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

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

The use of isoxazoline and isoxazole scaffolding in the design of novel thiourea and amide liquid-crystalline compounds

• Itamar L. Gonçalves,
• Rafaela R. da Rosa,
• Vera L. Eifler-Lima and
• Aloir A. Merlo

Beilstein J. Org. Chem. 2020, 16, 175–184, doi:10.3762/bjoc.16.20

• Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal Institute of Chemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 10.3762/bjoc.16.20 Abstract A series of novel thiourea and amide liquid crystals containing 5-membered isoxazoline and isoxazole rings

• . Thiourea and amide derivatives were predominantly SmA mesophase inductors. A nematic mesophase was observed only for thioureas and amides containing an isoxazole ring. Additionaly, the liquid crystal behavior was also dependent on the relative position of nitrogen and oxygen atoms on the 5-membered

• heterocycle. Keywords: amides; isoxazole; isoxazoline; liquid crystal; thiourea; Introduction Thioureas are a structurally diversified group of organic compounds, with technological applications in different areas. The structural diversity of the thiourea moiety is linked to possibly one or both nitrogen

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• use of an inexpensive catalyst, simple reaction conditions, simple work-up without column chromatographic purification for most of products and high yields. Keywords: [3 + 2] cycloaddition; isoxazole; pyrrole; silver catalysis; ynamide; Introduction Silver-catalyzed transformations of alkynes have

• employment of isoxazole nucleophiles in gold-catalyzed formal [3 + 2] cycloaddition reaction of ynamides [31][32], and zinc-catalyzed the reaction of ynol ethers [33], giving the respective multi-substituted pyrrole derivatives efficiently (Scheme 2a) [34][35]. The reaction proceeds via an α-imino gold

• reported [42]. Results and Discussion An initial experiment was carried out with ynamide 4a and isoxazole 5 as the selected substrates based on the known procedure developed by Ye’s group [31]. With pyrrole 6, a 42% yield was obtained using AgNTf2 (5 mol %) catalyst and DCE as the solvent at 80 °C for 2 h

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• functionalized imidazo[1,2-a]pyridines. Mechanistically, the reaction proceeded by Michael type addition of 2-AP and nitrostyryl isoxazole. Further, a CuI-promoted one-electron oxidation followed by loss of a hydrogen radical and a proton, led to the formation of enamine 55. The so formed enamine underwent

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• isoxazole-bearing α-amino esters 46a,b were also prepared via α-hydroxyimino esters. Their preparation started with the alkylation of diethyl malonate (4) with propargyl bromide to give compound 43 (which could not be separated from unreacted malonate and the bis-alkylated derivative). In the next step, [2

• + 3] cycloaddition reactions with nitroethane or 1-nitropropane gave the isoxazole-bearing compounds 44a,b in 23 and 33% yield, respectively. Then, oximation of these compounds gave the α-hydroxyimino esters 45a,b in 50 and 58% and upon their reduction, the expected α-amino esters 46a,b. As depicted

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also explored and the synthesis of other oxazole-bearing α

• function of 16, followed by its coupling with glycine or phenylalanine ethyl esters (respectively 20a and 20b) using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as a coupling agent to give the corresponding amides 21a,b. The isoxazole ring of these compounds was then

• NMR analysis of the crude reaction mixture. Indeed, a slow ring-opening reaction took place upon standing in solution to mainly give the isoxazole isomer 28 along with much less of the target oxazole-bearing α-hydroximino ester 29. Extensive trials to alter the selectivity of the ring opening using

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• . (3aR*,9aR*,Z)-3-Methyl-3a,4,5,8,9,9a-hexahydrocycloocta[d]isoxazole ((±)-16). Yellow oil; yield: 62%; Rf 0.37 (n-hexane/EtOAc 4:1); 1H NMR (CDCl3, 400 MHz): δ 1.80–1.87 (m, 2H, H-4), 1.95 (s, 3H, CH3), 2.02–2.19 (m, 3H, H-5, H-8), 2.21–2.36 (m, 1H, H-8), 2.4–2.54 (m, 1H, H-9), 2.97–3.06 (q, 1H, J1

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• structurally similar rotaxane in which the ammonium station is blocked by N-acetylation shows that the isoxazole moiety acts as a weak second binding station for the wheel. Oxidation of the TTF unit results in Coulombic repulsion between the wheel and the ammonium station which counteracts the energy of

• hydrogen bonding. Detailed electrochemical measurements and digital simulations revealed the ring still to be bound to the ammonium station in the TTF●+ state. However, after double oxidation a wheel distribution of 1:1 between the ammonium and the isoxazole station was found indicating a dynamic motion