Keywords
Abstract
This is the first systematic review on the synthesis and reactions of heterocyclic azides with acetylene and acetonitrile derivatives, alkenes, enamines and dicarbonyl compounds. Examples are given for the application of these reactions to the synthesis of mono-, bi- and tricyclic compounds and ensembles of various heterocycles, e.g., azines and azoles (including 1,2,3-triazole derivatives and nonaromatic 1,2,3-triazolines), amidines and diazo compounds. Methods for the synthesis of supramolecular structures, coordination compounds, ligands, bioconjugates and biologically active compounds based on reactions with heterocyclic azides are considered. The review describes the use of these transformations in biological chemistry to study processes in living systems, as well as in materials chemistry for the production of luminophores and sensors for metals. Original studies published mainly over the past 15 years are discussed.
The bibliography includes 222 references.
1. Introduction
Azides are widely used in modern organic synthesis for the preparation of amines, heterocyclic compounds with small, medium or macrocycles, natural compounds and their analogues and also for the design of new high energy materials. These compounds are highly reactive and are involved in reactions with nucleophiles and electrophiles, radical reactions and cycloaddition reactions with derivatives containing double or triple bonds.1,2 The copper-catalyzed azide-alkyne cycloaddition (CuAAC, referred also to as the click reaction), independently discovered by Meldal and Sharpless, and the related cycloaddition reactions catalyzed by ruthenium and miscellaneous metals resulted in the development of a powerful methodology for the synthesis of 1,4- and 1,5-disubstituted triazoles3--8 and, as a consequence, in the disclosure of new compounds with practically useful properties.9--27 Advances in the chemistry of azides are presented in the reviews2,3,15,19,24 and the fundamental monograph by Bräse and Banert.1 However, these publications address mainly the reactions of aromatic azides. Reviews focused on the properties and transformations of heterocyclic azides are lacking in the literature. Meanwhile, the recent years have witnessed a significant increase in the number of papers dealing with the synthesis and the chemical and biological properties of azides of the heterocyclic series.2,9,16,23,26--47 New methods for the synthesis of these compounds were developed, kinetic studies of their decomposition were performed, and theoretical studies of their structures and reactivity were conducted.33--47 Heterocyclic azides are successfully used in organic synthesis to prepare various heterocycles, diazo compounds, amidines, bioconjugates and other practically useful organic compounds.23,28 Some heterocyclic azides exhibit antiviral properties and other types of biological activity and were employed to prepare new luminophores and sensors for metal ions.23,28,43
This review is concerned with the chemistry of heterocyclic azides. This is the first review, in which methods for the synthesis of heterocyclic azides are analyzed and brought together. The reactions of these compounds with acetylene and acetonitrile derivatives, alkenes, enamines and active methylene dicarbonyl compounds are considered. Tetrazoles are demonstrated to be a potential source of azides in the cycloaddition to alkynes and acetonitrile derivatives. The review considers reactions of heterocyclic azides, which were applied to synthesize mono-, bi- and tricyclic compounds, amidines and diazo compounds, as well as different heterocyclic ensembles (of azines and azoles, in particular 1,2,3-triazole derivatives and nonaromatic 1,2,3-triazolines). These reactions were used to prepare supramolecular structures, ligands, metal complexes, bioconjugates and biologically active compounds. The review summarizes applications of heterocyclic azides in the biological chemistry to study processes in living systems and in the materials chemistry for the development of luminophores and sensors for metals.
2. Methods for the synthesis of heterocyclic azides
The methods considered in this Section are classified according to the nature of the reagent, which is used to introduce the azide group into heterocyclic compounds.
2.1. Reactions of diazonium salts with sodium azide
The reaction of diazonium salts with sodium azide is a conventional preparatively convenient method for the synthesis of aromatic azides. The similar reactions of heterocyclic diazo compounds afford heterocyclic azides.1 In these examples of the synthesis of heterocyclic azides, the authors, with rare exceptions, did not isolate heterocyclic diazo compounds but used them in situ for the reaction with sodium azide. For example, Vatsadze and co-workers48 performed the diazotization of aminopyrazoles 1 and 2 followed by the treatment with an aqueous solution of NaN3 and synthesized 4-azido- (3) and 5-azido-1H-pyrazole-3-carbocyclic acids (4) in two steps (Scheme 1).48
It is worth noting that Fabbrizzi et al.49 applied a similar approach nine years earlier. The diazotization of diamine 5 in the presence of sodium azide afforded diazide 6 in low yield (Scheme 2).
In order to synthesize a hybrid molecule of acridine with two triazole rings, Sparapani et al.50 investigated the diazotization of 2,8-diaminoacridine 7. It was demonstrated that intermediate diazo compound 8 can be used in situ for the reaction with sodium azide giving 2,8-diazidoacridine 9 in good yield (Scheme 3).
Zarei et al.51 demonstrated that 3-aryldiazonium silica sulfate 10 can be employed in the reaction with sodium azide to prepare 3-azidopyridine 11 (Scheme 4). The authors noted the thermal stability of the starting diazonium salts and a high reaction rate. Azide 11 generated in this way was used in situ for the synthesis of pyridyltriazole 12.
2.2. Replacement of a halogen atom and a nitro group by the reaction with sodium azide
The replacement of a halogen atom or a nitro group by the azide group is widely used in the synthesis of azido-containing heterocycles. In some cases, the reaction requires the activation. Thus, Rodrigues et al.52 found that low-molecular-weight polyethylene glycol (PEG-400) catalyzes the replacement of the halogen atom in 7-chlorothieno[3,2-b]pyridine 13 in the reaction with sodium azide giving azide 14 in high yield (Scheme 5).
By contrast, the nucleophilic substitution of chlorine atoms in 2,4-dichloro-7-methylpyrrolo[2,3-d]pyrimidine (15) by azide groups in the reaction with sodium azide in DMF occurs at room temperature and affords diazide 16 (Scheme 6).53 It was noted that this product is light-unstable.
The reaction of commercially available imidazolium chloride 17 with sodium azide afforded azide 18 containing the imidazolium ring (Scheme 7).54 Azide 18, synthesized in situ, can be utilized to transfer the diazo group to active methylene carbonyl compounds and acetonitrile derivatives (see Section 3.4). It is worth noting that azide 18 has an advantage over sulfonyl azides, because the reaction with this compound affords water-soluble by-products, which can easily be separated from the target compounds.
It was demonstrated that the nitro group can also be replaced by the azide group. For example, dinitro compound 19 can easily be transformed into diazide 20 under reflux in ethanol in the presence of sodium azide (Scheme 8).49
Baron et al.55 developed a method for the selective oxidation of one pyridine ring of molecule 21 followed by the nitration and the replacement of the nitro group by the azide group under the treatment with sodium azide. This process gave 4-azidodipyridine N-oxide 22 (Scheme 9).
Aromatic azides are commonly synthesized through the diazo transfer to the amino group using highly electrophilic azides.1,38 This promising method is still little used in the synthesis of heteroaromatic azides. The reaction of trifluorosulfonyl azide (23) with aminoglucose 24 made it possible to prepare 2-azidoglucose 25 (Scheme 10).56
2.3. Direct azidation of heterocycles with sodium azide
Zhu and co-workers57 developed an efficient method for the regioselective synthesis of 5-azido-8-aminoquinolines 27 based on the copper diacetate-catalyzed insertion of the azide group into the C–H bond of 8-aminoquinolines 26 in the presence of K2S2O8 (Scheme 11). The authors demonstrated that the acylamide group plays an important role in the regioselective CH-activation of quinolines.
2.4. Borylation-azidation of heterocycles
Srinivasan et al.58 proposed a one-pot method for the generation of 5-azidopyridine and 3-azidoquinoline derivatives involving the iridium-catalyzed C–H-borylation and the azidation catalyzed by copper trifluoromethanesulfonate (triflate, TfO). The generated azides were utilized in the in situ click reaction accompanied by the formation of 1-hetaryl-1,2,3-triazoles.58
Thus, using (–)-nicotine (28) as the starting reagent, Srinivasan et al.58 accomplished the regioselective synthesis of 3-azidonicotine 29 (Scheme 12). This method of synthesis of azidonicotine is of interest for medicinal chemistry and agriculture since nicotine and its derivatives are powerful ligands, which modulate nicotinic acetylcholine receptors, and also due to a considerable synthetic potential of azides.
Li et al.59 performed the one-pot two-step synthesis, involving the oxidation of quinoline 30 with 3-chloroperoxybenzoic acid and the oxidative C(2)–H azidation of N-oxide 31 with trimethylsilyl azide (TMSN3) in the presence of [bis(trifluoroacetoxy)iodo]benzene (PIFA). This synthesis afforded 2-azidoquinoline N-oxide 32 in good yield (Scheme 13).
The copper salt-catalyzed ortho-azidation of the aromatic ring of compound 33 with benzotriazolylsulfonyl azide 34 was used to synthesize a series of azides 35 containing different heterocycles (Scheme 14).60 It was demonstrated that the heterocycle plays an important role in directing the reaction towards the ortho position, which made it possible to develop a regioselective method for the synthesis of compounds 35.
2.5. Azidation of 4,4-dichloro-1,2-diazadienes
Nenajdenko and co-workers47 developed an original approach to the synthesis of 4-azido-2,5-disubstituted 1,2,3-triazoles based on the reaction of 4,4-dichloro-1,2-diazabuta-1,3-dienes 36 with sodium azide (Scheme 15). The authors demonstrated that the reaction afforded unstable intermediate 1,1-diazidoethenes 37, which underwent the elimination of a nitrogen molecule and 1,5-cyclization to give final products 38. This method was employed to prepare a large number of 4-azido-1,2,3-triazoles 38 containing various aryl and heteroaryl substituents at the 2 and 5 positions of the ring. Examples of these compounds are given in Scheme 15.
2.6. Multicomponent synthesis of 2-azidobenzimidazoles
Ramana and Punniyamurthy61 described the three-component synthesis of 2-azidobenzimidazoles with varying substituents in the benzene and imidazole rings. This method involves the tandem addition, substitution, electrocyclization, N-arylation and tautomerization. 2-Bromoaniline derivatives 39, sodium isothiocyanate and azide serve as the starting compounds. All reactions occur under mild conditions through the formation of unstable intermediates 40 to form target products 41 in moderate yields (Scheme 16).
