Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines

• Pavel S. Silaichev,
• Tetyana V. Beryozkina,
• Vsevolod V. Melekhin,
• Valeriy O. Filimonov,
• Andrey N. Maslivets,
• Vladimir G. Ilkin,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2024, 20, 17–24, doi:10.3762/bjoc.20.3

• synthesis of various nitrogen-containing heterocyclic compounds and have a variety of biological activities [1][2][3][4]. After the discovery of click chemistry [5][6] involving the CuAAC method of 1,2,3-triazole synthesis [7][8], there has been great interest of studing the chemical and biological

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

Active-metal template clipping synthesis of novel [2]rotaxanes

• Cătălin C. Anghel,
• Teodor A. Cucuiet,
• Niculina D. Hădade and
• Ion Grosu

Beilstein J. Org. Chem. 2023, 19, 1776–1784, doi:10.3762/bjoc.19.130

• primary alkyl bromides [36] and cooper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry [37]. In all these cases a templated metal ion–macrocycle complex is used to catalyze the rotaxane formation by connecting two components of the dumbbell-shaped molecule (Figure 1a). In this context, we

• CuAAC click chemistry [38][39][40]. The choice of CuAAC as key step to accomplish the synthesis of the [2]rotaxanes was motivated by its high efficiency [41]. In addition, this reaction proved its versatility for rotaxanes synthesis [15], including chiral [2]rotaxanes [42]. The macrocycles M1 and M2

• synthesis of the axle unit (compound 6 in Scheme 1) we considered a convergent synthetic approach that consist in preparation of the stopper, functionalized with azide groups, decoration of the central pyridine-based moiety with propargyl groups and their connection by CuAAC click chemistry. Thus, as

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

Radical chemistry in polymer science: an overview and recent advances

• Zixiao Wang,
• Feichen Cui,
• Yang Sui and
• Jiajun Yan

Beilstein J. Org. Chem. 2023, 19, 1580–1603, doi:10.3762/bjoc.19.116

• a thiol to a C–C double bond and was first reported in 1905 [80]. It is considered as a click chemistry reaction due to its high yield, stereoselectivity, rate, and thermodynamic driving force. Generally, the thiol–ene reaction is conducted under radical conditions, often photochemically induced [81

• Radical addition is a popular technique for post-polymerization modification of double-bond-containing polymers (Scheme 14). Thiol–ene and thiol–yne “click chemistry” are highly efficient radical processes well-adopted in synthetic chemistry, material fabrication, and chemical biology (cf. section 2.2

• process that usually qualifies for a definition of “click chemistry” [44]. A similar radical addition to vinyl groups takes place in ATRA despite the halogen atom transfer is mediated by a metal complex. Post-polymerization modification by ATRA was pioneered by Jérôme and co-workers [110][111]. In 2014

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

• with alkynes under click chemistry conditions (Scheme 48) [15]. The products were obtained in high yields (93–99%). Cazin and co-workers systematically investigated the [3 + 2] cycloaddition of a series of six azides with seven terminal alkynes catalyzed by different 1,2,3-triazolylidene–CuCl complexes

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

• (bromomethyl)benzene furnished geometrically differing bis(1,2,3-triazole) derivatives. The use of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as ligand for the click step turned out to be very advantageous. The compounds with 1,2-oxazinyl end groups can potentially serve as precursors of divalent

• carbohydrate mimetics, but the reductive cleavage of the 1,2-oxazine rings to aminopyran moieties did not proceed cleanly with these compounds. Keywords: alkynes; azides; copper catalysis; nucleophilic substitution; 1,2-oxazines; Introduction The concept of click reactions [1][2], in particular, the

• 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

Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO₂F₂)

• Xian-Lin Chen and
• Hua-Li Qin

Beilstein J. Org. Chem. 2023, 19, 901–908, doi:10.3762/bjoc.19.68

• (SO2F2) [43], a kind of inexpensive (about 1 $/kg), abundant, and relatively inert electrophile and one of the major sulfur fluoride exchange (SuFEx) click chemistry reagents [44][45], has been successfully applied as an electrophile to react with hydroxy groups to generate fluorosulfonate esters, being

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

• Dileep Kumar Singh Department of Chemistry, Bipin Bihari College, Affiliated to Bundelkhand University, Jhansi, Uttar Pradesh, 284001, India 10.3762/bjoc.19.29 Abstract Among all the available approaches in organic synthesis, the “click chemistry” protocol is very common nowadays to covalently

• -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

• of the synthesis and properties of various porphyrin-triazole hybrids, this review will discuss some of the key reactions involved in the preparation of triazole-linked porphyrin conjugates. Keywords: azide–alkyne; click chemistry; CuAAC; 1,3-dipolar cycloaddition; porphyrin; 1,2,3-triazole

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• the other hand, sodium azide in N,N-dimethylformamide (DMF) reacts with mono-6-O-tosyl-CDs to give CD monoazides in high yields. The obtained mono(6-azido-6-deoxy)-CDs (N3-CDs) are valuable precursors that can be used as starting materials in azide–alkyne click reactions; furthermore, they can be

