex [Cu(C186tren)]Br (C186trentris(2-dioctadecylaminoethyl) amine), which ex-hibits a good stability towards aerobic conditions is a versatile,highly reactive, and recyclable catalyst for the Huisgen cycloaddi-tion of azides with terminal/internal alkynes and is a useful catalystfor the preparation of click dendrimers (Fig. 3).






    C18H37 C18H37



    Fig. 3. Structure of [Cu(C186tren)]Br (C186trentris(2-dioctadecyl aminoethyl)amine).

    Scheme 71. Synthesis of b-hydroxy-1,2,3-triazoles 277.

    The reactions of azides 270 and acetylenes 271were carried outefficiently in solvents like toluene or n-octane (due to polarity ofthe compound selective precipitation of the products occurs fromlow polar solvents) using 0.05 mol % of catalyst, which afforded thecorresponding 1,4-disubstituted-1,2,3-triazoles 272 in good to ex-cellent yields (Scheme 70). Finally, they also investigated the syn-thesized copper-complex as catalyst in the synthesis of a 1,2,3-triazole-linked dendrimer.

    Scheme 70. Use of copper-complex toward the synthesis of 1,4-disubstituted-1,2,3-triazoles.

    Mandal et al. described the synthesis of a copper(I) chlorocomplex using an abnormal N-heterocyclic carbene (aNHC) salt,1,3-bis(2,6-diisopropylphenyl)-2,4-diphenylimidazolium. Conse-quently they used 0.005mol % of the complex as catalyst in the clickreactions of azides with alkynes to give 1,4-disubstituted 1,2,3-triazoles in excellent yields at room temperature under solvent-free conditions.116

    Song et al. synthesized ZnOeCuO core-branch hybrid nano-particles by copper oxide growth and controlled oxidation on ZnOnanospheres and used their catalytic activity and stability forultrasound-assisted [32] azide-alkyne cycloaddition reactions.They found remarkable enhancement of catalytic activity due to thehigh surface area and active facets of the CuO branches.117 Chenet al. used [Cu(phen)(PPh3)2]NO3 (1 mol %) as the catalyst in azi-deealkyne cycloaddition (CuAAC) reaction under solvent-freeconditions. Within 2e25 min good to excellent yields of 1,4-disubstituted 1,2,3-triazoles were obtained.118 Straub et al. re-ported a three-step synthesis of two representative bis-NHC-dicopper complexes as well as their catalytic performance in theazideealkyne cycloaddition.119

    Fabbrizzi and co-workers120 employed (2-aminoarenethiolato)copper(I) complex (1.0mol %) as a catalyst in CuAAC clickmethod inan organic solvent. Alonso and co-workers121 showed catalyticactivity of copper nanoparticles on activated carbon. They used thecatalyst in multi-component synthesis of b-hydroxy-1,2,3-triazoles276 or 277 from a variety of epoxides 273 and alkynes 274 in water(Scheme 71).

    Nageswar and his group developed a method for the prepara-tion of 1,2,3-triazoles 281 using magnetically separable copperferrite nanoparticles as the catalyst (Scheme 72).122 This one potprotocol to access 1,2,3-triazoles 281 involves initial substitution ofbenzyl halides 278 with sodium azide, which generated in situbenzyl azides followed by copper ferrite catalyzed cycloadditionreaction with alkynes 280 in water at 70 C. Most remarkably heretap water has been used as the solvent.

    Scheme 72. Synthesis of 1,2,3-triazoles using CuFe2O4 nanoparticles in tap water.

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    Fukuzawa and co-workers123 prepared Cu-complexes of iso-cyanate, and employed as catalysts in click reactions of azides withalkynes to give 1,4-disubstituted 1,2,3-triazoles. For the reactionbetween sterically hindered azides and alkynes they observed thatCuCl(TPh) has a particular efficiency to catalyze the reaction.Orgueira et al.124a devised a method for the regioselective synthesisof highly functionalized 1,2,3-triazoles 284 from terminal alkynes282 and azides 283 in the presence of Cu(0) catalyst. They gener-ated catalytic Cu(I) species by the reaction of 10 mol % coppernanosize activated powder and 1 equiv of an amine hydrochloridesalt (Scheme 73). They added an amine hydrochloride salt into thereaction mixture to enhance the dissolution of copper metal, andenhanced the formation of the Cu(I)-acetylide intermediate, whichis required for the regioselective cycloaddition.