3. Catalytic and thermal cycloaddition reactions of heterocyclic azides
3.1. Reactions with alkynes
Two decades after the discovery of the CuAAC reaction by Meldal and Sharpless, this reaction remains an efficient approach to the synthesis of 1,2,3-triazole derivatives.62--64 In recent years, the main trends in the development of this approach were related to the synthesis and utilization of new ligands and the directed synthesis of biologically active compounds, including bioconjugates and hybrids of triazoles with various heterocyclic compounds. In this Section, the data are classified according to the type of reaction products.
3.1.1. Synthesis of bicyclic ensembles of 1,2,3-triazole with miscellaneous heterocycles
Reactions of heteroaromatic azides 42 with acetylenes in the presence of copper or ruthenium salts are commonly used to synthesize bicyclic compounds containing miscellaneous heterocycles along with 1,2,3-triazole (Scheme 17).
In most cases, 1,2,3-triazoles were synthesized from heteroaromatic azides in the presence of different copper-based catalysts. Like in the reactions with aromatic azides, the reactions of heteroaromatic azides 42 with acetylenes in the presence of copper compounds give 1,4-disubstituted triazoles 43, while ruthenium catalysts promote the formation of 1,5-disubstituted triazoles 44 (see Scheme 17). This reaction was performed with numerous heterocyclic azides containing purine,65 thiophene,66--68 pyrazole,69 tetrazole,70 oxadiazole,71 pyridine,72--77 pyrazine,78 1,2,3-triazine,79 pyrimidine,80 indole,81--83 pyrrole,83 pyrrolopyridine,83 thienopyrrole,83 benzothiophene,84 benzisoxazole,85 benzothiadiazole,86 benzofuran,87 quinoline,88--91 cinnoline92 and thienopyridine moieties.93,94
The reactions of heteroaromatic azides with acetylenes can be catalyzed not only by monovalent copper salts47,95,96 but also by monovalent ruthenium salts.47,97 Meanwhile, a combination of divalent copper sulfate and sodium ascorbate is most commonly used in the synthesis of bicyclic triazoles.30,55,96,98--102 Sodium ascorbate reduces divalent copper to monovalent copper, which in situ catalyzes the reaction of azide with acetylene.
Rosado-Solano et al.99 synthesized hybrids of 1,2,3-triazole and 7-chloroquinoline by the reaction of dichloroquinoline 45 with sodium azide giving azide 46 followed by the reaction of the latter with phenylacetylene. The synthesized hybrid compounds 47 exhibited high insecticidal and antifeedant* activities (Scheme 18).
Avila et al.103 accomplished the three-step synthesis from 2-aminobenzothiazole 48 through the formation of intermediates 49 and 50 to prepare 6-nitrobenzothiazole 51 and used this compound as a versatile building block (Scheme 19). The authors synthesized triazolylbenzothiazoles 52--54 by the reaction of compound 51 with different acetylene derivatives in phosphoric acid in the presence of sodium nitrite and azide and in the presence of copper iodide with addition of N,N-diisopropylethylamine (DIPEA). Compound 54 exhibited neuroprotective properties in human neuroblastoma cells.103
Chattopadhyaya and co-workers104 synthesized 1,2,3-triazolylquinolines 56--62 by the copper(I) iodide-catalyzed reaction of phenylacetylene with azide 55 (Scheme 20). Some of these compounds were found to exhibit tuberculostatic activity. It was demonstrated that derivative 59 inhibits the growth of mycobacterium tuberculosis H37Rv up to 98% at a fixed concentration of 6.25 μg mL–1.104
Pirali et al.96 demonstrated that the replacement of the catalyst can lead to a change in the pathway of the reaction of azides with acetylenes. Thus, the use of copper sulfate as the catalyst facilitates the intramolecular cyclization involving the acetylene moiety and the NH group of quinoline 63 to form tricyclic compound 64 (Scheme 21). On contrast, the reaction of the same starting compounds in the presence of divalent copper acetate affords heterocyclic ensembles 65a-d containing the dihydroquinolone and triazole rings as the click reaction products.96 Using combinatorial chemistry methods, Pirali et al.96 synthesized a small library of this scaffold with different substituents at the 1 position of the triazole ring. For this purpose, the reaction was performed with azides containing electron-withdrawing or electron-donating substituents, hydrogen bond donors and acceptors and ionized functions. Compounds 65a-d were tested for the ability to inhibit the signalling pathway of phosphoinositide 3-kinase (PI3K). Derivative 65d bearing the 3-carboxybenzyl group at the 1 position of the triazole ring showed the highest inhibitory activity.96
Pokhodylo et al.105 synthesized the bicyclic ensemble of nonaromatic 1-phenylpyrrolidine-2,5-dione and 1,2,3-triazole in high yield. The reaction of 3-azido-1-phenylpyrrolidine-2,5-dione with phenylacetylene was performed in the presence of the CuI–Et3N system as the catalyst.
* Antifeedants are compounds protecting plants and materials from consumption by animals.
3.1.2. Synthesis of tricyclic ensembles based on 1,2,3-triazole
The reaction of azido-substituted dipyridines or bis(azidocarbazoles) with acetylenes gives linearly fused tricyclic compounds.55 Thus, Baron et al.55 found that 4-azidodipyridine N-oxide 22 (see Scheme 9) smoothly reacts with arylacetylenes in the presence of catalytic amounts of copper sulfate and sodium ascorbate in the two-phase dichloromethan-H2O system (Scheme 22). The reduction of the oxide function of intermediate dipyridine-substituted 1,2,3-triazoles affords compounds 66a-c, which react with [Ru(bpy)2Cl2] (bpy is 2,2|'|-dipyridine) to form ruthenium complexes 67a-c. These complexes were isolated as the corresponding hexafluorophosphates and were characterized by electrochemical and spectroscopic methods.55
The reactions of compounds 68 with ruthenium salts produced a series of RuII complexes 69.106 It was found that the structure of these complexes affects their ability to catalyze the cycloaddition reactions of 4-azidopyridine N-oxide (22) with acetylenedicarboxylic esters in water under ultrasonic (US) activation (Scheme 23). Complex 69a (R1=NO2, R2=H, R3=Cl) was found to be an efficient heterogeneous catalyst for the regioselective synthesis of tricyclic 1,4,5-trisubstituted 1,2,3-triazoles. It was demonstrated that this catalytic system is applicable to the preparation of tricyclic (71, 72) and tetracyclic (73) heteroaromatic ensembles based on azides 70 and 22.106
Elliott and co-workers107 utilized 4-azido-2,2’-bipyridine (74) to synthesize 1,2,3-triazoles containing two (66a) and three (75) pyridine rings or the ferrocenyl moiety (76). The cycloaddition of azide 74 to the corresponding alkynes was performed in the presence of the copper sulfate---sodium ascorbate catalytic system (Scheme 24).
The reaction of 3,6-diazido-1-propylcarbazole (77) with alkylacetylenes in the presence of the complex [Cu(MeCN)4]PF6, TBTA and DIPEA in dichloromethane gave another type of linearly fused tricyclic compounds 78a,b containing two triazole rings and a carbazole moiety (Scheme 25).108 The use of copper perchlorate hydrate in the presence of NaI and DBU made it possible to perform the one-pot synthesis of iodo derivatives 79a,b.108 It was demonstrated that the alkylation of compounds 78 and 79 with trimethyloxonium tetrafluoroborate occurs at the 3 position of the triazole ring to form bis(triazolium) tetrafluoroborates 80a,b and 81a,b, respectively.
Mullaney et al.108 studied in detail the properties of acyclic halogen- and hydrogen-bonding bis-triazolium carbazole receptors 80 and 81 by NMR titration experiments in an NMR cell, analyzing the changes in the signals in the 1H NMR spectra. Significant downfield shifts of the triazolium and carbazole protons observed upon the addition of appropriate ammonium salts are indicative of the binding of the anion within the receptor cavity. It was found that the binding energy of halide ions with iodine-substituted receptors 81 is much higher than the hydrogen-bonding energy for its analogues 80. Taking into account the ability of acyclic receptors 80 to 81 to bind anions, the authors108 synthesized the previously unknown rotaxane 83 based on triazolium salt 81c and isophthalamide 82 (Scheme 26). The NMR titration experiments in a mixture of aqueous solvents demonstrated that this rotaxane has a strong binding affinity for bromide.
3.1.3. Polycyclic ensembles of 1,2,3-triazoles
This Section considers the reactions of heterocyclic azides with acetylene derivatives giving compounds containing more than three rings. Among these products there are macrocycles, metal complexes and linearly fused triazole-containing heterocyclic compounds composed of moieties that are connected by different linkers.49,50,53,109--117
Bucevicius et al.53 performed the reaction of 2,4-diazidopyrimidine (84) with arylacetylenes using the CuI–DIPEA–AcOH system as the catalyst and synthesized 2,4-bis(aryl-1,2,3-triazol-1-yl)pyrrolo[2,3-d]pyrimidines 85 and 86 (Scheme 27). The authors reported that polycyclic triazoles 85 exhibit properties of D–π–A-π–D chromophores (D is a donor, A is an acceptor). The introduction of small polar substituents made it possible to tune the frontier molecular orbital energies and increase the energy gap between these orbitals to 0.9 eV, whereas the introduction of bulky substituents led to a decrease in the energy gap to 0.4 eV. It was demonstrated53 that these compounds exhibit the pronounced intramolecular charge transfer (ICT) from excited states of the derivatives with electron-donating groups. The optimization of ICT resulted in an increase in the fluorescence quantum yield of derivatives 85 to 73%.
With the aim of synthesizing compounds capable of complexation, Kлnig and co-workers110 modified 3,5-dichlorotriazine 87 to prepare azide 88, which was subjected to the click reaction with phenylacetylene (Scheme 28). However, the authors did not report the complexation properties of compounds 88 and 89.
Neidle and co-workers50 used the structural modeling for the design of a series of acridines linearly fused to two triazole rings and capable of selectively interacting with human telomeric quadruplex DNAs. The click reaction of 2,8-diazidoacridine (9) with arylacetylenes 90 gave compounds 91 (Scheme 29). The proposed selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures and also against duplex DNA using fluorescence spectroscopy. It was found that two lead compounds [n=2: R=NEt2, N(CH2)4] reduce the thermal stability of the c-kit quadruplexes and duplex DNA structures. Besides, these compounds have selective inhibitory effects on the proliferation of cancer cell lines. One compound, 91 (n=2, R=N(CH2)4), was found to inhibit the activity of the enzyme telomerase, which is selectively expressed in tumor cells.
