Reaction Of Nitrones Research Articles

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.

Unveiling the mechanism and selectivity of the [3 + 2] cycloaddition reactions of nitrone with acetylene derivatives leading to anticancer 4-isoxazoline derivatives from the MEDT perspective

The [3 + 2] cycloaddition reactions of N-methyl-C-(2-furyl) nitrone (a) with a series of acetylene derivatives (4b), (5b), and (6b) have been studied at the B3LYP-D3/6-31G(d) computational level within the framework of Molecular Electron Density Theory. Topological analysis allows classifying the nitrone (a) as a zwitterionic (zw-) three-atom component (TAC) associated with high energy barrier. These 32CA reactions follow a one-step mechanism under kinetic control with highly asynchronous bond formation. Bonding Evolution Theory (BET) analysis indicates that no new covalent CO and CC bonds form at the transition states (TSs). Interestingly, the global electron density transfer (GEDT) between 0.08 and 0.18 e predicts low polar character of forward electron density transfer (FEDF) type with the electronic flux from the nitrone (a) to the acetylene derivatives. Electron localization function (ELF) and atom-in-molecules (AIM) topological analysis of the electron density at the TS structures characterize the non-concerted nature of these one-step zw-type 32CA reactions.

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne-Nitrone Cycloadditions Involving Dibenzocyclooctadiyne.

The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure-activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.

Revealing the influence of tether length on the intramolecular [3 + 2] cycloaddition reactions of nitrones from the molecular electron density theory perspective

AbstractThe influence of ethylene substitution and the tether length between the two reacting counterparts on the selectivity and reactivity of the intramolecular [3 + 2] cycloaddition (IM32CA) reactions of cyclic nitrones leading to tricyclic isoxazolidines have been studied within the Molecular Electron Density theory at the MPWB1K/6‐311G(d,p) computational level. These zw‐type IM32CA reactions follow one‐step mechanism, and the activation barrier decreases with the introduction of electron withdrawing (EW) substituent at the alkene moiety in both the intramolecular and intermolecular versions. The IM32CA reactions involving unsubstituted alkene have non‐polar character with minimal electron density flux classified as null electron density flux type, while that involving the EW nitro substituted ethylene is more facile with a strong electron density flux from the nitrone to the ethylene moiety, classified as forward electron density flux type. The increase in the polar character of the IM32CA reaction decreases the activation Gibbs free energies associated with these intramolecular processes, while the highly polar IM32CA reactions are disfavored with respect to the intermolecular ones. Interestingly, the preferred regioselectivity observed in low polar IM32CA reactions having three methylene units between the nitrone and ethylene frameworks is reversed to that in nitrones separated with four methylene units, in conformity with the experimental outcome. Finally, electron localization function and quantum theory of atoms‐in‐molecules studies reveal that, in general, these IM32CA reactions involve early transition state structures in which the formation of new C‐C and C‐O single bonds have not yet started.

Synthesis of Angular Polycyclic Aromatic Molecules via Rh(III)‐Catalyzed C−H Annulation of Nitrones with Cyclic 2‐Diazo‐1,3‐diones

AbstractWe herein disclose a simple and general method for the synthesis of chromendiones through Rh(III)‐catalyzed C−H functionalization/annulation reactions of nitrones with cyclic 2‐diazo‐1,3‐diones by using nitrone group as a traceless directing group. This method exhibits high efficiency and broad functional group compatibility. The derivatization of these chromendiones has been also demonstrated to further strengthen the synthetic utility of the transformation.

Three-Component Synthesis of Di-Keto Aziridines and Highly Functionalized Alkenes from Sulfoxonium Ylides, Nitrosoarenes, and Alkynes.

A catalyst-free one-pot three-component method of sulfoxonium ylides, nitrosoarenes, and alkynes for the synthesis of highly functionalized di-keto aziridines and alkenes is described. This strategy features the catalyst-free and additive-free approach, the employment of safe, more stable, and readily accessible sulfoxonium ylides, which bear a much wider substrate scope as starting materials. In terms of terminal alkynes, a cascade reaction of nitrone formation/1,3-diploar cycloaddition/Baldwin rearrangement is involved to afford a wide variety of di-keto aziridines. However, highly functionalized alkenes could be obtained instead of di-keto aziridines through the same nitrone formation/1,3-diploar cycloaddition and another different rearrangement reaction when internal alkynes are employed as starting materials.

