Isoxazoline Ring Research Articles

Isoxazoline-Ring Fused Derivatives of Sc3n@C80 and C60: The Internal Effect on the Exohedral Configuration

Fullerenes are unique among all carbon allotropes as their molecular structures can be fully confirmed by single-crystal X-ray diffraction. With metal atoms or metal complexes encapsulated, endohedral metallofullerenes (EMFs) redistribute electrons between the internal unit and the cage, and thus afford different electronic structures and different chemical properties compared to empty fullerenes. However, because of the relatively low yield of endohedral metallofullerenes, only a limited number of chemical modifications have been reported for them. In this work, an isoxazoline ring was added to Sc3N@C80 for the first time to form only one mono-adduct with high regio-selectivity (2b). An analogous product was obtained for empty cage C60 (2a). X-ray crystallography has revealed their structures, as shown in Fig. 1. The addition site of exohedral moieties of C60 was the [6,6]-bond while it is a [5,6]-bond for Sc3N@C80. Inside the Sc3N@C80, disorder of the Sc atoms represents the dynamic motion of the cluster, and the sum of the three Sc–N–Sc angles (342°) suggests that the trimetallic nitride cluster slightly derives from a coplanar structure, confirming the motion control effect of the exohedral modification. Moreover, it is very interesting to find that the configuration of exohedral moieties differed in 2a and 2b.In detail, the methoxy indicated by the arrow shown in Fig. 1 occurs at opposite sides of the benzene plane. These results reveal the significant internal effect on the exohedral configuration. Figure 1. Drawings of 2a and 2b showing thermal ellipsoids at the 30% probability level. Arrows indicate the special methoxy group that changes conformations when added to different fullerenes. Solvent molecules are omitted for clarity. Figure 1

Competitive retro‐cycloaddition reactions in heterocyclic fullerene bis‐adducts ions: selective removal of the heterocyclic moieties

We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-, pyrrolidino- and methanofullerene moieties. The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions.

Investigations on intramolecular 1,3-dipolar cycloadditions for the synthesis of isoxazolo-annulated pyrrolidines, piperidines and azepanes

Pyrrolidines, piperidines, and azepanes with annulated isoxazole, isoxazoline or isoxazolidine rings were prepared by intramolecular 1,3-dipolar cycloadditions of nitrones or nitrile oxides. The corresponding 1,3-dipoles were obtained from N-Boc-protected and N-allyl-, N-propargyl- or N-(3-butenyl)-substituted 2-aminoethanal or 3-aminopropanal.

Synthesis of soluble core cross-linked polystyrene star polymer by application of acrylate-nitrile oxide ‘click chemistry’ using metal-free reagents

In the present work, we have established a novel and environmentally benign method, whereby a 1,3-dipolar cycloaddition reaction has been applied using a non-toxic reagent, iodosobenzenediacetate [PhI(OAc)2], instead of the conventional copper-based reagents for the development of star-branched polymers. Here we have demonstrated the synthesis of core cross-linked star (CCS) polymers via the formation of isoxazoline ring using ‘click reaction’ between acrylate functionalities in a polymer chain and in situ generated nitrile oxide groups from a cross-linker added externally. In the initial step, a well-defined styrenic block copolymer with acrylate-functionalized middle-block was synthesized by controlled radical polymerization (RAFT) using α,α′-xylyl-bis(dithiobenzoate) as a chain transfer agent using 4-vinyl benzyl chloride and styrene as comonomers. Thereafter, the chlorobenzyl groups were converted into acrylate by reaction with acrylic acid. In the following step, core cross-linked star (CCS) polymers were synthesized by reacting the above block copolymer and oxime-functionalized cross-linkers (bi- and tetra-functional) using PhI(OAc)2 ‘click chemistry’. Formation of CCS polymers was confirmed from NMR, FTIR, GPC and DLS studies.

Solid-Phase Synthesis of Diverse Spiroisoxazolinodiketopiperazines

A convenient, efficient protocol to prepare diverse spiroisoxazolino-diketopiperazines via a parallel solid-supported synthesis was developed. The key steps are (1) a coupling reaction of an amino acid; (2) tosylation with concomitant β-elimination to form an α, β-unsaturated ester; (3) a 1,3-dipolar cycloaddition with an oxime to form isoxazoline rings; and (4) cyclic cleavage to release the product from the resin. All reaction steps and workup procedures were modified to allow the use of automated or semiautomated equipment. A 100-member demonstration library with two diversity sites was prepared in good purity and acceptable overall yields.