It is worth noting that the development of this approach by Mendes et al.109 led to the design of polycyclic compounds, which contain two quinoline moieties connected via the bis(triazolyl)phenylene linker. The microwave (MW)-assisted CuI-catalyzed cycloaddition of 4-azidoquinoline (92) to 1,3-diethynylbenzene (93) afforded polycyclic compound 94 (Scheme 30) submitted for biological evaluation. The quaternization of the nitrogen atom of quinoline 92 with methyl iodide easily produces 4-azido-N-methylquinolinium 95. However, attempts to perform the reaction of this salt with dialkyne 93 failed. Therefore, product 96 was synthesized by the direct methylation of base 94.109 Salt 96 showed high activity against a number of cancer cell lines, including cancer stem cells. The eradication of cancer stem cells provides an efficient route to new effective anticancer drugs.98
Dobscha et al.111 used carbazole (97) to prepare azides 98a--c and bifunctional building blocks 99a--c. The latter were utilized to synthesize AAA-type C(3)-symmetric tricarbazole macrocycles (100a--c) with different alkyl chains containing three carbazole rings and three triazole rings (Scheme 31). For example, macrocycle 100c with a long alkyl substituent was prepared in seven steps in an overall yield of 35% with respect to the starting carbazole 97. Intermediate carbazole 99c containing the azide and alkyne groups in the 3 and 6 positions, respectively, was generated in the reaction of iodine derivative 98c with trimethylsilylacetylene (TMSA) in the presence of the CuI–PdCl2(PPh3)2 catalytic system.111 In the final step, compound 99c underwent trimerization to give final product 100c in moderate yield.
In order to establish the general features of the transformation of carbazoles 101 and 102 into macrocycles, Dobscha et al.111 developed a stepwise method for the synthesis of compounds 100 (Scheme 32). The concept of the stepwise synthesis of the tricarbazole macrocycle scaffold is based on the progressive growth of the oligomer chain. Examining possible synthetic pathways based on different preparations of building blocks led the authors to the stepwise protection---deproection scheme, enabling the control of the chain growth of macrocyclic precursors. This approach made it possible to prepare tris(triazole-carbazoles) 100 in yields from 70 to 80% in the macrocyclization step (the overall yield was 5-25%).
In the cited study,111 the authors presented the first evidence that the reaction sequence controls the hierarchical assembly of non-biological macrocycles; in the case under consideration, on graphite surfaces. Scanning tunneling microscopy showed that the first steps of the process affect the next levels of supramolecular ordering.
3.2. Reactions with alkenes
Reactions of heterocyclic azides with alkenes are less common in the literature compared to the reactions with acetylenes. These reactions afford nonaromatic 1,2,3-triazolines as primary products, which are less stable than 1,2,3-triazoles and can undergo different transformations.118 The stabilization of such compounds is most often accomplished using transformations into aromatic 1,2,3-triazoles. The metal-catalyzed reactions of azides with acetylenes are currently most commonly applied to synthesize 1,2,3-triazoles, while the data on the reactions of azides, including heterocyclic azides, with alkenes are scarce. Only the reactions with activated alkenes, such as sterically hindered or electron-rich (including enols and enamines), were described in the literature. The reactions of enamines with heterocyclic azides are considered in Section 3.3.
3.2.1. Synthesis of 1,2,3-triazoles by organocatalytic reactions
Yuan et al.119 studied the organocatalytic reaction of allyl ketones (e.g., allyl phenyl ketone) with aliphatic and aromatic azides, in particular with 2-azidopyridine, in the presence of heterocyclic carbenes. The authors demonstrated that this reaction of 1,4-dimethyl-1,2,4-triazolium tetrafluoroborate (103a) with bases in acetonitrile at 80 °C afforded 1,2,3-triazoles 104 in the highest yields (Scheme 33).
The reaction mechanism shown in Scheme 34 provides an explanation for the formation of the final product. Initially, the adduct A is formed through hydrogen bonding between the starting ketone and catalyst 103a.119 Then the intermediate A reacts with azide RN3 to form intermediate azide B, and the catalyst returns to the catalytic cycle. The intermediate B undergoes a 1,3-sigmatropic hydrogen shift and is transformed into the intermediate C. The 1,5-electrocyclization of the latter affords the intermediate D. The final step involves the aerobic oxidation of the intermediate D giving product 104.
In continuation of their work, Li et al.120 performed experimental and theoretical studies of the reaction of acrolein and its derivatives (105) with aliphatic, aromatic and heteroaromatic azides in the presence of 1,4-dimethyl-1,2,4-triazolium iodide (103b) and significantly extended the field of application of this process (Scheme 35).
It was demonstrated120 that, in the absence of a catalyst, the reaction does not afford triazoles 106. The monitoring of the reaction by mass spectrometry showed a molecular ion with a mass corresponding to the ion D (Scheme 36). Based on these data, the authors proposed the mechanism, involving the oxidation of the intermediate A to form ketone B, the reaction of the ketone with azide, the subsequent oxidation of the resulting triazoline C giving triazole D, the elimination of the catalyst, its reintroduction into the reaction cycle and the formation of final product 106.
Li et al.121 demonstrated the use of the iminium catalysis in the 1,3-dipolar cycloaddition of azides to α, β-unsaturated ketones 107 (Scheme 37). These reactions can be performed using different dialkylamines as the catalyst, which made it possible to synthesize 1-substituted 1,2,3-triazoles 108 in high yields with high regioselectivity.121 Aliphatic, aromatic and heterocyclic azides can be subjected to this reaction.
The mechanism of this reaction involves the initial reaction of α,β-unsaturated ketone 107 with the catalyst (piperidine) to form the iminium intermediate A existing in equilibrium with dienamine B.121 The latter undergoes the 1,3-dipolar cycloaddition with azide, generating the intermediate C, which is converted into the intermediate D through the elimination of piperidine. The subsequent aerobic oxidation of the intermediate D affords final product 108 (Scheme 38).
3.2.2. Reactions of sterically hindered alkenes
Margetić et al.122 described the reaction of alkenes 109 with acetylenedicarboxylic acid ester giving norbornene derivatives 110 and investigated the reaction of these products with aromatic and heteroaromatic azides. It was shown that this reaction performed at room temperature under high pressure requires a shorter time and affords triazolines 111 in good yields (Scheme 39). It is worth noting that the reactions of heterocyclic azides produce the corresponding triazolines in higher yields compared to the reactions with aromatic derivatives. Polycyclic triazolines 112 were synthesized in a similar way.
The prolonged heating of polycyclic compounds 112a,b in chloroform at 80 °C leads to the simultaneous transformation of the triazoline ring and the cyclobutene moiety selectively producing triazolines 113 containing an imino group in the side chain (Scheme 40).
According to the mechanism proposed by Margetić et al.,122 the reaction starts with the intramolecular 1,3-dipolar cycloreversion of compound 112, resulting in the cleavage of the triazole and four-membered aliphatic rings to form diazoimine 114 (Scheme 41). The next step involves the 1,3-migration of a hydrogen atom giving zwitterion 115. According to the density functional theory (DFT), this zwitterion is 26.2 kcal mol–1 more stable than diazoimine 114. The intramolecular 1,5-electrocyclization of zwitterion 115 affords the final product 113.
3.2.3. Reactions of 2-hydroxynaphthalenes
In order to synthesize dihydroorotate dehydrogenase inhibitors, Pan et al.123 performed the reactions of aromatic and heterocyclic azides with hydroxynaphthoquinone (116) and prepared a series of naphtho[2,3-d][1,2,3]triazole-4,9-diones (Scheme 42). It was demonstrated that the synthesized compounds 117a-f exhibit the desired biological activity at micromolar concentrations.123
Almost simultaneously and independently of Pan et al.,123 Zuo et al.124 performed the reaction of naphthoquinone 116 with another set of heterocyclic azides under the same conditions (see Scheme 42). Compounds 117g-k described in the study124 were found to show an inhibitory effect on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.124
Houk and co-workers125 performed kinetic studies of the reactions of aromatic azides and 4-azidopyridine with norbornene and showed that the activation energy of the reaction of 4-azido-2,3,5,6-tetrafluoropyridine (20.6 kcal mol–1) is lower than that for pentafluorophenyl azide (21.8 kcal mol–1). The authors also demonstrated that in this reaction, the dominant molecular orbital interaction is that between the lowest molecular unoccupied orbital (LUMO) of azide and the highest occupied molecular orbital (HOMO) of norbornene. Therefore, the reaction of azides with sterically hindered alkenes can be assigned to inverse electron demand cycloaddition reactions.
3.2.4. Reactions of acetaldehyde derivatives. Synthesis of amides
Xie et al.126 found that aldehydes containing the active methylene or methine group react with aromatic or heteroaromatic azides and benzyl azide derivatives to form amides. The authors optimized the reaction conditions and demonstrated that the reactions in DMSO in the presence of KOH or Cs2CO3 with, e.g., cyclohexanecarbaldehyde (118) can be used to prepare various amides 119 in high yields (Scheme 43).
More recently, Gu et al.127 studied this reaction in the presence of the ionic liquid 1-n-butyl-3-methylimidazolium (bmim) chloride. The authors developed a one-pot method and demonstrated its application to the preparation of amide 119a on a gram scale (Scheme 44).
The formation of 1,2,3-triazolines as intermediates in this reaction was confirmed by additional experiments.127 Thus, triazoline 120 was isolated in 98% yield and identified in the reaction of phenyl azide with cyclohexanecarbaldehyde (118) (Scheme 45). The treatment of triazoline 120 with a saturated ammonium chloride solution gave a cyclohexanecarboxylic acid anilide 119a. Based on these data, Gu et al.127 proposed the reaction mechanism, involving the generation of enolate anion 118’, which reacts with azides to form triazoline 120. The elimination of a nitrogen molecule completes the formation of anilide 119a.
3.3. Reactions with enamines
3.3.1. Reaction pathways of azides with enamines in relation to azides of the heterocyclic series
This Section is devoted to the reactions of heterocyclic azides with enamines with an emphasis on the application of these reactions in organic synthesis for the preparation of amidines, diazo compounds, 1,2,3-triazoles and 1,2,3-triazolines, in particular mono- and bicyclic compounds, and ensembles of 1,2,3-triazoles with miscellaneous heterocycles. In general terms, the possible reaction pathways of heterocyclic azides with enamines are presented in Scheme 46. As seen in this scheme, this reaction initially affords triazolines 121. A number of triazolines were isolated in the individual state and characterized by spectroscopic methods. However, most of these compounds are unstable and are transformed into more stable organic compounds. In this Section, the data on the reactions of heterocyclic azides available in the literature are classified according to the type of the products shown in Scheme 46.
