Cycloaddition Of Nitrones Research Articles

Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N',N'-tetraalkyldiaminomethane in the presence of an IrIII complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.

Exploration and Development of Nitrone Chemistry.

Nitrones are widely used as 1,3-dipoles in organic synthesis, but control of their reactions is not always easy. This review outlines our efforts to make the reactions of nitrones more predictable and easier to use. These efforts can be categorized into (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.

Theoretical analysis of mechanism and regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method

Theoretical analysis of mechanism and regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method

Asymmetric [3 + 3] cycloaddition of cinnamaldehyde-derived N-aryl nitrones with 2-indolemethanols enabled by chiral phosphoric acid.

We described a chiral phosphoric acid (CPA) catalyzed asymmetric [3 + 3] cycloaddition of cinnamaldehyde-derived N-aryl nitrones with 2-indolylmethanols to prepare various indole-fused 1,2-oxazines in high yields (up to 96%) with excellent enantioselectivity (>99% ee). Control experiments indicate that hydrogen bonding plays important roles in controlling the enantioselectivity of products. This strategy provides an efficient pathway to construct enantioenriched indole-fused 1,2-oxazines from N-aryl nitrones with 2-indolylmethanols.

A Convenient Synthesis of Novel Isoxazolidine and Isoxazole Isoquinolinones Fused Hybrids.

Isoxazolidine, isoxazole, and isoquinolinone rings are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, facile and efficient pathways have been developed for the preparation of fused frameworks bearing those heterocycles. The successful approaches for both isoxazolidine/isoquinolinone and isoxazole/isoquinolinone hybrid syntheses relied initially on 1,3-dipolar cycloadditions of nitrones and nitrile oxides to indenone and 2-propargylbenzamide, respectively. The construction of the isoquinolinone lactam system followed by performing a selective Schmidt reaction for isoxazolidine derivatives (two steps overall), whereas the isoxazole lactams were reached via an Ullmann-type cyclisation (three steps overall). Key observations were made regarding the stereo- and regioselectivities of the reactions employed, and small libraries of the targeted hybrids were prepared, demonstrating the general applicability of these strategies.

Synthesis of Spirooxindole-1,2-oxazinan-5-ones through 2,2,2-Trifluoroethanol Promoted [3 + 3] Cycloaddition of N-Vinyl Oxindole Nitrones and Oxyallyl Cations.

A variety of spirooxindole-1,2-oxazinan-5-one derivatives were prepared in moderate to excellent yields through 2,2,2-trifluoroethanol (TFE)-promoted [3 + 3] cycloaddition of N-vinyl oxindole nitrones with oxyallyl cations generated from α-tosyloxy ketones under mild reaction conditions. Mechanistic studies revealed that [3 + 3] cycloaddition might involve two possible reaction pathways, including direct [3 + 3] cycloaddition of N-vinyl oxindole ntirones with oxyallyl cations, or the addition of TFE to N-vinyl oxindole nitrones, sequential addition to oxyallyl cations, elimination, and cyclization. The present method features mild reaction conditions, broad substrate scope, good functional group tolerance, easy gram scalable preparation, and new applications of TFE.

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane

AbstractBy resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single‐electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three‐electron‐type nucleophilic substitution triggered cyclopropane ring‐opening and a diastereoselective 6‐endo‐trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio‐ and stereoselectivity, nicely complementing the well‐developed Lewis acid catalyzed cycloaddition of donor‐acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional‐group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane.

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single-electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three-electron-type nucleophilic substitution triggered cyclopropane ring-opening and a diastereoselective 6-endo-trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio- and stereoselectivity, nicely complementing the well-developed Lewis acid catalyzed cycloaddition of donor-acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional-group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.

2,4,5,7-Tetranitrofluorenone Oximate for the Naked-Eye Detection of H-Bond Donors and the Chiroptical Sensing of Enantiopure Reagents.

