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

Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines)

• Michał Nowacki and
• Krzysztof Wojciechowski

Beilstein J. Org. Chem. 2018, 14, 194–202, doi:10.3762/bjoc.14.14

• reaction with 2,4-dichloronitrobenzene (2f), where we obtained 3-(indol-2-yl)-2,1-benzisoxazole 10 instead of the expected indoloquinoline. In an analogous reaction with 1-nitronaphthalene (2g) condensed isoxazole derivative 11 was formed (Scheme 3). The formation of 2,1-benzisoxazoles in reactions of

• construction of the quindoline system. Synthesis of condensed pyridines mediated by a σH-adduct. Formation of condensed isoxazole derivatives. Reaction of unprotected indole ester 1c with 4-chloronitrobenzene. A plausible mechanism for the formation of 11-(phenylsulfonyl)indolo[3,2-b]quinolines. The synthesis

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• ). It is believed that the initially formed α-cyanooximes 85 undergo rapid cyclization to isoxazole derivatives 86. Interestingly, in the case of a more sterically hindered 3-chloronorcamphor oxime, the corresponding α-cyanooxime 85a was obtained, which did not undergo cyclization to isoxazole

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• protons around 6.7–7.7 ppm as well as signals for other substituents. The 1H NMR spectra of N-(1-arylethyl-2-(tert-butylamino)-2-oxo)-N-(5-methylisoxazol-3-yl)-3-phenylpropiolamides 9 exhibit a broad signal for the amide NH group at ≈7.9 ppm, singlet for the isoxazole CH at ≈6.3 ppm, a singlet for the CH

• group in the position 1 at ≈6.0 ppm, a singlet for the isoxazole CH3 group at ≈2.3 ppm, a singlet for the tert-butyl CH3 groups at ≈1.2 ppm, peaks for the aromatic protons around 6.8–7.5 ppm as well as signals for other substituents. As it was found earlier for 2-aminopyrimidines [107][108][109] GBB-3CR

• analysis (Figure 3). In the case of compounds 9 the presence of NOE between the signals of the methyl group and the CH group in the isoxazole moiety allowed to distinguish closely located signals of two CH groups (Figure 4). Ultimately, the structure of compounds 9 was proven by an X-ray analysis of

Isoxazole derivatives as new nitric oxide elicitors in plants

• Anca Oancea,
• Emilian Georgescu,
• Florentina Georgescu,
• Alina Nicolescu,
• Elena Iulia Oprita,
• Catalina Tudora,
• Lucian Vladulescu,
• Marius-Constantin Vladulescu,
• Florin Oancea and
• Calin Deleanu

Beilstein J. Org. Chem. 2017, 13, 659–664, doi:10.3762/bjoc.13.65

• -disubstituted isoxazoles on nitric oxide and reactive oxygen species generation in Arabidopsis tissues was studied using specific diaminofluoresceine dyes as fluorescence indicators. Keywords: chemical elicitor; 1,3-dipolar cycloaddition; isoxazole; nitric oxide; nitrile oxide; reactive oxygen species

• ; Introduction Isoxazoles are an interesting class of N-heterocyclic compounds intensely studied mainly due to their wide range of biological activity [1][2]. Isoxazole compounds show antiviral [3][4], antithrombotic [5][6][7][8][9], analgesic [9], COX-2 inhibitory [10][11], anti-inflamatory [9][11

• ], antinociceptive [12] and anticancer [13] activities. Several isoxazole derivatives have GABAA antagonist [14] and T-type Ca2+ channel blocking activities [15]. Commercial drugs featuring an isoxazole moiety include the COX-2 inhibitor Valdecoxib and the β-lactam antibiotics Cloxacillin and Dicloxacillin. An

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• moieties may increase or decrease the biological activity. A series of isoxazole fused 1-indanones 64 with increased anti-inflammatory and antimicrobial activity has been synthesized by Giles et al. [46]. In this synthesis, diethyl phthalate (61) was reacted with ethyl acetate to obtain indane-1,3-dione

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• dihydropyridine, hydantoin, imidazole, indole, isoquinoline, isoxazole, oxazole, 4H-pyran, pyrazine, pyridazine, pyridine, pyridinone, pyrimidine, pyrimidone, pyrrole, 3H-quinazolin-4-one, quinoline, 1H-quinolin-4-one, and thiophene. For heterocycles that are composed of a fused aromatic ring, such as

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

• Ilya V. Efimov,
• Marsel Z. Shafikov,
• Nikolai A. Beliaev,
• Natalia N. Volkova,
• Tetyana V. Beryozkina,
• Wim Dehaen,
• Zhijin Fan,
• Viktoria V. Grishko,
• Gert Lubec,
• Pavel A. Slepukhin and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2016, 12, 2390–2401, doi:10.3762/bjoc.12.233