Structure and stability of isoxazoline compounds

Structure of isoxazoline compounds formed via the reaction of alkyl-substituted benzonitrile oxides with ethylene was determined by X-ray diffraction method. Isoxazoline ring is flattened, the bond lengths in it depend slightly on the nature of substituents (CH3, C2H5) and their position in the benzene ring and the angle of rotation relative to the isoxazoline ring. The connection N-O has a length 1.422 A. Thermal decomposition of isoxazolines in a liquid phase (160–280°C) is accompanied by the release of acetaldehyde and aromatic nitrile. Both the structure of the cycle and its stability is practically independent of the structure of an aromatic substituent. The rate constant of the initial stage is characterized by the low significance of kinetic parameters, E = 104°8 kJ mol−1 and log a(A/c) = 7.2±0.8. The results obtained are rationalized in terms of biradical mechanism of isoxazoline ring-opening that includes an efficient recombination of the biradical and its disappearance as a result of synchronous multi-center rearrangement with the release of acetaldehyde.

Synthesis of Podophyllotoxin and its Derivatives via NiCl2/NaBH4 Reduction of Isoxazoline Ring

Synthesis of Podophyllotoxin and its Derivatives via NiCl2/NaBH4 Reduction of Isoxazoline Ring

(2RS,5'RS)-3',4'-Bis(4-chloro-phen-yl)-3,4-dihydro-spiro-[acridine-2,5'(4'H)-[1,2]oxazol]-1(2H)-one.

The title compound, C27H18Cl2N2O2, represents a racemic mixture of the corresponding R,R and S,S diastereomers. The isoxazoline ring adopts an envelope conformation with the spiro C atom deviating by 0.093 (2) Å from the rest of the ring. The six-membered keto-substituted carbocycle has a sofa conformation with the methyl­ene C atom adjacent to the spiro center deviating by 0.289 (2) Å from the mean plane of the remaining atoms. In the crystal, mol­ecules are linked via C—H⋯Cl inter­actions and C—Cl⋯O halogen bonds [2.958 (2) Å, 171.39 (7)°], which generate bifurcated R 2 1(6) ring motifs resulting in C 2 1[R 2 1(6)] chains running parallel to [010].

3-(4-Chloro-phen-yl)-5-phenyl-4,5-di-hydro-1,3-oxazole.

In the title compound, C15H12ClNO, the isoxazoline ring adopts an envelope conformation with the C atom bearing an unsubstituted phenyl ring as the flap atom. The chlorinated phenyl group is nearly in-plane with the four coplanar atoms of the heterocycle and the corresponding mean planes enclosing an angle of 1.16 (7)°. The unsubstituted phenyl group attached to the envelope flap atom approaches a nearly perpendicular orientation relative to the isoxazoline ring with a dihedral angle of 74.93 (7)°. In the crystal, weak C—H⋯O, C—H⋯N and C—H⋯π inter­actions connect the mol­ecules into layers perpendicular to the a axis.

Syntheses of Isoxazoline-Based Amino Acids by Cycloaddition of Nitrile Oxides and Their Conversion into Highly Functionalized Bioactive Amino Acid Derivatives

The present account illustrates the syntheses of isoxazoline-based amino acids by the cycloaddition of 1,3-dipolar nitrile oxides to the C–C double bond of unsaturated amino acid derivatives, with focus on the regio- and stereoselectivities of the transformations. Emphasis is also placed on the syntheses of highly functionalized amino acids by means of isoxazoline ring opening. The syntheses of various pharmacologically active compounds and their analogues via the above strategies are described. 1 Introduction 2 1,3-Dipolar Cycloadditions of Nitrile Oxides 3 Syntheses of Isoxazoline-Based Amino Acids 3.1 Syntheses of Isoxazoline α-Amino Acids 3.2 Syntheses of Isoxazoline γ-Amino Acids and Their Transformation into Bioactive Derivatives 3.3 Syntheses of Isoxazoline β-Amino Acids 3.3.1 Syntheses of Highly Functionalized Cyclic β-Amino Acids by 1,3-Dipolar Cycloaddition of Nitrile Oxides 4 Cycloaddition of Nitrile Oxides to Amino Acid Precursors 5 Summary and Outlook

Carbohydrate nitrone and nitrile oxide cycloaddition approach to chiral sulfur heterocycles and nucleosides

S-Alkenyl and -alkynyl carbohydrate derivatives were prepared from 1,2:5,6-O-diisopropylidene-α-D-allofuranose. Nitrones and nitrile oxides generated from these derivatives led to the formation of 6, 7, and 11-membered chiral sulfur heterocycles fused to isoxazolidine, isoxazoline and isoxazole rings. Some of these sulfur heterocycles were converted to nucleosides. The 11-memebered sulfur compound was found to gelate hydrocarbon solvents.

