Isoxazole Ring Research Articles

A Divergent Route to Eravacycline.

A convergent route to eravacycline (1) has been developed by employing Michael-Dieckmann cyclization between enone 3 and a fully built and protected left-hand piece (LHP, 2). After construction of the core eravacycline structure, a deprotection reaction was developed, allowing for the isoxazole ring opening and global deprotection to be achieved in one pot. The LHP is synthesized from readily available 4-fluoro-3-methylphenol in six steps featuring a palladium-catalyzed phenyl carboxylation in the last step.

The degradation mechanism of sulfamethoxazole under ozonation: a DFT study.

Sulfamethoxazole (SMX), a kind of antibiotic, remains in the environment and threatens public health. Ozone as a strong and green oxidant was widely used for selective oxidation degradation of residual SMX. However, it is hard to elucidate the detailed oxidation mechanism through current experimental approaches. A theoretical study has been carried out herein for exploring possible ozonation pathways of SMX. Two reaction mechanisms, viz., direct addition (DA) and H atom transfer (HAT), are considered. The results show that the primary oxidation of aromatic rings (benzene or isoxazole rings) of SMX follows the DA mechanism, featuring an electrophilic addition. Whereas, the oxidation of amino and methyl groups of SMX follows the HAT mechanism. Following the proposed mechanisms, the primary oxidation products detected in previous experiments could reasonably be obtained according to the current calculations. More importantly, O3 molecules as an electrophilic agent feasibly attack the moiety having a large orbital contribution to the highest occupied molecular orbital (HOMO) of sulfonamides. This result suggests that the primary ozonation site of sulfonamides could be theoretically predictable through the information of their frontier molecular orbitals. Meanwhile, a positive correlation between the O3-mediated HAT energy barriers and bond dissociation energies has been found for N-H and C-H bond oxidations.

Synthesis of 3,5-Diarylisoxazole Derivatives and Evaluation of in vitro Trypanocidal Activity

Chagas disease is included in the neglected tropical diseases list and is endemic to 21 Latin American countries. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole and both result in many significant side effects. The study describes the synthesis and biological evaluation of 3,5-disubstituted isoxazoles. Isoxazoles were obtained by reaction of flavones and hydroxylamine and either alkylated at the free hydroxyl group and/or nitrated at the isoxazole ring. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as a reference compound for the in vitro assay and mammalian L929 cells were employed to evaluate cytotoxicity. A majority of the compounds tested were very active and the most active isoxazole against amastigote and trypomastigotes of T. cruzi was slightly more potent than the current medicine benznidazole.

SYNTHESIS OF ISOXAZOLE AND AZOLE ENSEMBLES BASED ON 1,3-DIPOLAR CYCLOADDITION REACTION OF ENAMINES WITH NITRILE OXIDES

2-(1,2,3-Thiadiazol-5-yl)enamines and 3-(1,2,3-triazol-4-yl)enaminones react with arylhydroxamoyl chlorides at room temperature with the exclusive formation of 3-aryl-4-(1,2,3-thiadiazol-5-yl)- and [4-(1,2,3-triazol-4-yl)carbonyl]isoxazoles in high yields. The proposed mechanism includes in situ generation of nitrile oxides, which participate in the (3+2)-dipolar cycloaddition reactions leading to the formation of the isoxazole ring. Authors: Ilya V. Efimov, Yuri M. Shafran, Natalya N. Volkova, Nikolay A. Belyaev, Pavel A. Slepukhin, Vasiliy A. Bakulev*

ChemInform Abstract: Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst.

The iridium catalyst [IrCl(cod)]2 -phosphine-I2 (cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H2 . The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine-oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent.

Synthesis of C 2-Symmetric Isoxazole-Fused BINOL: An Entry to Sterically Crowded Atropisomeric Systems

A fluorescence-active modified BINOL with heteroaromatic fused rings containing two different heteroatoms is synthesized in good yield. Its racemate form is well characterized by chiral HPLC analysis. The molecule bears sterically hindered geometry and has potential for stereochemical properties normally exhibited by BINOLs. The molecule has two ends with different ligating atoms in the form of hydroxy groups at one end and isoxazole ring heteroatoms on the other end. This feature may be useful for molecular recognition of both hard and soft cations.

