organocatalytic routes toward substituted 1,2,3-triazolesszolcsanyi/education/files/chemia... ·...

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Cite this:Chem. Commun., 2015,

51, 10797

Organocatalytic routes toward substituted1,2,3-triazoles

Jubi John, Joice Thomas and Wim Dehaen*

The present feature article describes the different organocatalytic routes for the synthesis of substituted

1,2,3-triazoles. This methodology has recently gained much attention due to its many advantages like

high regioselectivity, substrate scope, high yields, and access to novel molecules. The review is divided

into 4 different sections based on the active intermediate of the triazole synthesis reactions. The

mechanism of each approach is critically discussed and in addition, the advantages and disadvantages of

each method are described with relevant examples.

Introduction

N-Heterocyclic compounds containing 1,2,3-triazole ring systemshave found a broad spectrum of applications in the field ofsynthetic, medicinal and material chemistry.1–14 Even though

these motifs have not been isolated from natural sources, theyare found to be effective amide surrogates in bioactive moleculesbecause of the large dipole, H-bonding capabilities, and remark-able metabolic stabilities towards enzymatic degradation.8–14

The amide-triazole bioequivalence of 1,2,3-triazole heterocycleswas exploited for the generation of many privileged medicinalscaffolds exhibiting anti-HIV, anticancer and antibacterialactivities.8–14 They also serve as key synthetic intermediates inmany industrial applications such as agrochemicals, corrosion

Molecular Design and Synthesis, Department of Chemistry, KU Leuven,

Celestijnenlaan 200F, 3001 Leuven, Belgium.

E-mail: [email protected]

Jubi John

Dr Jubi John is a native ofMulakuzha (Kerala), India. Heobtained his PhD in syntheticorganic chemistry at the Univer-sity of Kerala under the super-vision of Dr K. V. Radhakrishnan(National Institute for Interdisci-plinary Science and Technology,Thiruvanathapuram). Soon after,he was awarded a CEA-Eurotalentspostdoctoral fellowship to work inthe group of Dr Eric Doris at theAlternative Energies and AtomicEnergy Commission of France

(CEA) at Saclay. In 2011, he joined the group of Prof. Dr HenningHopf as an Alexander von Humboldt fellow at the Institute forOrganic Chemistry of Technical University of Braunschweig,Germany. He then joined the group of Prof. Dr Wim Dehaen at theKU Leuven, Belgium in 2013. During his 2 year postdoctoral stint inLeuven, he was actively involved in several medicinal andheterocyclic chemistry projects. Presently he is working as a‘‘young scientist’’ at the National Institute for InterdisciplinaryScience and Technology, Thiruvanathapuram.

Joice Thomas

Joice Thomas was born inThiruvanvandoor (Kerala), India.He received his PhD degree inChemistry in 2011 at the KULeuven, Belgium, under thesupervision of Prof. Wim Dehaen,working on the synthesis andapplication of homo(hetera)-calixarenes. Currently, he isworking as a postdoctoral fellowin the laboratory of Prof. W.Dehaen, focusing mainly onmedicinal chemistry anddeveloping general metal-free

route towards the synthesis of 1,2,3-triazole heterocycles. Hepublished more than 30 articles in international journals abouthis work on heterocyclic and supramolecular chemistry.

Received 19th March 2015,Accepted 1st June 2015

DOI: 10.1039/c5cc02319j

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FEATURE ARTICLE

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retardants, polymers, optical brighteners, photostabilizers,pigments and metal chelators.1–7

The synthesis of 1,2,3-triazoles by the classical Huisgen1,3-dipolar cycloaddition of azides with alkynes under thermalconditions has not been applied much in organic synthesisowing to the poor regioselectivity (1,4- and 1,5-disubstituted1,2,3-triazoles), low chemical yield and elevated tempera-tures.15–18 A key event that has heralded a renaissance intriazole chemistry is the pioneering discovery of a copper(I)-catalysed version of azide–alkyne cyloaddition reaction(CuAAC) made independently by Sharpless and Meldal in2001. This reaction is considered as the ‘‘paradigm’’ of all‘‘click reactions’’.19–23 The unique feature of the CuAAC reac-tion as compared to its uncatalysed counterpart is the highregioselective synthesis of 1,4-disubstituted 1,2,3-triazoleaccompanied by a significant rate acceleration. This reactiondisplays advantages such as superb substrate scope, easyhandling, insensitivity to oxygen and water and in additionaffords the product in high yields. Another major breakthroughin the application of the Huisgen cycloaddition reaction isthe regiospecific synthesis of isomeric 1,5-disubstituted 1,2,3-triazole via Ru(II)-catalysed azide–alkyne cyloaddition reaction(RuAAC).24–26 Contrary to CuAAC reaction, RuAAC was successfullyapplied to internal alkynes, thus giving access to fully substituted1,2,3-triazole derivatives (Fig. 1).