    Scheme 73. Use of copper nanosize activated powder in dipolar cycloadditionreaction.

    Scheme 75. Use of copper(I)-N-heterocyclic carbene in CuAAC reaction.

    Scheme 76. Cu/Pd transmetalation relay catalysis in three-component click reaction.

    Yus and co-workers124b disclosed that copper nanoparticlescatalyze the 1,3-dipolar cycloaddition of azides and alkynes witha comparable rate to those of microwave chemistry. b-Hydroxy-triazoles with high regioselectivity in excellent yields are preparedby Yadav et al.125a via click method where 2-azidoalcohols derivedin situ from epoxides and sodium azide undergo smooth couplingwith alkynes under neutral conditions. Reiser and co-workers125b

    used copper(I) isonitrile complex as heterogeneous catalyst forthe Huisgen azide-alkyne 1,3-dipolar cycloaddition under mildconditions in water. The catalyst can be recycled for at least fiveruns without significant loss of activity.

    Lipshutz et al.126 have developed a new heterogeneous catalystconsisting of copper and nickel oxide particles supported withincharcoal, which catalyzes azide-alkyne click reactions nicely.Through the series of compounds expected 1,4-regioselectivity wasuniformly observed (Scheme 74).

    Scheme 74. Cu, nickel oxide and charcoal supported CuAAC.

    Scheme 77. Copper in charcoal (Cu/C) as catalyst in click reaction.

    Copper nanoparticles have been used to catalyze the 1,3-dipolarcycloaddition of a variety of azides and alkynes forming corre-sponding 1,2,3-triazoles in excellent yields.127a Further a combina-tion of copper(I)-N-heterocyclic carbene complex and aromatic N-donors were utilized for azide-alkyne cycloaddition (CuAAC) underreductant-free conditions.127b Yamamoto et al.127c accomplisheda click method through a three-component coupling (TCC) reactionbetween alkynes 288, allyl methyl carbonate 289, and TMSN3 toget allyltriazoles 290 mediated by a bimetallic catalyst Pd(0)-Cu(I)[i.e., Pd2(dba)3.CHCl3 (2.5 mol %), P(OPh)3 (20 mol %), and

    CuCl(PPh3)3 (10 mol %)]. Later on, the product was further deal-lylated by the treatment of ozone with ruthenium catalyst to getthe substituted triazole 291 (Scheme 75).

    Boons et al.127d demonstrated the use of Pd(0)-Cu(I) catalyst inSonogashira cross-coupling-desilylation-cycloaddition reaction se-quence providing 1,4-disubstituted 1,2,3-triazoles in good yields. Aheterogeneous copper catalyst by immobilizing copper nano-particles in aluminum oxyhydroxide fiber has been developed andapplied to [32] Huisgen cycloaddition at room temperature,whichpromoted the reaction smoothly. The catalyst is effective for bothnonactivated alkynes as well as activated ones with various azides,and are recycled five times with comparable catalytic efficacy ineach case.127e Xu et al. used Cu/Pd transmetalation relay catalysis inthree-component click reaction of azide, alkyne, and aryl halide tosynthesize a variety of 1,4,5-trisubstituted 1,2,3-triazoles in onestep. As CuAAC generally works only on terminal alkynes, thus theapproach is supposed to serve as an alternative solution for theproblem of the click reactions of internal alkynes (Scheme 76).128

    In another report Kong et al. prepared polyvinylpyrrolidone (PVP)coated copper(I) oxide nanoparticle and used them to catalyze azide-alkyne click reactions inwater under aerobic conditions. Itwas foundto be more efficient catalytic system inwater and less toxic than thecommonly used CuSO4/reductant catalyst systems.129 Lipshutzet al.100dused10mol% copper in charcoal (Cu/C) to prepare triazoles300 from azides and alkynes in 0.5 M dioxane. Under basic condi-tions, the reaction accelerates decreasing the reaction time drasti-cally. In case of microwave irradiation at elevated temperaturereaction time also decreases significantly. Later in another report,Bruce H. Lipshutz et al. used recyclable Cu/C to generate variousazides in situ from the corresponding amines and simultaneouslyinvolve them in [32] cycloadditionwith terminal alkynes leading tothe synthesis of triazoles in good yields (Scheme 77).130

