Dipolar Cycloaddition Reactions of Enamines and ...

DOI: 10.1002/ejoc.201701031

Microreview

Cycloaddition

The Rich Chemistry Resulting from the 1,3-Dipolar Cycloaddition Reactions of Enamines and Azides Vasiliy A. Bakulev,*[a] Tetyana Beryozkina,[a] Joice Thomas,[b] and Wim Dehaen*[c] Abstract: Enamines exhibit exceptionally high reactivity in their 1,3-dipolar cycloaddition reactions with azides in comparison with other dipolarophiles. This review includes the reactions of various types of enamines with azides of different nature, including catalytic processes. The initial products of the reaction, 1,2,3-triazolines, are generally unstable and very reactive compounds which are prone to undergo various ring transformations. This provides the background for new syn-

thetic methods and novel reaction types. The formation of a variety of products derived from the reaction of enamines with azides such as mono-, di-and tri-substituted 1,2,3-triazoles, including N-unsubstituted derivatives, fused, conjugated and spiro heterocycles, two types of amidines and diaminoalkenes are classified in this review according to the type of stabilization/transformation of the intermediate triazolines.

1. Introduction 1,3-Dipolar cycloaddition reactions are a versatile and efficient synthetic approach to a huge variety of heterocyclic compounds.[1] The study of cycloaddition of azides to acetylenes and other dipolarophiles have expanded our knowledge on pericyclic processes and have allowed to explore the principles of both click chemistry and dynamic combinatorial chemistry[2] offering new possibilities for the synthesis of a variety of valuable organic compounds. The classical Huisgen synthesis of 1,2,3-triazole derivatives by reaction of azides with monosubstituted acetylenes usually requires harsh conditions, has poor regioselectivity and low yields of reaction products and therefore has not been used much in organic synthesis.[3] A breakthrough improvement was made by the use of copper[4] and ruthenium catalysts.[5] In contrast to the noncatalyzed Huisgen cycloaddition of azides to acetylenes, the copper catalyzed azide alkyne cycloaddition (CuAAC) and ruthenium catalyzed azide alkyne cycloaddition (RuAAC) reactions are regiospecific and form, depending on the type of catalyst either 1,4- or 1,5-disubstituted 1,2,3-triazoles. At the same time, a large rate acceleration occurs. Thus, the cycloaddition between phenyl azide and DMAD occurs at room temperature in 24 h. Sharpless has considered CuAAC reaction as “the cream of the crop” of click reactions.[1] [a] Ural Federal University, Mira st. 19, Yekaterinburg 620002, Russia [email protected] http://toslab.com/ [b] Department of Chemistry, The Bridge@USC and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, USA [c] Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium [email protected] http://chem.kuleuven.be/en/research/mds/losa ORCID(s) from the author(s) for this article is/are available on the WWW under https://doi.org/10.1002/ejoc.201701031. Eur. J. Org. Chem. 2018, 262–294

However, the toxicity of the copper and ruthenium catalysts to living cells and incompatibility with some biomolecules are disadvantages that hamper broad use of metal-catalyzed reactions of azides with alkynes in chemical biology.[6] Copper free reactions of azides with strained alkenes, as explored by Bertozzi and co-workers are an alternative approach to 1,2,3triazoles, and also can be categorized as click reactions. This strain promoted azide–alkyne cycloaddition (SPAAC) has attracted much attention in the last years due to interesting applications in chemical biology and material science.[6g] We have turned our attention to the cycloaddition reactions of azides with enamines due to the unprecedented high reactivity and regioselectivity of the latter in comparison with similar reactions of simple alkenes. Thus, substitution of the 2hydrogen atom in styrene by a pyrrolidinyl moiety increases the rate of the reaction with phenyl azide 50000-fold[7] which is even higher than the rate enhancement of the copper free “click” reaction of strained alkynes to azides. Recently, based on the high reactivity and regiospecificity of the reaction of azides with enamines, novel organocatalytic approaches to 1,2,3-triazoles and to the transformation products of 1,2,3-triazolines have seen fast development.[8a,8b] There have been a few reviews published which include reactions of azides with enamines as a part of the chemical properties of enamines[8a–8g] or which are directed to only one aspect of this reaction. In this review, we will discuss the reactions of acyclic, endo- and exocyclic enamines with aliphatic, aromatic, heteroaromatic, sulfonyl and phosphoryl azides, including catalytic processes. The intermediate products of the azide–enamine cycloaddition, 1,2,3-triazolines, are prone to various ring transformations affording a variety of methods A–G (vide infra) for the synthesis of 1,2,3-triazoles, amidines, diaminoalkenes and fused pyranones. The features of these different pathways will be reported in detail in this review.

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2. Synthesis of 5-Amino-1,2,3-triazolines 5-Amino-1,2,3-triazolines, as the initial products in the reaction of enamines with azides, were firstly described by Fusco et al. in 1961[9] and a bit later by Bianchetti et al., Pocar et al., Bolis et al., Cook et al.[10] and Munk.[11] These authors have shown that aryl azides readily undergo addition to various types of enamines 1a under relatively mild conditions to form mono-, bi-, and tricyclic 5-amino-1,2,3-triazolines 2a–c as single regioisomers in very good yields[9–11] (Scheme 1). Later on, reactions of enamines 1 with aromatic,[10,12–19] heteroaromatic,[20–23] alkyl-[18,24,25] and vinyl azides[26] were applied for the synthesis of mono-,[9–11,14,16,19,20,26] bi-[9,14,19,20,22,26,27] and polycyclic[12,21,26,27] 5-amino-1,2,3-triazolines 2, including fused heterocycles. A few examples of the use of alkoxycarbonyl, benzoyl and sulfonyl azides for the synthesis of Ncarbonyl-5-amino-1,2,3-triazolines[12,19] and N-sulfonyl-1,2,3-triazolines[28,29] are reported. 2,2′-Disubstituted enamines were used to prepare 5,5′-disubstituted triazolines[17] including spiro compounds.[18] The 5-amino fragment of the triazolines formed in the reaction can be either a cyclic amine,[9–15,17–24,26,27] a dialkylamine[14a] or an amido[16] moiety. Though the reaction of enamines with azides leading to 5-amino-1,2,3-triazolines appears to be general, it is limited by the low stability of the triazolines. However, one paper appeared with a report on the

Scheme 1. Syntheses of 1,2,3-triazolines from enamines and aryl azides.

X-ray data of N,N-diethyl-1-(4-nitrophenyl)-4,5-dihydro-1H-1,2,3triazol-5-amine.[14b] Formed as initial products, 5-amino-1,2,3triazolines can easily undergo various transformations and rearrangements that are described in the following sections. Munk and Kim were the ones who first categorized the reaction of azides with enamines as a 1,3-dipolar cycloaddition process.[11] They have shown that 5-amino-1,2,3-triazolines are initially the only products formed in the reaction and based have given an explanation for the influence of the enamine

Vasiliy A. Bakulev graduated from the Ural State University in 1972, defended Candidate (1972, Ural State University) and Doctoral (1990, Moscow State University) theses. Currently holds the position of Professor, Head of Organic Synthesis Technology Division, Ural Federal University. Scientific interests include chemistry of heterocyclic compounds and pericyclic reactions of compounds containing heteroatoms. Author of 176 articles, 2 monographs, and 9 review articles.

Tetyana V. Beryozkina graduated from Kharkiv National University (Ukraine) in 1999, defended Candidate thesis in 2004. Currently works as a senior researcher at the Organic Synthesis Technology Division, Ural Federal University. Scientific interests include chemistry of heterocycles and the synthesis of nanostructured conjugated polymers. She is author of 41 articles, 1 monograph, and 2 review articles.

Joice Thomas was born in Thiruvanvandoor (Kerala), India. He received his PhD degree in Chemistry in 2011 at the KU Leuven, Belgium, under the supervision of Prof. Wim Dehaen, working on the synthesis and application of homo(hetera)- calixarenes. Soon after, he worked as a postdoctoral fellow in the same group for four years, focusing mainly on medicinal chemistry and developing general metal-free route towards the synthesis of 1,2,3-triazole heterocycles. Presently, he is working in the group of Prof. Valery Fokin at the Bridge@USC, California. He published more than 50 articles in international journals about his work on heterocyclic and supramolecular chemistry.

Wim Dehaen was born in Kortrijk, Belgium. He obtained his Ph D in 1988 on a study concerning the rearrangements of 5-diazoalkyl-1,2,3triazole derivatives. After postdoctoral stays in Israel (1988-1990), Denmark (3 months in 1990), the United Kingdom (three months in 1994) and Belgium (most of 1990–1998) he was appointed associate professor at the University of Leuven (Belgium) in 1998, and full professor at the same university in 2004. Close to 500 articles have appeared in international journals about his work on heterocyclic and supramolecular chemistry.

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Microreview nitrogen on the regioselectivity of the reaction: the conjugation of the electron-releasing amino group with the C=C bond activates the electrophilic attack of the nitrogen atom attached to the phenyl towards the positively charged α-carbon atom.[7] Systematic kinetic studies for the reaction of β- and α-aryl enamines with a series of aromatic azides were made by the Munk group[7a] and recently by Xie et al.[30a] The higher reactivity found for carbonyl and sulfonyl azides in comparison with aryl azides[12,19,28,29] was supported by high level theoretical calculations.[30b] Data obtained included rate constants, Hammett ρ values and activation parameters and allowed for arranging reaction rates for azides and enamines in the following series (Figure 1, Figure 2, and Figure 3).

Figure 2. Effects of 2- and 3-substituents on the reactivity of enamines 1b,c.

Figure 1. Reactivity order of azides. Figure 3. Reactivity order of enamines 1d–k.