Metal- and Additive-Free Synthesis of α-Hydroxyamino Ketones Enabled by Organophotocatalyst

AbstractWe report herein a straightforward method for the synthesis of α-hydroxyamino ketones, which involves the benzoylation reaction of nitrones with 2-benzoyl-2-phenylbenzothiazoline under organophotocatalysis. This method offers access to a variety α-hydroxyamino ketones without the use of any transition-metal catalyst or base. Control experiments suggested that the reaction proceeded through a benzoyl radical addition to nitrone. Benzothiazoline was found to be a more suitable radical precursor than Hantzsch ester.

Construction of 1,2-dihydro-1,3,5-triazines via reactions involving amidines.

1,2-Dihydro-1,3,5-triazine compounds were synthesized through three sets of reactions of amidines with, respectively, paraformaldehyde, aldehydes and N-arylnitrones under different conditions. The catalysts used in these three reactions were Cu(OAc)2, ZnI2 and CuCl2·2H2O, respectively. Most of the substrates tested for these reactions provided the target products in moderate to good yields. In the reactions involving paraformaldehyde, Cu(OAc)2 also accelerated the release of formaldehyde from paraformaldehyde during the catalytic reaction process. In the case of the reactions involving nitrones, CuCl2·2H2O not only catalyzed the normal progress of the main reaction, but also promoted the reaction of nitrones to produce nitroso compounds and aldehydes.

Synthesis of Sterically Shielded Nitroxides Using the Reaction of Nitrones with Alkynylmagnesium Bromides.

Sterically shielded nitroxides, which demonstrate high resistance to bioreduction, are the spin labels of choice for structural studies inside living cells using pulsed EPR and functional MRI and EPRI in vivo. To prepare new sterically shielded nitroxides, a reaction of cyclic nitrones, including various 1-pyrroline-1-oxides, 2,5-dihydroimidazole-3-oxide and 4H-imidazole-3-oxide with alkynylmagnesium bromide wereused. The reaction gave corresponding nitroxides with an alkynyl group adjacent to the N-O moiety. The hydrogenation of resulting 2-ethynyl-substituted nitroxides with subsequent re-oxidation of the N-OH group produced the corresponding sterically shielded tetraalkylnitroxides of pyrrolidine, imidazolidine and 2,5-dihydroimidazole series. EPR studies revealed large additional couplings up to 4 G in the spectra of pyrrolidine and imidazolidine nitroxides with substituents in 3- and/or 4-positions of the ring.

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.

Design and synthesis of novel enantiopure Bis(5-Isoxazolidine) derivatives: insights into their antioxidant and antimicrobial potential via in silico drug-likeness, pharmacokinetic, medicinal chemistry properties, and molecular docking studies

A series of novel compounds, mono-5-isoxazolidines, and bis (5-isoxazolidines) derivatives, were prepared as bicycloadducts. The new series of isoxazolidines were designed and synthesized via 1,3-dipolar cycloaddition reaction of nitrones with 3,9-Divinyl-2,4,8,10-tetra oxaspiro (5-5) undecane in the context of new antimicrobial and antioxidant drugs discovery and were fully characterized by FT-IR, 13C-NMR, and 1H-NMR spectroscopy. The physicochemical properties of all the novel cycloadducts, like bioactivity score and lipophilicity, were predicted using calculative methods. Similarly, the pharmacokinetic properties such as metabolism, absorption, distribution, and excretion (ADME) were also predicted. Most of the tested compounds exhibited antimicrobial properties to varying degrees against various bacterial species, including the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli, and the Gram-positive bacteria Streptococcus pyogenus and Staphylococcus aureus, Antifungal properties were also observed against the tested fungi like Candida albicans, Aspergillus niger, and Aspergillus clavatus. The activity data exhibited that most compounds have high activity as compared to the standard drugs. In the range of graded doses, the results of some selected compounds revealed that some are high antioxidants while others are moderate or weak antioxidants. As evidenced by the molecular docking studies, the synthesized compounds showed good binding mode better than a standard drug, against the protein of a Pantothenate Synthetase enzyme (PDB-2X3F).

