Synthesis of Heterocycles through Denitrogenative Cyclization of Triazoles and Benzotriazoles

During the past few decades, there has been considerable growth in the development of denitrogenative reactions of triazole skeletons to construct valuable cyclic compounds, particularly heterocycles. Despite the inherent difficulty of the ring-opening of triazole derivatives, many novel and efficient approaches have arisen in this area mainly with the use of transition metal (such as rhodium, palladium, silver, copper) catalysis, photolysis, or free radical mediated reactions. Generally, these procedures begin with the ring-opening of 1,2,3-triazoles or benzotriazoles followed by N₂ extrusion and subsequent diverse transformations, which enable the rapid synthesis of various heterocycles in a single step. To avoid overlap with other related reviews, this minireview covers the recent advances in the denitrogenative cyclization of 1,2,3-triazoles since 2016 and the denitrogenative cyclization of benzotriazoles since 2012.     

NH-1,2,3-三唑合成进展

NH-1,2,3-三唑是一类具有重要生理活性的含氮杂环化合物, 是用途广泛的药物中间体. 通过N-烃基化反应, NH-1,2,3-三唑还可以区域选择性的合成各种2-取代-1,2,3-三唑类化合物, 因此是有价值的有机合成中间体. 鉴于NH-1,2,3-三唑在有机合成化学和药物化学中的潜在应用价值, 结合本课题组的研究工作, 对于NH-1,2,3-三唑的主要合成方法, 尤其是近十年来的合成研究进展进行了回顾和展望. 对一些典型的反应机理研究也进行了综述.     

A Theoretical Study on the Tautomerism of C-Carboxylic and Methoxycarbonyl Substituted Azoles

DFT calculations (B3LYP/6-31+G^**) have been carried out on 106 tautomers and conformers of NH-azoles bearing CO₂H and CO₂CH₃ groups. The following azoles systems have been studied: 2-substituted pyrroles, 2-substituted indoles, 2-substituted imidazoles, 2-substituted benzimidazoles, 4(5)-substituted imidazoles, 3(5)-substituted pyrazoles, 3-substituted indazoles (1H and 2H), 3,4(5)-substituted-1,2,3(5)-triazoles, 2,3(5)-substituted-1,2(3),4-triazoles, 4(5)-1,2,3,4(5)-tetrazoles. In the case of pyrazole, 3,5-disubstituted derivatives have also been computed, including four dimers.Dedicated to our friend Professor Vladimir I. Minkin on his 70th anniversary.     

1,3-Dipolar cycloadditions of MeOPEG-bounded azides

1,3-Dipolar cycloadditions of MeOPEG-supported azide 2 with a variety of dipolarophiles have been studied. 1-MeOPEG-supported 1,2,3-triazoles 4 and 5, 1,2,3,4-tetrazoles 12 and aziridine 14 were obtained in nearly quantitative yields. The removal of the MeOPEG moiety from the 1,2,3-triazole nucleus was achieved by acidic cleavage of the cycloadduct mixtures 4 and 5 giving 4- and 5-substituted-1,2,3-triazoles 6 and 7.     

Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines and Pyridazines

Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dicarbonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-triazolo[1,5-a]pyrazines and their benzo-fused quinoxaline and quinoxalinone-containing analogs. Recent applications detail the use of these heterocycles in medicinal chemistry (c-Met inhibition or GABA_A modulating activity) as fluorescent probes and as structural units of polymers.     

1,2,3-三唑化合物的合成研究进展

1,2,3-三唑化合物是重要的N-杂环化合物, 近年来被广泛应用于工业生产、药物研发、材料科学等多个领域. 因此1,2,3-三唑的合成受到越来越多的关注. 从合成不同取代类型的1,2,3-三唑化合物入手对近年来研究发现的合成方法的进展进行了综述.     

Dual Reactivity of 1,2,3,4‐Tetrazole: Manganese‐Catalyzed Click Reaction and Denitrogenative Annulation

A general catalytic method using a Mn‐porphyrin‐based catalytic system is reported that enables two different reactions (click reaction and denitrogenative annulation) and affords two different classes of nitrogen heterocycles, 1,5‐disubstituted 1,2,3‐triazoles (with a pyridyl motif) and 1,2,4‐triazolo‐pyridines. Mechanistic investigations suggest that although the click reaction likely proceeds through an ionic mechanism, which is different from the traditional click reaction, the denitrogenative annulation reaction likely proceeds via an electrophilic metallonitrene intermediate rather than a metalloradical intermediate. Collectively, this method is highly efficient and offers several advantages over other methods. For example, this method excludes a multi‐step synthesis of the N‐heterocyclic molecules described and produces only environmentally benign N₂ gas a by‐product.     