Hydrogen bonding greatly influences rates and equilibrium positions of chemical reactions, conformations, and sometimes even stereochemistry. This study reports on tetranitrofluorenone oximate, a novel dye capable of naked-eye detection of hydrogen-bond donating species (HBDs) and of rapid determination of H-bond donation strength by hypsochromic shift monitoring. In addition, the molecule possesses atropisomeric conformations, of M and P configuration, as evidenced in solid and solution state studies by X-ray diffraction and electronic circular dichroism (ECD), respectively. In the latter case, enantiopure bis-thioureas were the most effective HBDs to promote a chiral induction (diastereoselective recognition, Pfeiffer effect); the ECD results being rationalized by time-dependent density functional theory (TDDFT) calculations. Based on these experiments, bis-thioureas were used as chiral reagents in asymmetric 1,3-dipolar cycloadditions of structurally-related nitrones; the ECD sensing of the stereoinduction between bis-thioureas and the oximate serving as an indirect method of selection of the most effective HBD for asymmetric synthesis.

Synthesis of Functionalized 2‐Pyrrolidinones Bearing N‐Trifluoromethylphenyl through A Formal [4+1] Cycloaddition of Cinnamaldehyde Nitrones and 1‐Ethynylnaphthalen‐2‐ols

AbstractA variety of functionalized 2‐pyrrolidinones bearing N‐trifluoromethylphenyl moieties were prepared in moderate to good yields with high diastereoselectivity through copper(II)‐catalyst and base co‐catalyzed formal [4+1] cycloaddition of cinnamaldehyde nitrones with 1‐ethynylnaphthalen‐2‐ols in the presence of m‐CPBA as the oxidant. The triple bond of 1‐ethynylnaphthalen‐2‐ol served as one‐carbon synthon for the pyrrolidinone ring formation. Mechanistic studies revealed that m‐CPBA played an important role to interrupt the intramolecular O‐cyclization to afford the 2‐pyrrolidinones. Moreover, the reaction could be easily performed at gram scales and the obtained products were selectively converted into diverse pyrroline scaffolds.

A New Way to the Synthesis of Tricyclic Compounds via Nitrone 1,3- cycloaddition Dipolar Reaction.

This study aimed at developing new methodologies for 1,3-dipolar cycloaddition. A new series of tricyclic derivatives (13a-d) were synthesized via 1, 3-dipolar cycloaddition of nitrones (8a-c) and (9a-c) using intramolecular cyclisation at the reflux of toluene and radical intramolecular cyclisation in the presence of tributyltin hydride and AIBN as an initiator in benzene, which are two techniques to prepare cycloadducts (11a-d), followed by cleavage of the N-O bond performed using Sml in THF. The structures of these new tricyclic derivatives have been confirmed by Mass, 1H-NMR (1d, 2d), 13C-NMR, and IR spectral data. In summary, we have investigated the possibility of synthesizing some new and straightforward methods to access an A-C-D tricyclic skeleton of morphinans from symmetrical arylcyclohexadienes.

Catalyst-Free, Multicomponent Reaction of Iodonium Ylides, Nitrosoarenes, and Olefins for the Synthesis of Isoxazolidine Derivatives

AbstractA general and efficient three-component protocol for the synthesis of isoxazolidines has been developed. A range of nitrosoarenes, olefins, as well as iodonium ylides can be subjected to this reaction to generate the N-aryl isoxazolidines derivatives with moderate to excellent yields. In addition, we demonstrate that this approach employs the 1,3-dipolar cycloaddition of nitrones generated in situ from iodonium ylides and nitroso compounds, with olefins in the absence of any catalysts and additives.

Total Synthesis of Kopsone

A total synthesis of kopsone was achieved, featuring stereoselective preparation of an acyclic aldehyde having a protected hydroxylamine moiety via Ireland-Claisen rearrangement and intramolecular cycloaddition of an eight-membered cyclic nitrone to form the 2-azabicyclo[3.3.1]nonane skeleton.

Organocatalytic (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes: a facile access to enantioenriched 1,2-oxazinanes.

The first asymmetric (3+3)-cycloaddition of ortho-substituted phenyl nitrones with aryl cyclopropane carbaldehydes has been demonstrated by secondary amine catalysts. While the other ortho-substituents gave 1,2-oxazinanes, ortho-hydroxy ones provided a novel class of tetrahydrochromeno-1,2-oxazine cores via rare 1,3-aryl migration, followed by cyclization. An unusual type of asymmetric approach was also recognized.

