First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• compounds to give diarylated (oxoalkyl)malonates [6]. In the reaction using tin(II) chloride as the Lewis acid, the ring opening and nucleophilic attack of the nitro group occur, to produce functionalized isoxazolines (reaction d) [7]. In contrast, denitration under basic conditions generates highly

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

• phosphate buffer under weakly acidic conditions (pH 4.0) at room temperature for 15–24 h and generated 3,5-disubstituted isoxazolines and 3,4,5-trisubstituted isoxazoles in good yields (Figure 1) [28]. Notably, no metal catalysts were used in this method. The development of organic reactions in water not

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• nitriles in moderate to good yields. Zhang and co-workers developed an efficient methodology for the synthesis of cyanated isoxazolines from the corresponding alkenyl oximes under mild reaction conditions (Scheme 25) [48]. The dual role of tert-butyl nitrite as oxidant and as a nitrogen source further

• catalyst. Synthesis of cyanated isoxazolines from alkenyl oximes catalyzed by [RuCl2(p-cymene)]2 in the presence of tert-butyl nitrite. Proposed mechanism for the synthesis of cyanated isoxazolines from alkenyl oximes. Oxidative cyanation of differently substituted alcohols. Cyanation of tertiary amines

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• view of chemodifferentiation. The reactions were performed with various olefin metathesis catalysts to find the most optimal conditions (Figure 1). The starting divinyl-substituted bicyclic isoxazolines were synthesized according to literature methods, as shown in Figure 2, utilizing nitrile oxide

• oxide 1,3-dipolar cycloaddition/ROM/CM strategies was presented. The stepwise functionalization of norbornadiene across the ring olefin bonds generated fluorine-containing alkenylated cyclopentane-fused isoxazolines. The synthetic protocol was based on selective nitrile oxide cycloaddition to the

• norbornadiene C=C bond, followed by ROM of the resulting cyclopentane-fused isoxazolines. In the final step, selective CM by chemodifferentiation of the newly created olefin bonds on the resulting alkenylated derivatives took place. As coupling olefin partners in CM reactions, several commercial fluorine

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

• heteroaromatic systems, especially those comprising two heteroatoms such as pyrazoles [28][29], isoxazoles [30], and thiazoles [31][32]. Recently, we reported the selective fluorination of isoxazoles, to give monofluorinated isoxazoles 3 or trifluorinated isoxazolines 4 in moderate to good yields (Scheme 1) [33

Synthesis of 3-substituted isoxazolidin-4-ols using hydroboration–oxidation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles

• Lívia Dikošová,
• Júlia Laceková,
• Ondrej Záborský and
• Róbert Fischer

Beilstein J. Org. Chem. 2020, 16, 1313–1319, doi:10.3762/bjoc.16.112

• -hydroxypyrrolidines certainly makes the 4-hydroxyisoxazolidines important and valuable structural fragments in drug discovery. Keywords: 2,3-dihydroisoxazoles; diastereoselectivity; heterocycles; hydroboration–oxidation; isoxazolidin-4-ols; Introduction 2,3-Dihydroisoxazoles (often referred to as 4-isoxazolines

• alcohols. As a consequence, we assumed that the hydroboration–oxidation reaction of 2,3-dihydroisoxazoles would be an excellent way to prevent this obstacle. Recently, Kang et al. [29] reported the first hydroboration–oxidation reaction of the 5-substituted 4-isoxazolines even though the access to 4

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

• reactions of oxime radicals. These reactions are classified into cyclizations involving C–H bond cleavage and cyclizations involving a double C=C bond cleavage. Keywords: iminoxyl radicals; isoxazolines; oxidative cyclization; oxime radicals; oximes; Introduction Free radicals in which an unpaired

• or 61). As a result of the reaction, a 5-membered cycle is formed via the formation of C–O (products 58 and 60) or C–N bond (product 61) in accordance with the ability of oxime radicals to act as O- or N-radicals. The formation of the heterocycles, mainly isoxazolines/isoxazoles, from unsaturated

• the β-position were transformed into isoxazolines or isoxazoles by oxidative cyclization [114] under the action of TEMPO and K2CO3 (Scheme 23). The presence of aryl substituents at the β-position of the oxime contributed to high yields of the desired products (63a–c, 55–87%), in the presence of only