3.3.2. Formation of stable 1,2,3-triazolines
The reaction of azides with enamines initially affords 1,2,3-triazolines.28 In a number of the reactions of enamines 122 with heterocyclic azides, researchers obtained 1,2,3-triazolines 123 stable under ambient conditions (Scheme 47).28,128 Known triazolines 123 are limited to ensembles containing the pyridopyridone (123a), pyran (123b-i) or pyridine (123j) rings in the 1 position and also alkyl and aryl substituents in the 4 position of the triazoline ring. Hence, it can be suggested that the presence of electron-deficient heterocyclic substituents in the 1 position of triazolines 123 enhances the stability of nonaromatic triazolines.
The reaction of azides with endocyclic enamines 124, in which the aliphatic ring contains the endocyclic C=C bond, affords fused 1,2,3-triazolines. It appeared that triazolines 125a-y do not undergo aromatization and they were isolated as the final reaction products (Scheme 48).129--133 Julino et al.132 found that all reactions, which were examined in their study, gave only cis-annulation products 125l-o. In the synthesis of 1,2,3-triazoline 125y, the authors also identified amine 126 as the minor product generated through the reduction of the azido group (see Scheme 48).28
3.3.3. Synthesis of amidines. Elimination of a nitrogen molecule from triazoline and contraction of an annulated ring
The reaction of highly electrophilic azide 127 with endocyclic enamine, cyclohexen-1-ylmorpholine (124a), also afforded triazoline 128 (Scheme 49).134 However, amidine 129 was detected as an alternative product,28 generated through the contraction of the 1,2,3-triazoline-annulated alicyclic moiety and the elimination of a nitrogen molecule from intermediate triazoline 130.
The reactions of other highly electrophilic azides with endocyclic enamines 124 occur only through this pathway of transformation of triazolines 130 and give amidines 131 in low yields (Scheme 50).28,135
The reaction of azide 132 with enamine 124a afforded amidine 133 (Scheme 51), whereas the expected aziridine 134 was not detected in the reaction mixture.28
Another highly electrophilic azide, 5-azido-1-methyl-4-nitro-1H-imidazole (135), behaves in a similar way in the reaction with endocyclic enamines 124.133,136 The mechanism of formation of amidines 136 proposed in the studies133,136 involves the in situ generation of enamine 124 from appropriate amines 137 and cyclic ketones 138 followed by their reaction with azide 135 and also the formation and contraction of the alicyclic moiety of triazoline 139 (Scheme 52). It should be emphasized that compounds 136 were synthesized using a one-pot three-component method. Triazolines 139a,b proved to be quite stable, which made it possible to isolate them from the reaction mixture in the individual state and partially characterized. The stability of compound 139a is apparently attributed to the presence of the pyrrolidine moiety. The stability of cyclopentanone derivative 139b is apparently due to the high reaction barrier, resulting in the formation of the strained four-membered ring.
It is worth noting that under short-term reflux in ethanol or methanol, triazoline 139b is transformed into amidines 140 and 141 containing the alkene and alkoxy groups (Scheme 53).137
The mechanism of formation of amidines 140 and 141 proposed in the study137 involves the simultaneous opening of the triazoline and pentane rings of molecule 139b giving intermediate diazo compound 142 (Scheme 54). This diazo compound is transformed into carbene 143 through the elimination of a nitrogen molecule. The carbene is stabilized through the transformation into stable alkene 141 and ethers 142. Apparently, this reaction pathway is attributed to a higher hindrance of triazoline-annulated cyclopentane compared with six-membered (and larger) rings and the fact that the reaction mechanism involving the contraction of the alicyclic moiety presents a significant barrier.
It is worth noting that azides 144 and 145 react with enamines 124b,c at room temperature to form amidines 146 and 147 containing the methoxybutyl moiety (Scheme 55).137 Presumably, the reaction proceeds through the formation of intermediate 1,2,3-triazolines 148 and 149. Interestingly, in one case, the reaction affords, along with amidine 147b (50% yield), aminocyclopentanone 150 in a comparable amount (41% yield). It was suggested137 that compound 150 is formed through the hydrolysis of intermediate diaminocyclopentene 151.
3.3.4. Synthesis of 1,2,3-triazoles. Elimination of secondary amine from triazoline
The most commonly used procedure for transformations of unstable 1,2,3-triazolines 152 is based on their aromatization giving 1,2,3-triazoles 153 accompanied by the elimination of amine and the a and b bond cleavage (Scheme 56).28,138--140 In these reactions, the electronic effect of the substituent R1 was not revealed. Meanwhile, either an electron-deficient heterocycle or a carbonyl function should be present in the β position of enamine 154.
Thus, the reaction of azidoimidazoles 155 with azolylenamines 156 in DMF at room temperature afforded tricyclic ensembles 157 containing the imidazole, triazole or other azole (Az) rings (Scheme 57).138
Similarly, the reactions of azidoquinoline, azidobenzothiophene, azidobenzothiazole and azidotetrahydrofurans afforded linearly fused heterocyclic compounds 158a-e containing moieties of the starting azides in the 1 position of the triazole ring.130,139,140
It is worth noting that we found the only example, in which the substituent at the α position of enaminone 159 does not cause changes in the type of the reaction product. The reaction of this compound with azide 160 in chloroform produces 1,2,3-triazole 161 in moderate yield (Scheme 58).129
The above transformations give 1,2,3-triazoles (mainly unsubstituted at the 5 position of the ring); therefore, they have common features with CuAAC reactions (see Section 3.1). Meanwhile, the click reactions afford exclusively 1,2,3-triazoles with the free 5 (copper-catalyzed reactions) or 4 (ruthenium-catalyzed reactions) positions. Hence, the reactions of α-substituted enamines similar to those presented in Scheme 58 hold promise for increasing chemical diversity of 1,2,3-triazoles.129
3.3.5. Synthesis of diazo compounds and formamidines through cycloreversion of the triazoline ring
Another direction of the transformation of 1,2,3-triazolines 162 involves the c and d bond cleavage giving diazo compound 163 and amidines 164a,b (Scheme 59). The reaction of azinium tetrafluoroborates 165a,b with enaminone 166 is an example of reactions proceeding exclusively through this pathway.141
The similar reaction of azidoimidazole 135 with enamine 167 in DMF at room temperature affords imidazolyldiazomethane 168 and amidine 169 (Scheme 60).138
In the cited study,138 the authors performed the reaction of azide 135 with enamine 170 and obtained 1,2,3-triazole 171 along with amidine 172, which indicates that the reaction proceeds through two pathways. In this case, the formation of diazo compound 173 was not observed (Scheme 61).
3.3.6. Active methylene amidines. Tandem elimination of a nitrogen molecule/sigmatropic hydrogen shift
The radically different pathway of the ring transformation involves the elimination of a nitrogen molecule from 1,2,3-triazolines 174 accompanied by the sigmatropic hydrogen shift to form amidines 175 (Scheme 62). This direction of the 1,2,3-triazoline ring opening is apparently due to the electron-withdrawing properties28,125,142 of the substituent R1 in azides rather than due to the type of the substituent R2 in enamines 176. These reactions were described for enamines with R2=Ar,125,142 Pri,28 Bn28,142 and Et.28,142
As demonstrated in relation to 4-(2-methylprop-1-en-1-yl)morpholine (177), the β-substitution at the double bond of enamines does not hinder the elimination of a nitrogen molecule from intermediate triazolines 178a,b, which are presumably generated in the reactions with electrophilic azides 179a,b (Scheme 63).129,142 Burger et al.129 suggested that the reaction initially affords 1,3-dipoles 180a,b,which can be stabilized through both the 1,2-H-shift giving amidines 181a,b and 1,3-dipolar cyclization to form 2-(morpholino)aziridines 182a,b followed by the hydrolysis giving 5-aminothiazoles 183a,b. It is worth mentioning that the reaction of 4-azido-3-nitrochromone 184 with enamine 177 affords exclusively amidine 185.
Notably, a similar tandem elimination of a nitrogen molecule and sigmatropic shift (see Scheme 63) was observed in the reactions described in the following Sections: in Section 3.2.4 devoted to the synthesis of amides from aldehydes and in Section 3.3.3, which considers the methods for the synthesis of amidines with simultaneous contraction of the triazoline-annulated carbocycle. Actually, all these reactions involve the elimination of the N2 molecule from the initially formed triazoline followed by the 1,2-shift of either a hydrogen atom (see Sections 3.2.4 and 3.3.6) or the alkyl group (see Section 3.3.3). Therefore, the trend in the generation of the 1,2,3-triazoline intermediate is of a general character and brings together the reactions of heterocyclic azides with different substrates.
3.4. Reactions of heterocyclic azides with active methylene carbonyl compounds and nitriles
3.4.1. Reactions with 1,3-dicarbonyl compounds
The reaction of aromatic azides with 1,3-dicarbonyl compounds (Dimroth reaction), along with CuAAC reactions, is an efficient method for the synthesis of 1-aryl-1,2,3-triazoles.143,144 The reactions of heteroaromatic azides with carbonyl compounds, in particular 1,3-dicarbonyl compounds, are less represented in the literature compared with aryl azides. Meanwhile, a greater diversity of heterocyclic azides compared with aromatic azides resulted in a wider range of triazole ensembles with miscellaneous heterocycles. It should be taken into account that heteroaromatic azides are also able to transfer the diazo group28 and can be used to synthesize aliphatic diazo compounds.
This Section summarizes the literature data on the reactions of heterocyclic azides with mono- and dicarbonyl compounds. The data are classified according to the type of the heterocycle bound to the azide group.
3.4.1.1. Five-membered heterocyclic azides
3.4.1.1.1. Azido-1,2,5-oxadiazoles
Batog et al.145 studied the 1,3-dipolar cycloaddition of 4-azido-1,2,5-oxadiazoles (azidofurazans) 186 to 1,3-dicarbonyl compounds. The authors used the following starting compounds: azidofurazans containing amino, methoxy, methyl and phenyl groups and 1,3-diketones 187 with different substituents R2 and R3 (Scheme 64). The reactions involving azide 186a (R1=NH2) were studied in most detail. The conditions of the synthesis were optimized by varying the solvents (EtOH, MeOH, H2O, aqueous ethanol) and activating bases (Et3N, MeONa, Na2CO3, K2CO3, MgCO3). It was demonstrated that these transformations (with rare exceptions) afforded triazolylfurazans 188 and 189 as the major products, which are formed in good yields through the cycloaddition of azides 186 to 1,3-dicarbonyl compounds.