Thus, introduction of electron-acceptor groups to aryl azides and electron-donating substituents to enamines enhances the reaction. This behavior is consistent with the simple FMO theory.[7b] The mechanism and regioselectivity of the enamines 1d–f,h with aryl azides was studied by Munk using the semi-

empirical Complete Neglecting Differential Overlapping (CNDO) method.[7b] 39 Years later, Munk joined to the Houk group to study the same objects using a higher level of calculations with M06-2X/6-311+G(d,p), SCS-MP2/6-311+G(d,p)//M06-2X/6-311+

Scheme 2. Concerted (1,3) and stepwise (2) pathways for the reaction of enamine 1e with phenyl azide. Ball-and-stick models adapted with permission from ref.[30b]. Copyright 2013 American Chemical Society. Eur. J. Org. Chem. 2018, 262–294

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Scheme 3. Stereochemical features for the reaction of aryl azides with enamines.

G-(d,p), and B97D/6-11+G(d,p) methods with the IEF-PCM solvation model for chloroform and ethanol.[30b] Both concerted (1,3) and stepwise (2) (Scheme 2) pathways were found for the formation of the observed product 2d. The authors[30b] showed that the lowest energies of the transition states (TS) for the reactions of enamines 1e with phenyl azide TS1e→2d involve the concerted, asynchronous formation of new bonds as shown in Scheme 2. The transition state for the observed product 2d was found to be 7 kcal/mol lower than the one for the isomeric products that were not formed. This clearly explains the formation of 1,5-diaryl-triazolines 2 as exclusive products. TS 1e→1e′ corresponding to the triazene intermediate formation is disfavored by 4.5 kcal/mol. The reasons why the observed reactions have a lower TS were explained with the help of the distortion/interaction model developed by the Houk group for various kinds of organic reactions.[30c] The lowest energy of the transition state for the formation of 2d in comparison with an alternative, unobserved way to 2d′ is a consequence of the more favorable distortion energy. The effect of the solvent on the reactivity of indole towards tosyl azide was studied by Zhou et al. by DFT calculations with the B3LYP/6-31+ G(d,p) level of theory and the polarized continuum model. It has been shown that the energy activation for the reaction of indole with tosyl azide drops down for 4.5 kcal if the solvent DMSO was taking into account.[30d] This is in agreement with the asynchronous transition state found for this type of reaction.[30] Munk et al. paid attention to the superior reactivity of pyrrolidine enamine 1d in comparison with piperidine enamine 1e and morpholine enamine 1f[7] and it was clearly explained by the distortion energy control of the reactivity of the enamines 1d and 1e. Only the five-membered ring of pyrrolidine can be planarized, giving maximum overlap, which reduces the distortion energy with 3.1 kcal and this favors the formation of the triazoline. Stereochemical features of the reaction between 4-nitrophenyl azide and 2,3-dialkyl enamines have been first studied by Bianchetti et al.[13] They have shown that a cis-trans equilibrium mixture of the enamines 1 reacts with the aryl azides, Eur. J. Org. Chem. 2018, 262–294

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yielding exclusively trans-triazoline 2 (Scheme 3). Enamines of type 1-trans undergo cyclization ca 10 times faster than the 1cis isomer. At higher temperature or in the presence of acidic catalysts, the trans-triazoline 2 epimerizes, thus affording a cistrans equilibrium mixture.[13] The stereocourse of the cycloaddition of azides to enamines 1, bearing at position 3 a tetraphenyl norbornene moiety, was studied by Almirante et al.[15] The reaction of a mixture of enamines 1l and 1m with aryl azides was examined and it was shown that both cycloadducts 2e and 2f are clearly formed by the approach of the aryl azide to the exo side of the norbornene system (Scheme 3). In a series of publications[10,14,18] the reversibility of the cycloaddition reaction of azides to enamines was clearly shown. Rossi and Trimarco demonstrated this phenomenon with an example of the cycloreversion of benzothiepino[4,5-d]1,2,3-triazolines 2g (Scheme 4).[14] Thermolysis of five compounds of this series in refluxing acetonitrile or ethanol was shown to afford the starting enamines 1n and azides. The authors managed to trap the formed 4-nitrophenyl azide by reaction with morpholinocyclohexene 1o to afford the triazoline 2b.

Scheme 4. Reversibility of enamine reactions with azides.

The reversibility of the reaction of 2-alkylidenedihydroquinolines with azides was also demonstrated by Quast et al.[18]

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Scheme 5. Selective addition of azides to enamine double bonds.

Bianchetti et al. followed by Cardoen et al. have reported that 1,4-dialkyl-substituted 2-morpholinobuta-1,3-diene,[31a–31c] 2-morpholinocyclohexa-1,3-diene derivative[31b] and 1-diethylamino-1,3-butadiene[31d] give site- and regioselective cycloaddition with 4-nitrophenyl azide and p-toluenesulfonyl azide in much the same manner as with simple enamines. The cycloaddition reactions of organic azides with 2-amino-1,3-dienes, 1amino-1,3-dienes, and 2-aminobut-1-en-3-ynes were investigated by Brunner et al.[19] Azides react smoothly with aminodiene 1p in a [3+2] cycloaddition which takes place exclusively at the enamine C=C bond (Scheme 5). The dihydro-1,2,3-triazoles 2h were isolated from the reaction with 4-nitrophenyl azide and ethyl azidocarbonate, confirming the higher reactivity of the enamine double bond in comparison with a “conjugated” double bond. Enamine 1q, bearing an acetylene group conjugated with an enamine double bond is also capable of reacting with various types of azides (Scheme 5). However, only 4-nitrophenyl- and ethoxycarbonyl azide react at high pressure to form the cycloaddition products 2i (R = 4-NO2C6H4, CO2Et) in moderate to good yields.[19] The acetylene function remains unaffected. Dienamines in which the double bond of the diene system is included in a ring[18] are shown to be capable of reacting with various azides to form triazolines and their decomposition products. Thus, Quast et al. have demonstrated[18a] that alkylidenedihydroquinolines 1r are capable of adding phenyl azide to form the spirocyclic [3+2] cycloadducts 2j (Scheme 6). Only two compounds 2jd and 2jf were isolated as crystalline substances and characterized by X-ray crystallography, others 2ja– c,e,g were characterized by their NMR spectra. The reaction of methylene compounds 1ra, 1rc and ethylidene compound (E)1re was shown to be complete within one day, however the isopropylidene compounds 1rb, 1rd and the neopentylidene compound (E)-1rf required 6–10 days at room temperature. The ethylidene compound (E)-1re yielded two isomeric products 2je(l + u) [see definition for like (l) and unlike (u) diastereomers in reference[18d]] in the ratio 13:7. By contrast, the 2-neopentylidenedihydroquinoline (E)-1rf afforded a single product which was isolated and assigned the configuration (u)-2jf by invoking Eur. J. Org. Chem. 2018, 262–294

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the well-known cis stereospecificity of [3+2] cycloaddition reactions. After chromatographic treatment, product 2jf undergoes partial diastereomerization yielding a mixture of (l)- and (u)-2jf (13:7). This epimerization was explained by the reversible ring opening of triazoline 2jf to triazene 2jf′. The latter undergoes ring closure to form both l and u diastereomers.

Scheme 6. Reactions of alkylidenedihydroquinolines 1r with phenyl azide.

Five years later, the Quast group reported the results of a systematic study for reactions of cyclic ketene N, X (C, N, O, S) acetals with organic azides ranging from alkyl to strongly electron-deficient azides, e.g. picryl azide and sulfonyl azides.[18c,25] They have demonstrated the formation of two primary products, cycloadducts 2k and zwitterionic triazenes 2k′[18d] and also the products of the transformation of spiro triazolines 2k (Scheme 7, the latter are discussed in Section 2.3). Alkyl azides react exclusively with ketene N,N-acetals that are derived from 1H-triazole and 1H-imidazole, while almost all aryl azides react with N,X (X = N, O, S) acetals. Both reactions lead to cycloaddi-

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analogous to those observed in the reactions of enamines, thus 5-amido-1,2,3-triazolines 2l and 2m are obtained, generally in good yields.[16] As representative reactions of endocyclic enamines: 1-methylindoles,[14c] 1-methyltetrahydropyridines,[14d,14e] 4-oxo-4Hbenzothiopyrans[14f ] and 1,4-dihydroquinoline[14g] with sulfonyl and aryl azides lead to 1,2,3-triazolines fused to heterocyclic rings. Recently, a two-step method was introduced by Adolfsson et al. for the synthesis of highly functionalized triazolines in high yields involving a Mo(CO)6-catalyzed reduction of tertiary amides to enamines followed by in situ cycloaddition with organic azides.[32]

3. Ring Transformations of 5-Amino-1,2,3triazolines

Scheme 7. Reactions and mechanism of exocyclic enamines with azides.

Kadaba has studied the reaction of enamides with various aryl azides and has shown that enamides 1t react considerably slower than enamines 1 (Scheme 8). The reaction products are

Though many stable 5-amino-1,2,3-triazolines are known (see section 2.1) this non-aromatic ring can undergo several reactions on heating or after treatment with acid and bases. 5Amino-1,2,3-triazolines are subject to various ring transformations, giving a variety of methods for the synthesis of mono-, diand tri-substituted 1,2,3-triazoles, fused pyranones and other valuable organic species or intermediates such as amidines, diamino alkenes and diazo compounds. Scheme 9 includes an overview of the ways of transformation (A–G) for 1,2,3-triazolines 2 formed after cycloaddition reactions of various azides with enamines 1. Thus, elimination of alkylamines (pathway A) and dialkyl sulfon- or phosphoramides, most likely via a twostep process as shown in Scheme 9 (pathway B) affords various 1-substituted- (3) and 1-unsubstituted 1,2,3-triazoles 4. One of the proposed mechanisms for diazo group transfer of enamines 1 (R3 = H) with highly electrophilic azides involves the initial formation of triazolines which via elimination of amides of aryland alkylsulfonic and hetarylcarboxylic acids afford a variety of 1,4,5-trisubstituted 1,2,3-triazoles 3 (R1 = EWG) (pathway C). 1,2,3-Triazolines bearing a sulfonyl or carbonyl group at position 1 are prone to undergo a cycloreversion (retro-[3+2] cycloaddition) (pathway D) reaction to form diazo compounds 5′ and amidines 5. Elimination of dinitrogen (from N-sulfonyl- or Nheteroaryl-1,2,3-triazolines) often takes place spontaneously during their generation from enamines and azides bearing strong EWG, to form amidines 6 that are functionalized at the β-position (pathway E) or the rearranged diaminoalkenes 7 (pathway F). Transformation of 1,2,3-triazolines bearing 2-pyran4-yl at position 1 of triazoline 2 proceeds with nitrogen loss and participation of a double bond of the pyranone ring to form a pyrano[4,3-b]pyrrole-4-one 8 (pathway G). These pathways A-G will be reviewed in detail in the following subsections.