Iron(II)‐Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.     

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases

1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87–92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl₃ was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82–92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky’s rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-β-lactamase.     

Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione-linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties

Copper-catalyzed reaction of N-propargyl isoindoline-1,3-dione and 4-azidomethyl coumarins / 4-azidomethyl-1-aza coumarins under click chemistry conditions afforded 1,4-disubstituted 1,2,3-triazoles, whereas ruthenium catalysis yielded isomeric 1,5-disubstituted 1,2,3-triazoles. The two regioisomers have been distinguished by NOE studies. UV absorption for a given pair of isomers exhibited similar trend, whereas fluorescence measurements showed considerable differences. Photo physical studies on the interaction of azides with copper and ruthenium have also been performed.     

Asymmetric Synthesis of Axially Chiral Isoquinolones: Nickel‐Catalyzed Denitrogenative Transannulation

The first Ni⁰/bis(oxazoline)‐catalyzed asymmetric denitrogenative transannulation of 1,2,3‐benzotriazin‐4(3H)‐ones with bulky internal alkynes to form novel axially chiral isoquinolones in an atroposelective manner has been developed. This method provides direct asymmetric access to axially chiral isoquinolones with excellent functional‐group tolerance in excellent yields and stereoselectivities from readily available starting materials under mild reaction conditions. These axially chiral isoquinolones exhibit high cytotoxicity against a number of human cancer cell lines. DFT calculations reveal the nature of the transition state in the key annulation step.     

Synthesis of 1,5-disubstituted tetrazole-1,2,3 triazoles hybrids via Ugi-azide/CuAAC

A new synthetic strategy to obtain new linked 1,5-disubstituted tetrazole-1,2,3-triazoles via the Ugi-azide reaction followed by a copper-catalyzed alkyne-azide reaction (CuAAC) was developed. This strategy used solvent-free conditions for the Ugi-azide reaction. This two-step strategy affords the products in moderate to good yields. To the best of our knowledge, this is the first report using the CuAAC reaction as a post-condensation process in an Ugi-azide reaction and therefore, the first describing the synthesis of 1,5-disubstituted tetrazole (1,5-DS-T) linked to the 1,2,3-triazole moiety, which are molecules that may have potential applications in medicinal chemistry.     

Metal-free and azide-free synthesis of 1,2,3-triazoles derivatives

1,2,3-Triazoles, significant five-membered ring N-heterocycles, are main structural moieties in well-designed materials, pharmaceutical agents, bioactive products, and synthetic intermediates. In the research of life sciences and pharmaceuticals, by seeing the spacious applications of 1,2,3-triazoles, the progress of metal-free method is exceedingly desirable to evade the heterocyclic product metal contamination. Moreover, on a larger scale, the toxicity and explosiveness of azides makes azides discommode and hard to hold, to synthesize 1,2,3-triazoles. The need to steer the development of the synthesis of 1,2,3-triazoles toward more maintainable synthesis is a pressing issue. There are rare methods to construct 1,2,3-triazoles under azide-free and metal-free environments. These rare methods are compiled in this review. The afford of the collection and compilation of azide-free and metal-free synthesis methodologies of 1,2,3-triazole in single podium is supportive and crucial for synthetic chemist to extend the diversity of the synthesis of 1,2,3-trizoles through green protocol.     

[4 + 1] Annulation of in situ generated azoalkenes with amines: A powerful approach to access 1-substituted 1,2,3-triazoles

1-Substituted 1,2,3-triazoles represents ‘privileged’ structural scaffolds of many clinical pharmaceuticals. However, the traditional methods for their preparation mainly rely on thermal [3 + 2] cycloaddition of potentially dangerous acetylene and azides. Here we report a base-mediated [4 + 1] annulation of azoalkenes generated in situ from readily available difluoroacetaldehyde N-tosylhydrazones (DFHZ-Ts) with amines under relatively mild conditions. This azide- and acetylene-free strategy provides facile access to diverse 1-substituted 1,2,3-triazole derivatives in high yield in a regiospecific manner. This transformation has great functional group tolerance and can suit a broad substrate scope. Furthermore, the application of this novel methodology in the gram-scale synthesis of an antibiotic drug PH-027 and in the late-stage derivatization of several bioactive small molecules and clinical drugs demonstrated its generality, practicability and applicability.     

