Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• [4]. Notable previous efforts include the synthesis of benzothiazine scaffolds connected to other heterocyclic moieties such as piperazine [5], triazole [6][7], hydantoin [8], and pyrazole moieties [9][10]. Very few examples of pyrazolobenzothiazines presenting an amide moiety are published. This

• to inhibit p38α MAPK and 0.5 µM for TNF-α [10]. Pyrazolobenzothiazines containing a triazole moiety have also been studied as potential antibacterial drugs [7]. Other applications of N-substituted benzyl/phenyl acetamide pyrazolobenzothiazines include superoxide anion and DPPH radical scavenging

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

• , results in a spiro-cyclized intermediate XLI that affords the final product by deprotonation and loss of the copper species. Four-component reactions Two different four-component procedures catalyzed by Cu(OTf)2 are reported in the literature, both to access 1,2,3-triazole derivatives. The first one is a

• aldehydes and phenols. The mechanism involves the reaction of the azide with the hemiacetal XLII generated in situ from the aldehydes and alcohols, followed by coupling with the alkynes to form the triazole ring. Both, copper triflate and copper metal are essential for the success of the reaction. On the

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• further diversification of the triazole products, including chemoselective transition metal-catalysed cross-coupling reactions using bifunctional boryl/germyl species. Keywords: chemoselectivity; click chemistry; copper; germanium; triazole; Introduction Since its inception, click chemistry has been

• azide precursors and the formation of a single 1,4-disubstituted triazole product, the copper-catalysed azide–alkyne cycloaddition (CuAAC) remains the archetypal click reaction (Scheme 1) [5]. The reaction has shown applicability on small and large scale, as well as under flow conditions [6], and

• clean conversion to the desired triazole products 1–21 without any observable degermylation or other side reactions that could be anticipated based on transmetalation to Cu [43]. The generality of the CuAAC process was explored using a range of azides (Scheme 2a), with variation of the germanyl alkyne

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• relevant for the cytotoxic activity. The 1,5-disubstituted tetrazole-1,2,3-triazole hybrids synthesized by our group [26] had similar effects to the present compounds, suggesting that 1,5-disubstituted tetrazole and indole are pharmacophoric fragments with significant biological and pharmacological

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• tetrathiafulvalene (TTF) and a triazole ring (Figure 7A) [61]. CD was located around the TTF moiety under neutral conditions; however, it moved to the triazole ring, following TTF oxidization. Meanwhile, the structural control by exploring the solvent polarity was reported by Harada and co-workers using the α-CD

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• usage of directing groups and any metal catalyst. Also, the electronic nature of a substituent at the C4 position of the starting triazole did not negatively impact the regioselectivity. Further, C4 and C5 disubstituted triazoles also produced the N2-arylated product. Remarkably, this is the only

Investigation of a bimetallic terbium(III)/copper(II) chemosensor for the detection of aqueous hydrogen sulfide

• Parvathy Mini,
• Michael R. Grace,
• Genevieve H. Dennison and
• Kellie L. Tuck

Beilstein J. Org. Chem. 2024, 20, 2818–2826, doi:10.3762/bjoc.20.237

• /bjoc.20.237 Abstract The chemosensor properties of a bimetallic terbium(III)/copper(II) complex functionalized with a 4-(2-pyridyl)-1,2,3-triazole ligand for the detection of Cu2+ ions and, aqueous and gaseous hydrogen sulfide was investigated. The 4-(2-pyridyl)-1,2,3-triazole ligand functions both as

• 4-(2-pyridyl)-1,2,3-triazole). A europium(III)/copper(II) complex [Eu(triazole-DPA)3·3Cu]3+(Figure 1), functionalized with 4-(2-pyridyl)-1,2,3-triazole serving as both an antenna chromophore and a receptor for Cu2+ ions, previously demonstrated theoretical limits of detection (LoD) of 1.1 μM for

• (DO2A)(triazole-DPA)·Cu]+ (Ln = Eu and Tb, Figure 1). We found that both sensors gave good sensitivity for detection of aqueous H2S, however, only the europium variant, [Eu(DO2A)(triazole-DPA)·Cu]+, gave a luminescent increase in the presence of gaseous H2S. Exposure of [Tb(DO2A)(triazole-DPA)·Cu]+ to