Despite these spectacular advancements, the toxicity of theheavy metals to living cells and biomolecules like DNA is alimiting factor for their broader applications in bio-materialchemistry and chemical biology.27 As an approach to metal-freeclick chemistry, Bertozzi and co-workers have developed ametal free, strain promoted, 1,3-dipolar cycloaddition reactionbetween azide and cyclooctyne (SPAAC) to form 1,2,3-triazolesfor bioconjugate chemistry.28,29 Other methods such as thenucleophilic attack of reactive acetylide species to organicazides30 and very recently a modification of the Sakai reactionusing amines and a,a-dichlorotosylhydrazones31 and a cascademulticomponent reaction of primary amines, propynones and

active azides via an a-diazoimine intermediate32 have beendeveloped. Nevertheless, all these methods have their advan-tages and limitations. For instance, an SPAAC reaction wouldlead to a mixture of regioisomers whereas the Sakai reactionwould lead to a less functionalized 1,4-disubstituted triazoleand the multicomponent reaction involving a-diazoimine to the1,5-regioisomer. Moreover, multistep reactions are usuallyrequired for the synthesis of their starting materials.

In the past decade, the versatile utility of organocatalyticreactions to synthesize different heterocyclic scaffolds hasreceived a lot of attention and gives great opportunities formedicinal chemists.33,34 This area has grown into one of thefrontiers of organic synthesis to address scaffold diversity incompound collections. In particular, the progress in amino-catalysis through an enolate, enamine or iminium ion intermediatehas been successfully investigated. Very recently, the direct accessto diversely functionalized 1,2,3-triazoles via organocatalysis hasemerged as an exciting research area. This is because, in contrastto metal catalysts, organocatalysts are eco-friendly, insensitive tooxygen and water, and easy to be designed and synthesized. Manycases of the recently developed organocatalytic triazole synthesesare ingenious extensions of the previously reported Dimrothreaction. L’abbe, in his review published in 1971, describedDimroth reaction as ‘‘the condensation of organic azides withactive methylene compounds in the presence of an equimolaramount of organic or inorganic base leading to highly substituted1,2,3-triazoles in a regioselective manner’’ (Fig. 2).35 This is not tobe confused with the Dimroth rearrangement, a general rearran-gement reaction in which an exocyclic atom is exchanged with anendocyclic one.36 Dimroth 1,2,3-triazole synthesis can be consid-ered as the lead example for the synthesis of 1,2,3-triazoles viaorganocatalytic pathways. However, these methods often sufferfrom a narrow substrate scope and modest functional grouptolerance. The recent advancement in organocatalysis can largelyovercome these limitations. The key advantages of this methodol-ogy are metal free synthesis, high regioselectivity, and easy accessto diversely functionalized 1,2,3-triazoles that are inaccessible by

Fig. 1 1,2,3-Triazole synthesis via Huisgen and metal catalyzed cycloadditions.

Fig. 2 Dimroth reaction for 1,2,3-triazoles synthesis.

Wim Dehaen

Wim Dehaen was born in Kortrijk,Belgium. He obtained his PhD in1988 under the guidance of Prof. G.L’abbe on a study concerning therearrangements of 5-diazoalkyl-1,2,3-triazole derivatives. Afterpostdoctoral stays in Israel (1988–1990), Denmark (3 months in1990), the UK (3 months in 1994)and Belgium (1990–1998) he wasappointed associated professor atthe KU Leuven (Belgium) in 1998,becoming a full professor at thesame university in 2004. Up to

mid 2015, over 420 publications have appeared in internationaljournals about his work on heterocyclic and supramolecular chemistry.