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

• study of gels derived from low molecular mass gelators [15][16], and consequently the investigation of gelators of low molar mass with liquid crystal proprieties remains active [17][18]. In addition, isoxazolines and isoxazoles have been identified as promising templates in liquid crystal development

• differential scanning calorimetry (DSC). Results and Discussion Synthesis In order to generate molecular structural diversity in thioureas, three sets of amines carrying 5-membered isoxazolines/isoxazoles (see Scheme 1) were employed and condensed with acyl isothiocyanates, as outlined in Scheme 2. Amines 3, 4

• , 8, 9, 12 and 13 were then prepared by [3 + 2]-1,3-dipolar cycloaddition of nitrile oxide (ArCNO) formed in situ from oximes and a number of alkenes as dipolarophiles, to yield the precursors of the cycloadducts isoxazolines 2, 7 and 11 regioselectively. The cycloadducts were subjected to SnCl2

Application of chiral 2-isoxazoline for the synthesis of syn-1,3-diol analogs

• Juanjuan Feng,
• Tianyu Li,
• Jiaxin Zhang and
• Peng Jiao

Beilstein J. Org. Chem. 2019, 15, 1840–1847, doi:10.3762/bjoc.15.179

• our continuous efforts in asymmetric syntheses and applications of chiral 2-isoxazolines [49][50][51]. Results and Discussion Our synthesis commenced with a chiral 3,5-disubstituted-2-isoxazoline 3 or 4, which were prepared from silyl nitronate through an asymmetric 1,3-dipolar cycloaddition developed

• be easily converted into several syn-1,3-diol analogs, demonstrating the usefulness of chiral 2-isoxazolines. Experimental 1: To a dry Schlenk tube were added Cu(OTf)2 (144 mg, 0.4 mmol), chiral bisoxazoline B (139 mg, 0.52 mmol) and anhydrous CH2Cl2 (4 mL) under N2. After stirring at room

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

• functionalized derivatives such as bicyclic lactones, γ-lactams or isoxazolines, derived from various cyclodienes and to evaluate their chemical behavior under Ru-catalyzed ring-opening conditions (Scheme 2). First, the ring opening of racemic bicyclic γ-lactone (±)-3 (derived from cyclodiene 1 via β-lactam

• most efficient. The observed results regarding the current ROM processes were somewhat surprising, the overall comparison of these experimental investigations in the ROM may depend strongly on the structure of the substrates. The valuable dialkenylated compounds (lactones, lactams, isoxazolines) with

• stereogenic centers. The resulting diolefinated aminolactones, isoxazolines or lactam derivatives with multiple stereogenic centers might be considered to be interesting highly-functionalized three-dimensional compounds for further derivatizations. Extensions of the ROM of various bicyclic, conformationally

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores

• Sang Won Park,
• Soong-Hyun Kim,
• Jaeyoung Song,
• Ga Young Park,
• Darong Kim,
• Tae-Gyu Nam and
• Ki Bum Hong

Beilstein J. Org. Chem. 2018, 14, 1028–1033, doi:10.3762/bjoc.14.89

• of pharmaceutical and medicinal chemistry [6][7][8][9][10][11]. Not surprisingly, the construction of diverse heterocyclic cores including isoxazolines and pyrazolines has garnered much attention from synthetic chemists [12][13][14][15]. Among precedent synthetic methods, the functionalization of

• , diverse halonium sources have been utilized for the synthesis of isoxazolines via halocyclization. Furthermore, transition metal-, visible light, and hypervalent iodine-mediated oxidative cyclization protocols provide isoxazoline backbones bearing diverse substituents such as –SR, -CF3, -OH and halogens

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• located in the γ-position through a β to γ flip (Scheme 7). The formation of isoxazolines (±)-15 and (±)-16 in the presence of 1 equiv of Deoxofluor involves rather simple reaction steps as only one of the hydroxy groups is transformed into a leaving group in each case (T13 and T14, respectively). In

