Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• piperazinone ring. Keywords: benzodiazepine; click reaction; multicomponent reaction; one-pot; piperazinone; polycyclic; triazole; tetrazole; Ugi–azide reaction; Introduction Triazole, tetrazole, and benzodiazepine are privileged heterocyclic rings commonly found in drug molecules and functional materials [1

• . After evaporation of the solvent MeOH, the residue was redissolved in 2 mL of MeCN and heated at 130 °C for 2 h in a sealed vial to give product 7a in 90% yield after purification via Cu-free intramolecular click reaction (Scheme 3C) [46]. This Cu-free intramolecular cyclization provides key practical

• , the reaction of 0.2 mmol each of 1a and 2a led to the formation of Int-I which then reacted with 0.2 mmol each of 9 and 4 to form 1,5-DS-T 5b which consequently underwent lactamization to form 6a followed by an intramolecular click reaction to afford highly condensed polycyclic product 8a in 92

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• methods, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the so-called click reaction [7], has received substantial attention for the selective synthesis of various 1,2,3-triazoles that are of utmost importance in the synthesis of biologically active compounds such as active

• 1.31 mmol NaN3 at 85 °C. After 8 h, 1.06 mmol phenylacetylene (2a), 0.01 mmol CuI, and 0.1 mmol Et3N were added to initiate the click reaction. The mixture was stirred at 30 °C for 12 h. The GC analysis showed complete conversion, and after the workup procedure, 88% 3a was isolated with 98.5% purity

• synthesis of benzyl azide, detailed experimental procedures, and characterization of prepared compounds are reported in Supporting Information File 1. General procedure for click reaction in CyreneTM In a 4 mL screw-cap vial, 1.15 mmol of benzyl azide (1a), 1 mmol corresponding acetylene, 0.1 equiv Et3N

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

• 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

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• preparation and host assembly. The synthesis adheres to a two-synthon approach which relies on the connection of two building blocks through a CuAAC click reaction (Scheme 1). Building block S1, the azide, is not modified in this work and the preparation is achieved with an overall yield of 43% via the

• troubles with the formed complexes in this respect. The final step of the ligand preparation is the CuAAC click reaction. The protecting Boc group of the 8-hydroxyquinoline units was cleaved during the workup right away resulting in ligand L-H2 with 44% yield. Self-assembly in DMSO with zinc(II) via its

• experiments (500 MHz, 500 µM, DMSO-d6, 25 °C) with mixtures of studied analytes showing the selective formation of the 1:1 oxalate host–guest complex [(C2)@L2Zn2]2− in all cases. Two-synthon approach for ligand preparation via CuAAC click reaction of an azide-functionalized, protected 8-hydroxyquinoline and a

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

• dozens of kilodaltons. The main advantage of the gel shift assay is to obtain quantitative information of the protein’s probe modification extent, considering high efficiency of the click reaction. Given the bulkiness of the PEG–azide linker, the bioorthogonal reaction needs some optimization, including

• or scale down and partially automatize the protocol or both. The standard mass spectrometry-based chemical proteomics workflow requires up to 1 mg of total protein, acetone protein precipitation after the ‘click’ reaction to remove the excess of the biotin-containing reagent, desalting of the

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

• high efficiency under physiologically active conditions and the absence of any toxic metal ions. SpAAC is biorthogonal, which allows for the specific labeling and imaging of biomolecules even in living cells and organisms. Recently, a more rapid click reaction was desired and the strain-promoted

• metal-free click reaction was employed to crosslink a partially azidated poly(vinyl chloride). The crosslinking proceeded by simply mixing the polymer and crosslinker in THF and evaporating, and the formation of the crosslinked polymer film was confirmed by the strain–stress curves. The developed method

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

• Sonogashira cyclization sequence from (triisopropylsilyl)butadiyne (118). Subsequent immediate desilylation and Click reaction with organoazides lead to 4-pyrazolyl-1,2,3-triazoles 119 (Scheme 42) [139]. Notably, in some examples, it was even possible to synthesize the organoazides in situ from alkyl halides