Mechanistic details of domino [3+2] cycloaddition/[3,3] sigmatropic shift reactions of N-vinyl nitrones with isocyanates

This work elucidates the mechanistic aspects of the reaction of N-vinyl nitrone with isocyanates at the M06-2X/6-311++G(d,p) level of theory. Formation of the 5-membered dioxazolidine from the reaction of nitrone with isocyanate proceed through either a one-step or stepwise mechanism depending on the nucleophilicity of the three atom components (TACs). The cis and trans dioxazolidine leads to the formation of 9-membered heterocycles through a [3,3] sigmatropic shift reaction (the rate-determining step). Two stereo-genic centers are observed, and four 9-membered heterocycles are possible depending on the orientation of the substituents on the TACs. The selectivity of the 9-membered heterocycles is mainly controlled by their kinetics, and at elevated temperatures, product-cis_cis will be the predominant product due to kinetic reversibility which is consistent with reported experimental data (Zou et. al. Adv. Synth. Catal. 359 (2017) 3545–3550). Global electron density transfer (GEDT) calculations revealed the polar nature of the cycloadditions.

Stereoselective Synthesis of Novel Chiral Open-Chain D-Ribose and D-Glucose- Derived Nitrones through 1,3-Dipolar Cycloaddition of Maleimide and Maleic Acid and Investigation of Their Antimicrobial Activity Via Molecular Docking and ADMET Studies

Novel biologically active N-Sugar-derived isoxazolidines derivatives (2a, 2b, 3a, 3b) have been synthesized diastereospecifically by 1,3-dipolar cycloaddition reaction of nitrones (a, b) with maleimide and maleic acid. Nitrones were prepared in a pure form as chiral open-chain sugar-derived nitrones in an effort to explore a new type of antimicrobial agents. FTIR, 1H NMR, and 13C NMR spectrometric analysis characterized the structures of the compounds. The synthesized compounds were examined for their antimicrobial activity using the disk diffusion method against Gram-negative bacteria Escherichia coli; the Gram-positive bacteria staphylococcus aureus and against pathogenic fungi Candida albicans and Microsporum gypseum. Isoxazolidines (3a, 2a, 3b) proved to have strong antimicrobial activity compared to the standard drugs, as well as Drug-likeness and pharmacokinetic characteristics were predicted. Pharmacokinetic studies indicated that most derivatives exhibit acceptable predictive ADME properties and excellent fit with the Lipinski rules. Molecular docking was used to examine the binding interactions of the most active analogues with the active site of the DNA gyrase enzyme (PDB id 1KZN). Results showed that the enhanced activity of compounds (3a, 3b, 2a) exhibited stronger docking scores binding to the active site than the Nitrofurazone (standard drug). These findings suggest that analogues (3a, 3b) can be used as the best candidates for designing and discovering novel antimicrobial agents.

A Molecular Electron Density Theory Study of the Lewis Acid Catalyzed [3+2] Cycloaddition Reactions of Nitrones with Nucleophilic Ethylenes

AbstractThe BF3Lewis acid (LA) catalyzed [3+2] cycloaddition (32CA) reaction of 1‐pyrroline‐1‐oxide (PNO) with 2,3‐dihydrofuran (DHF) has been studied within the molecular electron density theory (MEDT) at theωB97X‐D/6‐311G(d,p) computational level. Electron localization function (ELF) characterizes PNO and the corresponding PNO : BF3complex as zwitterionic species. Conceptual DFT indices allow classifying PNO and DHF as marginal electrophiles and strong nucleophiles, while the PNO : BF3complex is a strong electrophile. Consequently, while the non‐catalyzed 32CA reaction is non‐polar, the BF3catalyzed one has a high polar character, revealed by the analysis of the global electron density transfer (GEDT) at the transition state structures. The BF3catalyzed 32CA reaction, which is classified as of reverse electron density flux (REDF), presents highexostereoselectivity, and totalorthoregioselectivity. The presence of the BF3catalyst decreases the activation enthalpy of the 32CA reaction in dichloromethane by 7.5 kcal mol−1, as a consequence of the increase of the polar character of the reaction, in complete agreement with the experimentally observed acceleration.

