Synthesis Of Isoxazolines Research Articles

Visible-Light-Mediated Three-Component Strategy for the Synthesis of Isoxazolines and Isoxazoles.

Isoxazolines and isoxazoles commonly serve as core structures of many therapeutic agents and natural products. However, the metal-free and catalysis-free strategy for the synthesis of these privileged motifs at room temperature remains a challenging task. Herein, we report a three-component strategy to afford diverse isoxazolines and isoxazoles via [3 + 2] cycloadditions of in situ-formed nitronates and olefins/alkynes under visible-light irradiation.

The synthesis of isoxazolines and dihydrooxazines by Pd-catalyzed oxyalkynylation alkenyl oximes with alkynyl bromides

Synthesis of isoxazolines and dihydrooxazines bearing an alkyne group by Pd-catalyzed oxyalkynylation of alkenyl oximes with alkynyl bromides. This new approach has a broad substrate scope and good functional tolerance.

Synthesis of isoxazoline and pyrazoline derivatives

Synthesis of isoxazoline and pyrazoline derivatives

Koser’s Reagent Mediated Oxidation of Aldoximes: Synthesis of Isoxazolines by 1,3-Dipolar Cycloadditions

AbstractA metal- and base-free, robust, and convenient approach for the synthesis of isoxazoline derivatives is reported. This protocol involves 1,3-dipolar cycloaddition between in situ generated nitrile oxides from the corresponding aldoximes using [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser’s reagent) and maleimides, styrene and acrylonitrile. The described methodology is very attractive as it is operationally simple, has broad scope, and does not require any base, metal, or other additives.

Ring Closure of Nitroalkylmalonates for the Synthesis of Isoxazolines under the Acylation Conditions

AbstractAcylation of nitroalkylmalonates was found to yield substituted isoxazoline derivatives. This redox‐neutral transformation has a wide substrate scope and produces target products with yields up to 92%. Various substituents (aryl, alkyl, and ester) at the C3 and C4 positions of the resulting isoxazolines were also tolerated. A quick assembly of the isoxazoline ring starting from nitroalkenes and malonates was successfully developed. Control experiments showed that the intramolecular ring closure is the most likely key mechanistic step. Subsequent transformations into pyrrolidine and furane derivatives demonstrated the synthetic utility of the obtained products.magnified image

Intramolecular Electrochemical Oxybromination of Olefins for the Synthesis of Isoxazolines in Batch and Continuous Flow

AbstractA highly regioselective protocol for the synthesis of isoxazolines through cascade C−O and C−Br bond formation has been developed. The electrochemical approach uses traceless electrons as a sole source of oxidant, thus avoiding the use of stoichiometric organic or inorganic oxidants and provides a mild and environmentally benign alternative pathway for the synthesis of a wide range of valuable substituted isoxazolines from alkenyl oximes in good yields.

Hypervalent-iodine mediated one-pot synthesis of isoxazolines and isoxazoles bearing a difluoromethyl phosphonate moiety.

A one-pot, regioselective 1,3-dipolar cycloaddition of in situ generated (diethoxyphosphoryl)difluoromethyl nitrile oxide toward selected alkenes and alkynes is reported. This protocol enables facile access to 3,5-disubstituted isoxazolines and isoxazoles bearing a CF2P(O)(OEt)2 moiety in good to excellent yields, under mild reaction conditions.

Acyclic nitronate olefin cycloaddition (ANOC): regio- and stereospecific synthesis of isoxazolines.

We report the first demonstrations of intra- and intermolecular acyclic nitronate olefin cycloaddition (ANOC) reactions that enable the highly efficient syntheses of isoxazolines bearing various functional groups. This general approach to accessing γ-lactone fused isoxazolines was hitherto unprecedented. The room temperature transformations reported herein exhibit wide substrate scopes, as evidenced by more than 70 examples, including the generation of five tricyclic isoxazolines. The robustness of this methodology was confirmed by a series of trials that afforded highly functionalized isoxazolines. Both experimental results and density functional theory calculations indicate that these transformations proceed via the in situ formation of acyclic nitronates together with concerted [3+2] cycloaddition and tert-butyloxy group elimination processes to give regio- and stereospecificity.