Triazolylfurazans 188 and 189 were successfully synthesized in the presence of different bases, such as triethylamine, alkali metal carbonates and MgCO3 (see Scheme 64). It was demonstrated that water can be used as the solvent in the reactions of azide 186a with 1,3-dicarbonyl compounds. This reaction with cyclohexane-1,3-dione (190) gives product 189 containing, apart from the oxadiazole ring, the cyclohexanone-1,2,3-triazole moiety.143,145
Only in two cases, the reaction of azidofurazans with 1,3-diketones did not yield 1,2,3-triazoles. In one case, the reaction of azide 186a with 1,3-dioxoindan (191) occurred through the diazo transfer to form diaminofurazan 192 and diazo compounds 193 and 194 (Scheme 65). Diazo compound 194 was formed through the dimerization of diketone 193 followed by the reaction of the intermediate dimer with azide 186a. In the second case, the reaction of azidofurazan 195 with acetylacetone (187a) gave 4-aminofurazan 196. Batog et al.145 did not detect the corresponding diazo compound because of the low stability of such derivatives under the reaction conditions.
Later, this research group146 published the data on the synthesis of ensembles of three heterocycles (197-199) by the reaction of azidofurazans with 1,3-diketones (Scheme 66). The transformations were performed in ethanol, aqueous ethanol or aqueous acetone in the presence of Et3N or K2CO3 and a small molar excess of diketone. For example, tricyclic ensemble 197 was synthesized from bicyclic azide 200 and diketones 187.
Among the synthesized triazolylfurazans, there are compounds exhibiting various biological activities.147 In particular, these derivatives activate soluble guanylate cyclase and display anticancer activity.
In order to extend the range of biologically active triazolylfurazan derivatives, Batog et al.147 synthesized compounds 202, in which two triazolylfurazan moieties are linked by the diaminomethylene bridge, by the reaction of azide 201 with diketones 187 in the presence of triethylamine as the base (Scheme 67).
3.4.1.1.2. Thienylazides
Degl'Innocenti et al.148 synthesized two isomeric azides, 3-azido-2-formyl- (203) and 2-azido-3-formylbenzo[b]thiophenes (204), and compared their reactions with 1,3-dicarbonyl compounds 187. It was found that the reactions of azide 203 with diethyl malonate, ethyl acetoacetate and acetylacetone in ethanol or benzene in the presence of piperidinium acetate afford condensation products 205 in moderate yields (Scheme 68). Azide 204 reacts with acetylacetone (187a) in the presence of piperidinium acetate differently from azide 203. In benzene, the reaction involves the cycloaddition giving bicyclic compound 206, whereas the reaction in ethanol occurs through the diazo transfer to form amine 207 (cf. Scheme 65). In both cases, the corresponding diazo compound was not detected in the reaction mixture.
3.4.1.1.3. 5-Azidoimidazoles
Kitamura et al.54 found that 2-azido-1,3-dimethylimidazolinium chloride 18 efficiently transfer the diazo group to 1,3-dicarbonyl compounds (Scheme 69).
With the aim of examining the field of application and limitations of this method, Kitamura et al.54 studied the diazo transfer to different 1,3-dicarbonyl compounds 187 and 208. Diketones and compounds containing simultaneously the ketone and alkoxycarbonyl groups easily react with azidoimidazole 18 to give the corresponding diazo compounds 209 in high yields. Diazo transfer reagent 18 was utilized to synthesize cyclic diazocarbonyl compounds 210.54
The diazo transfer reactions of active methylene compounds 187 and 208 afford mixtures of diazo compounds 209 and 210 and azide conversion products, such as imidazolidine-2-imine 211 and imidazolidin-2-one 212. In the case of the most commonly used tosyl azide, the reaction gives, apart from diazo compounds, tosylamide, which is often difficult to separate from the diazo compound. In this reaction, reagent 18, unlike tosyl azide, is transformed into water-soluble imine 211, which can easily be separated from the target diazo compound by washing the reaction mixture with water.
3.4.1.2. Six-membered heterocyclic azides
3.4.1.2.1. Azido derivatives of pyridine and quinoline
The reactions of azidoazines with 1,3-dicarbonyl compounds afford 1,2,3-triazoles containing azinium rings in the 1 position as the major products.
Thus, Kaushik et al.149 synthesized 4-acetyl-5-methyl-1-(3-pyridyl)-1H-1,2,3-triazole (213) in moderate yield by the reaction of 3-azidopyridine (11) with acetylacetone (187a) in the presence of sodium methoxide (Scheme 70). Triazole 213 was used as the substrate to prepare chalcone analogues 214. It is worth noting that in this case, the Claisen-Schmidt condensation with aldehydes occurs selectively. Thus, the reaction involves only the acetyl group of compound 213.
Holla et al.150 synthesized triazoles 215 and 216 in moderate yields from 4-azido-8-trifluoromethylquinoline (217) and acetylacetone (187a) or ethyl acetoacetate (187b), respectively (Scheme 71). The synthesis of triazole 216 was accompanied by the hydrolysis of the ethoxycarbonyl group to the carboxyl one. The synthesized compounds were utilized in the synthesis of drugs with high antibacterial activity.
Kumari et al.151 used acetylacetone (187a), 4-azido-7-chloroquinoline (218), aromatic aldehydes 219, isatin (220) and proline (221) as the reagents and performed the one-pot five-component synthesis of compounds 222 containing the carbonyl-bridged spiroxindole and 1,2,3-triazole moieties (Scheme 72). Additional experiments demonstrated that synthesized triazoles 223 and 224 and spiro compound 225 are intermediates in the synthesis of spiropyrans 222. Presumably, the reaction proceeds through intermediate 226.151
Singh et al.152 studied the reaction of 4-azido-7-chloroquinoline (218) with cyclic 1,3-dicarbonyl compounds 208b--d giving bicyclic ensembles 227 bearing the cyclohexanonetriazoles and 7-chloroquinoline moieties (Scheme 73).
Dyadyuchenko et al.153 demonstrated that the treatment of pyridotetrazoles 228 with acetylacetone or ethyl acetoacetate in the presence of Et3N gives rise to the triazole ring, like in the case of azides (Scheme 74). The reaction produced 1-pyridinyltriazoles 229 in moderate yields. Apparently, under the conditions of the synthesis, the equilibrium tetrazole ring opening occurs to give the azide form, which is involved in the reaction.
3.4.1.2.2. Azidopyridazines
In 2014, Brooke et al.153 published the synthesis of analogues of compound 230a, a known inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). In order to establish the structure--inhibitory activity relationship for the glycolytic enzyme, a series of differently substituted acetyltriazoles 230-232 were synthesized by the reactions of heterocyclic azides with acetylacetone 187a (Scheme 75). It was demonstrated that the variation of the substituent in the triazole or pyridazine moiety does not cause a significant change in the inhibitory activity of the compound. Meanwhile, the introduction of small substituents on the phenyl ring leads to a slight increase in the activity.
3.4.1.2.3. Azidopyrimidines
Raauf et al.155 reported the three-step synthesis of derivatives of the bacteriostatic antibiotic trimethoprim (233) containing the triazole ring. In the first step, trimethoprim (233) was transformed into aminoimidazopyrimidine 234 by the reaction with bromoacetic acid (Scheme 76). Then the diazotization of amine 234 followed by the treatment with sodium azide gave heterocyclic azide 235. In the third step, the reaction of azide 235 with acetylacetone and ethyl acetoacetate in the presence of sodium ethoxide afforded triazoles 236a,b in 59 and 81% yields, respectively. These products exhibited antibacterial activity at the level of trimethoprim (233).
El-Etrawy and Abdel-Rahman156 performed the reaction of 6-azido-1,3-dimethyluracil (237) with ethyl acetoacetate (187b) under reflux in ethanol in the presence of sodium ethoxide (Scheme 77). It was found that the triazole ring formation is accompanied by the hydrolysis of the ester group of intermediate ester 238 giving acid 239. It is worth noting that Holla et al.150 also observed the hydrolysis of the ester group in the reaction with sodium ethoxide or methoxide.
3.4.1.2.4. Azidotriazines
Mikhailychenko et al.157 and Chesnyuk et al.158 published the results of research on the reactions of azido derivatives of sym-triazines with dicarbonyl compounds. In the study,157 a new procedure was developed for the synthesis of azidotriazines 240, involving the reaction of trimethylammonium salts 241 with sodium azide (Scheme 78). The cyclization of azides 240 with acetylacetone and ethyl acetoacetate gave 1-triazinyl-1,2,3-triazoles 242 in high yields.
In the study,158 the authors synthesized pyrrole-containing azides 244 by the Clauson--Kaas reaction of aminoazides 243 with 2,5-dimethoxytetrahydrofuran (Scheme 79). The reaction of azides 244 with acetylacetone and ethyl acetoacetate in DMF in the presence of Et3N produced tricyclic ensembles 245 containing the pyrrole, triazine and triazole rings.
The research on the reaction of azidotriazines with 1,3-dicarbonyl compounds was further developed by Ma and co-workers.159 The authors demonstrated that 2-azido-4,6-dimethoxy-1,3,5-triazine (240a, R1=R2=OMe) is a safe and efficient diazo transfer reagent and developed a procedure for the synthesis of diazodiketones 246 from azide 240a and different 1,3-dicarbonyl compounds 187 (Scheme 80). The optimal reaction conditions include the use of highly polar DMSO as the solvent and NaHCO3 as the base.159
In continuation of their work, this research group160 found the conditions, under which the reaction of azido derivatives of 4,6-disubstituted sym-triazines with active methylene compounds affords triazoles 247 as the major products (see Scheme 80). The authors suggested that the nature of the solvent plays a key role in this process. As opposed to aprotic solvents (e.g., DMSO), in which the diazo transfer reaction is the major process,159 the regiospecific [3+2]-cycloaddition occurs in water to give trisubstituted 1,2,3-triazoles 247. The optimal reaction conditions are as follows: a mixture of H2O and DMSO (1:1) in the presence of K2CO3 at room temperature. This method was used to synthesize triazoles 247 in high yields by the reaction of azide 240a with a series of 1,3-dicarbonyl compounds 187. High regioselectivity was observed in all reactions, in which unsymmetrical dicarbonyl compounds 187 were utilized.159,160 Apart from azide 240a, the reaction with acetylacetone was performed using a series of other azido-1,3,5-triazines 240 (see Scheme 80). These reactions produced triazinotriazoles 248 in yields from 50 to 92%, which confirmed a wide field of application of this method. Yan et al.160 proposed the reaction mechanism, which accounts for the solvent effect on the reaction pathway and which was confirmed by DFT calculations.