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    In another report Alonso et al. also described click methodcatalyzed by copper nanoparticles on activated carbon to synthe-size 1,2,3-triazoles from organic halides, diazonium salts, and aro-matic amines in water.131,132 Santoyo-Gonzalez et al. developeda one-pot, three-component tandem azidation/CuAAC of cyclicsulfates or cyclic sulfamidates the fast and efficient preparation of(alkyl sulfate)- and (alkyl sulfamidate)-1H-1,2,3-triazoles 304. Un-der microwave irradiation Si-BPMA$Cu or Si-BPA$Cu served asthe excellent heterogeneous catalyst to simplify the manipulationand the isolation procedure (Scheme 78).133

    Scheme 78. Si-BPMA$Cu/Si-BPA$Cu heterogeneous copper catalyst in click reaction.

    Scheme 80. Copper(II) thioxanthone carboxylate catalyzed photochemical azide-alkyne cycloaddition (CuAAC).

    1,4,5-Trisubstituted 5-dialkylamino-1,2,3-triazoles are compar-atively difficult to prepare probably due to the strong oxidizingproperty of the amine electrophile (R2N) or the low reactivity ofthe MeC bond in the intermediate. Hu et al. used showed facileformation of reactive 5-copper(I)-1,2,3-triazole intermediate in thepresence of the amine (R2N) electrophile by using polymericcomplex 1-copper(I)-alkyne as a substrate leading to the synthesisof 1,4,5-trisubstituted 5-dialkylamino-1,2,3-triazoles.134

    Xia et al. prepared cross-linked polymeric ionic liquid material-supported copper (Cu-CPSIL), imidazolium loaded Merrifield resin-supported copper (Cu-PSIL) and silica dispersed CuO (CuO/SiO2)and used them as efficient catalysts for the one-pot synthesis of 1,4-disubsituted-1,2,3-triazoles from the reaction of alkyl halides withsodium azide and terminal alkynes in water at room tempera-ture.135 Vijayakumar et al. synthesized and characterized CuOnanoparticles and consequently applied it as an efficient reusablecatalyst in click chemistry to prepare xanthene substituted 1,2,3-triazoles 307 (Scheme 79).136

    Scheme 79. Efficient reusable CuO nanoparticles-catalyzed click synthesis of xanthenesubstituted 1,2,3-triazoles 307.

    Scheme 81. Copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) to achieve thethree-fragment-bearing scaffolds.

    Tale et al. developed (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl)methanol (MBHTM) as efficient click ligand to accelerate copper-catalyzed [32] azideealkyne cycloaddition at low catalyst loading(catalyst loading decreases from 10 to w1 mol %).137 Silvia Dez-Gonzalez et al. used minute amount (0.5 mol %e50 ppm) of com-mercially available [CuBr(PPh3)3] to catalyze azide-alkyne

    cycloaddition reactions under strict click conditions. The processrequired neither any additive nor any purification step to isolatepure 1,2,3-triazole products.138

    Yagci et al. combined thioxanthone carboxylate moiety withcopper(II) ions by ion exchange reaction to synthesize copper(II)thioxanthone carboxylate 310. Subsequently, it was used as an ef-ficient photocatalyst in photochemically induced copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, which isdevoid of any additional ligands. It was believed that during thecatalytic process, intramolecular photoinduced electron transferwas stimulated to reduce copper(II) ions to generate copper(I)species, which catalyzes the CuAAC reaction (Scheme 80).139

    In another report Yamamoto et al. prepared nanoporous copper(CuNPore) catalysts with tunable nanoporosity from Cu30Mn70 al-loy by controlling the de-alloying temperature under free corrosionconditions. They showed that the tunable nanoporosity of CuNPoresignificantly enhanced its catalytic activity in click chemistrywithout using any supports and bases.140

    Page et al. developed a copper catalysed azideealkyne cyclo-addition (CuAAC) in liquid ammonia. Compared with that in con-ventional solvents only 0.5 mol % copper(I) catalyst give exclusively1,4-substituted 1,2,3-triazoles with excellent yields (up to 99%).From deuterium exchange experiments with phenyl acetylene-d1 itwas revealed that the acidity of the alkyne is increased around1000-fold with catalytic amount of copper(I) in liquid ammonia.141