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

• heterocycles using nitrosoalkenes as intermediates. An early example is the reaction of sulfonium ylides 92 with α-halo ketoximes 1 leading to isoxazolines 93 reported by Bravo [11] and Gilchrist [83] (Scheme 35). The process is believed to proceed via the generation of a nitrosoalkene intermediate (NSA

• observed. Triphenylarsonium ylides were also studied in the reaction with nitrosoalkenes, yet lower yields of isoxazolines 93 were obtained as compared to sulfonium ylides [11]. Following the same reaction pattern, Cheng and co-workers [84] applied diazo compounds 96 instead of sulfonium ylides 92 in the

• addition of dicarbonyl compounds to a nitrosoalkene followed by a silver-mediated radical cyclization of the resulting oximes 6 to final isoxazolines 100. Importantly, the reaction is well-tolerated by various substituents both in halooxime and in dicarbonyl compounds producing isoxazolines 100 in moderate

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

• Somaia Kamouka and
• Wesley J. Moran

Beilstein J. Org. Chem. 2017, 13, 1823–1827, doi:10.3762/bjoc.13.177

• cyclization of N-propargylamides and the second involves the cyclization of β-amidoketones. These are proposed to proceed through different mechanisms and have different substrate scopes. Keywords: amides; catalysis; cyclization; hypervalent iodine; isoxazolines; Introduction Hypervalent iodine reagents are

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

• known as reactive 1,3-dipoles involved in 1,3-dipolar cycloaddition reactions with various dipolarophiles generating five-membered heterocyclic compounds, such as isoxazoles, isoxazolines, oxadiazoles, oxadiazolines, dioxazolidines etc. [23][24][25]. Intermediate nitrile oxides are usually generated in

• compounds with isocyanates in the presence of tertiary alkylamines [33]. Generally, the cycloaddition reactions of nitrile oxides to alkenes yield isoxazolines or a mixture of isoxalines and isoxazoles. Cycloaddition reactions of nitrile oxides to alkynes yield isoxazoles directly, without a catalyst, but

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

• at the B3LYP/Def2-TZVP level of theory combined with D3BJ dispersion correction. The reactions of benzonitrile oxide with both E- and Z-imidazolyl enamines have been shown to proceed stereoselectively to form trans- and cis-isoxazolines, respectively. The preference of E-isomers over Z-isomers

• chemistry over the years [1]. Isoxazoles have been found in natural products [1], and they exhibit anticancer [2], antiviral [1], anti-inflammatory [3], antidiabetic [4], anti-Alzheimer [5] and many other types of biological activity [6]. Isoxazolines and isoxazoles have been applied as chemosensors, liquid

• enamines 1a–e with hydroxamoyl chlorides 2a–h mainly afford aromatic isoxazoles 4b,d,f–p and intermediate isoxazolines were not detected by TLC analysis. Conversely, TLC allowed to observe the formation of imidazolylisoxazolines 3 as a result of the reaction of enamines 1a,b with hydroxamoyl chlorides 2

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• process involves the 1,3-dipolar cycloaddition of alkynes 182 with in situ generated nitrone 185 to afford isoxazolines 186 which rapidly rearrange to aziridinylphosphonates 183. An efficient method for the synthesis of 1,2,3-triazoles is the copper(I)-catalyzed Husigen cycloaddition of azides with

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• formation of a C,O-bond and generation of the five-membered heterocycle. Hydroxy, carboxy and oxime moieties were tested as nucleophiles for this reaction, leading to the corresponding tetrahydrofurans, γ-lactones and isoxazolines, respectively. The chemistry depicted in Scheme 13 was also used for the

N–O Cleavage reactions of heterobicycloalkene-fused 2-isoxazolines

• Jaipal R. Nagireddy,
• Geoffrey K. Tranmer,
• Emily Carlson and
• William Tam

Beilstein J. Org. Chem. 2014, 10, 2200–2205, doi:10.3762/bjoc.10.227

• bond cleavage reactions of heterobicycloalkene-fused 3-methyl-2-isoxazolines were investigated. Optimal cleavage conditions were found with Raney nickel/AlCl3 mediation in aqueous methanol. The reaction provided a diverse collection of novel heterobicycle-fused β-hydroxyketones with good to excellent