3.1 Synthesis of 1,2,3-Triazoles

Scheme 8. Reactions of enamides with aryl azides. Eur. J. Org. Chem. 2018, 262–294

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Based on the reaction of azides with enamines 1, various 1,2,3triazoles 3, 4 can be prepared directly or via a two-step synthesis by treatment of intermediate 1,2,3-triazolines 2 with acid or base, or by heating them in organic solvents (Scheme 10). The aromatization of the triazoline ring occurs as a result of the 267


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Scheme 9. Various pathways to transform 5-amino-1,2,3-triazolines.

elimination of neighboring substituents either from the C4 and C5 or from the C4, C5 and N1 positions of the 1,2,3-triazoline ring.

Scheme 11. Synthesis of 4-carbonyl-substituted- and 4-cyano-1,2,3-triazoles. Scheme 10. Aromatization of 1,2,3-triazolines 2 by elimination of small molecules.

Elimination of Dialkylamines Elimination of dialkylamines is a widely used approach toward 1,2,3-triazoles. The elimination process of dialkylamines is facilitated by the presence of electron withdrawing groups in position 4 of the triazoline ring, which increases the acidity of the C4–H bond.[33–37] Thus, enamines 1u derived from secondary amines and 1,3-dicarbonyl compounds were immediately converted into the corresponding 4-benzoyl-1,2,3-triazoles 3a on treatment with aryl azides (Scheme 11).[33a] Reactions of 2morpholino-1-nitro- and 1-cyano-ethenes with aryl azides take place very similarly to afford 1-aryl-4-nitro- (3b) and 4-cyano(3c) 1,2,3-triazoles.[34,35] Eur. J. Org. Chem. 2018, 262–294

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Reactions of enamines and azides can be promoted either in eutectic solvents[36a] or by microwave irradiation.[36b] Louërat et al. have investigated enamines 1v bearing ester and phosphonate substituents in position 3 of the enamine, and showed them to be converted to aromatic triazoles 3d after reaction with diethyl (azidomethyl)phosphonate, while needing more time and higher temperature than for the reactions of enamines without these substituents[36b] (Scheme 12). Thus, 1-phosphorylmethyl-substituted triazoles 3d were prepared in moderate yields. Better yields (70–86 %) are obtained in solvent free conditions at 100 °C. A partial loss of regioselectivity was found when the process was performed under microwave irradiation to form a mixture of regioisomers 3d and 3da. This fact was explained by dipolar polarization under microwave exposure.[36b] Diaz-Ortiz et al. proposed, based on DFT calculations,

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Scheme 12. Syntheses of 1,2,3-triazoles bearing phosphonate groups.

that 3d and 3da were kinetic and thermodynamic products, respectively. Conventional heating leads to formation of the kinetic product only. Conversely, under microwave irradiation both products 3d and 3da were obtained.[36c] However, we propose that enamines can be partially transformed,[8c] under the conditions of microwave irradiation, to acetylenes which gave a mixture of regioisomers in the reaction with azide as shown by the same authors.[36] A variety of 1,4-diaryl-1,2,3-triazoles of type 3e were prepared by reaction of enamines 1w with aryl azides (Scheme 13). In turn, these compounds were used to prepare triazoles 3ea which exhibited VEGFR-1 and VEGFR-2 inhibitory activity comparable with Vatalanib TM.[37]

Scheme 13. Synthesis of 1,2,3-triazole derivatives that inhibit angiogenesis.

5-Amido-triazolines of type 2l,m, derived from enamides, were treated with KOH in methanol to form 1-aryl-4,5-unsubstituted 1,2,3-triazoles 3f together with amides 3f′ (Scheme 14).[16a] Rossi and Trimarco have demonstrated the use of this protocol for the synthesis of 1,4,5-trisubstituted 1,2,3triazoles.[16b] 5-Vinyl-1,2,3-triazoline 2q was prepared from dienamine 1p after reaction with 4-nitrophenyl azide, and eliminated morpholine on heating at reflux temperature in aqueous acetic acid to form 5-vinyl-1,2,3-triazole 3ga in good yield (Scheme 15). Eur. J. Org. Chem. 2018, 262–294

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Scheme 14. Transformation of 5-carbamoyltriazolines to triazoles.

Phenyl azide reacted with dienamine 1p at room temperature to form directly 5-vinyl-1,2,3-triazoles of type 3g in moderate yield. The corresponding triazoline was not detected. Dimorpholinobutadiene 1x reacted smoothly with 4-nitrophenyl azide at room temperature to furnish the 4-(1-morpholinoethenyl)triazole 3g′ in 61 % yield. Cycloaddition at the other, more highly substituted enamine bond was not observed, even when 2 equivalents of the azide were supplied. Thus, diene 1x reacts as a 1-aminodiene and yields a 1,4-disubstituted triazole 3g′, chemo- and regioselectively.[19] Alkyl azides are less reactive towards enamines and it may take a long time to complete the reaction, and sometimes heating at higher temperature is needed. However, Palacios et al.[24] have found that the cycloaddition reaction of azides with cyclopentenylpyrrolidine 1y proceeds in good yield at room temperature, affording amino substituted triazoline 2r (Scheme 16). However, attempts to prepare the corresponding aromatic triazole from triazoline 2r by thermolysis failed. This may be due to the ring strain resulting from the fusion of two five-membered rings. Interestingly, when cyclohexenylpyrrolidine 1y (n = 2) was used, triazoline 2r was not isolated, but spontaneous aromatization to triazoles 3h took place in 60–70 % yields by elimination of pyrrolidine. Promising biological activity was found for conjugated bisazoles, bearing an isoxazole ring.[38] Therefore Bakulev et al.

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Scheme 15. Syntheses of 4-vinyl- and 5-vinyl-1,2,3-triazoles.

Scheme 16. Synthesis of N-alkyl-substituted 1,2,3-triazoles 3h.

turned their attention to the self-condensation of 3-azolyl enamines of type 1z and their cycloaddition to azides (Scheme 17).[39] It was found that the reaction of enamines with azides is faster in comparison to enaminones. This process can be carried out in solvent free conditions, affording a high yield of 4-azolyl-1,2,3-triazoles 3i with 1,2,3-thiadiazole and isoxazolyl substituents in the 4-position of the triazole. Because dimethylamine is eliminated from the intermediate 1,2,3-triazolines, 3azolylenamines 1z can be considered as synthetic equivalents of difficultly available azol-5-yl alkynes. A straightforward route for the synthesis of different 4-acyl1,2,3-triazoles 3j from readily available building blocks such as methyl ketones 9, N,N-dimethylformamide dimethyl acetal (DMF DMA) and organic azides has emerged from the group of Dehaen and co-workers (Scheme 18).[40] Previously, these classes of compounds were synthesized in multistep manner where the CuAAC reaction between organic azide and dipolarophiles such as acetylenic carbinols or unstable ynones is the key step in this transformation. Interestingly, this protocol offers a single-step one-pot multicomponent reaction which at first involves the in situ formation of an enaminone intermediate 1aa by a condensation reaction with a methyl ketone and DMF DMA either by microwave (MW) irradiation at 150 °C over a Eur. J. Org. Chem. 2018, 262–294

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

period of 25 minutes or by conventional heating at 100 °C over a period of 12 h. This reaction is followed by a 1,3-dipolar cycloaddition reaction with an organic azide and the previously formed 1aa enaminones in toluene at 100 °C over a period of 12 h, which delivered α-ketotriazoles 3j in a regiospecific manner. The reaction could tolerate various aromatic, aliphatic and heterocyclic ketones, acetyl ferrocene and different organic azides. However, higher equivalences of aliphatic ketones and a longer reaction time were required for aliphatic azides to obtain sufficiently high yields while using these substrates. Other diverse building blocks such as secondary azides placed on a protected sugar or on a deoxynucleoside (AZT) as well as an azido derivative of porphyrin could be effectively transformed into their corresponding acyl triazole derivatives 3jg, 3jh using this procedure. The importance of this method was further exemplified by functionalizing various bioactive natural products containing acetyl functional groups to the corresponding 4acyl-1,2,3-triazole 3j derivatives. Thus, by using this protocol dif-

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Scheme 18. Generality of the 4-acyl-1,2,3-triazole 3j synthesis.

ferent natural products which include acetovanillone, a steroid hormone such as pregnenolone and a pentacyclic triterpenoid such as platanic acid provided the expected products 3jk–3jl, which contain an α-ketotriazole, in good to excellent yields. This work was further extended towards the synthesis of novel oligotriazole bidentate ligands 3jm–3jp having possible applications in the field of supramolecular chemistry. As a proof of concept, preliminary investigation on the anion binding (chloride anion) properties of one of these receptors 3jn was investigated using 1H NMR spectroscopic studies. Furthermore, applying this protocol to acetyl triazole 3jd enabled the synthesis of previously inaccessible symmetrical and asymmetrical diphenylditriazole ketones in good yields. Above all, the method also offers a new platform for regiospecific decoration of triazole heterocycles with several delicate scaffolds and functional groups such as α,β-unsaturated ketones, α,β-diketone, nitro and nitrile groups with high efficiency. The abovementioned examples demonstrate advantages of this method such as superb substrate scope due to inexpensive, commercially available building blocks, high yields of products, metal-free syntheEur. J. Org. Chem. 2018, 262–294

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sis and access to novel triazole skeletons containing functional groups which facilitate structure activity relationship studies in the drug discovery process. An interesting application of the reaction of enamines with azides was found by the Tanaka group for the synthesis of monocyclic- and fused 1-[N-(phenylsulfonyl)-benzohydrazonoyl]-1,2,3-triazoles 3k[41] (Scheme 19). The latter were prepared in low to moderate yields by 1,3-dipolar cycloadditions of hydrazonoyl benzyl azides with enamines 1a at room temperature. In turn, sulfonylhydrazones 3k were subjected to a Bamford–Stevens reaction in benzene at reflux to form 1,2,4-triazines 10 in 28–54 % yield via an unstable carbene intermediate. Peng and Zhu discovered that, in competition with the “traditional” dialkylamino elimination, the elimination of BrCF2H is possible from the intermediate triazoline 2t formed in the reaction of ethyl 3-bromodifluoromethyl-3-pyrrolidinoacrylate 1ab with benzyl azide. This affords a mixture of 5-bromodifluoro-1benzyl-1,2,3-triazole 3l′ and 5-pyrrolidino-1-benzyl-1,2,3-triazole 3l (Scheme 20). More reactive aryl azides react with

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Scheme 19. Synthesis and transformation of triazolylhydrazones 3k.