3.4.1.3. Reactions of heterocyclic azides with 1,3-dicarbonyl compounds in the presence of secondary amines. Enamine organocatalysis
The synthetic methodology of organocatalysis is an alternative to the metal salt catalysis. This methodology was applied to the synthesis of 1,2,3-triazole derivatives by the reaction of carbonyl compounds with aromatic azides in the presence of secondary amines. The mechanism of this transformation involves the generation of enamines 249 from dicarbonyl compounds 187 and amines followed by their rapid cyclization under the treatment with azides to form 1,2,3-triazoles 250 (Scheme 81).24,28,161,162
Thus, Saraiva et al.163 described the synthesis of bifunctional compounds 251 containing triazolylcarboxylate and 7-chloroquinoline moieties based on the pyrrolidine-catalyzed cycloaddition of azide 218 to 1,3-dicarbonyl compounds 187 (Scheme 82). Compounds 251 exhibited antioxidant activity.
Sokolnikova et al.164 reported the advantages of the use of diethanolamine over diethylamine and demonstrated these advantages in relation to the synthesis of bicyclic 1,2,3-triazole ensembles containing the 1,2,4-triazole and 1,2,3-triazine rings in high yields.
3.4.2. Reactions with acetonitrile derivatives
The reaction of heterocyclic azides with acetonitriles 252 under basic conditions generally gives 5-aminotriazoles 253 (Scheme 83). In the presence of an appropriate substituent in the ortho position with respect to the azide group, further reactions of 253 can occur to form fused polycyclic systems 254. In some cases, the Dimroth rearrangement takes place giving isomeric triazole 255. This reaction is generally regioselective and has a predictable outcome. In most studies, this reaction was considered as a method for the synthesis of polyheterocyclic compounds with valuable promising properties for application in medicine, engineering and agriculture.165--170
3.4.2.1. Five-membered heterocyclic azides
3.4.2.1.1. Azidothiophenes
This Section summarizes the studies, in which the cycloaddition of azidothiophenes to acetonitriles was used to synthesize polycyclic systems containing the pyrimidine ring, because a substituent suitable for cyclization was present almost in all cases in the ortho position with respect to the azide group. In most cases, these polycyclic compounds were successfully synthesized.
For instance, Westerland171 studied the reaction of acetonitrile derivatives 252a,b [R=Ph (a), CO2Et (b)] with 3-azidothiophenes 256 and 257 bearing the cyano or protected aldehyde group, respectively, at the 2 position (Scheme 84). The reactions of 3-azido-2-cyanothiophene (256) with a fourfold excess of sodium ethoxide afforded triazolopyrimidines 258a,b through the sequential formation of the triazole and pyrimidine rings. The reaction of 3-azido-2-(dimethoxymethyl)thiophene (257) with acetonitriles 252a,b in ethanol in the presence of sodium ethoxide gave aminotriazoles 259, which underwent cyclization to [1,5-a]pyrimidines 260 in 50% acetic acid. The transformation using ethyl cyanoacetate (252b) is complicated by the saponification of the ester group and the resulting carboxylic acid is readily decarboxylated, which accounts for the low yield of 5-amino-1,2,3-triazole 259b. The decarboxylation of triazolopyrimidine 260b under reflux in toluene for 0.5 h produces unsubstituted heterocycle 260c.
Pokhodylo et al.172--175 published a series of papers on the reactions of 2-azido- and 3-azidothiophenes with acetonitriles. The presence of the alkoxycarbonyl group in the ortho position with respect to the azide group allows the preparation of polycyclic systems in high yields. The cycloaddition of acetonitriles 252a,c-f to 2-azidothiophenes 261 in the presence of sodium methoxide apparently occurs through the formation of intermediate aminotriazoles 262 (were not isolated) within 1-2 min; the process is accompanied by heat release. The reaction affords thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines 263 (Scheme 85).175
The reaction of 3-azidothiophenes 264 with active methylene nitriles 252c,e-h in the presence of sodium methoxide at room temperature produced thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines 265 isomeric to tricyclic compounds 263 (Scheme 86).174
In the study,172 the authors described the reactions, which give either aminopyrimidines 267 and 268 or triazoles 269 and 270 depending on the substituent in the 3 position of the thiophene ring of compound 266 and acetonitrile derivative 252. It was demonstrated that 270 is not transformed into pyrimidine 271 through the cyclization involving the benzoyl and amino groups (Scheme 87).
In continuation of research, these authors173 studied the reactions of azidothiophenes 261 and 264a with malononitrile dimer 272. It appeared that these reactions produce pyrimidones 273 and 274 fused to both the thiophene and triazole rings (Scheme 88). The structures of the reaction products were investigated in detail by NMR spectroscopy.
The researcher group166 from the University of Palermo prepared tetracyclic systems 276 by the reactions of nitriles 252a,c with azides 275 (Scheme 89) and then modified these systems at the pyrimidine nitrogen atom. This allowed the authors to synthesize a series of compounds and evaluate them for anticancer activity, the substituents being selected using the Virtual Lock and Key approach.176 Several derivatives exhibited high antiproliferative activity.166 As in most of the above examples, the reactions of azidothiophene with acetonitriles directly afford triazolopyrimidines 276; only in one case, intermediate aminotriazole 277 (X=N, R=CN) was isolated in 35% yield.
Campos et al.177 failed to prepare tetracyclic compounds 279 from arylacetonitriles 252i (R=Ar) and 3-azido-substituted pyrazinothiophene 278 by means of procedures described in the literature166,173 and developed a new method based on the use of DMSO in the presence of DBU (Scheme 90). The authors suggested that this reaction proceeds through the formation of intermediate 5-amino-1,2,3-triazoles, which undergo cyclization into pyrazino[2’,3’:4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines 279 upon treatment with an aqueous solution of ammonium chloride.
In the past decade, it was found that triazolothienopyrimidines display valuable biological properties. Thus, they act as serotonin 5-HT6 receptor antagonists,168 inhibitors of kidney urea transporter UT-B167 and inhibitors of human immunodeficiency virus type 1 (HIV-1) replication.165 Ivachtchenko et al.168 performed the reaction of sulfonylacetonitriles 252j,k with 3-azidothiophenes 264 under reflux in a basic medium and obtained key intermediates 280 in 80--90% yield. The latter compounds were utilized to synthesize a library of compounds with the general structure 281 (Scheme 91). Kim et al.165 reported the synthesis of triazolothienopyrimidines 281-283. In these reactions, intermediate cycloaddition products 280 and 284 are generated under the same conditions (under reflux in ethanol with sodium ethoxide). Anderson et al.167 synthesized building blocks 280 by this reaction at room temperature. (see Scheme 91).
3.4.2.1.2. Azido derivatives of pyrroles, indoles, pyrazoles, isoxazoles and imidazoles
In order to synthesize potential DNA intercalators with anticancer activity, Lauria et al.169,178--180 conducted systematic studies on the reactions of acetonitrile derivatives with various azidoazoles containing an ester group in the ortho position with respect to the azide group. In most cases, the reactions produce polycyclic systems similar to those described above for thiophenes (see Scheme 89). The authors demonstrated179 that the reaction of azidopyrroles 285 and 286 with acetonitriles 252a,c,g [R=Ph (a), CN (c), C(O)NH2 (g)] gave pyrrolo[1,2,3]triazolo[1,5-a]pyrimidines 287 and 288 and examined the possibility of Dimroth rearrangements occurring in these compounds (Scheme 92). After unsuccessful attempts to perform this rearrangement in an 20% aqueous solution of KOH or on heating in ethanol, the following appropriate conditions were found: heating of the reagents under reflux in DMSO in the presence of trace water. Under these conditions, triazolopyrimidines 287 and 288 with R=Ph are quantitatively rearranged into isomeric pyrrolo[1,2,3]triazolo[1,5-a]pyrimidines 289 and 290 (see Scheme 92). Attempts to perform this rearrangement with other derivatives 287 and 288 failed apparently because of their poor solubility in DMSO.
2-Azidoindoles 291 react with acetonitriles 252a-c,g,m under conditions similar to those used for the reactions of pyrroloazides, but they undergo faster cyclization through the formation of intermediates 292 to pyrimidines 293 (Scheme 93).178 However, attempts to prepare isomeric triazolopyrimidines 295 from 3-azidoindoles 294 and cyanoacetic esters 252b,m [R=CO2Et (b), CO2Me (m)] failed. Thus, after 48 h only 3-aminoindole 296, which was the starting compound for the synthesis of azide 294, was detected in the reaction mixture.169
In continuation of their research, Lauria et al.180 studied the reaction of 1-methyl-5-azidopyrazole-4-carboxylate 297 with acetonitriles 252a,c,g (Scheme 94). In this case, the cycloaddition did not occur at room temperature. Thus, after 24 h the reaction mixture contained mainly the starting compounds, whereas the heating in ethanol under reflux made it possible to prepare triazolopyrimidines 298 within 8 h. Like pyrrole derivatives, compounds 298 undergo the Dimroth rearrangement to isomeric tricyclic compounds 299 under reflux in aqueous DMSO (see Scheme 94). Later, Hassan et al.181 described the synthesis of compound 298 (R=C(O)NH2) at room temperature in 94% yield.
Since the pyrazole ring of compound 300 contains an aldehyde group, the reaction of active methylene compounds 252 occurs primarily with this group. For instance, Chen et al.182 synthesized acrylonitrile-containing compound 301a in 95% yield by the reaction of aldehyde 300 with malononitrile (252c) at room temperature in ethanol in the presence of a small amount of pyridine (Scheme 95). The reaction of azidoaldehyde 300 with cyanoacetic ester (252b) required refluxing in ethanol in the presence of sodium methoxide. In this case, the reaction produced 5-azidopyrazole 301b (55% yield) and pyrazolo[3,4-d][1,2,3]triazine 302 (20% yield).182
Along with the domino reactions, there are examples of the synthesis of aminotriazoles from compounds, which do not contain the ethoxycarbonyl or cyano group in the ortho position with respect to the azide group. Thus, Dmitrieva et al.183 performed the reaction of azides 303 with malononitrile (252c) to prepare ensembles of pyrazolo[3,4-b]pyridine and triazole 304 in the presence of triethylamine as the base (Scheme 96). Syrota et al.184 utilized the stronger base, potassium tert-butoxide, for the cycloaddition of N-substituted cyanoacetamide 252n to 3-azidopyrazole 305 to prepare triazole 306. The latter compound was used as one of intermediates in the synthesis of fused diazepines 307.
