Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• amidation Recently, Cao and co-workers reported the copper-catalyzed synthesis of 1,2,4-triazole derivatives via an N-acyl nitrene intermediate [76]. As illustrated in Scheme 3, dioxazolones 4 and N-iminoquinolinium ylides 5 served as reactive substrates, leading to the formation of various polycyclic 1,2,4

• -triazole analogues 6. Both dioxazolones 4 and N-iminoquinolinium ylides 5 demonstrated excellent tolerance in this transformation. Notably, electron-rich dioxazolones exhibited slightly higher reactivity. The proposed catalytic cycle for the copper-catalyzed synthesis of 1,2,4-triazole derivatives is

• ) nitrenoid intermediate INT-7. Subsequent nitrene insertion, protodemetalation, and intramolecular cyclization furnish the desired 1,2,4-triazole. 1.3 Three-component formation of N-acyl amidines In 2019, N-acyl amidines were prepared from dioxazolones using a copper catalyst with terminal alkynes and

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• intermediate XXXV. Finally, the final product 35 is yielded via a 1,3-hydride shift. The reaction between diazo derivatives, nitriles, and azodicarboxylates catalyzed by Cu(OTf)2 is an efficient synthetic method to obtain 2,3-dihydro-1,2,4-triazole derivatives 36 (Scheme 27) [45]. The reaction proceeds via a

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• -derivatives of thiazole or pyridine, this process leads to the formation of the corresponding thioethers with a methylene linker. At the same time, thiolated 1,3,4-oxadiazole or 1,2,4-triazole undergo alkylation at the nitrogen atom in the reaction with 3,5-di-tert-butyl-6-methoxymethylcatechol to form the

• compounds leads to an increased lipophilicity and, as a result, facilitates the transfer of the molecule through cell membranes to the target site [22]. 1,2,4-Triazole derivatives also play a key role in medicinal chemistry, especially in the development of new antivirals [23][24] and antibacterial agents

• activity against the HeLa cancer cell line [22]. 1,2,4-Triazole thioglycoside derivatives have antiviral activity against influenza strains H3N2 and H5N1 [31][32]. The 1,2,4-triazole-3-thione-imidazole hybrids displayed potential antibacterial activity against E. coli, S. aureus [33]. Heterocyclic thione

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• 47, can be accessed from polyfunctional hydrazine derivatives via multicomponent reactions. For the preparation of pyrazoles 47, 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol (44), phenylacyl bromides 45, and benzoylacetonitriles 46 were chosen as starting materials (Scheme 13) [67]. Thereby

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• -membered aromatic azacycles, imidazole completely failed to undergo the present N-alkenylation, whereas the reaction of 1,2,4-triazole was too sluggish to allow for the isolation and unambiguous characterization of the expected product. Next, the reaction of pyrazole (2a) was explored using different

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• -5-mercapto-1,2,4-triazole (AMTA)-functionalized Fe3O4 nanoparticles coated on silica, based on Khalafi-Nezhad’s approach. Optimum catalytic activity was attained when adding 10 mg of the nanocomplex to the reaction mixture, in solvent-free conditions at 80 °C and after a time period of 1.5–8 hours

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• pyrazole derivatives (including indazole), benzimidazole, 1,2,3-triazole, indole, carbazole, indoline, quinazoline, and isoquinoline. Nevertheless, many heterocyclic motifs still remain beyond the attention of researchers. For example, glutarimides that incorporate tetrazole and 1,2,4-triazole substituents

• varying characteristics were selected as substrates for the studied insertion reaction, encompassing both aromatic and non-aromatic compounds differing in the number and arrangement of nitrogen atoms (Scheme 3). Notably, several of these heterocycles, including tetrahydroquinoline, 1,2,4-triazole, and

• literature [30]. Despite the low reactivity (the reaction was carried out for 5 days with triple portion of the catalyst), the yield of the N–H insertion product involving 1,2,4-triazole was unexpectedly high (80%). Compound 6l was obtained as a single regioisomer. The reaction with tetrazoles is also

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• trifluoromethylated hydrazonoyl halides. [3 + 2]/[3 + 3] Cycloadditions of trifluoromethylated hydrazonoyl halides. Substrate scope for [3 + 2] cycloadditions with trifluoroacetonitrile imines reported by Jasiński’s team and other groups. Synthesis of trifluoromethylated 1,2,4-triazole and 1,2,4-triazine derivatives