Feature Article ChemComm


other means and this entails economic advantages by using cheapand readily available building blocks. This remarkable organo-catalysed reaction is a lead for the rapid and easy access to triazoleheterocycles having high synthetic and biological importance.37

The objective of the present review is to summarize therecent developments in organocatalytic reactions for the synthesisof functionalized 1,2,3-triazole heterocycles and we have excludedthe previous reports on base catalysed Dimroth reactions, sincethis topic was reviewed before.35 Our discussion is organizedaccording to the different reactive intermediates involved in theorganocatalytic transformation. In the first part, different enam-ine mediated Huisgen 1,3-dipolar cycloaddition reactions will bereported followed by a subdivision on an iminium ion mediatedreaction. The third section deals with enolate mediated reactions.The last part of the review deals with different triazole syntheseswhere an intermediate compound was formed by an organo-catalytic reaction.

1,2,3-Triazoles via enamine intermediate

As early as in the 1960’s the reactions of isolated enamines withorganic azides were reported to furnish substituted 1,2,3-triazoles.38 In the present section different reactions involvingthe catalytic formation of enamine intermediates and cyclo-additions of these species with organic azides are discussed. In2008, Ramachary et al. described a proline catalyzed synthesisof fused triazoles from Hagemann’s ester.39 When the cyclicenone was treated with tosyl azide in the presence of proline,the reaction afforded NH-1,2,3-triazoles in excellent yields(Scheme 1). The reaction proceeds via the formation of adienamine 4 onto which cycloaddition of the azide takes place.The triazole compound 6 is formed by the elimination of thecatalyst, proline. It was found that for substituted Hagemann’sester, a solvent induced tosyl group hydrolysis takes place toafford the NH-triazole 3. In the case of simple enones the tosyl

group was found to be intact under the reaction conditions ascan be seen in triazoles 3g and 3h. Both aliphatic and aromaticsubstituted Hagemann’s esters furnished the correspondingfused NH-triazoles in good yields.

Interestingly, when the catalyst was changed to a benzylamine, the sole product was an a-diazo ketone 7 (Scheme 2).39

The mechanism of the reaction as proposed by the authorsstarts with the formation of dienamine 8 by the reaction ofbenzyl amine and the enone 1. This is followed by the amina-tion of the dienamine 8 with tosyl azide 2. The aminationproduct 9 then undergoes a rearrangement which is followed bythe elimination of tosylamide and finally the hydrolysis of theresulting imine 10 to afford the diazo ketone 7.39 Earlier reportshave shown that an a-diazo imine would undergo an intramolecularcyclisation to form a triazole40 hence it is very unlikely that thehydrolysis would happen at the intermediate 10. The authors havealso suggested an alternate ‘dienol’ mechanism which seems moreprobable.

Recently, the same authors reported the synthesis of trisub-stituted 1,2,3-triazoles via an enamine intermediate by treatingcyclic enones with aryl azides in the presence of pyrrolidine ascatalyst.41 The reaction was performed in DMSO at roomtemperature with 10 mol% of the catalyst. The reaction wasfound to be general for both substituted and simple Hage-mann’s esters. Moreover, different substituents on the aryl ringof the azide component were tolerated. These triazoles 12 weresubjected to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)oxidation to afford a variety of benzotriazoles 13 (Scheme 3).

The regiospecific synthesis of trisubstituted triazoles fromactive methylene compounds and organic azides was reportedby Wang and coworkers.42 An organic azide, when treated withthe active methylene compound in the presence of 5 mol% ofdiethylamine in DMSO at 70 1C, furnishes the substituted 1,2,3-triazole 19 in excellent yields (Scheme 4). The reaction wasfound to work with a variety of active methylene compoundsand substituted aryl azides and could also tolerate a wide rangeof substituents. It is noteworthy to mention that aliphatic azide(benzyl azide) also was reported to afford the expected product19k in good yield. The reaction time varied from 1 to 48 hoursScheme 1 Synthesis of NH-1,2,3-triazoles via an enamine intermediate.

Scheme 2 Synthesis of a-diazo ketone via an enamine intermediate.