Within the framework of the program on the synthesis of new 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazolone derivatives and evaluation of their anticancer properties and radiosensitivity, Aly and El-Gazzar185 synthesized aminotriazole 309 in high yield by the reaction of azide 308 with malononitrile 252c (Scheme 97). However, this bicyclic ensemble did not exhibit significant biological activity.
The reaction of 3-azido-5-methylisoxazole (310) with acetonitrile 252i (R=4-MeOC6H4) affords aminotriazole 311, containing the isoxazole ring in the 1 position, in low yield (Scheme 98).186 It is worth noting that compound 311 and its analogues, containing mainly aryl substituents in the 1 and 4 positions of the triazole ring, were patented in 2009 as nicotinic acetylcholine receptor modulators.186
Nenajdenko and co-workers187 synthesized ensembles composed of the triazole and isoxazole moieties by the reactions of 5-aryl-3-azidoisoxazoles 312 with malononitrile (252c) and 2-cyanoacetic ester (252b) (Scheme 99) and reported that the NMR spectra of these products show double sets of signals. The authors attributed this to the presence of two tautomeric forms (313 and 314).
Despite the fact that thioamides, like cyanoacetamides, react with aromatic azides to form 5-arylamino-1,2,3-triazole-4-carbothioamides,188 the reactions of these compounds with heterocyclic azides can have different outcomes. For example, amidines 316 were synthesized from 5-azidoimidazole 135 and cyanothioacetamides 252o through a rearrangement of intermediate triazoles 315 (Scheme 100).188 Apparently, the heterocyclic substituent in the 1 position plays a key role in the 1,2,3-triazole ring opening. Attempts to perform this rearrangement with 5-amino-1-aryltriazole-4-thiocarboxyate failed.188
3.4.2.1.3. Azido derivatives of triazoles, oxadiazoles and thiadiazoles
The reaction of 4-azidotriazole 38a (R1=R2=Ph) with malononitrile (252c) afforded product 317 consisting of two triazole rings with different substituents (Scheme 101).47
It was demonstrated that 4-amino-3-azido-1,2,5-oxadiazoles 318 react with acetonitriles 252c,g,i,p in the presence of potassium carbonate to form (1H-1,2,3-triazol-1-yl)furazans 319;189 in some cases, the reaction occurs in water (Scheme 102). Compounds 319 undergo the Dimroth rearrangement into diaminofurazans 320 over 1 h on heating in DMF, except for 1,2,3-triazole derivatives containing the thioamide group in the 4 position. Attempts to subject the latter compounds to a rearrangement failed. The results obtained in the study189 were used by another research group190 to synthesize high energy materials based on triazolylfurazan 319 (R=CN). In continuation of their works, Batog et al.147 synthesized diamine 321 in good yield through the double cycloaddition of malononitrile (252c) at the azido groups of compound 201. The reactions of this diazide with 2-cyanoacetamide and cyanoacetic ester gave only diamine 322 (see Scheme 102) in 76 and 79% yield, respectively.
3.4.2.2. Six-membered heterocyclic azides
There are a few studies on the reactions of acetonitriles with azides containing six-membered heterocycles. The transformation pathways and the structures of the reaction products are generally similar to the above examples for azido derivatives of five-membered heterocycles. The reaction of 3-azidoquinuclidinol (323) with phenylacetonitrile (252a) giving aminotriazole 324 (Scheme 103) is presented in the patent.191 The authors evaluated compound 324 for biological activity against nicotinic receptors.
The reaction of azide 218 with malononitrile (252c) afforded triazole 325 (Scheme 104). The structure and the spectroscopic, electronic, photophysical and thermodynamic properties of this product were studied by both experimental and computational methods.192
Acetonitrile derivatives were used along with dicarbonyl compounds (Section 3.4.1) within the framework of studies of methods for the synthesis of azido-1,3,5-triazines and their interactions with active methylene reagents.193,194 The reaction of azido-1,3,5-triazine 240a with malononitrile (252c) and cyanoacetamides 252g,q afforded Dimroth rearrangement products 326 (Scheme 105).160 Meanwhile, Chesnyuk et al.193 synthesized related compounds under similar reaction conditions and assigned the structures of exotic tetrazines 327 to these compounds. It should be mentioned that the 1H NMR spectra of compounds 327 showed signals of impurities (apparently, tautomers), they were not sufficiently well assigned and the X-ray diffraction data were not reported in the studies.160,194 Nevertheless, it can be stated that the products of the both reactions presented in Scheme 105 have similar NMR spectra. Thus, the proton signals at δ 15.05-15.10 and a broadened signal at δ 8.5-9.8, which are observed in the spectra of compounds 326 and 327, belong, most likely, to two NH groups. Based on these data, we believe that both research groups160,193 synthesized compounds 326 containing the triazolylamino-1,3,5-triazine skeleton.
2-Azidoquinoline-3-carboxaldehyde 328, like pyrazole 300, reacts with cyanoacetic ester (252m) and malononitrile (252c) involving mainly the aldehyde group (Scheme 106).194 In the former case, the reaction affords acrylate 329; in the latter case, tricyclic compound 330 is produced. The mechanism of the formation of the latter compound involves two competitive processes: the reaction with the participation of an aldehyde group and malononitrile giving the cyclopentene moiety and the insertion of nitrene, which is generated from the tetrazole ring, into the C-H bond of malononitrile (252c) to form the imidoyl dicyanide moiety of compound 330.
2-Cyano(thio)acetamides 252 [R=C(X)NR1R2; X=O, S] show a specific behaviour in the reactions with heterocyclic azides 331. Thus, Bakulev and co-workers195 prepared a series of 1,2,3-thiadiazole-4-carbamidines 332 by this reaction, whereas the reactions of cyanothioacetamides and cyanoacetamides with aromatic azides produced 4-amino-1-aryltriazoles 333 (Scheme 107).196
4. Tetrazoles as a source of heterocyclic azides in organic synthesis
The azide-tetrazole tautomeric equilibrium is considered as one of the key properties of hetaryl azides.197 This phenomenon was studied in detail by experimental and theoretical methods.198--200 It was demonstrated that the position of equilibrium depends on the substituents, the solvent and the temperature. For example, Thomann et al.98 studied the effect of the substituents on the isomer ratio of 2-substituted 4-azidopyrimidines 334-336 and the possibilities of using tetrazolopyrimidines in the synthesis of 1-pyrimidyl-1,2,3-triazoles 337-339 (Scheme 108). For this purpose, the structures of the synthesized compounds were thoroughly analyzed by NMR and IR spectroscopy and X-ray crystallography. Based on these data, it was demonstrated that the isomer ratio can be controlled by varying the substituents on the ring. It was shown that the tetrazole form can act as a disguise for the azido group (compounds 340-342) masking its high reactivity in metal-catalyzed reactions with acetylene derivatives. It is worth noting that tetrazoles containing substituents that stabilize the cyclic form exhibited much lower reactivity in these processes (see the transformation 342→343) or did not react with acetylenes (triazole 345 was not generated from tetrazole 344).98 Meanwhile, tetrazoles 340 and 341, existing in equilibrium with azides 335 and 336a, are easily transformed into 1,2,3-triazoles 338 and 339. The authors noted that the rate of the CuAAC reaction of tetrazoles is affected by the following three factors: the ratio of the tetrazole and azide forms and the electronic and steric effects of the substituents98 (see Scheme 108).
Using the acid sensitivity of tetrazole derivatives 340 and 342, Thomann et al.98 developed a pH-dependent method for the selective azide-alkyne cycloaddition based on tetrazoles. The reaction involving cyclic alkyne 346 in aqueous media affords a mixture of isomeric triazoles 347 and 348 (Scheme 109).
Avila et al.103 demonstrated that tetrazole 349 reacts with 6-cyanopentyne (350) to form compound 351 bearing the benzothiazole and triazole rings in low yield (Scheme 110). A similar product containing the benzothiazole and pyridine rings was described in the studies.201,202
Gevorgyan and co-workers203 found the optimal conditions for the reaction of pyridotriazoles 352 with terminal acetylenes (Scheme 111). Copper triflate served as the catalyst and toluene as the solvent. Under the optimal conditions, pyrido-, quinolino- and qunoxalinotriazoles 353 were synthesized in high to moderate yields.203
5. Use of reactions of heterocyclic azides in biological chemistry
In recent years, CuAAC-based bioorthogonal reactions were often used in biological chemistry204 to study biological processes in cells of living organisms. However, examples of the application of heterocyclic azides in bioorthogonal reactions are scarce. Xiang et al.205 reported the synthesis of CuI-chelated cyclen micelles and the successful use of these micelles as a nanocatalyst for the reactions of azides with acetylenes both in water and living cells. 3-Azido-7-hydroxycoumarin 354 (Scheme 112) reacts with phenylacetylene and propargyl bromide giving hetaryltriazoles 355 in high yields.205 The potential of the intracellular catalysis of click reactions involving azide 354 and phenylacetylene (see Scheme 112) by copper(I)-chelated cross-linked cyclen micelles (CuI@cCMs) was examined in experiments with living cells by confocal microscopy. The experimental results demonstrated that CuI@cCMs is not only an efficient catalyst for transformations in solutions but also an ideal catalyst for the intracellular click reaction due to activation of the azide-alkyne cycloaddition.
6. Heterocyclic azides in the synthesis of bioconjugates
High antiviral and anticancer activity of modified nucleosides and their use as drugs (e.g., the commonly known drugs ribavirin, zidovudine, etc.) have attracted attention of many research teams to these compounds. This Section describes the reactions of heterocyclic azides, in particular of glycosyl azides, with acetylene derivatives and active methylene carbonyl compounds and acetonitriles giving biologically active bioconjugates.
6.1. Reactions of azidonucleosides with acetylene derivatives
The reactions of heteroaromatic azides with cyclooctyne or azocine easily occur in the absence of metal catalysts to give 1,2,3-triazole-containing purine and pyrimidine nucleotides and nucleosides.30,70,83,202,206--212 The steric hindrance in the cycloalkyne molecule is a driving force for these processes.
In the studies,208,211 an efficient method was developed for the synthesis of highly functionalized triazole derivatives based on the reactions of azidoadenine nucleosides and nucleotides 356a-c with cycloalkynes 346, 357 and 358 (Scheme 113). It is worth noting that these transformations occur in the absence of a catalyst or microwave irradiation both in aqueous solutions and cell culture media at ambient temperature and give products 359-361.