• -5-substituted isoxazoles that are otherwise difficult to obtain. Keywords: β-azolyl enamine; [3 + 2]-cycloaddition; isoxazole; isoxazoline; nitrile oxide; Introduction The biological activity and technically useful properties of isoxazoles have made them the focus of both medicinal and materials

• ). It makes prospective the synthesis of new derivatives of isoxazoles conjugated with other azole rings. The few synthetic methods for 4-(azol-5-yl)isoxazoles published in the literature involve the formation of either azole or isoxazole rings in the final step [1][13][14]. Cyclization reactions of 2

• -azolyl enamines bearing isoxazol-5-yl, imidazol-4-yl and imidazol-5-yl moieties with aryl, pyridyl and cyclohexylhydroxamoyl chlorides, pointing to a concerted mechanism of this reaction. Results and Discussion The starting enamines 1a–e bearing imidazole (1a,b) and isoxazole (1c–e) rings were prepared

Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N–O bond-forming cyclization of 2-azidobenzoic acids

• Daria Yu. Dzhons and
• Andrei V. Budruev

Beilstein J. Org. Chem. 2016, 12, 874–881, doi:10.3762/bjoc.12.86

• -azidobenzoate anion photolysis that results in the heterocyclization product. Selected examples of biologically active, fused 2,1-isoxazole derivatives. Photochemical cyclization of substituted 2-azidobenzoic acids and possible reaction mechanism [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• reaction conditions. An intramolecular cross-benzoin condensation between aldehyde and ketone moieties was developed by Suzuki in 2003. The isoxazole-fused cyclohexanone 51 endowed with an aryl aldehyde underwent a smooth cross-benzoin cyclisation in the presence of the thiazolium catalyst 19 and DBU

• . Although the presence of an isoxazole moiety is not a prerequisite for the success of this annulation, its rigid nature presumably renders the reaction highly stereoselective [47]. This simple and mild method allowed the construction of orthogonally protected polycyclic quinones from readily available

Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

• Jochen Kraft,
• Martin Golkowski and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 166–171, doi:10.3762/bjoc.12.18

• substitution product only in traces. The authors attributed the inefficiency of ligand A to the cleavage of the spiro moiety resulting in the formation of thermodynamically more stable aromatic isoxazole B (Figure 1). As part of our ongoing research program towards the design of carbohydrate derived ligands

• substitution using similar PyOx ligands are currently under investigation and will be published elsewhere. Pd-catalyzed cleavage of spiro-bis(isooxazoline) ligand A to isoxazole B and Pd-complex D prepared from spiro-oxazoline C. Synthesis of 2-benzylsulfanyl-1,3-oxazolines 7 and 8. Pd-catalyzed cross coupling

Pyridylidene ligand facilitates gold-catalyzed oxidative C–H arylation of heterocycles

• Kazuhiro Hata,
• Hideto Ito,
• Yasutomo Segawa and
• Kenichiro Itami

Beilstein J. Org. Chem. 2015, 11, 2737–2746, doi:10.3762/bjoc.11.295

• hereroarenes that has been known to be very sluggish with typical ligand systems [68][69][70][71][72]. In this paper, the C–H arylation reactions of isoxazole, indole, and benzothiophene are presented. In addition, direct observation and isolation of PyC-gold(III) complexes are described. Results and

• heteroarene substrates toward oxidative conditions [103][104][105][106][107], their original conditions usually do not work well for these substrates. For example, when isoxazole (1a: 1 equiv) [108][109][110][111] was treated with 1-bromo-4-(trimethylsilyl)benzene (2a: 1 equiv) in chloroform/methanol solution

• heteroarenes with arylsilanes. Direct observation and isolation of carbene-gold(III) complex. Mes = 2,4,6-Me3C6H2, Xyl = 2,6-Me2C6H3, Dip = 2,6-iPr2C6H3. Effect of ligand and oxidant in gold-catalyzed oxidative C–H arylation of isoxazole 1a.a AuCl(PyC)-catalyzed oxidative C–H arylation of heteroarenes with

Fe(II)/Et₃N-Relay-catalyzed domino reaction of isoxazoles with imidazolium salts in the synthesis of methyl 4-imidazolylpyrrole-2-carboxylates, its ylide and betaine derivatives

• Ekaterina E. Galenko,
• Olesya A. Tomashenko,
• Alexander F. Khlebnikov,
• Mikhail S. Novikov and
• Taras L. Panikorovskii