Scheme 20. Competition of BrCF2H and dialkylamine for elimination.

enamines 1ab, eliminating pyrrolidine, and the expected 5fluoroalkylated 1,2,3-triazoles 3l′ are obtained in high yields.[42] Elimination of Carboxylic, Phosphoryl and Sulfonyl Amides

tuted 1,2,3-triazole ring conjugated to various azoles 4a in 52– 93 % yields accomplished by the formation of N,N′-dimethyl tosyl or mesyl amides (Scheme 22).[39d]

5-Amino-triazolines 2 bearing at position 1 carboxylic, phosphoryl and sulfonyl groups can undergo elimination of the corresponding amides to 1-N-unsubstituted 1,2,3-triazoles 4 (direction B in Scheme 9).[43] These reactions were used to prepare 1,2,3-triazoles bearing electron-withdrawing substituents at position 4 of the ring, such as nitro, arylsulfonyl and carbonyl groups (Scheme 21).

Scheme 21. Synthesis of 1-N-unsubstituted 1,2,3-triazoles.

Recently, we have shown that the reaction of β-azolyl enamines 1z with tosyl and mesyl azides affords an N-unsubstiEur. J. Org. Chem. 2018, 262–294

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Scheme 22. Synthesis of 1-N-unsubstituted 4-azolyl-1,2,3-triazoles.

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Microreview These experiments[39d,43] have shown that the elimination of amides is a good method for the synthesis of N-unsubstituted 1,2,3-triazoles. It should be noted that because of low stabilities, the 1,2,3-triazolines, bearing electron-withdrawing substituents at position 1 can undergo dinitrogen elimination and cycloreversion (way d–F in the Scheme 9) concurrent to elimination of the amides, and this may decrease the yields of N-unsubstituted 1,2,3-triazoles. Elimination of Hydrogen Cyanide 5-Amino-5-cyano-1,2,3-triazolines 2u formed from the reaction of 2-aminoacrylonitriles 1ac with aryl azides (Scheme 23), undergo spontaneous aromatization by elimination of hydrogen cyanide to form 1,5-disubstituted 1,2,3-triazoles 3n in 75–95 % yields, and the nitrile 3m is not formed.[35] The outcome of this reaction may be expected due to the better leaving group capacity of the cyanide anion but is complementary to the one previously reported (Scheme 11) in which the elimination of dialkylamines took place to afford 4-cyano-1-aryl triazoles 3c.

formation of enamine intermediate) and organic azides by using pyrrolidine as the base (Scheme 24).[44] This one-pot reaction involves the formation of a key triazoline based intermediate B which then undergoes a Cope elimination in the presence of an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) afforded the expected triazoles 3o in good to excellent yields and high level of regioselectivity. This reaction seems to be general and high yielding in the case of different acetaldehyde derivatives and aromatic azides. On the other hand, a lower yield was observed in the case of aliphatic azides. The utility of this reaction was further shown by synthesizing Trypanosoma cruzi trans-sialidase inhibitor 3od in a straightforward, atom-economical manner using inexpensive and readily available building blocks. Transformation/Ring Cleavage of Spirocyclic 1,2,3Triazolines Quast et al. described a convenient synthesis of 5-alkyl (3p) and 5-aryl (3q) amino-1,2,3-triazoles in good to excellent yields where base-mediated aromatization of the triazoline ring took place during eliminative ring cleavage of spirocycles 2v,w, containing next to the 1,2,3-triazoline, a tetrazole (2v) or benzimidazole (2w) ring (Scheme 25).[45] This process is facilitated by the inherent strain of the spirocycle 2 and the formation of an aromatic compound. This method presents a unique methodology for the synthesis of 5-amino substituted-1,2,3-triazoles 3p,q not available by CuAAC reaction.

Scheme 23. Synthesis of 5-dialkylamino-1,2,3-triazoles.

Elimination of N-Hydroxypyrrolidine Wang et al. recently reported an interesting one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles 3o through a 1,3-dipolar cycloaddition between enolizable aldehydes 11 (via the in situ

Scheme 25. Synthesis of 5-amino substituted 1,2,3-triazoles 3p,q from spiroheterocycles 2v,w.

Scheme 24. Synthesis of 1,4-disubstitued 1,2,3-triazoles 3o in one-pot. Eur. J. Org. Chem. 2018, 262–294

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Stereoisomeric spirotriazolines 2e and 2f undergo aromatization of the triazoline ring due to a process alike to the Grob fragmentation affording triazole 3r (shown below with compound 2f ). The reaction proceeds slowly in CHCl3 at room temperature to give 5-amino-1,2,3-triazoles 3r in moderate yields[15] (Scheme 26). Aromatization of triazolines formed in the reaction of endocyclic enamines with azides occurs after air oxidation to afford 1,2,3-triazoles fused to other heterocyclic rings.[14c–14g] 273


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Scheme 27. Syntheses of 1,4,5-trisubstituted 1,2,3-triazoles 3 via diazo transfer reaction. Scheme 26. Transformation of triazoline 2f to triazole 3r.

Diazo Group Transfer Reactions (pathway C) One of the proposed mechanisms for diazo group transfer of enamines 1ad with sulfonyl and some hetaryl azides involves the initial formation of triazolines which via elimination of amides of aryl- and alkyl sulfonic and arylcarboxylic acids afford a variety of 1,4,5-trisubstituted 1,2,3-triazoles 3 (pathway C). Sulfonyl azides provide three nitrogen atoms in their reaction with tertiary enamines to form 4,5-disubstituted 1,2,3-triazoles (Path B, Scheme 9). Conversely, the similar reaction with secondary enamines having an additional electron withdrawing group affords 1,4,5-trisubstituted 1,2,3-triazoles 3 where the N2 and N3 nitrogen atoms originate from the sulfonyl azide and the N1 atom is derived from the enamine molecule (Scheme 27).[46a–46l] A variety of mechanisms for this reaction was offered to explain the features of the reaction (Scheme 28).[46a] The first one involves cycloaddition of azides to enaminones 1ae to form triazolines 2x. The latter then undergoes Dimroth rearrangement to isomeric product 2x′ which eliminates sulfonamide to afford the final aromatic triazole 3a. The other mechanisms involve the formation of either triazene 12 or diazoimine 13 intermediates and subsequent cyclizations to the final products. Because in the latter mechanism[46b] the formation of intermedi-

ate diazoimines 13 is postulated, this synthetic methodology is formally named “a diazo transfer reaction”. An alternative way to this type of compounds is reaction of heterocyclic diazo compounds with enamines.[46c] Melo et al. carried out the comparative study of the two methods and has shown that the method based on sulfonyl azide generally gives better yields.[46c] The diazo transfer method was successfully used to prepare 1,2,3-triazoles 3s bearing glucosyl ester groups inhibiting human immuno virus reverse transcriptase, compounds that may have interesting antiviral properties (Scheme 29).[46d] Iminov et al. applied the reaction of mesyl azide with enamines to prepare 5-trifluoromethyl-4-carboxylic ester derivatives 3t (Scheme 30).[46a] They have found that the typical reaction conditions for this method, namely NaH in acetonitrile, are not suitable to prepare the desired compounds. However, the use of DBU as the catalyst at –20 °C allowed to prepare ethyl 5-trifluoromethyl-4-carboxylate derivatives 3t in 75–85 % yields. Furthermore, the antiviral compound 5-trifluoro substituted Rufinamide 3v was prepared from ester 3t by saponification with alkali followed by amidation with ammonia in very good yield. (Scheme 30). A novel variant of the diazo transfer method towards triazoles, based on a cascade Michael addition/deacetylative di-

Scheme 28. Proposed mechanisms for diazo transfer reaction. Eur. J. Org. Chem. 2018, 262–294

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Scheme 29. Synthesis of nucleoside analogs of 1,2,3-triazole-4-carboxylic acid 3s.

azo transfer/cyclization reaction of primary amines 14, propynones 15 and sulfonyl azides was reported by Cheng et al.[46e] This resulted in the regiospecific synthesis of 1,5-disubstited 1,2,3-triazoles 3w (Scheme 31) in 75–85 % yields. The reaction takes place under relatively mild conditions, and is tolerant to

the use of various terminal acetylenes and alkylamines. The vast majority of thermal 1,3-DCs run at 85 °C or lower. The triazoles 3w can be also prepared from enamines 1ae confirming the plausible mechanism of the reaction.

Scheme 32. Plausible mechanism[47] for formation of 1,5-disubstituted-1,2,3triazoles 3w.

Scheme 30. Synthesis of rufinamide derivatives 3t.