• yields (66–95%) and without the need for chromatographic purification. Keywords: azabicycloalkene; β-hydroxyketone; 2-isoxazoline; oxabicycloalkene; Raney nickel; Introduction 2-Isoxazolines 1 are practical precursors to countless structural motifs found in nature. Various carbonyl compounds 2, β

• -hydroxyimines 3, β-hydroxynitriles 4, β-aminoketones 5, γ-aminoalcohols 6 and oximes 7 can all be readily attained through ring cleavage of 2-isoxazolines using suitable reagents for each transformation (Scheme 1) [1][2][3][4][5][6][7]. In recent years, there has been considerable interest in applying this

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

• Raoni S. B. Goncalves Michael Dos Santos Guillaume Bernadat Daniele Bonnet-Delpon Benoit Crousse BioCIS CNRS, Faculté de Pharmacie, Labex-LERMIT, Univ Paris Sud, 5 rue J. B. Clément, 92290 Châtenay-Malabry, France 10.3762/bjoc.9.275 Abstract Functionalized 3-trifluoromethyl-2-isoxazolines and 3

• -trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to

• 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

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• pyrrolidines, isoxazolines and their derivatives [49][50][51][52]. We therefore considered that it should be possible to develop a mild and practical flow-based process to form isothiocyanates from the corresponding reactive nitrile oxide intermediates. Our strategy makes use of two immobilised reagents (a

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO₄

• Leandro Lara de Carvalho,
• Robert Alan Burrow and
• Vera Lúcia Patrocinio Pereira

Beilstein J. Org. Chem. 2013, 9, 838–845, doi:10.3762/bjoc.9.96

• respective carbonylated isoxazolines and, therefore, causing a decrease in yield. These last compounds could be identified through 1H and 13C NMR spectroscopy. The signals at 9.5 ppm, and 201 and 159 ppm revealed the presence of an aldehyde function and a sp2 carbon bond of an isoxazoline ring (spectra not

Titanium-mediated reductive cross-coupling reactions of imines with terminal alkynes: An efficient route for the synthesis of stereodefined allylic amines

• Kebin Mao,
• Guoqin Fan,
• Yuanhong Liu,
• Shi Li,
• Xu You and
• Dan Liu

Beilstein J. Org. Chem. 2013, 9, 621–627, doi:10.3762/bjoc.9.69

• ], iodocyclocarbamates [19] and isoxazolines [20]. Although it has been reported that allylic amines can be synthesized by methods such as amination of allylic alcohols [21][22][23][24], direct allylic amination of simple alkenes [25][26][27], Morita–Baylis–Hillman reaction [28], alkenylation of imines [29][30][31][32

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• dipolarophiles to yield aryl isoxazolines with the boronate ester function intact and available for subsequent reaction. Keywords: dipolar cycloaddition; heterocycle; nitrile oxide; hypervalent iodine oxidation; pinacol boronic acid esters; Introduction Metal-mediated coupling reactions to form carbon–carbon

• convenient substrate would be the arylboronate nitrile oxide 1, which would undergo 1,3-dipolar cycloaddition to give isoxazolines 2. This latter compound could in turn be coupled with heterocycles or aryl groups to give insecticidal [5] derivatives of type 3 (Scheme 1). The utility of arylboronic acids and

• alkenes [15], alkynes [16][17], and benzyne [18][19], to give Δ2-isoxazolines and isoxazoles. These are interesting sources of bioactive compounds in their own right, but isoxazoles are particularly valuable for their latent functionality as β-hydroxyketones, β-aminoalcohols, 1,3-diols, and a range of

Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines

• Melinda Nonn,
• Loránd Kiss,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2012, 8, 100–106, doi:10.3762/bjoc.8.10

• opening of the isoxazoline reductive ring to the corresponding highly functionalized 2-aminocyclopentanecarboxylates occurred stereoselectively with good yields. Keywords: amino acids; cycloaddition; functionalization; isoxazolines; reduction; Introduction Isoxazoline-fused amino acids are important

• bioactive derivatives in organic and medicinal chemistry (e.g., conformationally restricted aspartate and glutamate analogues) [1][2][3][4][5][6]. As a consequence of their ability to undergo reductive ring opening, isoxazolines are of interest as precursors for the synthesis of highly functionalized