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depending on the substrate. The triazole synthesis neededconsiderably less time when electron poor azides (1 hour for19j) were used in comparison with electron rich analogues(24 hours for 19h). The authors postulate an enamine mechanismas mentioned in the above reactions (Schemes 1 and 3) but theyalso proposed that the reaction could proceed via the formation ofan enolate as seen in the Dimroth reaction.35

Semenov and co-workers efficiently utilized the reactiondeveloped by Wang et al. described in Scheme 3 for thesynthesis of a class of 1,2,3-triazole analogues of combretasta-tin.43 They treated different b-ketoesters 20 and b-ketonitriles23 with various aryl azides in the presence of 5 mol% diethyl-amine to afford the corresponding substituted triazoles 21 and

24 in good yields (Scheme 5). Different transformations werecarried out on these products to study the structure activityrelationship. It was found that the decarboxylated compounds22a (IC50 � 20 nM) and 22b (IC50 � 10 nM) were active even atnanomolar concentrations as potent antimitotic microtubuledestabilizing agents.

Soon after, the groups of Pons–Bressy and Wang indepen-dently reported an efficient triazole synthesis starting fromunactivated ketones.44,45 The optimized conditions reportedby Pons–Bressy et al.44 required 20 mol% of proline as catalystand a 2 : 1 ratio between ketone and azide in dichloromethaneas solvent (Scheme 6). Conventional heating of the reactionmixture at 80 1C needed 5–6 days for completion. The longreaction time was reduced to 1 hour by upon microwaveirradiation at 80 1C, which proved to be equally high yielding.It has been found that the reaction worked only with aryl azideswith electron donating substituents (26a–26c). The reactionproceeded with high regio- and chemoselectivity with bothcyclic and acyclic ketones. The reaction conditions from Wangand coworkers45 required the use of pyrrolidine (20 mol%) asthe catalyst and DMSO as the solvent. The reaction at 80 1C took10–24 hours for completion. It has been shown that the

Scheme 3 Synthesis of fused 1,2,3-triazoles and benzotriazoles via anenamine intermediate.

Scheme 4 Synthesis of substituted 1,2,3-triazoles from active methylenecompounds.

Scheme 5 Synthesis of substituted 1,2,3-triazole analogues of combretastatin.

Scheme 6 Synthesis of substituted 1,2,3-triazoles from unactivated ketones.



reaction worked well (26g–26j) with a variety of substitutedcyclic ketones and phenyl azide (Scheme 6). These reactionsalso follow the enamine pathway as discussed earlier. A notabledrawback of these two methods is the less/no reactivity ofaliphatic azides under the reported conditions.

Using the developed enamine catalyzed triazole synthesismethod Wang et al. prepared the CB1 cannabinoid receptorantagonist intermediate.45 Trisubstituted 1,2,3-triazole 29 wassynthesized by treating the dichloro-phenyl azide 28 with theactive methylene compound 27 in the presence of 20 mol% ofpyrrolidine as catalyst in DMSO (Scheme 7).

The first organocatalytic synthesis of substituted 1,2,3-triazoles in water was reported by the group of Wang.46 Theydesigned the use of a catalyst molecule with suitable hydro-phobic groups that could bring reactants together and thusforce the reaction to occur in hydrophobic pockets. Thesemicelles could shield the enamine intermediate from water,thereby resulting in a reaction which is comparable to thosecarried out in organic solvents. Optimization studies led to theconclusion that the prolinamide catalyst 30 bearing two n-octylchains gave the best yield for the synthesis of substitutedtriazoles in water (Scheme 8). The reactions of both activatedand unactivated methylene compounds with aryl azides inwater at 80 1C furnished the corresponding trisubstitutedtriazoles in good to excellent yields. The regioselective outcomeremained unchanged for this green methodology when comparedto the reactions carried out in organic solvents.

A straightforward route towards 4-alkenyl-1,2,3-triazolesfrom unsaturated aldehydes came from the same group(Scheme 9).47 This reaction requires 10 mol% of DBU inaddition to the secondary amine catalyst, diethylamine. Theauthors found that the yield was diminished considerably inthe absence of either secondary amine catalyst or DBU. Thealkenyl triazole synthesis was found to be general regardlessof the electron donating or withdrawing substituents on thea,b-unsaturated aldehydes and aryl azides. As seen in thereactions described above, aliphatic azides showed poor reac-tivity (32f). The present triazole synthesis also worked well with

a long aliphatic chain containing aldehyde 32d and p-extendedunsaturated aldehyde 32e. The mechanism of the reactioncommences with the condensation of diethylamine and unsatu-rated aldehyde 31 to form the iminium species 33. Dienamineintermediate 34 is formed from 33 by a base (DBU) induceddeprotonation. Regioselective inverse electron demand cycloaddi-tion takes place between the dienamine 34 and the aryl azide tofurnish the triazoline species 35. The elimination of diethylaminethen takes place from 35 to yield the desired 4-alkenyl-1,2,3-triazole.