    Miquel A. Pericas et al. prepared a library of modular tris(triazolyl)methane ligands and screened them in copper catalysed azide-ealkyne cycloaddition (CuAAC).142

    Trabocchi and his group proposed a versatile click-based ap-proach in developing libraries of densely functionalized scaffoldscontaining three fragments (Scheme 81).143 By this process Clickchemistry has been used for modular strategy involving only re-actions performed inmild conditions starting from readily availablebuilding blocks in order to synthesize highly functionalized

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    molecules which are suitable candidates for high-throughputscreening and multiple receptors targeting in a drug discovery.

    Scheme 85. Synthesis of 4-aryl-5-cyano-/4-aryl-5-carbethoxy-1H-1,2,3-triazoles 326.

    4. Use of other non-copper catalysts

    Limitations of copper-catalyzed click methods mainly arise inthe field of bioconjugation and in vivo imaging due to the toxicnature of copper. The reaction between azides and alkynes in bi-ological environment is rarely observed due to their inertness inabsence of copper. Therefore, the importance of copper-free clickreactions has been realized. However, only limited click reactionsare reported that are not catalyzed by copper. In this section, wewill discuss some dipolar additions used in organic synthesis thatare not catalyzed by copper catalysts.

    Synthesis of substituted 1H-1,2,3-triazole-4-carboxylic ester 317have been performed by the reaction of aryl azides 315, ethyl 4-chloro-3-oxobutanoate 316, and either O- or S-nucleophiles in thepresence of a base catalyst. It has been observed that the reactionmost probably proceeds via [32] cyclocondensation between arylazide 315 and ethyl 4-chloro-3-oxobutanoate 316 followed by nu-cleophilic substitution of chlorine in the chloromethyl group(Scheme 82).144

    Scheme 82. Synthesis of 1H-1,2,3-triazole-4-carboxylic esters 317.

    Wu et al.145 carried out a base-promoted cycloaddition reactionbetween aryl azide 315 trimethylsilyl alkynes 318 to generate 1,5-disubstituted 1,2,3-triazoles 319 regioselectively in good yields atambient temperature (Scheme 83).

    Scheme 83. Base-promoted synthesis of 1,2,3-triazoles 319.

    Scheme 86. Tetraalkylammonium hydroxide catalyzed synthesis of 1,5-disubstituted1,2,3-triazoles.

    Lewis base-catalyzed three-component cascade reaction for thesynthesis of diverse 4,5-disubstituted-1,2,3-(NH)-triazoles 323have been reported in good to excellent yields.146a The newlysynthesized (NH)-triazoles 323 contain C-4 vinyl group, which canbe further converted into other triazole derivatives (Scheme 84).

    Scheme 84. Synthesis of 4,5-disubstituted-1,2,3-(NH)-triazoles.

    4-Aryl-5-cyano- or 4-aryl-5-carbethoxy-1H-1,2,3-triazoles 326are synthesized by [32] cycloaddition reactions of 2-aryl-1-cyano-or 2-aryl-1-carbethoxy-1-nitroethenes 324 with TMSN3 undersolvent-free conditions in presence of TBAF catalyst (Scheme85).146b

    Novel tricyclic 1,2,3-triazoles starting from cyclic epoxides viathe sequential azidolysis, propargylation and 1,3-dipolar cycload-dition without any copper catalyst have been synthesized.147

    Jagerovic et al. synthesized a series of new N1-, N2- and N3-substituted 1,2,3-triazole derivatives by cycloaddition of butyltinazide with substituted alkynes followed by N-alkylation.148a Fokinand co-workers148b synthesized 1,5-diarylsubstituted 1,2,3-triazoles 329 in high yield from aryl azides 328 and terminal al-kynes 327 in DMSO catalyzed by tetraalkylammonium hydroxide(Scheme 86).

    Fokin and co-workers149a surveyed the catalytic activity ofa series of ruthenium(II) complexes in azide-alkyne cycloadditionsand found that the [Cp*RuCl]4 complexes to be most reactive to-wards this cycloaddition. In the presence of such type of catalystssecondary azides react with terminal alkynes producing a largerange of 1,5-disubstituted 1,2,3-triazoles. Herein, some examples ofclick reactions employing ruthenium catalysts have been discussed.Takasu and co-workers prepared trifunctional thioureas bearing1,5-disubstituted triazole tether by Ru-catalyzed Huisgen cycload-dition (Scheme 87).149b

    Scheme 87. Use of ruthenium(II) complexes in azide-alkyne cycloadditions.

