Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• native amino acids, by enzymatic coupling, or by bioengineering for the incorporation of non-canonical amino acids [18][19]. In fact, incorporating non-natural amino acids significantly broadens the scope of reactions that can be used in bioconjugation. As an example, click chemistry comprises one

• potential to overcome these limitations, particularly by enabling modifications under mild and controlled conditions. Unlike classical methods, such as thiol chemistry [22] or widely used click reactions [33], photocatalysis could provide innovative solutions to produce ADCs, especially in terms of

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• dynamic covalent chemical (DCC) self-assembly followed by click-chemistry functionalization, containing chiral residues for organocatalysis. (C) Example of a 3D-MOF, comprised of metal clusters linked by dicarboxylate linkers, containing TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) residues for

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

• established as a powerful approach for molecule synthesis. Strategies within click chemistry include several widely used reactions such as the (hetero-)Diels–Alder reaction [1][2], alkene hydrothiolation [3], and an array of amide-bond-forming chemistries [4]. However, by virtue of the access to alkyne and

• 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

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , this strategy may offer a broad selection of compounds with biological interest. Asgari et al. [63] described an efficient two-step approach for the synthesis of triazolobenzodiazepines in good to excellent yields (Scheme 17). The protocol is initiated by Ugi-4CRs followed by sequential click

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

• behavior is a rotational barrier of the phenylamide residue which is visible for the complex [L2Zn2] and the free ligand L-H2 due to splitting of the neighboring methylene unit (Hh). An important sidenote is that preliminary tests with the deprotected click product of non-functionalized dipropargylamine as

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

• probe–proteins enrichment [94]. The underlying and unifying advantage of these protocols is the use of a mixture of hydrophilic and lipophilic carboxylate-coated magnetic beads to replace the protein acetone precipitation after CuAAC. After the ‘click’ between the probe–protein conjugates and affinity

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

• introduced into octadehydrodibenzo[12]annulene. In this report, the synthesis of new octadehydrodibenzo[12]annulene derivatives, regioselective double addition of organic azides, and an application to crosslinking polymers are described. Keywords: annulene; click chemistry; polymerization; strain-promoted

• azide–alkyne cycloaddition; Introduction The strain-promoted azide–alkyne cycloaddition (SpAAC) is one of the most representative metal-free click chemistry reactions [1][2][3][4][5]. SpAAC has been mainly employed in bioconjugation in the fields of chemical biology and medicinal chemistry due to its

• 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

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

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

• 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

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• -ynylcarbamoyl)-1,3-dioxolane-2-carboxamide [3] and FAM azide, 5-isomer (Broadpharm BP-22544, San Diego, CA) by click chemistry [29] and was purified by flash column chromatography on silica gel. Preemergence efficacy of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine-based FAT inhibitors 7b, 7c, and 13b as well as

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

• trisubstituted 3-iodoindoles, which are valuable substrates for the synthesis of, e.g., blue emitters in good yield [16]. The power of double click reactions toward functionalized bis(1,2,3-triazole) derivatives has been demonstrated in the Full Research Paper by Reissig and Yu. The authors successfully combined

• 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

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• physicochemical properties of the family of these compounds that have been investigated is provided to clarify their potential for future applications. Keywords: click chemistry; donor–acceptor conjugate; intramolecular charge transfer; photoluminescence; photoinduced electron transfer; Introduction Push–pull

• optoelectronics) [1][2]. The synthesis of push–pull chromophores is often achieved through click-type reactions between electron-rich alkynes and electron-deficient alkenes, which is a reliable and atom-economical method. Diverse chromophores can be obtained via this method, depending upon the choice of alkynes

• of click-type [2 + 2] cycloaddition (CA)–retroelectrocyclization (RE) reactions, offering means for preparing these coveted push–pull chromophores [7]. A review conducted in 2023 comprehensively explored the optoelectronic properties of TCBDs along with their photovoltaic applications [8]. The

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