Synthesis of New 3, 5-Diaryl-4, 5-Dihydroisoxazole-4- Carbonitriles via 1, 3-Dipolar Cycloaddition Reaction

Abstract : Aromatic aldoximes 1a-i undergo oxidative dehydrogenation with CrO 2 to give nitrile oxides, which are trapped in situ by 4-methoxycinnamonitrile 2 to afford of ethyl 3,5-diaryl-4,5-dihydroisoxazole-4-carbonitriles 3a-i in good yield . Key words : Isoxazoles, isoxazolines, magtreive TM , antimicrobial, antioxidant. I. Introduction Isoxazoles and isoxazolines are very useful heterocycles in organic and heterocyclic chemistry [1]. Isoxazolines also serves as important building blocks for the synthesis of various biologically active molecules [2]. The isoxazoles are known to exhibit significant number of biological applications such as hypoglycemic, analgesic, anti-inflammatory and HIV-inhibitory activity [3], also found to exhibit antibacterial [4], antifungal [5], antioxidant [6], potent selective agonists at human cloned dopamine D4 receptors [7], COX-2 inhibitory [8], antinociceptive [9], anticancer [10], and antibiotic, antitumour, insecticidal activities [1,2]. They serve as prodrug for the anti-arithretic agent [11]. Vijay V. Dabholkar and co-workers [12] reported the synthesis and their antimicrobial activity of fused isoxazolines. Joshi and et al [13] reported that isoxazoles acts as potential antitubercular agents. The most convenient synthesis of isoxazoline and isoxazole ring system has been executed in the literature via 1, 3-dipolar cycloaddition reactions of alkenes and alkynes with nitrile oxides generated

Síntese e caracterização de copolímeros de cadeia lateral derivados de acrilatos de 4,5-di-hidroisoxazol e do (-)-mentol

Five monomers 5-[4-(5-cyano-4,5-dihydroisoxazol-3-yl)phenoxy]undecyl acrylate (7a); n-alkyl 3-{4-[5-(acryloyloxyundecyl)oxyphenyl]}-4,5-dihydroisoxazole-5-carboxylate (7b,c for n-butyl and n-hexyl, respectively); 3-{4-[5-(acryloyloxyundecyl) oxyphenyl]}-4,5-dihydroisoxazole-5-carboxylic acid (7d) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl acrylate (9) and the corresponding copolymers 10a-d,11 and homopolymers 12 from 7a and 13 from 9 were designed and synthesized. Except for acrylate 9 which is derived from (-)-menthol, all of the monomers belong to the series containing the isoxazoline ring linked to the acrylate unit by a flexible spacer chain of eleven methylene units. They presented low glass temperature and despite birefringence behavior, these copolymers showed no mesomorphic properties.

Efficient synthesis of spiroisoxazoline oxindoles

The synthesis of spiroisoxazoline oxindoles containing ester groups at position 4′ and aromatic or ester groups at position 3′ of the isoxazoline ring is reported. The compounds were synthesized in yields up to 94% by 1,3-dipolar cycloaddition of 3-methylene indolin-2-ones and chlorooximes in the presence of triethylamine or zinc.

1,2,4-Triazole d-ribose derivatives: Design, synthesis and antitumoral evaluation

Herein we report the design, synthesis and characterization of novel 1,2,4-triazole d-ribose derivatives, as well as their synthetic precursors. The antitumoral activity against T cell lymphoma cell line of these products was studied. Structures containing a 1,2,4-triazolic ring linked by sulfur to the carbohydrate moiety showed a moderate antiproliferative activity. The presence of the second heterocyclic ring did not show significant changes in their biological activity. Meanwhile, structures with 3-thiobenzyl-5-substituted-1,2,4-triazole ring linked by nitrogen leads to compounds with a biphasic behavior, stimulating cell proliferation at low concentrations and inhibiting it at higher ones. An increment in the polarity was associated with a decrease in the activity of the evaluated compounds. A preliminary antitumoral screening pointed the 1,2,4-triazolic structures linked to protected sugars as promising leaders for further studies.