    Ruthenium-catalyzed Huisgen [32] cycloaddition reaction ofynamides with various azides are performed to yield 1-protected 5-amido 1,2,3-triazoles.150 Catalytic amount of [Cp*RuCl2]n promote1,3-dipolar cycloaddition of trifluoromethylated propargylic

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    alcohols with azides to afford 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles exclusively in high yields.151 Bar-luenga et al. employed palladium catalysts in presence of ligandslike xantphos in the synthesis of 1H-1,2,3-triazoles from sodiumazide and alkenyl bromides. In this method instead of vinyl azide1H-1,2,3-triazoles are formed.152a

    Wu et al. disclosed a methodology for the synthesis of 4,5-disubstituted-2H-1,2,3-triazoles 335 by the treatment of 2-alkynylbenzonitriles 333 with sodium azide in DMSO at 140 Cunder microwave irradiation in 60e99% yields (Scheme 88). Inaddition to that if 8 equiv of ZnBr2 was added with 8 equiv of so-dium azide in DMF at 100 C tetrazolo[5,1-a]isoquinolines wasformed up to 87% yield.152b Microwave synthesis of C-carbamoyl-1,2,3-triazoles by 1,3-dipolar addition has also been reported byKatritzky and co-workers.152c

    Scheme 88. MW-assisted synthesis of 1,2,3-triazoles 335.

    Scheme 90. Synthesis of benzotriazoles via [32] cycloaddition of azides with in situgenerated arynes.

    Scheme 91. Synthesis of 1-alkyl benzotriazoles via benzyne mechanism.

    Yao and co-workers153 used nitro group of chromene moiety inclick chemistry to achieve the synthesis of 4-aryl-1,4-dihydrochromeno-[4,3-d][1,2,3]triazole derivatives 338 in DMSOat 80 C under catalyst-free conditions (Scheme 89).

    Since the initial reports in the 1980s on the application ofbenzotriazole derivatives in organic synthesis,154 tremendousprogress has been achieved in this field in due course of time. Nowbenzotriazole intermediates are frequently used in various organictransformations.155 Benzotriazoles are well known as one of thepharmacologically significant structural motifs found in many bi-ologically active compounds used as anti-cancer, anti-fungal, anti-inflammatory and anti-depressant agents.156

    Scheme 89. Synthesis of 4-aryl-1,4-dihydrochromeno[4,3-d] 1,2,3-triazoles 338.Scheme 92. Regioselective synthesis of enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-pyrazin-6-ones.

    Feringa et al.157a have reported the synthesis of benzotriazoles341 by the reaction of azides with arynes (generated in situ) via[32] cycloaddition. KF paired with 18-crown-6 led to full con-version of starting materials to the benzotriazole at room temper-ature in good yields. Screening of various fluoride salts in

    combination with different crown ethers showed that CsF with 18-crown-6 ether in 1:1 ratio in acetonitrile was found to be optimalconditions (Scheme 90). Larock and co-workers157b also synthe-sized various triazoles employing the similar strategy. Zhang andMoses158 synthesized substituted benzotriazoles 341 via clickchemistry through benzyne mechanism.

    Numerous 1-alkyl benzotriazoles 344 were synthesized in goodyields by the reaction of various alkyl azides 343 with 2-(trime-thylsilyl) phenyl triflate 342 in the presence of CsF in acetonitrilevia fluoride triggered azide-benzyne cycloaddition (Scheme 91).159

    Ankati and Biehl160a synthesized functionalized benzotriazolesemploying click method through benzyne mechanism. Chan-drasekaran et al.160b developed a regioselective synthesis of severalenantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-pyrazin-6-ones 347 and 348 from primary amines and a-amino acid de-rivatives (Scheme 92). Huang and co-workers161 checked the con-trol of regioselectivity over gold nanocrystals of different surfacesfor the synthesis of 1,4-disubstituted 1,2,3-triazole through theclick reaction. They used gold nanocubes, octahedra, and rhombicdodecahedra to investigate their catalytic efficiency and productregioselectivity for the azide-alkyne cycloaddition reaction for thefirst time. The size of the rhombic-dodecahedral gold particles wassystematically tuned with high uniformity to explore the effect ofsize on reactivity.