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• of N2H4·H2O (2.9–3.0 equiv) with a catalytic amount of TsOH·H2O (0.05 equiv) in refluxing EtOH or 1,4-dioxane resulted in the formation of mixtures of macrocycle 5, pyrazolyl-1,2,4-triazole 10, and a very small amount of bis-pyrazole 6 according to NMR data (Table 1, entries 22 and 23). It is

• noteworthy that triazole 10 was the major product in dioxane (10/5/6 = 86.5:13:0.5, Table 1, entry 23). Again, macrocycle 5 was separated from this mixture by crystallization from DMF, and pyrazolyl-1,2,4-triazole 10 was isolated from the mother liquor. The structure of compound 10 was established based on

• reduced pressure to obtain a mixture of 5 and 6 in only a slightly changed ratio (84:16 according to the 1H NMR spectrum). It should be noted that Scheme 6 also explains formation of pyrazolyl-1,2,4-triazole 10 by the reaction of 8 with N2H4·H2O in the presence of TsOH·H2O (Table 1, entries 22 and 23

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins

• Chandra Sekhar Tekuri,
• Pargat Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2023, 19, 1216–1224, doi:10.3762/bjoc.19.89

• -tetraarylporphyrins 1 were synthesized from the corresponding 2-nitro-meso-tetraarylporphyrins in two steps by following the literature procedure [42]. The first step involved an amination of copper(II) 2-nitro-meso-tetraarylporphyrins by using 4-amino-4H-1,2,4-triazole in the presence of NaOH in refluxing ethanol

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• target compounds, which contained two pharmacophores – [1,2-a]pyridine (1H-imidazo[1,2-b][1,2,4]triazole) and peptidomimetic moieties – were evaluated for their antibacterial activity and exhibited a weak effect. Drugs possessing imidazo[1,2-a]pyridine unit. Drugs possessing peptide unit. Diversity of

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

• Elenilson F. da Silva,
• Krist Helen Antunes Fernandes,
• Denise Diedrich,
• Jessica Gotardi,
• Marcia Silvana Freire Franco,
• Carlos Henrique Tomich de Paula da Silva,
• Ana Paula Duarte de Souza and
• Simone Cristina Baggio Gnoatto

Beilstein J. Org. Chem. 2022, 18, 1524–1531, doi:10.3762/bjoc.18.161

• , University of São Paulo, Ribeirão Preto, SP 14040-020, Brazil 10.3762/bjoc.18.161 Abstract Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants. Currently, ribavirin, a nucleoside analog containing a 1,2,4-triazole-3-carboxamide moiety, is a first-line

• with COVID-19 precautions; however, they state that less RSV cases now could reduce immunity and they fear there will be a rebound in infections after the pandemic [4][5][6][7]. As a therapeutic resource, ribavirin, a nucleoside analog prodrug containing a 1,2,4-triazole-3-carboxamide moiety (RBV

• -triazole ring introduced by click chemistry in order to mimic the 1,2,4-triazole-3-carboxamide structure of RBV. This strategy was based on the bioisosteric relationship between both rings established in several papers [32][33][34]. Studies have made modifications at the C-3 and C-28 positions of

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• Plasmodium has been developed and is reported in the literature [24]. Results and Discussion The vinylic SN reaction of 2-nitroperchlorobutadiene (1) with four equivalents of the azoles such as 1H-pyrazole, 1H-1,2,4-triazole, or 1H-benzotriazole affords similarly to [25] the corresponding 1,1

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ], 6,7-dihydro-6-oxo-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine [17], 1,2,4-triazino[5,6-b]indole [18], 1,3,4-thiadiazoline [19], 1,3,4-oxadiazoline [19], 1,2,4-triazoline [19], 3-mercapto-1H-1,2,4-triazole [20], 1,3,4-oxadiazole-2(3H)-thione [20], 4-amino-5-mercapto-4H-1,2,4-triazole [20], and 1,2,4

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• ). It is interesting to note that heterocyclic nitrogen atoms can also react with cyanoguanidine. For example, Zeng et al. reported the conversion of 1,2,4-triazole derivatives into their related biguanide products in good 70% yield by simple reflux heating in ethanol (Scheme 10). The resulting

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• receptor (CCK1R) located in the gastrointestinal tract. It is a potential target for treating obesity and diabetes [5]. Although derivatives of 1,2,3-triazolobenzodiazepines are less studied as to their 1,2,4-triazole fused analogs, 1,2,3-triazolobenzodiazepinone A (Figure 2) has already reached clinical