Discovery, development, chemical diversity and design of isoxazoline-based insecticides

Isoxazoline is a 5-membered heterocycle present in the active compounds of many commercial veterinary anti-ectoparasitic products. The molecular target of isoxazolines is the inhibition of GABA-gated chloride channels in insects. These facts have inspired the use of the isoxazoline scaffold in the design of novel insecticide compounds. The main strategies used for isoxazoline synthesis are either the 1,3-dipolar cycloaddition between a nitrile oxide and an alkene or the reaction between hydroxylamine and an α,β-unsaturated carbonyl compound. This review highlights the utilization of isoxazoline as insecticide: its mode of action, its commercial preparations and its consideration in the design of novel insecticides. Similarity analyses were performed with 235 isoxazoline derivatives in three different cheminformatic approaches - chemical property correlations, similarity network and compound clustering. The cheminformatic methodologies are interesting tools to use in evaluating the similarity between commercial isoxazolines and to clarify the main features explored within their derivatives.

Palladium-Catalyzed Enantioselective Synthesis of Isoxazolines

Key words isoxazolines - enantioselectivity - asymmetric catalysis - palladium catalysis

Recent advances in the oxime-participating synthesis of isoxazolines.

Isoxazoline compounds are used as important intermediates for the synthesis of organic molecules, which are widely used in the chemical and life science industries. Oxime-participating cyclization has emerged as an efficient strategy for the construction of isoxazolines. This review is devoted to highlighting the main achievements (since 2010) in the development of methodologies for the synthesis of isoxazolines. According to the reaction mechanism, the oxime-participating synthesis of isoxazolines can be mainly classified into four reaction types: iminoxyl radical-initiated intramolecular cyclization, intermolecular radical addition-initiated cyclization, intramolecular nucleophilic cyclization, and [3 + 2] cycloaddition. Meanwhile, miscellaneous examples are also illustrated, such as [2 + 2 + 1] cycloaddition. Representative reactions will be discussed for each of the highlighted synthetic strategies. In addition, the enantioselective synthesis of isoxazolines is also illustrated in this review.

Synthesis of Isoxazolines and Oxazines by Electrochemical Intermolecular [2 + 1 + n] Annulation: Diazo Compounds Act as Radical Acceptors.

Reported herein is an unprecedented synthesis of isoxazolines and oxazines through electrochemical intermolecular annulation of alkenes with tert-butyl nitrite, in which diazo compounds serve as radical acceptors. Notably, [2 + 1 + 2] and [2 + 1 + 3] annulations occur when styrenes and allylbenzenes are used as substrates, respectively. The latter reaction undergoes group migration to form more stable radical, manifesting radical route instead of conventional 1,3-dipolar cycloaddition occurs. Moreover, scale-up experiments suggest the potential application value of these transformations in industry.

Redetermination of the Structure of a Water-Soluble Hypervalent Iodine(V) Reagent AIBX and Its Synthetic Utility in the Oxidation of Alcohols and Synthesis of Isoxazoline N-Oxides.

The structure of a water-soluble hypervalent iodine(V) reagent AIBX is re-examined through its single-crystal X-ray analysis and theoretical calculations including Mayer bond order and localized orbital locator (LOL) and AIBX is believed to be a pseudocyclic iodylarene because of the strong electron-withdrawing nature of the trimethylammonium cation on its phenyl ring, which would decrease the electron density of carboxylic anion and make the ortho-carboxyl oxygen anion incapable to form hypervalent bond with iodine atom. However, the cyclic benziodoxole structure of AIBX could be obtained by adding a Brønsted acid, which was supported by the calculation result including the increase of Mayer bond order and the shortening of the I-O bond length. Moreover, the fact that the system of AIBX and TFA could oxidize various alcohols to their corresponding carbonyl compounds would indicate that AIBX constitutes a cyclic benziodoxole structure under acidic conditions. In addition, an efficient method has been developed for the synthesis of isoxazoline N-oxides via AIBX-induced dehydrogenative cyclization using β-keto esters as substrates and methyl nitroacetate as a nucleophile.