    Mani and Fitzgerald162 disclosed the one-pot intramolecular1,3-dipolar cycloaddition approach for production of triazole-fusedheterocyclic compounds 353 based on the strategy of in situ gen-eration of substituted diazomethanes in a two-step sequence fromthe corresponding aldehydes 349, which endure smooth cycload-dition with a cyano group to yield the desired fused 1,2,3-triazoles353 in good overall yields (Scheme 93).

  • Scheme 93. Synthesis of triazole-fused heterocycle. Scheme 96. Sc(OTf)3-catalyzed azide-alkyne cycloaddition.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835276

    4-Aryl-NH-1,2,3-triazoles 356 have been synthesized by 1,3-dipolar cycloaddition reaction of nitroolefins 354 and sodiumazide mediated by p-TsOH in high yields. p-TsOH was used as a vitaladditive in this type of 1,3-dipolar cycloaddition. This cycloadditionreaction tolerates a wide range of functional groups and is a reliablemethod for the rapid elaboration of readily available nitroolefinsand NaN3 into a variety of NH-1,2,3-triazoles (Scheme 94).163

    Scheme 94. p-TsOH-mediated synthesis of 4-aryl-NH-1,2,3-triazoles. Scheme 97. Synthesis of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepines.

    The 1,3-dipolar cycloadditions between substituted vinyl sul-fones 357 and sugar azide have been reported in conjunction withnew experimental results, and the origin of reversal of regiose-lectivity has been revealed using a distortion/interaction model.This study provides the scientific justification for combining or-ganic azides with two different types of vinyl sulfones for thepreparation of 1,5-disubstituted 1,2,3-triazoles 359 and 1,4-disubstituted triazolyl esters 360 under metal-free conditions(Scheme 95).164

    Scheme 98. Synthesis of 4,5,6,7,8,9-hexahydro-2H-cyclooctatriazole 372.Scheme 95. Synthesis of 1,5-disubstituted 1,2,3-triazoles and 1,4-disubstituted triazolylesters under metal-free conditions.

    An efficient synthesis of annulated 9H-benzo[b]pyrrolo[1,2-g][1,2,3]-triazolo[1,5-d][1,4]diazepines 363 has been developed bySc(OTf)3-catalyzed two-component tandem C-2 functionalization-intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction(Scheme 96). The reaction shows high substrate tolerance and pro-vides a library of fused heterocycles thatmay lead to novel biologicallyactive compounds or drug lead molecules.165

    Nguyen et al.166 developed an operationally simple, one-potmulticomponent reaction for the synthesis of 9H-benzo[f]imi-dazo[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepines 368 decoratedwith three diversification points via an atom-economical trans-formation incorporating R-diketones 364, O-azidobenzaldehydes

    365, propargylic amines 366, and ammonium acetate. This processinvolves tandem InCl3-catalyzed cyclocondensation and intra-molecular azide-alkyne 1,3-dipolar cycloaddition reactions(Scheme 97).

    The 1,3-dipolar cycloaddition reaction of boron azides 369 withalkynes 370 has been investigated experimentally and computa-tionally by Muller et al.167 At room temperature pinBN3(pinpinacolato) reacts with the strained triple bond of cyclo-octyne forming an oligomeric boryl triazole 371. Alcoholysis of theoligomer yields the 4,5,6,7,8,9-hexahydro-2H-cyclooctatriazole372. The oxygen-substituted azidoborane pinBN3 does not readilyreact with oxygen atoms carrying electron-poor alkynes at roomtemperature. Only the strained cyclooctyne undergoes a smoothreaction with pinBN3 yielding an oligomeric product that can becleaved into the expected triazole derivative by alcoholysis(Scheme 98).

    Molteni et al.168 disclosed 1,3-dipolar cycloadditions ofMeOPEG-supported azide with a variety of dipolarophiles, andsynthesized 1-MeOPEG supported 1,2,3-triazoles, 1,2,3,4-tetrazoles, and aziridine in nearly quantitative yields. Ganem andco-workers169a developed multicomponent dipolar cycloadditionreaction for the synthesis of densely functionalized oxazoles 375and tetrazoles 377. They used acyl cyanides 373 derived frommodified Passerini protocol and then applied click chemistry toform complex 1,3-oxazoles or tetrazoles from diazomalonic estersor alkyl azides, respectively (Scheme 99).