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

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• fractionated cell cultures of M. alba with 49 was followed by irradiation with 365 nm light to generate reactive carbene from diazirine. This sequence allowed the formation of covalent bonds between the synthetic probe and binding proteins. The resulting mixture was subjected to a copper-catalyzed click

• reaction with biotin azide, which led to selective pull-down with streptavidin agarose and isolation of the probe–protein covalent complex. Proteomic analysis of the isolated proteins narrowed down the MaMO and MaDA candidates, including several berberine bridge enzyme (BBE)-like enzymes. This FAD-linked

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

• 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

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

• –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

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• 4–9 (100 µM), irradiated at 365 nm, and subjected to the click reaction with TAMRA-N3. In-gel fluorescence scanning revealed that inhibitors 1, 2, 4, and 7 completely suppressed GrsA labeling by probe 3 in the proteomic environment (Figure 4b). Unlike the results obtained for the labeling of

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• nucleophilic substitution of benzylic bromides with sodium azide and a subsequent copper(I)-catalyzed double click reaction in one pot [17]. In summary, these contributions by renowned experts demonstrate the broad diversity of impressive catalytic domino, tandem, and one-pot processes towards many valuable

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes

• Nedra Touj,
• François Mazars,
• Guillermo Zaragoza and
• Lionel Delaude

Beilstein J. Org. Chem. 2023, 19, 1947–1956, doi:10.3762/bjoc.19.145

• and its substituents. The synthesis of 1,2,3-triazolium salts via a “click” reaction is a particularly attractive and straightforward strategy to prepare dithiocarboxylate zwitterions with two different alkyl or aryl groups flanking the carbenoid center and the adjacent CS2 unit. This is in sharp

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• under the catalysis of AcOH at 110 °C for 6 h afforded the monocycloaddition product 19a in 93% LC yield [71]. The isolated compound 19a was used for an N-propargylation to produce compound 20a in 94% LC yield. The following Cu-catalyzed click reaction afforded triazolobenzodiazepine 21a in 88% LC yield

• -aminoisobutyric acid, phenylglycine and valine with Ph or iPr groups could also be used for the synthesis of the monocycloaddition products for the post-condensation reactions. It is worth noting that in the one-pot synthesis involving an intramolecular click reaction, no Cu catalyst was used. A similar reaction

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• catalysts in the click reaction of azides with alkynes at rt [38]. As discussed earlier, Douthwaite and co-workers obtained Cu(I) bromide complexes 56a,b through deprotonation of the NHC precursor with Cu2O (Scheme 19). During workup of complexes 56a and 56b, two more complexes, 75 and 76, were isolated

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

• Hans-Ulrich Reissig and
• Fei Yu

Beilstein J. Org. Chem. 2023, 19, 1399–1407, doi:10.3762/bjoc.19.101

• acetonitrile/water as solvent furnished the exclusively isolated bis(1,2,3-triazole) derivative 12 in excellent 94% yield. These conditions of the one-pot nucleophilic substitution double-click reaction became the standard reaction conditions and were applied in most of the following experiments. When the

• aminopyran and aminooxepane derivatives and goal of this study employing alkyne component G and biazides in situ-generated from H. Synthesis of model compound 3 under conventional conditions and as a one-pot process employing benzyl bromide (5), alkyne 2 and sodium azide as precursors for the click reaction

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• -dipolar cycloaddition reaction between an azide and a terminal alkyne, also popular as "click reaction" or CuAAC reaction. Moreover, the 1,2,3-triazole ring also serves as a spacer and an electron transfer bridge between the porphyrin and the attached chromophores. In order to provide a critical overview

• includes a brief synthetic procedure with reaction conditions, product yields, and photophysical and other properties of the end products. Review Overview of CuAAC click reactions on porphyrins The CuAAC-inspired click reaction is particularly useful for the coupling of two different moieties comprising

• porphyrins used in the Cu(I)-catalyzed click reaction have been metalated prior to the reaction; otherwise, Cu metal can be inserted into the porphyrin cavity. As a result, the catalytic activity of Cu will decrease, it will be more difficult to remove, and more additional steps will be required to