Scheme 31. Cascade Michael addition/deacetylative diazo transfer/cyclization. Eur. J. Org. Chem. 2018, 262–294

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Microreview This transformation is dependent on the strength of the base used, giving the best yields of triazole 3w in the presence of 2 mol of LiOtBu. Therefore it is logical to propose the formation of the intermediate triazoline B (Scheme 32) as the result of the 1,3-dipolar cycloaddition of enolate A to tosyl azide. In the next step, intermediate B transforms to diazoimine C which undergoes 1,5-dipolar electrocyclization to form the final product 3w. The easiness of the cyclization of diazoimines C to 1,2,3triazoles was explained by a heteroelectrocyclization[47a,47b]/ pseudopericyclic mechanism.[47c]

3.2 Synthesis of Amidines (Pathways D and E) Amidines 5 and 6 are formed from 5-amino-1,2,3-triazolines 2 (Scheme 33) bearing strong electron withdrawing substituents at position 1 by both cycloreversion [2σ + 2σ + 2n](D)[20,48–58] and elimination of dinitrogen accompanied with a 1,2-R2 shift (E) (Scheme 9 and Scheme 33).[22,43c,d,48,50,59,58–65] Both types of transformation were first published by Fusco et al.[48a]

enamine as shown by the colors in Scheme 33. Examples of the reactions of various kinds of enamines with sulfonyl azides leading to amidines 5 are presented in Scheme 34. Thus, enamines 1 bearing an EWG at the β-position afford N-sulfonyl amidine 5 via cycloreversion of the intermediate triazoline 2 in good yields.[43c,39d] Conversely, the amidine 5 (R2 = COMe, R5 = Ts, R1 = Me, R3R4N = morpholine) was obtained in poor yield as a result of a side reaction between 1 and a mixture of side products.[49a,49b] A better yield (60 %) of amidine 5 R2 = COPh was obtained from the reaction of β-phenyl-α-benzoylenamine 1 with tosyl azide.[48b] The α-substituted enamines 1 with alkyl, phenyl, and alkynyl moieties yielded amidines 5 with the same substituents at the carbon atom of the amidine fragment.[43,19,48c,48d] Thermolysis of 1,2,3-triazolines bearing in position 4 an electron withdrawing ester group in high boiling solvents, e.g. toluene or xylene leads to amidines and diazoalkanes.[49] Gao et al. have shown that the enamines 1ah, substituted at the α-position by aryl groups, reacted with tosyl azide and underwent transformation of the intermediate triazoline of type 2 via pathway D exclusively, to afford a series of N-tosyl amidines 5a in good to excellent yields (Scheme 35).[50]

Scheme 33. Transformation of triazolines 1 to amidines 5, diazo compounds 5′ and amidines 6.

The synthetic pathway D leads to the formation of two products, amidines 5 and diazo compounds 5′.[20,28,43c,48b,c,49–54] The amidines 5 are constituted from a XN (mainly TsN) fragment of former azide molecule, and the other part derives from the

Scheme 35. Synthesis of amidines 5a.

Scheme 34. Some examples of products resulting from the reactions of amidines with sulfonyl azides. Eur. J. Org. Chem. 2018, 262–294

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Microreview Obviously, the introduction of tosyl and aryl at positions 1 and 5 of the triazoline ring facilitate the scission of both N–N and C4–C5 bonds to form diazoalkane and amidines 5 via path D. Interestingly, Xu et al. managed to isolate N-sulfonyl amidine 5b, containing in the molecule both amidine and diazoacetate groups, by reaction of cyclic β-keto ester enamine 1ai with perfluoroalkyl sulfonyl azides[51] (Scheme 36). Working with similar compounds, Contini et al. devised a multicomponent synthetic method to a series of tosyl amidines 5bb which involves the diazo group substitution in compound 5ba by reaction with a variety of acids HX[52] (Scheme 36). A novel approach to formamidines of type 5c from tertiary amines and sulfonyl azides in the presence of either diethyl azodicarboxylate (DEAD) or CCl4/CuCl was developed by Xu et al. (Scheme 37).[53a,53b] Thus, treatment of triethylamine by DEAD in the presence of tosyl azide in dioxane at ambient temperature affords amidines 5c (R4 = p-tolyl, R1 = R2 = Et) in 68–72 % yields.[53] The reaction was found to tolerate a wide range of alkyl substituents R1, R2 and R3. Morpholine was shown to remain unaffected in these circumstances. A number of aryl and alkyl sulfonyl azides bearing various functional groups such as methoxycarbonyl, methoxy, halo and nitro were successfully used in the synthesis of amidines 5c. Furthermore, DPPA and benzyloxycarbonyl azides can also react with triethylamine in the presence of DEAD to result in amidines 5d,e though in moderate to low yields. A plausible mechanism[53] includes the formation of an enamine of type 1aj which reacts with highly electrophilic azides to afford amidines 5c–e. Pathway E involves nitrogen loss and concomitant rearrangement of the substituent from the 5 to the 4 position (Scheme 9).

Scheme 36. Generation and transformation of cyclopentenotriazolines 2y to diazoalkylamidines 5b.

The latter can be accompanied by ring contraction if R1 and R2 are part of a ring. This approach allows to design highly substituted amidines 6. In this way, a variety of such amidines were obtained easily in a one-pot reaction starting from carbonyl compounds, amines and azides. Thus, Cassani et al.[54] have prepared a series of mixtures of diastereomeric amidines 6a–c by the reaction of tosyl azide with enamines 1ak generated from amino acid methyl esters (L-phenylalanine methyl ester, L-proline methyl ester and D-proline methyl ester) 17 and sym-

Scheme 37. Reaction of triethylamine derivatives with sulfonyl, diphenylphosphoryl and benzyloxycarbonyl azides. Eur. J. Org. Chem. 2018, 262–294

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Scheme 38. Highly asymmetric induction in the formation of amidines 6a–c from L- or D-proline methyl ester and linear ketones.

metrical linear ketones 18 or a 4-substituted cyclohexyl ketone 19 [R4–R5 = CH2–CH(Bn)–CH2] (Scheme 38). Though pathway E is accompanied in most cases by pathway D and a mixture of two types of amidines are formed, the amidines 6a–c require chromatographic separation from the cycloreversion products 5. As shown in Scheme 38, the ring transformation of type E provides a novel stereocenter. The amidines 6a–c prepared from L- or D-proline methyl ester and linear ketones showed the presence of a predominant diastereomer (de = 95–99 %) giving evidence for a high asymmetric induction of the overall process.[54] The groups of Reddy, Bakulev, Adiche, and Zhu have applied this approach to reactions of sulfonyl and heteroaryl azides with cyclic ketones, and aromatic and cycloaliphatic amines to afford a series of interesting ring contracted (size of the ring of cyclic ketones is smaller in one case) amidines.[55a–55d] The proposed mechanism includes the formation of intermediate triazoline via pathway E which undergoes [2σs + 2σσ + 2πs] cycloreversion to form compounds 6f (Scheme 39). The ratio of the different types of amidines obtained via the pathways E and D depends on the nature of both the enamine and the azide compounds used in their synthesis via transformation of the intermediate 1,2,3-triazolines. Introduction of carbonyl groups in the α- and β-positions of the enamine is shown to favor pathway D in the reaction with tosyl azide.[48] On the other hand, the introduction of alkyl or phenyl to the β-position facilitates pathway E to form amidines of type 6 (ref.[48] and references cited there). Kato et al.[43c] found the three directions B, D and E for the reaction of diphenyl phosphoryl azide with enamines derived from desoxybenzoin-type Eur. J. Org. Chem. 2018, 262–294

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Scheme 39. Synthesis of N-sulfonyl- and N-heteroarylcycloalkyl carboxylic acids 6d–f.

ketones 1am leading to 4,5-disubstituted-1,2,3-triazoles 4b (elimination of pyrrolidine amide of phosphoric acid via B), and both types of amidines 6 (elimination of dinitrogen via E) and 5 (cycloreversion products via D). Yields of the formed products can be found in the Scheme 40. As can be seen in the Table below, the yields of the rearrangement products are higher for the reactions of both enamines 1al [R1 = R2 = Ph and R1 = Ph, R2 = 2-pyridyl (Py)] with diphenyl phosphoryl azide (DPPA). The ratio of 6g/5f (E/ D) is slightly smaller in the latter case. This was explained by the smaller migratory aptitude of the 2-pyridyl as compared with the phenyl group. Interestingly, the reaction of the same

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Microreview As has been shown,[57,58] enamines formed from primary 20 and secondary amines 21 and phenylacetaldehyde 22 to afford, after reaction with tosyl azide, a mixture of the amidines 5g and 6h or only formamidine 5h, respectively (Scheme 41). It has also been shown that the direction of the reaction of 21 with aldehyde 22 and tosyl azide, leading to formamidine 5h (pathway D), drastically changed in favor of pathway E to form amidine 6i when 4-nitrophenyl azide was used.[57,58] Thermolysis of Triazolines with Aryl at Position 4 Lead to Amidines of Type 6i Also (via the E Pathway)[59]

Scheme 40. Reactions of phosphoryl azides or tosyl azide with enamines 1am.

azide with enamine 1al (R1 = Py, R2 = Ph), bearing pyridine at the β-position gave the opposite ratio of reaction products in favor of amidine 5f. The latter is the exclusive product of the reaction of tosyl azide with enamine R1 = Ph, R2 = Py. These data and those published by Croce et al.[56a] and Kitane et al.[56b] allowed to make the conclusion that both DPPA and pyrrolidine enamine strongly favor 1,2-migration. It was also demonstrated that raising the reaction temperature and the polarity of the solvent resulted in an increase of the cycloreversion product 5f in the reaction mixture.[43c]

Reactions of endocyclic enamines (both amino and C=C bond are incorporated in the ring) including indole derivatives with highly electrophilic azides have been shown to demonstrate an approach to amidines where one of nitrogen atom originates from the azide and another one from the starting unsaturated heterocycle.[60] Ritchie et al. and Xu et al. have shown that reaction of 2-methyl-1-piperidine[60a] or piperidine[60b] with tosyl azide affords cyclic amidines in moderate yields. The formation of enamines from sulfonyl azides and starting piperidines is proposed in.[60b] Chang et al. have devised a one pot method to cyclic amidines by tandem reactions involving intramolecular hydroamination followed by reaction of intermediate endocyclic enamines with sulfonyl, phosphoryl and carbonyl azides.[60c]This gives access to a variety of cyclic amidines containing pyrrolidine and piperidine rings[60a–60c] and 2-iminoindolines.[60d,60e] Interestingly, reaction of perfluorophenyl azide-functionalized silica nanoparticles with enamines generated from mannose and phenylacetaldehyde was used for the synthesis of glyconanoparticles.[61] Amidines, bearing fragments of 2H-pyran-2-one 6j,k, 6-fluoroquinolone 6l, polyfluorophenyl 6m, acridine 6n, 2-nitrobenzene 6o, indole 6p, 1-benzyl-6-methyl-1,2,3,4-tetrahydropyridine 6q, norcholestane 6r, were synthesized by reactions of 4-azido-2H-pyran-2-ones and 4-azidocoumarine with various β-aryl and alkyl enamines,[59,62a–62c] 7-azido-6-fluoro-