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines

• Geetanjali S. Sontakke,
• Rahul K. Shukla and
• Chandra M. R. Volla

Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42

• triazolylation of various heterocyclic N-oxides using sulfuryldiimidazole and 1,2,4-triazole, respectively. However, their protocol affords a mixture of C2- and C4-heteroarylated products [52][53]. More recently, Muthusubramanian and co-workers further expanded the scope of Keith’s protocol to a variety of

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• the synthesis of 3-substituted thietanes 400 from (1-chloroalkyl)thiiranes 398 (Scheme 84). Nitrogen-containing aromatic heterocycles, such as 2-chloro-5(6)-nitrobenzimidazole (401) and 3,5-dibromo-1,2,4-triazole (402), were used as nucleophiles in the reaction with chloromethylthiirane (398a) giving

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• Republic 10.3762/bjoc.16.27 Abstract Four-component reactions of 3-amino-1,2,4-triazole or 5-amino-1H-pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication were studied. Unusual for such a reaction type, a cascade of elementary stages led to the formation of

• 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines. Keywords: 5-amino-1H-pyrazole-4-carbonitrile; 3-amino-1,2,4-triazole; 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines; heterocycle; multicomponent reaction; ultrasonication; Introduction Tetrahydropyrimidines are heterocycles of high pharmacological

• . Therefore, the present work is devoted to the study of multicomponent reactions involving 3-amino-1,2,4-triazole or 5-aminopyrazoles, aromatic aldehydes, and pyruvic acid or its esters under ultrasonication. Results and Discussion It was discovered that MCRs involving 3-amino-1,2,4-triazole or 5-amino-1H

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• accessible by variation of the binucleophilic component 1 (instead of 1, 3-amino-1,2,4-triazole, 2-aminobenzimidazole, 3-aminopyrazoles, 4-amino-1,2,3-triazoles, etc. can be used [13]). However, a relatively low reactivity of amine 1 due to the electron deficiency of the tetrazole ring has been reported

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• )-5a was reacted with 3-bromo-5-methoxy-1H-1,2,4-triazole (128) to give N-protected bicyclic amino ester 129 which was next converted into (S)-(+)-127 in two standard steps (Scheme 33) [17]. Its enantiomer was prepared from (2R,1′S)-5a. Lacosamide ((R)-130) is a derivative of ᴅ-serine and has found

Synthesis of ([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)phosphonates and their benzo derivatives via 5-exo-dig cyclization

• Aleksandr S. Krylov,
• Artem A. Petrosian,
• Julia L. Piterskaya,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2019, 15, 1563–1568, doi:10.3762/bjoc.15.159

• available N-unsubstituted 2-hydrazinylpyridines and 2(1)-hydrazinyl(iso)quinolines. Due to the presence of the fused [1,2,4]triazole hetaryl pharmacophore fragment and a phosphoryl group in the obtained compounds they are of great interest as promising substances with potential biological activity

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• APRT limits the number of possible nucleotides that can be synthesized. Thus, for Thermus thermophilus HB27 APRT (TthAPRT), nucleotide synthesis is limited to the closest structural homologs of adenine (Table 1) [1]. Unfortunately, 1,2,4-triazole-3-carboxamide, its analogues, guanine, hypoxanthine, and

• phosphoribosyltransferase only [2]. Unfortunately, we did not find any product in reactions with compounds based on 1,2,4-triazole-3-carboxamide, which was also observed for E. сoli HPRT [15][16]. However, allopurinol and 8-azaguanine are substrates for TthHPRT, and 2-chloroadenine is a substrate for TthAPRT. For 2

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• furnishing the tricyclic 1,2,4-triazole-fused 1,4-benzodiazepines. Keywords: 1,4-benzodiazepine (BDZ); cyclization; hydrazones; oxidation; rearrangement; Introduction Heterocyclic compounds comprising a 1,4-benzodiazepine (BDZ) ring have been a topic of continued interest as they exhibit a wide spectrum of

• achieved when a third heterocycle, especially a 1,2,4-triazolo moiety, was attached to the seven-membered ring as part of 1,4-benzodiazepine [13][14]. Among various reported 1,2,4-triazole-annulated 1,4-benzodiazepines, triazolam (I), estazolam (II), alprazolam (III) and pyrazolam (IV) are prominent

• . Conclusion In summary, an appealing series of 1,2,4-triazole-fused 1,4-benzodiazepines 10 and 13 were prepared via the [3+ + 2]-cycloaddition reaction followed by a cationic [1,2]-rearrangement reaction. The procedure is general and has several advantages such as ready availability of starting materials