    Schmidt et al.170 applied click chemistry in ionic liquids based onalkylated imidazoles combined with microwave heating to remove

  • Scheme 102. Iridium-catalyzed 1,3-DC of azides and alkynes.

    Scheme 99. Synthesis of highly functionalized oxazoles and tetrazoles.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5277

    the hazards with volatile azides in intermolecular reactions and theproblem of removal of zinc salts from the acidic product. Beccalliand co-workers171 performed totally regioselective cycloadditionsof 1,3-dipoles nitrile oxide and azide with N,N-disubstitutedpropargyl amines leading to the formation of polyheterocyclicsystems. Zinc bromide has been used as catalyst to develop a simpleroute for the synthesis of Boc-protected tetrazole analogs 379 ofamino acids starting from N-Boc amino acids in a [23] cycload-dition of Boc-a-amino nitrile 378 and sodium azide (Scheme100).172

    Scheme 100. Synthesis of Boc-protected tetrazole 379.

    Scheme 103. Cycloaddition of azides with in situ generated arynes from benzobi-soxadisilole or 2,3-naphthoxadisilole 390.

    Charcoal impregnated with zinc can also catalyze the cycload-dition of organic azides and alkynes to provide the corresponding1,4-disubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles.173 Yao et al. developed a metal-free NH4OAc-catalyzed1,3-dipolar cycloaddition of boron-azides and nitriles leading to thesynthesis of tetrazoles with broad substrate scope and in excellentyields (Scheme 101).174

    Scheme 101. Metal-free NH4OAc-catalyzed 1,3-DC of boron-azides and nitriles.

    McNulty et al. described a maiden report of synthesis of novelsilver(I)acetate complex ligated to a 2-diphenylphosphino-N,N,-diisopropylcarboxamide ligand and their catalytic application onthe cycloaddition of azides with terminal alkynes at room tem-perature.175 Lim et al. performed cycloaddition of azides and ter-minal alkynes in H2O in the presence of catalytic amount of b-cyclodextrin as a phase transfer catalyst to synthesize 1,4-Disubstituted-1,2,3-triazoles.176

    Johansson et al. used ruthenium catalyst in azide-alkyne cy-cloaddition under microwave irradiation. They in situ generatedorganic azide from the primary alkyl halide and sodium azide inDMA under microwave heating followed by the addition of[RuClCp*-(PPh3)2] and the alkyne to get the desired cycloadditionproduct by continuing the microwave irradiation.177 Sun et al. re-ported an iridium-catalyzed intermolecular cycloaddition of azidewith electron-rich internal thio-alkynes (IrAAC) which can bea complementary to the well-known CuAAC and RuAAC click re-actions (Scheme 102).178

    Rao et al. developed a raney Nickel-catalyzed acetylene-azidecycloaddition reactions to form 1,2,3-triazoles. Unlike CuSO4/so-dium ascorbate reagent system, the process does not require a re-ducing agent.179 Chen and co-workers developed a simple andefficient synthetic method of 1,3-dipolar cycloaddition of azideswith arynes generated in situ from benzobisoxadisilole or 2,3-naphthoxadisilole 390 (Scheme 103).180 The reaction was con-trolled by electronic effects. Presence of electron-withdrawinggroups in the aryne moiety show high reactivity compared tothat of electron-donating groups.

    5. Photoclick chemistry

    In the recent decade photoclick chemistry has gained tremen-dous importance due to its wide utility in bioorthogonal chemistry,which is an important tool to visualize protein expression, trackprotein localization, measure protein activity, and identify proteininteraction partners in living systems. The initial idea was de-veloped from the earlier reports on robust photolysis of diaryltetrazole. Under UV-irradiation diaryl tetrazole efficiently undergophotolysis to release nitrogen. It leads to the formation of iminedipole, which spontaneously undergoes 1,3-dipolar cycloadditionwith alkenes to afford pyrazoline cycloadduct 394 (Scheme104).181a

  • Scheme 104. Synthesis of functionalized pyrazolines 394.

