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

• formation releasing Cu(OTf)2. The final bicyclic product 33 arises from isomerization and water elimination. Recently, Singh's research group developed a cascade process to access imidazo[1,2-a]pyridines-linked isoxazoles 35. Isoxazole carbaldehydes treated with 2-aminopyridines and isonitriles in the

• . From the mechanistic point of view, it is expected that the reaction proceeds via formation of an imine XXXIV between isoxazole carbaldehyde, activated by the copper salt, and 2-aminoazine, which in turn undergoes a non-concerted [4 + 1] cycloaddition involving isonitrile to give the imidazole ring of

• isoxazole-linked imidazo[1,2-a]azines 35. Synthesis of 2,3-dihydro-1,2,4-triazoles 36. Synthesis of naphthopyrans 37. Synthesis of benzo[g]chromene derivatives 38. Synthesis of naphthalene annulated 2-aminothiazoles 39, piperazinyl-thiazoloquinolines 40 and thiazolocoumarins 41. Synthesis of furo[3,4-b

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• only one azirine-2,2-dicarboxylic acid derivative from a certain isoxazole precursor. Herein, we would like to report a method for the synthesis of 2H-azirine-2,2-dicarboxylic acids and their various derivatives from a single starting material, 3-substituted 2H-azirine-2,2-dicarbonyl dichloride 2, via

• isoxazole ring, both with electron-donating and electron-withdrawing groups, and the tert-butyl-substituted isoxazole 1j, we proceeded to obtain dicarboxylic acids 6 (Scheme 2). The isomerization of isoxazoles 1 into diacyl chlorides 2 was achieved by applying the conditions for the isomerization of 3-aryl

• -5-chloroisoxazoles [25][26][27] using anhydrous FeCl2 as a catalyst and carrying out the reaction in acetonitrile at rt for 2 h. After TLC showed the disappearance of the starting isoxazoles 1, the reaction mixture was treated with water and acids 6a–i were isolated in 64–98% yield. Isoxazole 1j did

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt

• Dominik L. Reinhard,
• Anna Schmidt,
• Marc Sons,
• Julian Wolf,
• Elric Engelage and
• Stefan M. Huber

Beilstein J. Org. Chem. 2024, 20, 2401–2407, doi:10.3762/bjoc.20.204

• donors in recent years. Herein, a new structural motif for this compound class was developed: iodoloisoxazolium salts, bearing a cyclic five-membered iodolium core fused with an isoxazole ring. A derivative of this class was synthesized and investigated in the solid state by X-ray crystallography

• abstractions, e.g. to activate gold chloride complexes [18][19]. Therefore, besides the development of new bidentate catalyst motifs, we were still interested in the optimization of these “simpler” derivatives. Thus, we designed a new catalyst motif [20] featuring an isoxazole ring, XB donor 7Z, and compared

• it with our known iodonium species in the activation of Au(I)–Cl bonds. Results and Discussion As immediate precursor to the target structure 7Z, the literature-known isoxazole 10 was synthesized via a Cu(I)-catalyzed cycloaddition between (2-iodophenyl)acetylene (8) and benzyl nitrile oxide, which

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

• reaction of 1,3-diketones 1e and 1f with aliphatic amines was expected. Indeed, the reaction of 1,3-diketones 1e or 1f with benzylamine was sluggish, and a number of undefined side-products were formed (LC control). m-Isoxazole arylamine 3ea was isolated in low yield (21%) after heating for 6 days (Scheme

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• et al. (Scheme 13) [41]. Isoxazole: Homoibotenic acid (HIBO) analogues are known ligands with pharmacological bioactive profile towards ionotropic and metabotropic glutamate receptors (iGluR and mGluR). 4-Substituted HIBO compounds 97 and 98 (Scheme 14) portrayed by Madsen et al. [68] and Kromann et

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• synthesis of 2H-furan-3-ones from mestranol [23]. Initially, a 1,3-dipolar regioselective cycloaddition occurred between the alkyne group of mestranol and an alkanonitrile oxide generated in situ from the corresponding oxime, yielding isoxazoles 31. Later, a reductive ring cleavage of the isoxazole ring was

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

• , 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

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

• either annulation of an isoxazole fragment to a pyridine cycle or vice versa formation of a pyridine ring based on appropriately substituted isoxazoles. In the first case (Scheme 1A) 3-halo- [11][15][16][17][18][19] or 3-hydroxypyridines [8][20] bearing a suitable functionality in position 2 were used

• -b]pyridine took place, followed by a base-promoted decarbonylation/isoxazole ring opening. Such transformations have been previously reported for benzo[d]isoxazoles with a carbonyl or carboxyl group in position 3 or 3-unsubstituted benzo[d]isoxazoles [25][26][27][28][29]. This means that the formyl