Synthesis of Assemblies of Isoxazole and Azoles Based on 1,3-Dipolar Cycloaddition Reaction of Enamines with Nitrile Oxides

2-(1,2,3-Thiadiazol-5-yl)enamines and 3-(1,2,3-triazol-4-yl)enaminones react with arylhydroxamoyl chlorides at room temperature with the exclusive formation of 3-aryl-4-(1,2,3-thiadiazol-5-yl)- and [4-(1,2,3-triazol-4-yl)carbonyl]isoxazoles in high yields. The proposed mechanism includes in situ generation of nitrile oxides, which participate in the (3+2)-dipolar cycloaddition reactions leading to the formation of the isoxazole ring.

Controlled synthesis of BiVO4/SrTiO3 composite with enhanced sunlight-driven photofunctions for sulfamethoxazole removal

The presence of antibiotics in surface waters is paid more and more attention, which is difficult to be removed by conventional treatment technology, and photocatalytic technology is considered to be a promising method for antibiotics pollutant removal. In the present work, a novel heterojunction photocatalyst was successfully synthesized by self-template method under hydrothermal condition. The photocatalytic activity of as-prepared samples was investigated by degradation of sulfamethoxazole in aqueous solution. The BiVO4/SrTiO3 composites showed superior photocatalytic efficiency under xenon lamp irradiation. The recycling tests proved that BiVO4/SrTiO3 composite was high stability and easily separated. The degradation efficiency of BiVO4/SrTiO3 composite was also greatly influenced by active species. It indicated that approximately 50% TOC reduction was achieved after 1h photocatalytic reaction. The intermediates were investigated by LC-MS analyses, which revealed that the bonds of CO, CS, CC, CN, isoxazole ring and benzene ring were broken by attacking of active species.

Different acid-base behaviour of a pyrazole and an isoxazole with organic acids: crystal and molecular structures of the salt 3-(4-fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate and of the cocrystal 4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide-3,5-dinitrobenzoic acid (1/1).

Pyrazole and isoxazole rings differ only in the notional replacement of a potential hydrogen-bond-donor NH unit in pyrazole by a potential hydrogen-bond-acceptor O atom in isoxazole. It is thus of interest to compare the hydrogen-bonding characteristics of these rings. (4-Fluorophenyl)pyrazole undergoes protonation in the presence of 2,4,6-trinitrophenol to yield the salt 3-(4-fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate, C9H8FN2(+)·C6H2N3O7(-), (I), whereas there is no proton transfer between 4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide and 3,5-dinitrobenzoic acid, whose reaction gives the 1:1 cocrystal, C11H13N3O3S·C7H4N2O6, (II). The bond lengths in salt (I) provide evidence for aromatic-type delocalization in the pyrazolium ring and for extensive delocalization of the negative charge into the ring of the trinitrophenolate anion. The O atoms of one of the nitro groups in the trinitrophenolate anion are disordered over two sets of atomic sites having occupancies of 0.571 (6) and 0.429 (6), but all of the other substituents on the carbocyclic rings are fully ordered. The ions in salt (I) are linked by an extensive series of N-H...O hydrogen bonds to form a three-dimensional framework structure, and in cocrystal (II), the molecular components are linked by a combination of O-H...N and N-H...O hydrogen bonds to form complex bilayers. Comparisons are made with some related compounds.

Replacement of Oxygen by Sulfur in Small Organic Molecules. 3. Theoretical Studies on the Tautomeric Equilibria of the 2OH and 4OH-Substituted Oxazole and Thiazole and the 3OH and 4OH-Substituted Isoxazole and Isothiazole in the Isolated State and in Solution.

This follow-up paper completes the author’s investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔGsolv/MC values in calculating ΔGstot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0−3.4 solute−water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups.