Scheme 41. Synthesis of amidines 5h, g and 6h,i from multicomponent reactions of phenylacetaldehyde 22, primary 20 or secondary 21 amines and azides. Eur. J. Org. Chem. 2018, 262–294

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Scheme 42. Examples of various amidines 6j–r prepared by reaction of enamines with o-nitroaryl azide, heteroaryl azides and diphenyl phosphoryl azide.

quinolone with 1-dialkylamino cyclohexene[22] (Scheme 42), polyfluorophenyl azide with β-phenyl enamines,[30a] 9-azidoacridine with morpholinocyclohexene,[62d] o-nitrophenyl azide with β-phenyl and β-alkyl enamines,[63] 1-benzyl-2-azido-indole-3-carbaldehyde with propionaldehyde and L-methylprolinate or L-methylthiazolidine-3-carboxylate,[64] 1-benzyl-6methyl-1,2,3,4-tetrahydropyridine with tosyl azide in the presence of Ru3(CO)12,[60c] diphenyl phosphoryl azide with 1-dialkylaminocholestane,[65] respectively, according to pathway E[22,59–65] (Scheme 42).

3.3 Synthesis of Diaminoalkenes (Pathway F) Stephen and Marcus have found that elimination of dinitrogen from 1-benzoyl-5-amino-1,2,3-triazolines 2ab prepared from amino norbornene 1am by reaction with benzoyl azide leads to vicinal diaminoalkenes 7a existing in equilibrium with the tautomeric imine form 7a′ (Scheme 43).[12] Formation of vicinal diamines 7b (pathway F) together with amidines 5i (pathway D) took place when enaminones 1an (R = Me, Ph) were treated with tosyl azide in methanol at reflux

Scheme 43. Synthesis of diaminoalkenes 7a. Eur. J. Org. Chem. 2018, 262–294

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Microreview (Scheme 44). Interestingly, reaction of α-benzoylenamine 1an (R = Ph, R1, R2 = Et) proceeds via pathway D, only to give the products of cycloreversion of the triazoline ring, the amidines 5i (R = Ph).[48c,48e]

(Scheme 40). Thus, the result of the reaction of β-azolylenamines with tosyl azides depends on two factors, the nature of the enamines and the solvent used. A plausible mechanism for the formation of diaminoalkenes 7c is depicted in Scheme 46. Since a mixture of 1,2-diaminoethylene 7c and amidine 5j is formed in this reaction, it is logical to propose that the formation of compounds 7c starts from the intermediate triazoline 2ac. We propose that the second step involves the elimination of dinitrogen from triazolines 2ac to form aziridines 23. In its turn, aziridine could undergo transformation to the final reaction products 7c via ring opening of the aziridine ring to form a zwitterionic species A with a quaternary nitrogen atom, followed by consecutive 1,2-azolyl and 1,3-H shifts.[39d]

Scheme 44. Two directions D and F for reaction of α-carbonyl-substituted enamines 1an with tosyl azide.

We have found that the outcome of the reaction of β-azolylenamines 1z with tosyl azides is sensitive to small structural changes of the enamines.[39d] While enamines bearing isoxazole, 1,2,3-triazole, isothiazole, and oxadiazole rings react with tosyl azide in various solvents to form 4-azolyl-1-unsubstituted 1,2,3-triazoles 4a (see above, Scheme 22), the corresponding reaction of 4-(1,2,3-triazol-5-yl)-enamines 1za (Scheme 45), depending on the polarity of the solvents used, leads to formation of either triazole 4a in acetonitrile or to a mixture of vicinal diamines 7c (pathway F) and products of cycloreversion, formamidines 5j (R1R2 = Me, R4 = Ts) via D in hexane or dioxane or even in the absence of solvent at room temperature

Scheme 45. Reaction of β-triazolylenamines 1za with tosyl azide.

Scheme 46. Plausible mechanism for the formation of diaminoalkene 7c.

Two reports with selective and general ways to trans-diaminoalkenes of types 7d were published in 2011 and 2012 by the research groups of Chen and Contini, respectively.[51,66] When cyclic enamines 1ao were involved in reaction with sulfonyl azides, the vicinal diaminoalkenes 7d, existing in various tautomeric forms, were obtained in moderate to good yields (Scheme 47). Based on DFT calculations, Contini and Erba proposed a mechanism for the formation of the ethylenediamines 7 in which the triazolines 2ad decompose through a pericyclic mechanism, involving a sigmatropic 1,2-shift of the morpholino group at the same time as the dinitrogen loss.[67a] A similar mechanism was confirmed by G. Audrian et al. for the transformation of monocyclic N-mesyl- and N-trifluoromethylsulfonyl triazolines.[67b]

Scheme 47. Formation of cyclic diamino alkenes 7d. Eur. J. Org. Chem. 2018, 262–294

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Scheme 48. Multicomponent synthesis of amidines 5k and diaminoalkenes 7e via concurrent pathways E and F.

The competition of pathways E and F was shown by Contini et al. for the multicomponent reaction of N-benzylpiperidone, tosyl azide and proline ester leading to a mixture of diastereomeric forms for both amidines 5k and diamino alkenes 7e. The authors explained the formation of amidines 5 and diaminoalkenes 7 in the reaction by the existence of an equilibrium between two conformers B and B′ of the intermediate triazoline 2; the transformation of conformer B′ leads to amidine 5 and the transformation of conformer B generates imine 7e′ in equilibrium with diamine 7e. Remarkably, the combination of this process with the reduction of diamino alkenes 7 with NaBH(OAc)3 allowed to prepare isomer 24a in 50 % yield with minor isomer 24b (25 %) and amidine 5 (20 %). Compound 24a was used[67a] to prepare a semirigid dipeptide mimetic (Scheme 48). Interestingly, the proline catalyzed reaction of hydratropaldehyde with sulfonyl azides takes place via a different mechanism: the expected shift of either phenyl or proline does not occur and hydrolysis of the intermediate leads to 2-sulfonylamido-2phenylpropionaldehyde.[67c]

in situ when triazolines 2ae are used as the starting materials, nitrenes 26 are produced which rapidly undergo a cyclization by addition to the C=N double bond. 2,2-Disubstituted (2H)benzimidazoles (isobenzimidazoles) 27 are thus formed, which undergo a fast thermal 1,5-shift of the alkyl group towards nitrogen to form final product 25.

3.4 Denitrogenative Transformation of 5-Aminotriazolines to Heterocyclic Compounds (Pathway G) 2-Aminobenzimidazoles, pyrano[4,3-b]pyrrol-4-ones, benzazepines, benzodiazepines, 2-imino-1-alkyl-1,2-dihydroquinolines and tetrazines can be also prepared by transformation of triazolines, either starting from the latter or via a multistep one pot synthesis from carbonyl compounds, amines and azides. Thus, 5-amino-1-(2-nitroaryl)-1,2,3-triazolines 2ae were converted into 1-alkyl-2-aminobenzimidazoles 25 in refluxing triethyl phosphite in 60–85 % yields (Scheme 49).[63] From a mechanistic point of view the results are rationalized as follows. Reduction by triethyl phosphite of the nitro group is a wellestablished way to generate a reactive nitrene intermediate 26 from amidine 5l. Starting from amidines 5l isolated or formed Eur. J. Org. Chem. 2018, 262–294

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Scheme 49. Transformation of triazolines 2ae to 2-aminobenzimidazole derivatives 25.

Erba et al. have found that thermolysis of 4-aryl-5-morpholino-4,5-dihydrotriazoles 2af in various solvents affords a mixture of pyrano[4,3-b]pyrrol-4-ones 8 and amidines 6s (Scheme 50). As the latter did not transform to pyrrole 8 under the reaction conditions, the conclusion was made that forma-

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Scheme 50. Two directions of transformation of triazoline 2af to pyranopyrrolones 8 and amidines 6s.

tion of products 6s and 8 from triazolines 2af proceeds via independent ways.[59] The ratio of compounds formed was shown to depend on the solvent; toluene and propanol favor amidines 6s, and adding of trifluoroboron etherate in toluene favors compound 8. A plausible mechanism for the formation of bicyclic pyrroles as proposed by the authors includes the key intermediate aminoaziridine[59] as depicted in Scheme 50.

3.5 Transformations of Spirocyclic Triazolines to Fused Heterocycles Reactions of 2-methyleno heterocyclic compounds 1ap with different azides XN3 occurs via spirocyclic triazolines of type 2ag, which are relatively stable and were isolated in some cases, and afford both ring expansion products 6t via dinitrogen elimination and cyclic amidines 5m via elimination of diazo compounds (Scheme 51).[18,25,68,69]

Scheme 51. Transformation of spirocyclic triazolines 2ag to cyclic amidines 5m (Path D) and 6t (Path E).

Thus, Sato et al.[69] found that when a mixture of 2-ethylidene-1,2-dihydroquinoline 1aq and phenyl or ethoxycarbonyl azides was heated at 110–120 °C, 2-imino-2,3-dihydrolH-L-benzazepines 6u were produced in good yields (Scheme 52). Eur. J. Org. Chem. 2018, 262–294

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Scheme 52. Transformation of quinolines 1aq to benzazepine 6u.