Metal-Free Synthesis of Functional 1-Substituted-1,2,3-Triazoles from Ethenesulfonyl Fluoride and Organic Azides

The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu^I-catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.     

Flash vacuum pyrolysis of azolylacroleins and azolylbutadienes

2-Aryl-5-acroleinyl-1,2,3,4-tetrazoles (1a–d) and 2-aryl-5-butadienyl-1,2,3,4-tetrazoles (1e–g) were subjected to flash vacuum pyrolysis. Acroleinyl derivatives resulted in nitrogen extrusion to give nitrilimines followed by ring closure to give the corresponding indazoles 3a–d in good yields. On the other hand, butadiene derivatives underwent ring fragmentation to give p-substituted anilines without formation of the expected indazoles. Differences between thermal behaviour of 2-(4-chlorophenyl)-5-acroleinyl-1,2,3,4-tetrazole (1c) and 1-(4-chlorophenyl)-4-acroleinyl-1,2,3-triazole (2) were studied in details. DFT calculations have been used to examine the nitrilimine and carbene nature of the intermediates involved in the thermal reactions of azolyl derivatives.     

Synthesis of 2(5H)-Furanone Derivatives with Symmetrical and Unsymmetrical Bis-1,2,3-triazole Structure

The interesting bioactivities of 2(5H)-furanone, 1,2,3-triazole, and amino acid derivatives have promoted their combination into one multifunctional molecule. The symmetrical bis-1,2,3-triazoles and mono-1,2,3-triazoles with one free azide group are synthesized respectively by controlling the molar ratio of reactants, N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl ester and 1,4-diazidobutane. The unsymmetrical bis-1,2,3-triazoles are afforded by the subsequent reaction of mono-1,2,3-triazoles with other terminal alkynes with good to excellent yields in a short time under the same mild “click” reaction conditions. The 32 new compounds obtained in the reactions are characterized by Fourier transform infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Because of the diversity of four or five basic units in molecule, this methodology provides easy access to different chiral 2(5H)-furanone compounds with polyheterocyclic structure, especially with unsymmetrical bis-1,2,3-triazole moiety. Importantly, a simple approach is provided for the synthesis of unsymmetrical bis-1,2,3-triazoles using common diazides.     

1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics

Since the discovery of Cu(I)-catalysed click chemistry, the field of peptidomimetics has expanded to include 1,4-connected 1,2,3-triazoles as useful peptide bond isosteres. Here, we report the synthesis of triazole-containing analogues of the naturally occurring tyrosinase inhibitor cyclo-[Pro-Val-Pro-Tyr] and show that the analogues retain enzyme inhibitory activity, demonstrating the effectiveness of a 1,4-connected 1,2,3-triazole as a trans peptide bond isostere.     

Amine-catalyzed synthesis of N2-sulfonyl 1,2,3-triazole in water and the tunable N2-H 1,2,3-triazole synthesis in DMSO via metal-free enamine annulation

The selective synthesis of N²-sulfonyl and N²-H 1,2,3-triazoles via organocatalytic annulation of enaminone/enaminoester with sulfonyl azide has been realized. The unconventional selectivity providing N²-sulfoyl 1,2,3-triazoles takes place in pure water, wherein the hydrogen bond effect between water and the intermediate resulting from enamine-azide corporation accounts for the novel reaction selectivity. On the other hand, the reactions conducted in DMSO specifi...     

Strategic applications of Baylis-Hillman adducts to general syntheses of 3-nitroazetidines

A novel one-pot highly diastereoselective synthesis of substituted 3-nitroazetidines via an anionic domino process is described. The synthesis involves a high yielding annulation of Baylis-Hillman alcohols and their aldehydes with either N-aryl/tosylphosphoramidates or N-aryl/tosylphosphoramidates in combination with a task-specific ionic liquid [bmim][X-Y] to afford the corresponding 1,2,3-tri- and 1,2,3,4-tetrasubstituted azetidines, respectively. Plausible mechanisms for the formation of various 3-nitroazetidines have been suggested.