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• in MeOH at room temperature with a short reaction time. Some of them were further functionalized with a 1,2,3-triazole ring via copper-catalyzed azide–alkyne cycloaddition (CuAAC) and deprotected with trifluoroacetic acid. Several hybrids were evaluated against six cancer cell lines, displaying GI50

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

• -triazole, thiazole, or pyridine were synthesized by the reaction of 3,5-di-tert-butyl-o-benzoquinone or 3,5-di-tert-butyl-6-methoxymethylcatechol with different heterocyclic thiols. The S-functionalized catechols were prepared by the Michael reaction from 3,5-di-tert-butyl-o-benzoquinone and the

• corresponding thiols. The starting reagents such as substituted 1,3,4-oxadiazole-2-thiols and 4H-triazole-3-thiols are characterized by thiol–thione tautomerism, therefore their reactions with 3,5-di-tert-butyl-6-methoxymethylcatechol can proceed at the sulfur or nitrogen atom. In the case of mercapto

• -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

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• analogues, a novel tetrakis-triazole-based H-bond donor catalyst 111 was identified as most promising. Among different nucleophilic allylating reagents, 2-methallyltributyltin (107) emerged as optimal in terms of reactivity and enantioselectivity. It was speculated that the enantioinduction is realised via

• situ-generated N-acylquinolinium ions, catalysed by a tetrakis-triazole HBD catalyst [40]. Chiral phosphoric acid-catalysed aza-Cope rearrangement of in situ-formed N-α,α’-diphenyl-(α’’-allyl)methyliminium cations reported by Rueping et al. 2008 [41]. Tandem (R)-VANOL-triborate-catalysed asymmetric aza

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• interrupted CuAAC mechanism [65]. The thiotriazole product of this reaction, which is indistinguishable in the protein-level downstream analysis, is formed by coupling between protein free thiol groups and the triazole–copper adduct (Figure 4). However, its formation can be avoided by eliminating the free

• . The fragmentation of the triazole ring leaving the primary amine and b-ion resulting from the fragmentation of the TEV-recognition peptide sequence. The chemical cleavage of the linker to release probe–peptide conjugates is achieved mainly by the change of the pH or via reducing conditions to release

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• physical organic chemistry with data-driven analysis techniques, in particular MLR, to gain a greater understanding of the enantioselectivity-determining steps for a C–N coupling catalysed by CPA derivatives (Figure 15A) [143]. Based on their findings that π–π interactions between the catalyst’s triazole

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• ) is more energetically demanding than the counter monoadduct (out) due to steric factors. The second azide addition follows this step. The alkyne, which is diagonally positioned relative to the triazole group, shows the highest reactivity due to its significant distortion. This finding correlates with

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

•  5). In fact, arylamine 3fa, produced from furan-substituted 1,3-diketone 1f and a 5-fold excess of benzylamine, could be prepared in 18% crude yield (after 7 days, see Supporting Information File 1, page S9). Finally, all attempts to perform the reaction with 1,2,3-triazole 1,3-diketone 1g (σm/σp

• 0.043/0.011) with model amine series failed (7 days reaction time in each case). This result is in good agreement with low Hammett constants of the triazole-substituent of 1,3-diketone 1g, which are close to the calculated Hammett constants of the phenyl group (σm/σp 0.055/0.012). Quantum-chemical

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• selectivity, features a 1,2,3-triazole-4-yl unit as the substituent at the tertiary amine-containing quinuclidine motif, whereas C30 and C31 have an ethyl group attached to the ring in this position. Additionally, catalyst C31 has a longer-chain linker, but its squaramide NH groups are more acidic due to

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

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• electromediated by iodine would furnish aldehyde 56. Electrogenerated iodine would further assist the reaction with ammonia to form N-iodo aldimine intermediate 57. Subsequent radical cycloaddition between 56 and 57 would furnish cyclic hydrazinyl radical 58. Finally, the triazole would be obtained after hydrogen