Quast et al. described the ring expansion of five membered imidazolines to pyrazines and indolines to tetrahydroquinolines.[18] They also managed to isolate intermediate spirocyclic triazolines 2ah (R1 = R2 = Me, R3 = H, R4 = H, Ph) that under heating at 80–110 °C undergo loss of nitrogen to furnish the corresponding benzazepines 6u (Scheme 52). This experiment confirms the mechanism where the intermediate is a spirotriazoline 2ah. 1,2-Sigmatropic rearrangement of spiro compounds accompanied by dinitrogen elimination leads to ring expansion to benzazepine (cyclic amidine) 6u. Reactions of alkylidenes 1ar with methyl- and trifluoromethylsulfonyl azides affords both the products of ring expansion 6v,w and cycloreversion 5n (Scheme 53).[18] Photolysis of 2ai (R1 = R2 = R3 = Me, R4 = Ph) affords a mixture of the same type of products. Reactions of 2-alkylidenedihydroquinazolines 1as with sulfonyl azides can take place via three pathways to form isomeric ring expansion products 6x and 6y together with the products of cycloreversion, 2-iminodihydroquinazolines 5o (Scheme 54).[70] Though the yields of ring expansion products are poor and this reaction is not the best choice for the synthesis of this kind of compounds, this experiment has fundamental importance showing two different ways for the ring expansion

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Scheme 53. Ring expansion and cycloreversion of triazoline 2ai.

where either C–N = or C–N(Me) bonds of the ring can take part in the sigmatropic rearrangement process.

Scheme 55. Transformation of spirocyclic indolines 2ak to tetrahydroquinolines 6z.

Scheme 54. Three transformation directions of triazoline 2aj.

The general direction of the transformation of 2-methylene indolines on treatment with sulfonyl azides is the formation of 2-iminoindolines.[62] Conversely, Quast et al. have found that 2-isopropylidene indoline 1at[71] reacted with mesyl azide in toluene at 110 °C to form tetrahydroquinoline 6z in 98 % yield (Scheme 55).

Electrophilic azides react with the 5-alkylidenedihydrotetrazoles 1au already at low temperatures to produce high yields of 5-iminotetrahydro-1,2,3,4-tetrazines 30 (Scheme 56). The formation of 30 is interpreted in terms of an initial [3+2] cycloaddition leading to the unstable spiro compounds 2al. Ring opening of the dihydro-1,2,3-triazole ring generates the zwitterionic diazonium salt 29 which loses molecular nitrogen with concomitant ring expansion of the dihydrotetrazole ring by a nitrogen 1,2-shift.[71,72] A few tetrazines of type 30 are also obtained by a two-step one pot synthesis starting from tetrazolium salt 28.

Scheme 56. Transformation of spirocyclic triazolines 2al to tetrazines 30. Eur. J. Org. Chem. 2018, 262–294

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4. Organocatalytic Processes Involving Reactions of Enamines with Azides In recent years, advancement in enamine mediated organocatalysis has had a significant impact in the field of 1,2,3-triazole synthesis.[73–84,8a,8b] This reaction generally involves the catalytic formation of an enamine intermediate through the reaction of a carbonyl compound 31 and an amine catalyst, followed by its cycloaddition reaction with an organic azide. The resulting five-membered triazoline intermediate then undergoes spontaneous elimination of dialkylamine to give rise to the corresponding triazole derivative 3 in a regiospecific manner (Scheme 57). However, when a non-organocatalytic pathway is pursued, a two-step strategy is followed, which at first involves the synthesis and isolation of enamine 1 followed by its subsequent cycloaddition reaction with the azide partner. Thus by using the organocatalytic pathway, the challenges which are associated with the instability of enamine derivatives during their isolation and storage process, due to the reversibility of their formation, can be avoided. The organocatalyzed reactions as compared to conventional metal-free routes offer an operationally simple protocol, lack of sensitivity to moisture and oxygen, low cost and easy access to various 1,2,3-triazole derivatives that are difficult to obtain by other means.[8a,8b]

Scheme 57. Enamine mediated organocatalytic routes towards 1,2,3-triazole synthesis.

An organocatalytic approach was first used by Ramachary et al. for the synthesis of fused NH-1,2,3-triazoles by the reaction of Hagemann's esters with tosyl azide in the presence of 20 mol-% of proline as organocatalyst and DMSO as the solvent.[73] After this seminal report, many enamine mediated triazole forming reactions were published, which utilize secondary amines such as proline, pyrrolidine, or diethylamine as the catalysts of choice.[73–84] In general terms, the enolizable carbonyl compounds used in these reactions could be classified into three different categories according to the acidity of α-H atoms: (1) activated saturated ketones 32a and 32b, (2) activated unsaturated carbonyl compounds, which include α,β-unsaturated aldehydes 33 and Hagemann's esters 34 and (3) non-activated ketones, for example, cyclic and acyclic ketones 35 (Scheme 58). This is a fast-moving field now and the developments until the beginning of 2015 have been reviewed separately by the groups of Dehaen and Paixão.[8a,8b] Therefore, we will not discuss in detail developments which were already covered in Eur. J. Org. Chem. 2018, 262–294

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these reviews. Instead, we describe some of the recent new developments made by us and others utilizing the transiently generated enamine as one of the key synthetic intermediates for the 1,2,3-triazole ring formation.

Scheme 58. General examples of carbonyl compounds.

Very recently, a new organocatalytic pathway for the synthesis of 1,5-disubstituted, fully substituted or fused 1,2,3-triazoles have been discovered by the Dehaen group.[85] This method involves a multicomponent reaction (MCR) between readily available enolizable ketones 35, primary amines 36, and 4-nitrophenyl azide as a source of dinitrogen, under slightly acidic conditions in toluene at 100 °C (Scheme 59). Thus, this strategy enabled the synthesis of previously inaccessible 1,5-disubstituted 1,2,3-triazoles 3 via an organocatalytic pathway. In this reaction, an organic salt (R3NH3+CH3COO–) derived from the reaction between acetic acid and the primary amine was used in situ as the organocatalyst (Scheme 59). It is also important to note that this reaction can be extended to acid sensitive groups by leaving out the acetic acid, which will slow down the reaction but does not prevent it. The reaction is thought to proceed via a tandem sequence, which starts with the formation of a Schiff base 37 followed by its tautomerization to the corresponding enamine derivative 1ad. The latter then undergoes a regioselective 1,3-dipolar cycloaddition with 4-nitrophenyl azide to give the highly substituted triazoline intermediate 2am. Subsequently, acid catalyzed ring-opening, followed by tautomerization gives rise to an open chain triazene intermediate 38. This intermediate will cyclize with the loss of one molecule of 4-nitroaniline 39 to give the corresponding 1,2,3triazole 3x. The occurrence of the triazoline intermediate and acid catalyzed conversion to the 1,2,3-triazole was confirmed by 1H-NMR experiments. The authors also demonstrated the recycling of 4-nitrophenyl azide from the eliminated 4-nitroaniline 39 via a diazotization reaction followed by a substitution reaction of the resulting diazonium salt with NaN3. In this way, 4-nitrophenyl azide acts as a renewable diazo transfer reagent. The reaction was found to be general for a variety of inactivated aromatic and aliphatic enolizable ketones and could also tolerate a variety of substituents of interest such as pyridine, thiophene, indole, imidazole, carbazole, uracil, ferrocene and so on (Scheme 60).[85] However, fully functionalized triazoles were only obtained in the case of inactivated ketones such as aryl propanones or 5-nonanone whereas the activated ketones such as ethyl benzoylacetate exclusively gives the well-known Dimroth product. It is noteworthy that a variety of aliphatic amines including chiral amines and other sensitive amines such as allylamine and 2,2-dimethoxyethylamine were all well tolerated under these reaction circumstances. Extension of the protocol

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Scheme 59. Acid-catalyzed reaction between ketones and amines allow the triazolization reaction. R3NH3+CH3COO– is the result of in situ formation of the organic salt when CH3COOH reacts with R3NH2.

for the direct conversion of dendrimers containing multiple amino groups to the corresponding triazole heterocycle 3x in a safe manner is especially notable. Moreover, this methodology was effectively utilized for the transformation of bioactive natural products which contain either a primary amine or an

enolizable ketone to the corresponding triazole derivatives (3xa–3xk). While replacing aliphatic amines with aromatic ones (anilines), the yield of the reaction was less than 25 % due to the lower reactivity of the intermediate enamines so this can be seen as a limitation of the method.

Scheme 60. Some representative examples of the triazolization reaction. PMB = 4-methoxybenzyl. Eur. J. Org. Chem. 2018, 262–294

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Microreview As a continuation of this work, we recently reported the synthesis of various mono-, di- or fused NH-triazole derivatives through a simple extension of this triazolization strategy by the replacement of the primary amine by an ammonium salt, NH4OAc, as a source of the N1-nitrogen. (Scheme 61)[86] This reaction was found to be very effective and high yielding while using five equivalents of NH4OAc in a solution of DMF at 80 °C over a period of 12 h. It is worth mentioning that this method offers great diversity because of the easy availability of enolizable ketones in commercial sources and natural products. The previously reported strategies make use of less available and relatively expensive alkynes or nitroolefins as dipolarophiles. Furthermore, this triazolization strategy enables the synthesis of 4,5-fused NH-triazoles in a single step which otherwise would require multiple steps to obtain from the same cyclic ketones. A variety of aromatic and aliphatic acyclic and cyclic ketones were well tolerated under these reaction conditions with good to excellent yield ranging from 41 % to 93 % of isolated products. Interestingly, this methodology was extended to the synthesis of multiple triazole derivatives having supra-

molecular applications and also for the triazolization of variety of natural products (4aj–4ak) such as terpenes and steroid hormones containing enolizable ketones. The synthetic value of this NH-triazolization reaction was exemplified by synthesizing five known bioactive molecules and two different supramolecular host molecules in a single step, which would otherwise require significant effort (Scheme 62).[86] For instance, a previously reported thirteen step synthesis of the contraceptive agent 4al was brought down to a single step using the same starting material via this triazolization strategy, with an eightfold increase in the overall yield of the final product. It is worth mentioning that the unsymmetrical ketone 40a undergoes NH-triazolization in a regiospecific manner and gave the product 4ap derived from the highly substituted enamine.[86]However, in the case of the reaction with the unsymmetrical 2-ketone 40b and a primary amine 36, a mixture of two regioisomers (3y and 3z) was observed with higher preference for the compound derived from the most substituted enamine (Scheme 63).[86] In the light of these results, we rea-

Scheme 61. Generality of NH-triazolization reaction.