Beilstein J. Org. Chem. 2015, 11, 1732–1740, doi:10.3762/bjoc.11.189

• reaction with sulfur affording the corresponding imidazolethiones under very mild conditions. Keywords: imidazole; isoxazole; NHC carbene; pyrrole-2-carboxylate; relay catalysis; Introduction Pyrrole-2-carboxyate and imidazole units are present in bioactive pyrrole-imidazole alkaloids and pyrrole

• according to Scheme 2, whereby excluding the isolation of often unstable 2H-azirines [34]. Results and Discussion The synthetic scheme (Scheme 2) implies an implementation of all stages (1: generation of azirine 8 from isoxazole 7 under FeCl2 catalysis; 2: formation of phenacylimidazolium ylide 10 induced

• by Et3N; 3: activation of azirine 8 with Et3HN+Br−; 4: reaction of the activated azirine 11 with the imidazolium ylide 10) as a domino reaction under relay catalysis [35][36]. A simple procedure, consisting of stirring a mixture of isoxazole 7, phenacylimidazolium salt 9, FeCl2·4H2O and Et3N in MeCN

Development of variously functionalized nitrile oxides

• Haruyasu Asahara,
• Keita Arikiyo and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2015, 11, 1241–1245, doi:10.3762/bjoc.11.138

• -functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and

• alcohol 11j were also detected (Table 2, entries 18 and 19). In contrast to tosylated amides 8Ab and 8Bb, tosylated N-methyl-5-phenylisoxazole-3-carboxamide 12 exhibited higher reactivity. Upon tosylation under similar conditions 3 did not afford product 12, and isoxazole-3-carboxylic acid 5a, a

• water occurred even at low temperatures because of the higher electron deficiency of the isoxazole ring compared with carbocyclic rings. When, instead of water, less nucleophilic acetic acid was employed for the quench, 12 was isolated in 74% yield and the competitive hydrolysis of 12 was suppressed (6

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde

• Volodymyr V. Tkachenko,
• Elena A. Muravyova,
• Sergey M. Desenko,
• Oleg V. Shishkin,
• Svetlana V. Shishkina,
• Dmytro O. Sysoiev,
• Thomas J. J. Müller and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2014, 10, 3019–3030, doi:10.3762/bjoc.10.320

• δ 9.25, a broad multiplet including peaks for the aromatic protons, a singlet for the OH group, and a doublet for the NH-isoxazole group around δ 6.70–7.84, a multiplet for the 4-CH-group at δ 4.90, a singlet for the CH-isoxazole group at δ 4.71, a doublet for the 3-CH-group at δ 2.94 as well as

Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Yelizaveta G. Gorbunova,
• Ekaterina E. Galenko,
• Kirill I. Mikhailov,
• Viktoriia V. Pakalnis and
• Margarita S. Avdontceva

Beilstein J. Org. Chem. 2014, 10, 1896–1905, doi:10.3762/bjoc.10.197

• , isoxazolium N-ylides, were located by DFT calculations at the B3LYP/6-31G(d) level only for derivatives without a substituent in position 3 of the isoxazole ring. These isoxazolium N-ylides are thermodynamically and kinetically very unstable. According to the calculations and experimental results 2H-1,3

• Manning [4][5] discovered the Rh-catalyzed reaction of diazo esters with 3,5-dialkylisoxazoles, benzo[d]isoxazole and 3-chlorobenzo[d]isothiazole leading to the corresponding 2H-1,3-oxazines, 2H-benzo[e][1,3]oxazine and 2H-benzo[e][1,3]thiazine. The authors assumed that the reaction of isoxazoles A with

• diazo esters B involved an isoxazolium N-ylide intermediate C formed by an attack of the rhodium carbenoid onto the isoxazole nitrogen. Furthermore, ylide C could undergo either a 1,2-shift to directly generate oxazine E or a ring opening to 1-oxa-5-azahexa-1,3,5-triene D, followed by a 6π

A one-pot synthesis of 3-trifluoromethyl-2-isoxazolines from trifluoromethyl aldoxime

• Raoni S. B. Gonçalves,
• Michael Dos Santos,
• Guillaume Bernadat,
• Danièle Bonnet-Delpon and
• Benoit Crousse

Beilstein J. Org. Chem. 2013, 9, 2387–2394, doi:10.3762/bjoc.9.275

• yield the corresponding trifluoromethylated γ-amino alcohols. Keywords: aldoxime; amino alcohol; fluorine; isoxazole; isoxazoline; organo-fluorine; Introduction 2-Isoxazolines are five-membered heterocyclic compounds that have been widely applied in medicinal and organic chemistry. This nucleus is

• (relatively to 7.139 eV, which is the energy difference for the self-cycloaddition process), the dimerization pathway is favored and the yield of isoxazole drops. With only a single regioisomer being isolated, we also considered the coefficients (Table 3) and shapes (Figure 4) of frontier molecular orbitals

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265