Recently Wang et al. also reported an organocatalyticapproach for the synthesis of trisubstituted triazoles startingfrom allyl ketones (Scheme 10).48 For this regioselective meth-odology, the authors used a 2 : 1 mixture of aryl azide and allylketone in the presence of 10 mol% of diethylamine as catalystin DMSO. The reaction worked well with aliphatic, aromaticand heteroaromatic allyl ketones. In this reaction both aliphaticand aromatic azides gave excellent yields for substituted tria-zoles. The first step of the mechanism is proposed to be theformation of dienamine 38, which reacts with aryl azide to formthe intermediate 39. Then a 1,3-H shift takes place on 39 tofurnish the species 40 which undergoes intramolecular additionto afford triazoline 41. Hydrolysis and oxidation occurs onthe intermediate 41 to furnish the 1,4,5-trisubstituted triazole37. Strictly speaking, the alternative mechanism involvingbase induced isomerisation to a,b-unsaturated ketone andcycloaddition-oxidation via iminium intermediate as shownin Scheme 12 cannot be excluded.

The dienamine intermediate was proposed for the formationof fused 1,2,3-triazoles from Hagemann’s ester as reported byRamachary et al. (Schemes 1 and 3)39,41 and also for the reactionsstarting from unsaturated aldehydes and allyl ketones (Schemes 9and 10).47,48 The reactivity of Hagemann’s ester was found to befacile even at room temperature but the reactions of unsatu-rated aldehydes and allyl ketones were heated to 50 1C and80 1C respectively. The dienamine intermediates generated

Scheme 7 Synthesis of CB1 cannabinoid receptor antagonist intermediate.

Scheme 8 Synthesis of substituted 1,2,3-triazoles in water.

Scheme 9 Synthesis of olefin substituted 1,2,3-triazoles from unsaturatedaldehydes.



from Hagemann’s ester and unsaturated aldehydes were onlyreactive towards aryl azides (electron-poor) whereas intermedi-ate 38 generated from allyl ketone was reactive to both aliphaticand aromatic azides.

An organocatalytic approach towards arylselanyl-1,2,3-triazolescame from the group of Alves–Paixao.49,50 The use of 1 to 10 mol%of diethylamine was needed to catalyze the cycloaddition of activemethylene compounds and azidophenyl arylselenides 43 in DMSOat room temperature (Scheme 11). They successfully used bothb-keto esters and amides for the reaction. The presence ofelectron withdrawing substituents on the aryl group of theamide moiety seems to decrease the yield (44f). The positionof the arylselanyl group does not seem to influence the yield ofthe reaction. Moreover for 44h, a 6 : 1 regioisomeric mixturewas obtained. In the case of the reaction between b-ketoesters and aryl azides, microwave irradiation considerablydecreased the reaction time to 10 minutes. The authorspropose that the reaction proceeds via an enamine inter-mediate but the possibility for an enolate mechanism cannotbe ruled out.

1,2,3-Triazoles via iminium intermediate

Wang et al. very recently reported the synthesis of trisubstitutedtriazoles from a,b-unsaturated ketones. In this work, 10 mol%of piperidine was used as catalyst which proved to be effectivefor a number of substituted unsaturated ketones (Scheme 12).51

This transformation also worked efficiently for aliphatic,aromatic and heteroaromatic azides. The authors suggest apossible mechanism via an iminium intermediate. The firststep is the formation of the iminium intermediate 47 by thereaction of the unsaturated ketone 45 and the catalyst. Normalelectron demand cycloaddition takes place between the iminiumspecies 47 and the azide to generate the triazoline intermediate49. Hydrolysis of the iminium center and subsequent airoxidation of the triazoline 50 results in the formation of the fullysubstituted triazole.