Catalytic asymmetric transformation of nitrones and allenes to dihydropyridoindoles via chiral N,N′-dioxide/cobalt(ii) catalysis

A dia- and enantioselective multistep cascade reaction of nitrones with allenes to chiral dihydropyridoindoles promoted by a chiral N,N′-dioxide/Co(ii) complex was described.

Unveiling the intramolecular [3 + 2] cycloaddition reactions ofC,N-disubstituted nitrones from the molecular electron density theory perspective

The zwitterionic type intramolecular [3 + 2] cycloaddition reactions of nitrones show remarkable substituent effects and varying reactivities in the cases of cyclic and acyclic alkenes.

Regio- and stereoselectivity of the [3+2] cycloaddition of nitrones with methyl-acetophenone: A DFT investigation

A theoretical study of the regio- and stereoselectivities of the [3 + 2] cycloaddition reactions of nitrones with substituted alkene (methyl acetophenone) is investigated using density functional theory (DFT) and carried out at B3LYP/6-311+G(d,p) level. The reactivity of these cycloadditions is rationalized by FMO model, activation energy calculations, and philicity indexes. The electronic populations have been calculated from natural orbital, which based on charges by using NBO analysis, MK and CHelpG electrostatic population. The four possible pathways, fused and bridged regioisomeric modes, and the two stereoisomeric approaches endo and exo for the cycloaddition reactions are analyzed and discussed. Analysis of TS geometries and bond lengths demonstrate that these reactions follow a one-step mechanism with asynchronous transition states. The activation energy indicated a favored endo approach along the four reaction pathways.

1,3-Dipolar cycloaddition of nitrones: synthesis of multisubstituted, diverse range of heterocyclic compounds

The 1,3-dipolar cycloaddition reaction of nitrone is one of the most important methods for the synthesis of different sizes of heterocycles which have enormous applications in natural products, biologically active molecules and pharmaceuticals.

Regio- and stereoselective (3 + 2)-cycloaddition reactions of nitrones with cyclic allenes.

An effective approach to access functionalized 2H-cyclonona(deca)[d]isoxazoles and 15-oxo-3,10-methanobenzo[b][1]azacyclododecines has been developed by the reaction of N-aryl-C,C-bis(methoxycarbonyl)nitrones with cyclonona(deca)-1,2-dienes in a one-pot fashion. The reaction of N-aryl-C-(phenylcarbamoyl)nitrones with these allenes proceeds strictly regioselectively giving the mixtures of diastereomeric isoxazolidines containing a double bond at the C4-position of the isoxazolidine ring. The quantum chemical calculations show that the regioselectivity of these reactions is in good agreement with the reactivity indices of the considered compounds.

Diastereoselective thermal [3+2] cycloaddition reactions of nitrone possessing an amide functional group as hydrogen bond donor/acceptor

High diastereoselectivity in the [3+2] cycloaddition reactions of a series of maleimides with a nitrone capable of hydrogen bonding have been carried out. The cycloaddition reaction proceeded in highly diastereoselective manner leading to novel pyrrolo[3,4- d ]isoxazolidines with good yields. NMR studies revealed that in the performed cycloaddition reactions, a pair of diastereomers are formed in all cases and the cis -diastereomeric product is the favorite cycloadduct with de values up to 90%. It would appear that the presence of amide functionality at the phenyl moiety of nitrone can influence the diastereomeric ratio in the cycloaddition reactions and cis stereoselectivity is most likely dependent on the presence of this group. The nature of the cycloadddition process was interpreted in the framework of theMolecular Electron Density Theory.