• cation intermediate enabling the construction of pyrazole, triazole and oxadiazole derivatives, while the electrooxidation of unprotected NH2 hydrazones constitutes a useful mean to access to relevant diazo compounds as products or synthetic intermediates. When coupled with a second reactant

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• mild oxidation of primary and secondary benzylic alcohols to aldehydes and ketones as an alternative to λ5-iodanes. Results and Discussion Initially, we investigated a variety of pyrazole-, triazole-, and oxazole-substituted hydroxy-NHIs previously developed by our group [25]. However, none of them

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• ][10][11][12][13][14]. For example, such molecules can be utilized to access free amines [3][13] and undergo Staudinger-type ligations [14]. Furthermore, they can be very efficiently employed for triazole-forming 1,3-dipolar cycloadditions with alkynes (“click-chemistry”) [9][10][11][12]. As a

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• of Technology, Kaiserstraße 12, 76131 Karlsruhe, Germany 10.3762/bjoc.20.121 Abstract A synthesis route to access triazole–pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of

• the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In

• addition, the compatibility of the method with solid-phase synthesis is shown exemplarily. Keywords: azide; click reaction; CuAAC; pyrazole; triazene; triazole; Introduction Nitrogen-containing heterocycles are central scaffolds in medicinal chemistry and are incorporated in most small-molecule drugs [1

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• to Boulton–Katritzky rearrangement are furazanes and furoxanes. In the case of furazanes the recyclization leads to 1,2,3-triazoles with an oxime moiety in the side chain [13][14]. At the same time 1,2,3-triazole N-oxides are formed from similar furoxanes [15]. Furthermore, special attention is paid

• be noted that based on NMR spectroscopy data the synthesized product 3b exists as a mixture of E/Z isomers. Having in hands hydrazone 3 we tried to perform the Boulton–Katritzky rearrangement into corresponding 1,2,3-triazole 4. In order to achieve the best yields of product 4b we varied the used

• , intramolecular recyclization accompanied by opening of the isoxazole ring and formation of the N–N bond leads to intermediate B. Finally, target 1,2,3-triazole 4 is produced via acidification of anion B. Next, we tried to expand the presented rearrangement to hydrazones derived from aliphatic hydrazines (MeNHNH2

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• and Figure 2). Like the oxindole scaffold, 1,2,3-triazole is also considered a privileged unit in drug discovery since compounds having this structure have a broad spectrum of biological activities, and have been widely used to create anticancer drug candidates [24][25]. The copper-catalyzed azide

• –alkyne cycloaddition (CuAAC) reaction, or commonly entitled “click” reaction, is a widely and straightforward tool to access the 1,2,3-triazole ring [26][27]. Due to the presence of an alkyne group on the Ugi-adduct 5bb (Scheme 2) we decided to use the CuAAC reaction to introduce a 1,2,3-triazole unit

• into the scaffold. Benzyl azide (6), obtained using a previously reported procedure [27], was used in the CuAAC reaction. The α-acetamide carboxamide 1,2,3-triazole oxindole hybrid 7 was easily obtained in 61% yield using Cu(OAc)2 as catalyst, ascorbic acid, DMF as solvent, and microwave reaction

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• isoxazolo[4,5-b]pyridines 12 were obtained in pure form, however, cyclization of hydrazone 11a provided an inseparable mixture of two compounds which could be attributed to the target isoxazolo[4,5-b]pyridine 12a and triazole 13a formed as a result of Boulton–Katritzky rearrangement (Scheme 5). When this

• ). All other compounds 12 bearing no electron-withdrawing groups in the aryl moiety readily afforded the corresponding triazole derivatives in high yields under relatively mild conditions (K2CO3, DMF, 60 °C, Scheme 5). Substituents in the pyridine ring did not affect this transformation thus indicating

• that they do not participate in the stabilization of the pyridine-3-olate anion. It should be noted that the 4-(2-pyridyl)[1,2,3]triazole fragment is part of some pharmaceutically oriented molecules such as tradipitant, an experimental neurokinin-1 receptor antagonist [31], MU1787, a highly selective