Structural investigations of 5-hydroxy-4,5-dihydroisoxazoles

Abstract The X-ray diffraction data determined for eight 3-(R3), 4-(R4), 4,4-(R4/R4′) and/or 5-(R5) 5-hydroxy-4,5-dihydroisoxazoles [where R3 = Ph, R4/R4′ = H/H, R5 = CCl3 (1); R3 = 4-Br-C6H4, R4/R4′ = H/H, R5 = CCl3 (2); R3 = thien-2-yl, R4/R4’ = H/H, R5 = CCl3 (3); R3 = Ph, R4 = Ph, R4’ = OH, R5 = Me (4); R3 = Me, R4/R4′ = N–OH, R5 = Me (5); R3 = CF3, R4/R4’ = H/H, R5 = CMe2CH2OH (6); R3 = H, R4 = 4-I-C6H4, R4’ = H, R5 = 4-I-C6H4 (7); R3/R4 = –(CH2)3–, R4′ = H, R5 = CF2CF2H (8);] are discussed. The crystalline structure of compounds 1–3 is described for the first time and crystalline structure of compounds 4–8 has already been described in literature. It was found that the supramolecular auto-organization of 1–8 is characterized by hydrogen bonds invariably involving the hemiacetal hydroxyl group. Compound 5 is the only exception, where the hydroxyl oxime group is the participant in the hydrogen bond. Compounds 4 and 8 present intermolecular contact between the hydroxyl group of the hemiacetal and the nitrogen atom of the 4,5-dihydroisoxazole ring. Compound 7 presents similar interaction, where the hydroxyl contact is with the oxygen atom of the 4,5-dihydroisoxazole ring. Moreover, the crystal structure of compound 6 was stabilized by O–H⋯O interaction between the hydroxyl group of hemiacetal and the hydroxyl group of the alcohol function attached at the 5-position of 4,5-dihydroisoxazole. The crystal structure of compounds 1–3, as described here for the first time, was similar to that of compounds 4 and 7, showing a hydrogen bond O(51)-H(51)⋯N(2) between the hydroxyl group and the nitrogen atom of the isoxazoline ring. This means that the crystal structure of these compounds was governed by hydrogen bonds O–H⋯N, involving the hydroxyl of the hemiacetal group and the nitrogen atom of the 4,5-dihydroisoxazole ring. This interaction is relatively robust, showing a pattern in the crystal packing. Compounds 1–3 also have their crystal stabilized by more weak interactions of type Cl⋯Cl, involving the chlorine atom of the trichloromethyl group.

Synthesis of sidisterone, a phytoecdysteroid from Silene dioica (L.) Clairv.

The first synthesis of the natural phytoecdysteroid sidisterone is realized. It is based on the isoxazoline ring reductive cleavage of 20-hydroxy-20-isoxazolynylecdysterone, acid-catalyzed cyclization of the resultant ketodiol into a dihydrofuran derivative, and ozonolysis of the exocyclic double bond of the latter.

3,5-Bis(4-meth-oxy-phen-yl)-4,5-dihydro-isoxazole.

In the title compound, C17H17NO3, the five-membered isoxazoline ring adopts an envelope conformation with the chiral C atom at the flap position and 0.133 (2) Å out of the mean plane formed by the other four atoms. The two benzene rings form dihedral angles of 6.05 (5) and 81.52 (5)° with the C—C—N—O plane of the isoxazoline ring. The crystal structure is stabilized by weak C—H⋯O hydrogen bonds and C—H⋯π inter­actions.

(S)-[5-Methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl]methanol

In the title compound, C10H13NO2S, the thio­phene and isoxazoline rings are almost coplanar, the dihedral angle between their least-squares planes being 2.08 (1)°. The O—H atoms of the methyl hy­droxy group and the N atom of the isoxazole ring are orientated in the same direction to allow for the formation of inter­molecular O—H⋯N hydrogen bonds that lead to a supra­molecular chain along the a axis.

X-Ray diffraction study of the new ecdysteroid derivatives containing isoxazoline ring in the side chain

Crystal and molecular structure of (2β,3β,14α,20R,5′R)-14,20-dihydroxy-20-(3′-isopropylisoxazolin-5′-yl)-2,3-isopropylidenedioxy-5β-pregn-7-en-6-one and (2β,3β,14α,20R,5′R)-20-hydroxy-20-(3′-methylisoxazolin-5′-yl)-14-trimethylsilyloxy-2,3-isopropylidenedioxy-5β-pregn-7-en-6-one was investigated by XRD analysis. Compounds crystallize in the orthorhombic [space group P212121; a 1.751(2), b 12.146(2), c 19.660(4) A] and hexagonal [space group P61; a 14.138(3), b 14.138(3), c 27.597(7) A] crystal systems, respectively. These compounds, which resulted from the 1,3-dipolar cycloaddition of isobutyronitrile oxide or acetonitrile oxide to the corresponding steroid olefin, have 5′R-stereochemistry of the formed chiral center. The conformation of the side chain of molecules is stable due to the intramolecular hydrogen bonds.