    Scheme 107. Synthesis of pyrazolines via photoinduced 1,3-dipolar cycloaddition.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e52835278

    Lin et al. synthesized a series of polysubstituted pyrazolinesthrough photoactivated 1,3-dipolar cycloaddition procedure. Thereactive nitrile imine dipoles were generated in situ using a hand-held UV lamp at 302 nm followed by its spontaneous cycloadditionwith a broad range of 1,3-dipolarophiles leading to the pyrazolineswith excellent solvent compatibility, functional group tolerance,regioselectivity and yield (Scheme 105).181b

    Scheme 105. Synthesis of pyrazolines 397.

    Scheme 108. Photoinduced 1,3-dipolar cycloaddition with alkenes genetically en-coded in protein inside E. coli cells.

    Later on they discovered several diaryltetrazoles which can bephotoactivated in long-wavelength (around 365 nm) to be used inthe 1,3-dipolar cycloaddition reactions with electron-deficient andconjugated alkenes in organic solvents as well as protein-containing alkene in the aqueous buffer (Scheme 106).182

    Scheme 106. Use of diaryltetrazoles to access pyrazolines. Scheme 109. Tuning the HOMO energy of the nitrile imine dipoles.

    Consequently they elaborated the photoinducible 1,3-dipolarcycloaddition reaction for selective protein modification in bi-ological media. They attached the tetrazole group to the proteins byprotein semisynthesis followed by its treatment with a simple setof alkenes leading to the pyrazoline cycloadducts. Thus fluorescentpyrazolines were used to monitor the nonfluorescent protein la-beling in cellular systems (Scheme 107).183

    In another concurrent report, Lin et al. used a reverse protocol toselectively functionalize proteins via bioorthogonal chemistry. Thistime they choose alkene genetically encoded in a protein inside E.coli cells and selectively functionalize it with external tetrazolesusing photoclick approach (Scheme 108).184

    A fast photoclick reaction can be achieved either by increasingthe HOMO energy of the dipole or by decreasing the LUMO energyof dipolarophile. In their study Lin group choose to further improvetheir strategy by tuning the HOMO energies of the nitrile iminedipoles. In case of the tetrazole with H as R1 and 4-OMe as R2 theycould label an alkene-encoded protein inside Escherichia coli cells inless than 1 min (Scheme 109).185

    They further continued their study on bioorthogonal reactionson E. coli by genetically incorporating a photoreactive unnaturalamino acid, p-(2-tetrazole)phenylalanine (p-Tpa) into the myoglo-bin in E. coli site-specifically by evolving an orthogonal tRNA/aminoacyl-tRNA synthetase pair and the use of p-Tpa as a bio-orthogonal chemical handle for fluorescent labeling of p-Tpa-encoded myoglobin via photoclick reaction.186

    They used photoinduced 1,3-dipolar cycloaddition reaction instapling peptide side chains to reinforce stapled peptides basedon Karle and Balarams heptapeptidic 310 helix model. The result-ing pyrazoline staplers were found to exhibit unique fluorescenceconvenient for cell permeability study (Scheme 110).187

    Later on, in another example they applied photoinduced 1,3-dipolar cycloaddition reaction to staple a peptide dual inhibitorof the p53-Mdm2/Mdmx interactions.188 In a report Lin et al. syn-thesized a series of structurally novel photoactivatable macrocyclicdiphenyl tetrazoles by inserting a bridge between the two flankingdiphenyl rings. Compare to the acyclic tetrazole, several macrocy-clic tetrazoles showed improved reactivity toward a strained alkene

  • Scheme 110. Photoinduced 1,3-dipolar cycloaddition in stapling peptide side chains.

    Scheme 112. Photoinduced benzyne click reaction leading to benzotriazoles 423.

    M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5279

    in organic solvent thus making them suitable for the bioorthogonaltetrazoleealkene cycloaddition reaction in living systems.189

    They also introduced a series of photoactivatable diary-ltetrazoles for photoclick chemistry via scaffold hopping strat-egy.190 In another report they discussed the design of terthiophene-based photoactivatible tetrazoles. The new class of tetrazoles getactivated in 405 nm light and subsequently reacts with fumaratedipolarophile with the second-order rate constant with k2 ex-ceeding 103 M1 s1. They also demonstrated the utility of