1,2,3-Triazoles via enolate intermediates

Very recently Ramachary et al. reported an elegant synthesis of1,4-disubstituted triazoles from enolizable aldehydes(Scheme 13).52 There were earlier reports on the synthesis ofsubstituted triazoles from aldehydes, but all the methodsrequired the use of an excess amount of base and harshconditions.38 In this report, a variety of disubstituted triazoles52 were prepared from enolizable aldehydes 51 and aromaticazides with 10 mol% of DBU as catalyst. The reactions werecarried out in DMSO at room temperature and required only30 minutes for completion. The reaction was found to be generalfor aldehydes with electron rich and poor aromatic substituents.Aliphatic azides showed poor reactivity as seen in the reportsdescribed above (52g). The reaction proceeds via the formation ofan enolate 53 by the interaction of the catalyst with the aldehyde.The triazoline intermediate 56 can be formed from the enolateand azide either by a [3+2] cycloaddition (intermediate 54) or by a

Scheme 10 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from allyl ketones.

Scheme 11 Synthesis of arylselanyl-1,2,3-triazoles from active methylenecompounds.

Scheme 12 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from unsatu-rated ketones.



stepwise addition-cyclisation route (intermediate 55). The finalstep is a base induced H2O elimination thereby furnishing the1,4-disubstituted triazole 52. This method can be viewed as analternative to the copper catalyzed click reaction and is useful inthe cases where the aldehyde 51 is more accessible than thecorresponding monosubstituted alkyne.

After the report on the synthesis of 1,4-disubstituted tria-zoles from enolizable aldehydes, Ramachary and co-workersextended their methodology towards trisubstituted triazoles 58starting from enolizable ketones 57 (Scheme 14).53 The reactionwas found to be general with a variety of aryl azides containingboth electron donating and withdrawing groups. However, alsoin this reaction, aliphatic azides were not tested. It was foundthat the reaction was not affected by the substituents present

on the aryl group on the ketone. In the case of b-tetralone, theyield was found to decrease with the presence of the electrondonating substituent (58g–58h). By utilizing the developedstrategy the mGluR1 antagonist 58i was successfully synthe-sized in 90% yield which is well superior to the earlier reportwhich involved the use of three metals (Mg, Zn & Pd) for thesynthesis.54 The reaction also follows the same enolate pathwayas was described in the case of enolizable aldehydes (Scheme 13).

Wang et al. reported an interesting aerobic oxidative orga-nocatalytic intermolecular azide–zwitterion reaction for thesynthesis of functionalized triazoles (Scheme 15).55 The reac-tion was carried out with an activated alkene 59 and an organicazide in the presence of DBU as catalyst. This new reactionwas found to be general for different activated alkenes likea,b-unsaturated esters, amides, aldehydes, ketones, nitriles etc.The reaction also worked well with both aliphatic and aromaticazides. The mechanism of the reaction was proposed to startwith the formation of the enolate (zwitterion) 62 by the reactionof DBU with the starting a,b-unsaturated ester. Morita–Baylis–Hillman type addition of the zwitterion 62 takes place onto the

Scheme 13 Synthesis of 1,4-disubstituted 1,2,3-triazoles from enolizablealdehydes.

Scheme 14 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from enoliz-able ketones.

Scheme 15 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from activatedalkenes.



azide which results in the intermediate 30. Three plausiblereaction pathways were postulated from intermediate 63. Thefirst pathway involved the generation of the cyclic intermediate4,5-dihydro triazole 64 via a SN2 reaction of 63, which is finallyoxidized into the triazole. The second pathway proceeds by E2

elimination of DBU, which results in the olefin intermediate65. A 6p electrocyclization and an oxidative aromatizationsequence produce the final triazole product. The final routewas proposed to commence with the aerobic oxidation of 63towards the olefin intermediate 66. This intermediate 66 under-goes a 6p electrocyclization and subsequent DBU liberationfrom the intermediate 67 to furnish the product 61. The highregioselectivity of this reaction is clearly due to the presence ofvarious electron-withdrawing groups on the dipolarophiles 59.Another point to be noted is that the reaction was carried out ata small scale and under high dilution conditions for effectiveoxidation.