Hybrid liquid crystals tetrazolyl and isoxazolyl cinnamates

ABSTRACTIn this work, a series of isoxazolyl and tetrazolylcinnamic ester hybrid liquid crystals (HLCs) were synthesised and their mesomorphic behaviour was analysed. Cinnamic acid derivatives were prepared by Knoevenagel condensation of malonic acid and arylaldehydes. Five-membered tetrazoles and isoxazoles were prepared by [3 + 2] 1,3-dipolar cycloaddition. Tetrazoles were synthesised by sodium azide addition to arylnitrile, while isoxazoles were synthetised by arylnitrile oxide addition to alkenes to form isoxazolines, followed by MnO2-oxidation. Tetrazolyltolane compounds were also synthesised and their LC behaviour compared with cinnamic esters. HLCs containing isoxazole rings displayed a large mesophase range with high clearing temperature (Tc), with predominance of smectic mesophases SmA and SmC. The HLCs decomposed upon heating due to their high clearing temperature (>250°C). HLCs with tetrazole rings showed a narrow nematic mesophase range with enantiotropic or monotropic behaviour.

Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst.

The iridium catalyst [IrCl(cod)]2 -phosphine-I2 (cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H2 . The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine-oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent.

A rapid and efficient solvent-free microwave-assisted synthesis of pyrazolone derivatives containing substituted isoxazole ring

An efficient synthesis of 4-substituted pyrazolone derivatives was developed. 4-Substituted pyrazolone derivatives were synthesized in 78–97% yields starting from various 3-substituted isoxazole-5-carbaldehydes, ethyl acetoacetate and hydrazine under microwave irradiation and solvent-free conditions, and were characterized by HRMS, FTIR, 1H NMR and 13C NMR spectroscopy. SiO2 was found to possess favorable catalytic activity and dispersancy for the condensation reaction. The merits of this method include the environmentally friendly reaction conditions, simple operation, broad substrate, satisfied yields and the reuse of the silica. Moreover, the crystal structure of the compound 2-(4-chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)(3-phenylisoxazol-5-yl)methyl)-5-methyl-1H-pyrazol-3(2H)-one (5a) in the monoclinic space group C2/c was presented.

Detection of in Vitro Metabolite Formation of Leflunomide: A Fluorescence Dynamics and Electronic Structure Study.

The metabolic transformation of antirheumatic fluorescent drug leflunomide into its active metabolite teriflunomide through isoxazole ring opening has been monitored in vitro using steady state and time domain fluorescence spectroscopy and density functional theory. During metabolic reaction, absorption of leflunomide split into two bands resembling absorption spectra of teriflunomide. The fluorescence spectra reveal slow conversion of leflunomide to E and Z forms of teriflunomide in aqueous medium, which becomes faster at basic pH. The E form, which is more potent as a drug, becomes more stable with an increase in the basicity of the medium. Both molecules are associated with charge transfer due to twisting in the lowest singlet excited state. Excited state charge transfer followed by proton transfer was also observed in the Z form during the ring opening of leflunomide. Quantum yield and radiative decay rates have been observed to decrease for the metabolite because of an increase in nonradiative decay channels.

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma.2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes.3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation.4.The effort concluded with identification of azetidines as second-generation 5HT4 partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.

A facile access to novel heterocyclic analogues of chalcone from newly synthesized ketone containing isoxazole and a benzoxazinone ring

A series of novel heterocyclic analogs of chalcone containing isoxazole and benzoxazinone ring as a prime motif was rationally designed and synthesized. There is nothing in the literature about such α,β-unsaturated ketones.

Crystal structure of 4-(4-meth-oxy-phen-yl)-4',4'-dimethyl-3-p-tolyl-3',4'-di-hydro-1'H,3H-spiro-[isoxazole-5,2'-naphthalen]-1'-one.