Synthesis of Isoxazolines by the Electrophilic Chalcogenation of β,γ-Unsaturated Oximes: Fishing Novel Anti-Inflammatory Agents.

Herein, we describe a new strategy to prepare chalcogen-functionalized isoxazolines. The strategy involves the reaction of β,γ-unsaturated oximes with electrophilic selenium and tellurium species, affording 19 new selenium- and tellurium-containing isoxazolines in good yields after 1 h at room temperature. The method was efficiently extended to the synthesis of 5 new (bis)isoxazoline ditellurides. One of the prepared compounds, 3-phenyl-5-((phenylselanyl)methyl)-isoxazoline, demonstrated better anti-inflammatory and antiedematogenic effects than the reference drug Celecoxib.

General 5-Halomethyl Isoxazoline Synthesis Enabled by Copper-Catalyzed Oxyhalogenation of Alkenes.

A general and efficient oxyhalogenation of unsaturated ketoximes has been achieved through copper catalysis with diethyl bromomalonate, N-chlorosuccinimide, and N-iodosuccinimide, yielding 5-chloromethyl, 5-bromomethyl, and 5-iodomethyl isoxazolines in good to excellent yields.

Potassium iodate ($$\hbox {KIO}_{3}$$) as a novel reagent for the synthesis of isoxazolines: evaluation of antimicrobial activity of the products

Abstract A novel reagent for the synthesis of isoxazolines has been reported. Aryl aldoximes were made to react with alkenes in the presence of \(\hbox {KIO}_{3}\) as the oxidising agent. This new reagent has been useful as an oxidant in the synthesis of isoxazoline and its function is attributed to the generation of nitrile oxide, which is an important intermediate for the synthesis of the valuable heterocycle like isoxazoline.Graphical Abstract SYNOPSIS A novel reagent for the synthesis of isoxazolines has been reported. Aryl aldoximes were treated with alkenes in the presence of \(\hbox {KIO}_{3}\) as the oxidising agent to obtain isoxazolines.

Catalytic Enantioselective Synthesis of 3,4,5‐Trisubstituted Isoxazoline N‐Oxides and Regioselective Synthesis of 3,4,5‐Trisubstituted Isoxazoles

An efficient catalytic asymmetric synthesis of 3,4,5‐trisubstituted isoxazoline N‐oxides and regioselective synthesis of 3,4,5‐trisubstituted isoxazoles has been described. α‐Nitrocinnamates and α‐nitrobenzophenones were utilized as Michael acceptors respectively. Hydroquinine derived thiourea in combination with cesium carbonate was effective for the synthesis of isoxazoline N‐oxides whereas stoichiometric di‐isopropylethylamine (DIPEA) was the best choice for isoxazole synthesis. In both cases a range of aryl and heteroaromatic groups was tolerated.

Copper nitrate-mediated synthesis of 3-aryl isoxazolines and isoxazoles from olefinic azlactones.

A copper nitrate-mediated [2 + 2 + 1] cycloaddition reaction was developed for the expedient synthesis of pharmacologically interesting 3-aryl substituted isoxazolines and isoxazoles through C[double bond, length as m-dash]C bond cleavage. Copper nitrate is employed as a reaction promoter and precursor of nitrile oxides. The given approach features a new mode of cycloaddition from olefinic azlactones, copper nitrate and unsaturated compounds with wide substrate scope, good functional group tolerance and operational simplicity.

Synthesis of Isoxazolines and Isoxazoles via Metal-Free Desulfitative Cyclization

A novel, one-pot reaction for the synthesis of isoxazolines and isoxazoles is developed via a cascade process under metal-free conditions. The approach involves the formation of intramolecular C–N and C–O bonds and intermolecular C–C bonds from aromatic alkenes or alkynes and N-hydroxysulfonamides using hypervalent iodine(VII) and iodine as the oxidant. Activation of C–H and C–C bonds/construction of C–O bonds/elimination of SO2/C–N bond formation is achieved in sequence­ in the reaction system.

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

Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.