Miscellaneous reactions towards substituted 1,2,3-triazoles

All the reactions discussed above involved an organocatalysedcycloaddition step. There are a few reports that involve anorganocatalysed generation of an activated dipolarophile ontowhich cycloaddition of azide takes place. One such report camefrom our group which involves a multicomponent reactionbetween an aldehyde 68, nitro compound 69 and an organicazide (Scheme 16).56 In this reaction we used a catalytic amountof salts generated from a nitrogen base and an acid. Morpholine:p-toluene sulfonic acid salt 71 was found to be the best catalystfor the reaction. 1,4,5-Trisubstituted triazoles were obtained ingood to excellent yield when a mixture of the aldehyde, nitrocompound and azide was treated in toluene at 100 1C in thepresence of 5 mol% of the catalyst. The reaction could tolerateboth aromatic/heteroaromatic and aliphatic aldehydes, differentnitro compounds and both aliphatic and aromatic azides. In thecase of aldehydes with electron donating substituents a minoramount (o5%) of the other regioisomer was formed (70b).Electron rich azides gave better yield than the electron poorones. The main advantage of the method is the possibility tosynthesize a new class of substituted triazoles. The multicompo-nent reaction proceeds via the initial formation of an activatediminium intermediate 72 from the aldehyde 68 and morpholinesalt 71. The nitroalkene 74 is generated from 73 by the attack ofthe nitro compound along with the regeneration of the catalyst.Further Michael addition to these nitro alkenes 74 could occurto generate the dinitroglutaric ester 75. We believe that this is inequilibrium with the Knoevenagel product 74, and that theformation of triazole 70 can displace this equilibrium, whichis an example of thermodynamically controlled dynamic cova-lent chemistry. The presence of the strong electron-withdrawingnitro group on the dipolarophile 74 is the reason for the highregioselectivity of the cycloaddition process.57

Recently a study was reported by the group of Paixao whichinvolved the synthesis of 1,4-disubstituted triazoles.58 Initiallyalkylidene malononitriles were treated with organic azides inthe presence of the stoichiometric amount of DBU in DMSO,which afforded 1,4-disubstituted triazole in good yields

(Scheme 17). Furthermore, it was found that the reaction couldbe performed starting from the aldehydes 51 and by usingcatalytic amounts of malononitrile. However, it was proved thatthe reaction can work in the absence of malononitrile byRamachary et al.52 As proposed by the authors the mechanismof the reaction with the aldehyde 51 starts with the initialformation of alkylidene malononitrile 76 which converts to 77in the presence of base. Azide addition takes place onto the

Scheme 16 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles by a multi-component reaction approach.

Scheme 17 Synthesis of 1,4-disubstituted 1,2,3-triazoles.



alkene 77 to yield the triazoline intermediate 78. Base inducedelimination of malononitrile results in the formation of triazole52. The reaction conditions were harsh and also required moretime when compared to the reaction discussed above in Scheme 13.

Conclusions

The current surge in the interest for finding organocatalyticroutes towards highly functionalized 1,2,3-triazoles hasresulted in the introduction of several well-designed reactions.It can be clearly seen that organocatalytic reactions have lead tothe generation of highly functionalized/fused triazoles whichwere not possible to obtain by classical or metal catalyzedtriazole synthesis. These green methods normally use easilyaccessible starting materials, for example carbonyl compoundsand thus making them superior to methods involving alkyneswhich are expensive and less available. The reaction conditionsfor the triazole synthesis are highly dependent on the reactiveintermediate and thus enolate catalyzed reactions proceededquickly and under ambient conditions. Different bioactivetriazoles could be easily synthesized by organocatalysis.

There are still a lot of challenges that could be answered bydesigning clever organocatalytic reactions. For example, thesynthesis of a 1,5-disubstituted 1,2,3-triazole is still to beexplored. Most of the reactions discussed above are ratherlimited to aromatic azides which should be extended to aliphaticones. Easily available natural products containing enolizablecarbonyl groups could be easily functionalized using the abovementioned methods and thus could facilitate the structureactivity relationship studies of bioactive/drug-like molecules.Mechanistic studies of the reactions mentioned above are stilllacking, both in the theoretical and experimental point of view.Some of the reactions discussed above were done in a very smallscale and more effort has to be invested in validating thesereactions in bulk. These eco-friendly approaches still remain tobe applied in supramolecular and material chemistry. Anotherimportant aspect to be checked is the application of organo-catalytic triazole reactions in bioorthogonal chemistry.

Acknowledgements

We thank the University of Leuven and the FWO-Vlaanderen forfinancial support.

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