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• proceeded further, in uncatalyzed fashion at room temperature and yielded, after intramolecular azide–alkyne click reaction novel, structurally intriguing bistriazoles. Keywords: α-acetyl-α-diazomethane sulfonamide; intramolecular click reaction; uncatalyzed; room temperature; 1,2,3-triazoles

• molecular scaffold. Pondering various opportunities for post-condensational modifications of the 1,5-disubstituted 1,2,3-triazole core according to this strategy, we turned our attention to such powerful transformation as the azide–alkyne [3 + 2] cycloaddition (also known as the azide–alkyne click reaction

• ]bis([1,2,3]triazolo)[1,5-a:1',5'-d][1,4]diazepine (5a), i.e., the product of the tandem three-component 1,2,3-triazole synthesis followed by intramolecular azide–alkyne click reaction which, apparently, proceeded at room temperature. Product 5a was isolated in respectable 78% yield; therefore, the

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• silyl groups. Both other reagents used for the cleavage in CD chemistry (TBAF and BF3.Et2O) yielded byproducts that unnecessarily complicated the purification. The CuAAC "click reaction" in CD chemistry is also a well-known approach, allowing coupling reactions of azido-containing CDs with different

• catalytical amounts (0.02 equiv) [27] to semi-equivalent [12]. Optimal conditions for a click reaction are a subject to discovery in every case, because temperature, microwave or ultrasonic irradiation, and type of catalyst strongly influence the reaction time and yields. In the preparation of dimer 4, the

• , which can be easily done by shaking the reaction mixture with NaI ethanol/water solution in a separation funnel. The click reaction of compound 8 proceeds at a different rate than 3 under the same conditions. The coupling of 3 can be finished overnight with high yields, whereas the coupling of 8 is much

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• potential supramolecular ligand for 14-3-3ζ. We synthesized a GCP-Lys dimer coupled via Cu(I)-catalyzed click reaction to the chosen emitter equipped with two azide functions (Figure 1 and Supporting Information File 1) and investigated the photophysical properties in detail (Supporting Information File 1

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• investigated and the denitrogenative annulation towards imidazoloquinoxalines could be observed as a competing reaction depending on the alkyne concentration and the substitutions at the quinoxaline. Keywords: click reaction; CuAAC; denitrogenative annulation; imidazole; metal complexes; quinoxaline

Electrochemical vicinal oxyazidation of α-arylvinyl acetates

• Yi-Lun Li,
• Zhaojiang Shi,
• Tao Shen and
• Ke-Yin Ye

Beilstein J. Org. Chem. 2022, 18, 1026–1031, doi:10.3762/bjoc.18.103

• ketones, such as cyclohexanone (see Supporting Information File 1 for details). As illustrated in Scheme 3, the synthetic utility of α-azidoketone was further evaluated [37][38]. Click reaction between 2-azido-1-phenylethan-1-one (2) and ethisterone (28) [39][40][41] readily afforded the target triazole

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• to steric impediments at the phenanthroline site will not engage in complexation with a second phenanthroline (see HETPYP concept [85][86]). The concept was probed by using nanorotors [Cu2(55)(60)(X)]2+ as catalyst (10 mol %) for the click reaction of 9-(azidomethyl)anthracene (65) and (prop-2-yn-1

• -yloxy)benzene (66) at 55 °C (4 h) [94]. Notably, the fastest nanorotor [Cu2(55)(60)(64)]2+ afforded the highest yield of the click product 67 (62%) followed by nanorotors [Cu2(55)(60)(63)]2+ (44%) and [Cu2(55)(60)(62)]2+ (20%) (Figure 15). The analogous tendency was recognized in a second click reaction

• +) and generated a stoichiometric Cu+ output according to the AND gate logic only in truth table state (1,1). The released copper(I) ions self-assembled the four-component rotor [Cu2(55)(60)(73)]2+ which enabled catalysis of a click reaction. In summary, copper(I) ions as stoichiometric output of the AND