• group of compounds 7 should be protected prior to the attempted isoxazole ring formation. Indeed, reactions of 7a–c with ethylene glycol gave dioxolane derivatives 9a–c which were converted into isoxazolo[4,5-b]pyridines 10a–c in high yields under mild conditions (Scheme 4). The obtained result prompted

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

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

• 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to

Lewis acid-promoted direct synthesis of isoxazole derivatives

• Dengxu Qiu,
• Chenhui Jiang,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2023, 19, 1562–1567, doi:10.3762/bjoc.19.113

• Dengxu Qiu Chenhui Jiang Pan Gao Yu Yuan College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.19.113 Abstract Isoxazole derivatives were synthesized via a one-pot method utilizing 2-methylquinoline derivatives as template substrates, sodium

• nitrite as a nitrogen-oxygen source, and solely using aluminum trichloride as the additive. This approach circumvents the need for costly or highly toxic transition metals and presents a novel pathway for the synthesis of isoxazole derivatives. Keywords: aluminum trichloride; Lewis acid; isoxazole

• derivatives; sodium nitrite; transition metals; Introduction The isoxazole derivatives not only exist in many natural products [1][2][3] and pharmaceutical intermediates [4][5][6][7], but also have great application values in organic synthesis [8][9] (Figure 1). In the past decades, many methods have been

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• dihydropyrazoles 54 as products (Scheme 22) [59]. A credible pathway for the production of isoxazole 53 is illustrated in Scheme 23. The interaction of 1 with BF3·Et2O resulted in intermediate I that is in balance with I’. Cleavage of the N–S bond of I afforded cationic species PhS+ II, which activated the double

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• in 83 and the enantioregulation was achieved by BINOL-derived chiral phosphoric acid P22. An amine functionality was crucial in the isoxazole ring to enhance the nucleophilicity of the adjacent carbon atom. In addition, the amine hydrogen forms an H-bond with the catalyst along with another hydrogen

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• investigated for FPDs: the [4 + 2] cycloaddition with alkenes resulting in pyran-annulated products [27][28][29][30][31][32][33][34] and the [3 + 2] cycloaddition with nitrones resulting in isoxazole-annulated products [35][36][37] (Scheme 2). However, formal [4 + 1] cycloaddition reactions for FPDs remain to

• crystal X-ray analysis (CCDC 2201614). As evinced by the NMR data, only one diastereomer of product 3aa was obtained. Contrary to the isoxazole-annulated products of a [3 + 2] cycloaddition of nitrones to FPDs [35], product 3aa appears to be stable on storage in solution, which was confirmed by the fact

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

• Timur O. Zanakhov,
• Ekaterina E. Galenko,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2022, 18, 738–745, doi:10.3762/bjoc.18.74

• -triaryl-substituted and 1,2,5,6-tetrasubstituted nicotinates. Keywords: isoxazole; methyl nicotinate; molybdenum hexacarbonyl; 4-pyridone; ring expansion; Introduction Pyridine moieties are present in many natural products, drugs, pesticides and industrial materials. Pyridine fragments are used in drugs

• formation of pyridone 5 (route b), is less likely due to the lower electrophilicity of the ester carbon compared to the acyl carbon. To check this, isoxazole 1g was synthesized and reacted with Mo(CO)6 in wet acetonitrile at 60 °C for 2 d to give pyridone 2g in 45% yield. The reaction at 70 °C was completed

• ][28], we checked the possibility of using NaBH4/NiSO4·7H2O [25], H2/PtO2/NiRaney [26][27] and H2/NiRaney [28] to obtain pyridone 2g from isoxazole 1g. However, analysis of reaction mixtures, obtained by using the above reductants, showed the formation of a large amount of products, but pyridone 2g was

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

• -aminopyrazoles 5 with very similar EC50 values of about 0.5 μM are representatives of the different classes of compounds: 3,4-dihydroisoquinoline 5g, 4-fluorophenylpiperazine 5k, and isoxazole 5o. Furthermore, among the sulfides 9, the 4-chlorophenylthiopyrazole 9e stands out with an EC50 of 0.2 ± 0.04 µM

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

• alkynes to activate them for a decent yield of the isoxazole products, thus limiting the scope of the substrates in this method. In addition, this method requires high heat and produces very poor regioselectivity of the products [17][18]. The addition of copper catalysts in this route can help the

• reaction proceed at room temperature and improve both the regioselectivity and yields of the isoxazoles. However, these catalysts only work for the reaction with terminal alkynes and only produce 3,5-disubstituted isoxazole products (Figure 1) [19][20]. The synthesis of 3,4,5-trisubstituted isoxazoles from

• ). In addition, there are competing reactions leading to the O-trapping product and the C-trapping product of the nitrile oxides (Figure 2, paths C and D). We were interested in the optimization of the reaction conditions leading to the isoxazole products (path D, Figure 2). For this purpose, we chose 4