Heterocyclic Synthesis of Some New Isoxazolidine Derivatives via 1,3-Dipolar Cycloaddition of Nitrones to Styrene

A number of nitrones have been synthesized in three different procedures, starting with N-phenyl hydroxylamine, followed by the condensation reaction with some selected aldehydes. Furthermore, these nitrones were employed in the preparation of a number of new isoxazolidines. Cycloaddition reaction of nitrones to styrene produced the desired products.

Fast MacMillan's Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds.

The enantioselective 1,3-dipolar cycloaddition of nitrones and arylpropionaldehydes to generate highly functionalized scaffolds for application in drug discovery was herein investigated. The use of a second-generation MacMillan catalyst as hydrochloride salt consistently accelerated the reaction speed, allowing a decrease in the reaction time up to >100 times, still affording 4-isoxazolines with good to excellent enantiomeric ratios at room temperature. As a proof of concept, further functionalization of the isoxazoline core through Pd-catalyzed cross-coupling was performed, generating differently functionalized chemical architectures in high yield.

Cinchonidine-Catalyzed Synthesis of Oxazabicyclo[4.2.1]nonanones from N-Aryl-α,β-unsaturated Nitrones and 1-Ethynylnaphthalen-2-ols.

A variety of oxazabicyclo[4.2.1]nonanone derivatives were prepared in good yields through a cinchonidine-catalyzed cascade reaction of N-aryl-α,β-unsaturated nitrones and 1-ethynylnaphthalen-2-ols. Mechanistic studies show that the reaction undergoes a [4 + 3] cycloaddition of nitrones to vinylidene o-quinone methide generated in situ from 1-ethynylnaphthalen-2-ols in the presence of cinchonidine, 1,3-rearrangement of N-O vinyl moieties, ring-opening, and finally double intramolecular cyclizations to afford oxazabicyclo[4.2.1]nonanones over five steps in a one-pot reaction.

Sc(OTf)3-Catalyzed [3+2]-Cycloaddition of Diazoacetoacetate Enones and N-Aryl Nitrones: Diastereoselective Synthesis of Functionalized Isoxazolidines with Three Contiguous Stereogenic Centers

AbstractA catalytic [3+2]-cycloaddition using Sc(OTf)3 as a Lewis acid catalyst is developed. This catalytic 1,3-dipolar cycloaddition dia­stereoselectively transforms diazoacetoacetate enones and N-aryl nitrones into highly functionalized isoxazolidines bearing three contiguous chiral centers. The feasibility of the uncatalyzed 1,3-dipolar cycloaddition is postulated by DFT calculations and substantiated experimentally.

Metal‐free Kinugasa reaction catalyzed by external electric field

AbstractOriented external electric field (OEEF) is in recent interest for its ability to promote reactivity and selectivity in chemical transformations. This article reports facile metal‐free [3 + 2] cycloaddition for the Kinugasa reaction in the presence of OEEF. The free energy of activation is reduced by 4.9 kcal/mol due to a parallel electric field in the orthogonal direction to the reaction axis, Fy = 5.0 V Å−1. As a proof‐of‐principle of this model, a multidrug‐resistant (MDR) antibiotic, carbapenem could be envisioned from the [3 + 2] cycloaddition of a cyclic nitrone and an acetonide substituted acetylene. This reaction shows an interesting ambiaxial electric field‐induced catalysis with a reduced reaction barrier for anti‐parallel fields, −Fx (reaction axis) and −Fz and parallel field along +Fy. This is due to the out‐of‐plane bending of the acetonide unit containing two highly electronegative oxygen atoms. As a result, off‐axial tensorial responses to the electric‐fields on the barriers are observed. Such ambiaxial OEEF driven catalysis is interesting because it expands the utility of electric fields for large enzymes. Disorder and dynamical effects of side chains are envisioned to cause non‐null responses to applied field for parallel or anti‐parallel directions along axes.

Interception of 1,2-cyclohexadiene with TEMPO radical

Transient strained cyclic intermediates, such as strained cyclic allenes, are useful building blocks for the synthesis of structurally and stereochemically complex scaffolds. Trappings of strained cyclic allenes are thought to occur primarily through either two or one electron processes. Regarding the latter, diradical intermediates have been invoked in (2 + 2) cycloadditions and (3 + 2) nitrone cycloadditions. The present study questions if a monoradical pathway could exist for strained cyclic allene reactivity, as examined in the reaction of 1,2-cyclohexadiene and TEMPO radical. Our findings suggest the viability of this monoradical pathway.