In the title compound, C28H27NO3, the cyclo­hexa­none and isoxazole rings have envelope conformations, with the methyl­ene and spiro C atoms as the flaps, respectively. The mean plane of the isoxazole ring is inclined slightly to the p-tolyl ring, making a dihedral angle of 14.20 (9)°, and is nearly perpendicular to the mean plane through the tetra­lone moiety and to the meth­oxy­phenyl ring [dihedral angles = 83.41 (8) and 72.12 (9)°, respectively]. The crystal packing is stabilized mainly by van der Waals forces.

Role of biotransformation, sorption and mineralization of 14C-labelled sulfamethoxazole under different redox conditions

14C-sulfamethoxazole biotransformation, sorption and mineralization was studied with heterotrophic and autotrophic biomass under aerobic and anoxic conditions, as well as with anaerobic biomass. The 14C-radiolabelled residues distribution in the solid, liquid and gas phases was closely monitored along a total incubation time of 190h. Biotransformation was the main removal mechanism, mineralization and sorption remaining below 5% in all the cases, although the presence of a carbon source exerted a positive effect on the mineralization rate by the aerobic heterotrophic bacteria. In fact, an influence of the type of primary substrate and the redox potential was observed in all cases on the biotransformation and mineralization rates, since an enhancement of the removal rate was observed when an external carbon source was used as a primary substrate under aerobic conditions, while a negligible effect was observed under nitrifying conditions. In the liquid phases collected from all assays, up to three additional peaks corresponding to 14C-radiolabelled residues were detected. The highest concentration was observed under anaerobic conditions, where two radioactive metabolites were detected representing each around 15% of the total applied radioactivity after 180h incubation. One of the metabolites detected under anoxic and anaerobic conditions, is probably resulting from ring cleavage of the isoxazole ring.

Crystal structure of (5-chloro-2-hy-droxy-phen-yl)(3-methyl-isoxazolo[5,4-b]pyridin-5-yl)methanone.

In the title compound, C14H9ClN2O3, the fused pyridine and isoxazole rings are approximately planar, making a dihedral angle of 1.14 (16)°. The mol­ecule is twisted with the benzene ring and the mean plane through the fused pyridine-isoxazole ring system being inclined to one another by 47.03 (13)°. There is an intra­molecular O—H⋯O hydrogen bond forming an S(6) ring motif. In the crystal, mol­ecules are linked by C—H⋯N hydrogen bonds, forming chains propagating along [001]. The chains are linked by slipped parallel π–π inter­actions, involving inversion-related benzene rings, forming slabs lying parallel to the bc plane {inter-centroid distance = 3.770 (2) Å].

Synthesis of Various Schiff Bases Containing Isoxazole Ring and Their Applications with Thioglycollic Acid and Diverse Phosphorus Reagents

A series of Schiff bases bearing isoxazole and pyrazole rings were synthesized. Application of thioglycollic acid on two selective synthesized Schiff bases afforded the corresponding thiazolidin‐4‐one derivatives. On the other hand, following the multicomponents one‐pot Kabachnik– Fields reaction, the Schiff base generated in situ from 4‐chlorobenzaldehyde and 5‐methyl isoxazol‐3‐amine was trapped by phosphorus reagents to produce the corresponding amino phosphonates in moderate yields. However, the latter products could also be obtained in better yields (≥78%) by directly applying the dialkylphosphites to a selective synthesized Schiff base. Similarly, a series of α‐aminophosphonates could be obtained from 5‐chloro‐3‐methyl‐1H‐pyrazol‐4‐carbaldehyde, 5‐methylisoxazol‐3‐amine, and phosphorus reagents. Moreover, applying hexaalkyl triamido phosphites to the N‐(4‐chlorobenzylidene)‐5‐methylisoxazol‐3‐amine in ethanol afforded methylphosphonic diamide derivatives, whereas N‐((5‐chloro‐3‐methyl‐1H‐pyrazol‐4‐yl)methylene)‐5‐methylisoxazol‐3‐amine underwent dechlorination through reaction with hexaalkyl triamido phosphites to give the respective amine derivatives.