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• prove useful for accessing small quantities of medicinally interesting BCP-1,3,4-oxadiazole compounds for biological testing. Additionally, the reaction of 1,3-substituted isoxazole 1m under these conditions was investigated. Despite high degrees of decomposition, it was possible to isolate the desired

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• analysis, 1H, 13C, and 15N NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data. Keywords: β-enamino ketoesters; heterocyclic amino acids; 15N-labeled 1,2-oxazole; NMR (1H; 13C; 15N); 1,2-oxazole (isoxazole); X-ray structure analysis; Introduction 1,2-Oxazoles (isoxazoles) constitute an

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• ]. Recently, a Hg(OTf)2-catalyzed one-pot cyclization of nitroalkyne 175 and alkyne had been reported to synthesize indole derivatives 176. Based on this strategy, the one-pot method to synthesize indole derivatives had been developed [112]. Similarly, benzo[c]isoxazole was also formed in excellent yields

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines

• Greta Utecht-Jarzyńska,
• Karolina Nagła,
• Grzegorz Mlostoń,
• Heinz Heimgartner,
• Marcin Palusiak and
• Marcin Jasiński

Beilstein J. Org. Chem. 2021, 17, 1509–1517, doi:10.3762/bjoc.17.108

• -quinones, competitive reaction courses involving either ethylenic C=C or carbonyl C=O bonds were observed. For example, the more polar arylnitrile oxides and 1,4-benzoquinones reacted via addition to the C=C bond to give fused isoxazole derivatives [10][11][12] as well as with the C=O bond yielding

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

• containing an isoxazole moiety is of key interest in this study since previously our group reported [19] a successful usage of 3-aminoizoxazoles as unusual amine components in the Ugi-4CR reaction and here we continue to build molecular diversity of isoxazole-derived Ugi products and their successors

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides

• Vladimir Ilkin,
• Vera Berseneva,
• Tetyana Beryozkina,
• Tatiana Glukhareva,
• Lidia Dianova,
• Wim Dehaen,
• Eugenia Seliverstova and
• Vasiliy Bakulev

Beilstein J. Org. Chem. 2020, 16, 2937–2947, doi:10.3762/bjoc.16.243

• , Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium 10.3762/bjoc.16.243 Abstract N-Sulfonyl amidines bearing 1,2,3-triazole, isoxazole, thiazole and pyridine substituents were successfully prepared for the first time by reactions of primary, secondary and tertiary heterocyclic

• sulfonyl azides. With the purpose of the synthesis of heterocyclic N-sulfonyl amidines bearing various heteroatoms in the ring, namely nitrogen, sulfur and oxygen atoms, we have studied reactions of thioamides of 1,2,3-triazole-, isoxazole-, thiazolecarboxylic acids and 2,5-dithiocarbamoylpyridine with

• -carbothioamides 1i–l, the reaction of the primary thioamide of 2-aminothiazole-4-carboxyamide (1m) with sulfonyl azides 2a,c is succesful in n-propanol at reflux temperature, to afford N-sulfonyl amidines 3ab and 3ac bearing a 2-aminothiazole ring in very good yields (Scheme 4). 3-Methyl-5-phenyl-isoxazole-4-N

Thermodynamic and electrochemical study of tailor-made crown ethers for redox-switchable (pseudo)rotaxanes

• Henrik Hupatz,
• Marius Gaedke,
• Hendrik V. Schröder,
• Julia Beerhues,
• Arto Valkonen,
• Fabian Klautzsch,
• Sebastian Müller,
• Felix Witte,
• Kari Rissanen,
• Biprajit Sarkar and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2020, 16, 2576–2588, doi:10.3762/bjoc.16.209

• the [2]rotaxane NDIRot, which was obtained in 43% yield (Figure 3a). The formation of the isoxazole can be recognized by the strong downfield shift of the proton Hj in the 1H NMR spectrum (Figure 3b, for 2D spectra and signal assignment, see Supporting Information File 1, section 5.1). Furthermore, a

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles

• Kazuyuki Sato,
• Akira Kawasaki,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2020, 16, 1411–1417, doi:10.3762/bjoc.16.117

• Kazuyuki Sato Akira Kawasaki Yukiko Karuo Atsushi Tarui Kentaro Kawai Masaaki Omote Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan 10.3762/bjoc.16.117 Abstract Fluorescent molecules based on a fluorinated isoxazole scaffold were

• , fluorescent probes having an isoxazole scaffold are rare and the limited examples that are available also contain other fluorophores such as styryl, anthranyl, or pyrenyl groups in the molecules. We recently reported the synthesis of 3,5-diaryl-4-fluoroisoxazoles 3 that were found to have planar structures

• substituent into the isoxazole scaffold led to an increasing fluorescent intensity and exhibited a redshift in the emission intensity. Interestingly, the excitation maximum of 3 showed a redshift of approximately 20 nm with the incorporation of a single fluorine atom into the isoxazole scaffold in comparison