Scheme 62. Single-step synthesis of previously reported useful molecules. Eur. J. Org. Chem. 2018, 262–294

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Microreview soned that the relative acidic conditions and lower steric hindrance of the triazoline adduct of the NH-triazole as compared to that of the reaction conditions and steric hindrance of intermediate derived from the primary amine could help to solve this regiochemistry issue.[85,86]

Scheme 63. Triazolization of unsymmetrical ketones. PMBA = 4-methoxybenzylamine. PMB = 4-methoxybenzyl.

Initially, our attempts to synthesize the propargyl-substituted 1,2,3-triazole using propargylamine 41 as one of the building blocks via this triazolization strategy resulted in the formation of an undesirable unsymmetrical bis(triazole) 42 as the major product (Scheme 64).[87] This could be due to the elevated temperature (100 °C) used in this reaction which in turn results in the early-stage or late-stage Huisgen 1,3-dipolar cycloaddition reaction of 4-nitrophenyl azide with the propargyl group. As a solution to this, a Lewis-acid catalyzed reaction was devised which helps to proceed this triazolization reaction under relatively low temperature (60 °C) which yielded the desired Nsubstituted propargyl triazoles 43 in good to excellent yields.[87] Also, post functionalization of these triazoles via classical CuAAC reactions led to unique N,C-linked bis(triazole)s. It is worth mentioning that propargyl functionalized triazole derivatives were previously synthesized by using RuAAC with prop-

argyl azide, which is difficult to synthesize and unstable even at room temperature.[88] Therefore, this method has some unique advantages over the other existing methodologies. In general, this novel triazolization strategy allows the synthesis of triazoles from complex and diverse molecules containing enolizable ketones and amines which will provide a convenient approach to the rapid generation of large collections of diversely functionalized N-substituted 1,2,3-triazole or even propargyl and NH-triazole derivatives in a single step, with both established and underexplored biological and material properties.[85–87] To give a recent example, the triazolization reaction was applied to the rather delicate artemisinin natural product, to afford derivatives having promising anti HIV-properties.[89a] Further applications in dye chemistry[89b] and ionic liquid chemistry[89c] were recently reported by us, and a recent study[89d] was done on the selectivity of triazolization vs. other triazole forming reactions. We believe that this protocol will be of broad utility to researchers in both academic and industrial institutions. A straightforward route towards the synthesis of sulfonyl1,2,3-triazole 3aa was reported by the group of Alves starting from the reaction between β-keto sulfones 44 and organic azides (Scheme 65).[90] Among the different organocatalysts used, 5 mol-% of pyrrolidine was found to be the catalyst of choice in DMSO as the solvent, interestingly, even at room temperature. It is worth to mention that the synthesis of sulfonyl1,2,3-triazoles 3aa is found to be general regardless of the electron donating or withdrawing substituents on the dipole or dipolarophile. On the other hand, the authors did not present any examples to show the scope of the reaction with respect to aliphatic azides. As expected, this reaction also follows the general enamine pathway where an intermediate 1,2,3triazoline of type 2 could undergo aromatization via an elimination of a molecule of pyrrolidine and produce the desired sulfonyl-1,2,3-triazole 3aa in a regiospecific manner.

Scheme 64. Lewis-acid mediated synthesis of propargyl functionalized triazoles. Eur. J. Org. Chem. 2018, 262–294

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Scheme 65. Organocatalytic synthesis of 4-sulfonyl-1,2,3-triazoles.

Very recently, the same group reported the synthesis of fully functionalized 1,2,3-triazolyl carboxamides 3ab by utilizing ultrasound irradiation as a source of energy through an organocatalytic enamine–azide [3+2] cycloaddition reaction (Scheme 66).[91] The reaction was performed in DMSO as the solvent under ultrasonic irradiation (40 % of frequency) over a period of 20 min at room temperature with 5 mol-% of Et2NH as the organocatalyst. Longer reaction time or a decrease in the catalyst loading leads to the reduction in the overall yield of the desired product. While analyzing the scope of the reaction, it was observed that the electronic nature of the substituents had a mild role on the outcome of this reaction. An electron withdrawing group at the aromatic ring of β-oxo amide resulted in a lower yield as compared to an electron donating group. Similarly, sterically hindered aromatic azides also delivered the expected N-aryl-1,2,3-triazoyl carboxamides in slightly diminished yield. In order to prove the effect of sonication on the outcome of the reaction, the authors performed the similar re-

action under conventional condition but this required 8 h to furnish the desired products in comparable yields. Inspired by these organocatalytic reactions, Alves et al. reported a series of bifunctional conjugates 3ac containing triazolyl-carboxylates and 7-chloroquinoline derivatives via enamine mediated cycloaddition reactions as shown in Scheme 67. A preliminary investigation towards the biological activity of this class of compounds revealed their potential to act as antioxidant agents.[92] After the seminal report on the synthesis of various arylselanyl-1,2,3-triazoles from the group of Paixão, the same group extended their methodology for the synthesis of phenylselanyl1H-1,2,3-triazole-4-carbonitriles 3c via an enamine mediated cycloaddition reaction between 2-azidophenyl phenylselenides and various benzoylacetonitrile derivatives 47 using DMSO as the solvent in the presence of a catalytic amount of Et2NH (1 mol-%) (Scheme 68).[93] The electronic nature of the substituent on the aromatic ring of α-keto nitriles did not play any

Scheme 66. Synthesis of 1,2,3-triazoyl carboxamides under sonication conditions. Eur. J. Org. Chem. 2018, 262–294

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Scheme 67. Synthesis of chloroquinone derivatives of 1,2,3-triazole.

Scheme 68. Synthesis and post-functionalization of various phenylselanyl-1H-1,2,3-triazole-. 4-carbonitrile derivatives 3ca.

crucial role on the outcome of the reactions. However, a decrease in the yield was observed while replacing the aromatic group of the α-keto nitrile by a tertiary butyl group. The in vitro antioxidant activity of these compounds indicated that the selanyl-triazolyl carbonitrile exhibits significant antioxidant effects as compared to other synthesized compounds. Moreover, the authors also reported the post-functionalization of these selanyl-triazolyl carbonitriles to more complex selanyl-triazolyl tetrazole conjugates via a cycloaddition reaction with NaN3 by utilizing Al2O3/FeCl3 as a bifunctional catalytic system. Recently, a study was reported by the group of Li and coworkers, which involved the heterocyclization of 1,2-cyclohexanedione 48 through an enamine-mediated 1,3-dipolar [3+3] cycloaddition reaction with various organic azides (Scheme 69).[94a] Interestingly, different types of products were observed depending upon the type of solvents, organocatalysts and substrates used in these reactions. For instance, the reacEur. J. Org. Chem. 2018, 262–294

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tion with 1,2-cyclohexanedione, an aromatic azide and diethylamine as the organocatalyst in a respective molar ratio of 1:3:1 in CHCl3 at room temperature for 48 h led to triazabicyclo derivatives having general structure 49 with high level of regioselectivity. Remarkably, when the catalyst and solvent were changed to pyrrolidine and THF respectively, the sole product was a pyrrolidinium linked triazabicyclo derivative 51. Even more interesting is the fact that the replacement of the aromatic azide with an aliphatic one gave triazole fused cyclohexanone derivative 50 from an enamine-mediated [3+2] cycloaddition reaction. As proposed by the authors, the mechanism of the reaction starts with the initial formation of an enamine derivative 1av which then reacts with the aromatic azide to generate the intermediate A. After this, an intramolecular hetero aldol reaction takes place to generate 1,2,3-triazine-5-pyrrolidinium derivative 51.[94a] In the case of the pyrrolidine mediated reaction, this

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Scheme 69. Various cycloaddition reactions of 1,2-cyclohexanedione with azides.

derivative 51 is the final compound. Interestingly, in the case of other secondary amines such as diethylamine or piperidine, subsequent hydrolysis of this intermediate happens and affording the final product 49 through the regeneration of the catalyst. Another interpretation for the structures of products 49 and 51 was recently proposed by the Banert group based on careful analysis of the NMR spectra of the products of the reaction. They stated the products do not contain the bicyclic triazine and bicyclic ketone moieties; instead, cyclohexane-fused 4,5-dihydro-1,2,3-triazoles and the monocyclic β-ketoamides were formed, respectively.[94b] Organocatalytic reaction of carbonyl compounds with azides initiated by cyclic secondary amines was recently used for the synthesis of derivatives of curcumin bearing 1,2,3-triazole ring.[95]

Conclusions In this report we have shown that the reactions of enamines with azides, including the organocatalytic and multicomponent variants represent a powerful tool for design and synthesis of valuable heterocyclic and other organic compounds such as 1,2,3-triazoles, triazolines, benzimidazoles, pyrrolopyranes, amidines, diaminoalkenes and diazo compounds. Recently, based on this chemistry a general protocol for triazolization of various types of organic compounds, including biologically acEur. J. Org. Chem. 2018, 262–294

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tive and natural compounds was introduced to synthetic organic practice, complementing the click reaction to expand the scope of triazole chemistry. The study of the reactions of azides with enamines has been demonstrated to have theoretical interest since it is a useful probe of new mechanisms of the synthesis and transformations of nonaromatic heterocyclic compounds. Thus, the concept of reverse electron demand 1,3-dipolar cycloaddition was further developed with data of experimental and theoretical studies of the cyclization mechanism of enamines on treatment with azides. Furthermore, experimental data on rearrangements and transformations of the triazoline intermediates led to the discovery of novel rearrangements and cycloreversions. Based on the different transformations A–G of 1,2,3-triazolines, new methodologies for the synthesis of various types of organic compounds have been introduced. To give a recent example, the use of these transformations in material chemistry was demonstrated for the synthesis of glyconanoparticles. We expect that the reaction of azides with enamines will continue to find broad application in various fields of organic chemistry, in biological chemistry and in materials chemistry and technology.

Acknowledgments The authors thank the Russian Scientific Foundation (15-1310031) for financial support and Tomas Opsomer for careful proofreading.

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