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• studies, one of us (M. R. E. A.) felt intrigued by the potential of chemical hybridization of cholesterol through simple connections of pharmacophores including sugars, chalcones, quinolone, theophylline, and ferrocene using click chemistry [9][10][11]. Following this strategy, cholesterol was

• synthetic chemistry was expanded to click conjugates such as II and III, and the data was reported [10]. Recently, those studies were revisited, and we now obtained single crystals which allowed to unequivocally establishing the relative configurations of the products by X-ray crystallography. Accordingly

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

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

• -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

• triterpenes to synthesize 1,2,3-triazole derivatives via the Huisgen 1,3-cycloaddition reaction, but, as far as we know, this is the first report of the application of click chemistry to triterpenes with this objective [35][36][37]. Click chemistry is one of the most important tools used for the synthesis of

• biological compounds, including RBV derivatives [38][39]. Owing to the high yields, accessibility, and low cost, the click chemistry synthetic strategy is a promising option for use in medicinal chemistry studies [40]. The desired compounds 7 and 8 were obtained with yields of 68 and 59%, respectively

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

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• reactors (Scheme 12, case A). There, it performs a second role by also becoming a source for a copper catalyst, either by being released into solution or by acting as a surface-active species capable of promoting "click" reactions between alkynes and azides [76][77][78][79][80][81]. The process can be

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

• ) through nanomechanical motion. Recently, the suitability of the four-component rotors to act as catalysts in various click reactions was investigated having a look at nanorotors [Cu2(55)(60)(X)]2+ (with X = 62, 63 or 64), revealing an unexpected correlation between their rotational speed and catalytic

• 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

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• only is environmentally friendly, but also finds significant applications in biological systems (e.g., click reactions, bio-conjugation, and bio-orthogonal chemistry). One of such applications is ligation chemistry, in which “click” chemistry through a [3 + 2] biorthogonal cycloaddition between nitrile

• isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Producing good to excellent yields in short reaction time in aqueous media, our method has the potential for significant applications in biological systems (e.g., click reactions, bioconjugation

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• sialic acid derivatives in good yields and high purity via copper-catalysed azide–alkyne cycloaddition (CuAAC, click chemistry) and evaluated their activity towards TcTS and neuraminidase. Surprisingly, the compounds showed practically no TcTS inhibition, whereas ca. 70% inhibition was observed for

• (CuAAC, click chemistry), from α-azidosialic acid 1 and commercially available terminal alkynes (Figure 2B), and assessed their inhibitory activity towards TcTS and bacterial neuraminidase. Results and Discussion Synthesis of sialic acid derivatives A small series of anomeric 1,2,3-triazole-linked sialic

• acid derivatives was synthesised as outlined in Figure 2B. Emulating our previous work with anomeric azide CuAAC click chemistry [17][22][23][24], the well-known α-azidosialic acid 1 [25] was synthesised from N-acetylneuraminic acid in four steps [26] in good overall yield (55%). The assignment of the

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• the removal of metathesis catalysts is the formation of Ru-DMSO complexes, which do not eluate from a silica column [56]. This allowed us to remove at least the Ru contamination, but we were unable to subject 12 to further modifications such as cross metathesis or thiol-ene click reactions due to poor

• modifications, mainly for solubility reasons. Therefore, we decided to have a closer look into modifications of the longer side chain present in 11 and subjected it to thiol-ene click reactions. Since masked thiols are often found as zinc-coordinating functionalities in HDAC inhibitors, e.g., in the largazoles

• , we treated 11 with thioacetic acid and BEt3/air in THF to give 82% of the thiol-ene click product (Scheme 4). Careful analysis of the NMR spectra revealed that the intermediately formed radical cyclized in an intramolecular 5-exo-trig fashion with the internal double bond to form a tetrahydrofuran

Polymer chemistry: fundamentals and applications

• Bernhard V. K. J. Schmidt

Beilstein J. Org. Chem. 2021, 17, 2922–2923, doi:10.3762/bjoc.17.200

• materials [6]. This thematic issue covers a broad range of current topics in polymer chemistry, from synthesis to materials and applications. In the area of synthetic methods, the use of click photochemistry in polymer and organic molecule synthesis is presented, as well as the combination of polymers with

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• ]. The main approach in the synthesis of the tetrazoles is 1,3-dipolar cycloaddition between azide and nitrile. These reactions often follow the principles of “click” chemistry [20]. Although the formation of tetrazole in the Schmidt reaction of ketones was noted in the original study by Schmidt himself

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• such as antimicrobial properties. A work reported by Koshy et al. in 2018 was testing the use of injectable nanocomposite cryogels for versatile protein-drug delivery [37]. Injectable and porous cryogels were prepared using a bio-orthogonal click chemistry crosslinking approach with alginate employing

• tetrazine-norbornene coupling. Laponite nanoparticles were then incorporated within the walls of the cryogel. The results showed the so-called “click alginate” was able to produce cryogels with an interconnected porous structure, and high deformability allowing it to be used through a 16-gauge needle. The