A similar reaction was described for 5-azidouracils 362a,b (Scheme 114).211 This reaction afforded cycloadducts 363-365, the yields of which were determined by NMR spectroscopy (marked with the superscript a) and after the purification by reversed-phase high-performance liquid chromatography (RP HPLC) (see b).
It was found that the position of the azide group in the adenine molecule has no effect on its reactivity, whereas 5-azidouridine derivatives are much more reactive compared with 2-azido- and 8-azidoadenosines. Zayas et al.211 demonstrated that triazole-containing adenosines and uridines have fluorescence properties sufficient for their use for direct visualization of human breast adenocarcinoma (MCF-7 cell line) in living cells.
The reaction of azide 366 with acetylenes afforded a series of 2-triazolyl-5’-O-[N-(salicyl)sulfamoyl]adenosines 367 (Scheme 115). The biochemical and biological evaluation of these compounds as inhibitors of adenylating enzymes, which catalyze the arylation of adenine at the OH group of phosphate and are involved in siderophore biosynthesis by Mycobacterium tuberculosis.207 It was found that most of 4-substituted triazoles 367 exhibit activity at the subnanomolar level.
2-Arylethynyl derivatives of carbaadenosine were shown to be selective A3 adenosine receptor (A3AR) agonists.206 To enhance the stability of these compounds, Gupte et al.207 synthesized their analogues by replacing the ethynyl group with the 1,2,3-triazole moiety (Scheme 116). The reactions of azides 368 with substituted acetylenes afforded triazolyladenines 369 containing different substituents at the N(6) and C(2) atoms. The authors characterized the in vivo binding of these compounds to adenosine receptors in the concentration range of 0.3-12 nmol L–1 to assess their efficiency as agents against chronic neuropathic pain. The introduction of the 2-pyrimidyl group into molecule 369a leads to an increase in the in vivo duration of action of the drug. Compound 369b containing the 5-chloro-2-thienyl moiety retained 85% efficiency of analgesia for 1 h. It was found that the introduction of bulkier groups at the N(6) atom increases the duration of action of the synthesized derivatives206 (see Scheme 116).
Lakshman et al.210 demonstrated that 2,6-diazidopurines undergo the double CuAAc reaction to form 2,6-bis(triazolyl) derivatives of purine. It was also found that the 1,2,3-triazole ring is a good leaving group and it can be replaced by thiol moieties.83,202,209,213 Some adenosine derivatives containing the triazole ring were found to exhibit anticancer activity.83,202,209,213
The CuAAC reaction of azide 370 with alkyl- and arylacetylenes in the presence of copper sulfate and sodium ascorbate was used to synthesize bis(triazolyl)acyclic nucleoside analogues 371 (Scheme 117).70 These acyclonucleosides show inhibition of the tobacco mosaic virus growth. The authors suggested that the bis(triazolyl) ensemble is an important structural unit responsible for antiviral activity of compounds 371.
6.2. Natural compound conjugates
In order to synthesize new biologically active compounds, we performed the reaction of methylequol (372) with propargyl bromide and heterocyclic azides in the presence of K2CO3 and CuI214 and developed a facile one-pot method for the synthesis of hybrid molecules 373 containing equol moieties and different heterocycles, such as 1-methyl-4-nitroimidazole, pyrimidinedione, benzotriazole, thiophene, triazole, isoxazole and pyrazole (Scheme 118).
Hybrid molecules of coumarin, triazole and the above heterocycles were synthesized using a similar approach.215
6.3. Reactions of glycosyl azides with active methylene carbonyl compounds
Kundu et al.216 synthesized a large series of 1,4,5-trisubstituted glycosyl-1,2,3-triazoles 375 in good yields by the cycloaddition of glycosyl azides 374 to 1,3-dicarbonyl compounds 187 (Scheme 119).
6.4. Reactions of glycosyl azides with acetonitrile derivatives
The key step in the construction of a heterocyclic moiety in the synthesis of nucleoside analogues involves the cycloaddition of azido glycosides to acetonitriles or other appropriate compounds. Although this reaction was described in 1972,217 the procedure for the synthesis of 5-amino-4-carbamoyl-1-ribo(arabino)furanosyl-1,2,3-triazole in DMF in the presence of aqueous KOH on cooling to 0 °C continues to be used without changes or with insignificant modifications.170,218--221 The reaction occurs regiospecifically; however, in an alkaline medium the carbohydrate moiety is often partially or fully deprotected, which leads to a significant decrease in the yield of the target products. Another specific feature of this reaction is the furanose ring anomerization, which was mentioned not by all authors. This transformation depends on both the nature of the carbohydrate moiety and the reaction conditions, thereby suggesting the stepwise mechanism of the formation of the 1,2,3-triazole ring.
The cycloaddition of 2-cyanoacetamide (252g) to 2-deoxy-2-fluoro-L-arabinofuranosyl azide 376 was described by Ölgen and Chu218 (Scheme 120). The authors stated that α-azide 376 gives α-L-arabinofuranosyl-1,2,3-triazole 377 in 76% yield; β-azide produces the corresponding β-isomer in 51% yield. 2-C-methyl-β-D-ribofuranosyl azide 378 was synthesized from unprotected 1,2,3-triazole 379 using a similar procedure.219
Firestine et al.220 studied the reaction of azide 380 with tert-butyl cyanoacetate in order to prepare 1,2,3-triazole-4-carboxylate 381. It was demonstrated that the synthesis of the target product requires the use of sodium 2-cyanoacetate 252 (Scheme 121).
Yang et al.221 studied the cycloaddition of glycosyl azide 382 to cyanoacetamide (252g) and 3-bromopropiolate (383) (Scheme 122) (see also Section 3.1 devoted to reactions of heterocyclic azides with acetylenes). The reaction afforded triazoles 384 and 385. 8-Azaadenosines 386a--g were synthesized from amide 384 through the cyclization followed by the modification of the amide group into the amidine moiety. Compound 386g exhibited high activity against hepatitis B virus.
Salemeh et al.222 demonstrated that 3-azido-1-methylthio-β-D-galactopyranoside (387) also reacts with cyanoacetamide (252g) to form 1-glycosyl-1,2,3-triazole 388 (Scheme 123).
7. Conclusion
Heterocyclic azides exhibit diverse biological activity and have a spectrum of action different from that of aromatic analogues. An example is the antiviral drug zidovudine (3’-azido-3’-deoxythymidine) used in the treatment of human immunodeficiency virus (HIV) infection. Heteroaromatic azides react with cyclic alkenes at a higher rate compared with aromatic azides and give the target products in higher yields. It was found that the chemical reactions involving heterocyclic azides and enamines are characterized by a greater diversity compared with the similar transformations in the aromatic series. These reactions afford diazo compounds, N-hetarylamidines and 1,2,3-triazolines fused to nonaromatic carbocycles, which are inaccessible by the reactions with aromatic azides. Besides, the reactions of heteroaromatic azides with 1,3-dicarbonyl compounds and 2-cyanothioacetamides produce another type of compounds, such as 1,2,3-thiadiazole and 1,2,3-triazoline derivatives and different ensembles consisting of three heterocycles.
It was found that heteroaromatic azides undergo reactions which are not typical of their aromatic analogues, such as the diazo transfer to active methylene compounds, the tandem elimination of a nitrogen molecule/sigmatropic rearrangements in the transformations of 1,2,3-triazolines, the carbocycle contraction in bicyclic 1,2,3-triazolines and the azide-tetrazole ring-chain tautomerization.
This review is devoted to heterocyclic azides taking into account the differences in the properties of heterocyclic and aromatic azides, rich chemistry of heterocyclic azides, including reactions with alkenes, enamines, 1,3-dicarbonyl compounds and acetonitrile derivatives, which are extensively used in organic synthesis, medicinal and biological chemistry, and a large number of publications on this issue. This is the first systematic review on the methods of synthesis and reactions of heterocyclic azides with derivatives of acetylene and acetonitrile, alkenes, enamines and active methylene dicarbonyl compounds. It was demonstrated that heterocyclic azides can be utilized in biological chemistry to study the reactions in living systems, as well as in organic synthesis to prepare mono-, bi- and tricyclic compounds and ensembles of different heterocycles, luminophores and sensors for metals.
While analyzing the data during preparation of the review, we realized that, despite advances in the chemistry of heterocyclic compounds, the data on the kinetic studies of heterocyclic azides in reactions with compounds containing multiple bonds are scarce, the bioorthogonal reactions of these compounds are poorly known and the results of theoretical calculations are almost lacking. We believe that the further progress in this field will be related to the kinetic and theoretical studies, the development of new bioorthogonal reactions and the synthesis of new biologically active compounds based on heterocyclic azides.
This review was written with the financial support of the Russian Science Foundation (Project No.18-13-00161P).
8. List of abbreviations and designations
A3AR — A3 adenosine receptor,
Asc — ascorbate,
Boc — tert-butoxycarbonyl,
bmim — 1-n-butyl-3-methylimidazolium,
bpy — 2,2’-dipyridine,
B2Pin2 — bis(pinacolato)diboron,
cod — 1,5-cyclooctadiene,
CuAAC — copper-catalyzed azide-alkyne cycloaddition,
CuI@cCMs — copper(I)-chelated cross-linked cyclen micelles,
DBU — 1,8-diazabicyclo[5.4.0]undec-7-ene,
DCM — dichloromethane,
DFT — density functional theory,
DIPEA — N,N-diisopropylethylamine,
dtbpy — 2,6-di-tert-butylpyridine,
DQ — 3,3’,5,5’-tetra-tert-butyldiphenoquinone,
HIV-1 — human immunodeficiency virus type 1,
HOMO — highest occupied molecular orbital,
ICT — intramolecular charge transfer,
LUMO — lowest unoccupied molecular orbital.
MW — microwave irradiation,
PEG-400 — low-molecular-weight polyethylene glycol,
Pic — 4-picoline,
PIFA — [bis(trifluoroacetoxy)iodo]benzene,
PFKFB3 — 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3,
Py — pyridyl,
RP HPLC — reversed-phase high-performance liquid chromatography,
rt — room temperature,
TBAB — tetra-n-butylammonium bromide,
TBDMS — tert-butyldimethylsilyl,
TBTA — tris[(1-benzyl-1,2,3-triazol-4-yl)methyl]amine,
TFA — trifluoroacetic acid,
TfO — trifluoromethanesulfonate (triflate),
TMSA — trimethylsilylacetylene,
TMSN3 — trimethylsilyl azide,
Ts — p-toluenesulfonyl (tosyl),
US — ultrasound.