Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths

Bis(oxiranes) Containing Cyclooctane Core: Synthesis and Reactivity towards NaN₃

Reactions of oxirane ring opening provide a powerful tool for regio- and stereoselective synthesis of polyfunctional and heterocyclic compounds, widely used in organic chemistry and drug design. Cyclooctane, alongside other medium-sized rings, is of interest as a novel molecular platform for the construction of target-oriented leads. Additionally, cyclooctane derivatives are well known to be prone to transannular reactions, which makes them a promising object in the search for novel approaches to polycyclic structures. In the present work, a series of cyclooctanediones was studied in Corey-Chaykovsky reactions, and novel spirocyclic bis(oxiranes) containing cyclooctane core, namely, 1,5-dioxadispiro[2.0.2.6]dodecane and 1,8-dioxadispiro[2.3.2.3]dodecane, were synthesized. Ring opening of the obtained bis(oxiranes) upon treatment with sodium azide was investigated, and it was found that the reaction path is determined by the reciprocal orientation of oxygen atoms in the oxirane moieties. Diastereomers of the bis(oxiranes) with cis-orientation underwent independent ring opening, supplying corresponding diazidodiols, while in the case of stereoisomers with trans-orientation, domino-like reactions occurred, including intramolecular nucleophilic attack and the formation of a novel three- or six-membered O-containing ring. Summarily, a straightforward approach to polyfunctional compounds containing cyclooctane or oxabicyclo[3.3.1]nonane cores, employing bis(oxiranes), was elaborated

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD

Three-Component Heterocyclization of <i>gem</i>-Bromofluorocyclopropanes with NOBF₄: Access to 4‑Fluoropyrimidine <i>N</i>‑Oxides

Novel three-component heterocyclization involving <i>gem</i>-bromofluorocyclopropanes, nitrosyl tetrafluoroborate, and a molecule of the solvent (nitrile) yielding previously unknown fluorinated pyrimidine <i>N</i>-oxides is described. A two-step synthetic approach to 4-fluoropyrimidine <i>N</i>-oxides from alkenes under mild conditions is developed using this reaction. Mechanistic aspects of the heterocyclization are discussed

Electrochemically Deprotonated Chiral Nickel(II) Glycinate in Stereoselective Nucleophilic Addition to Michael Acceptors: Advantages and Limitations

A Ni­(II) glycine/Schiff base complex containing (<i>S</i>)-<i>o</i>-[<i>N</i>-(<i>N</i>-benzylprolyl)­amino]­benzophenone as an auxiliary chiral moiety was deprotonated using electrochemically generated azobenzene radical anion and used in nucleophilic addition to Michael acceptors, terminal 2,2- and 1,2-disubstituted alkenes ((2<i>E</i>)-1,3-diphenylprop-2-en-1-one, (<i>E</i>)-2-nitroethenylbenzene, 2-methylprop-2-enenitrile, Ni­(II) dehydroalanine complex), creating a preparatively convenient path for asymmetric functionalization of the α-glycine carbon in the Ni­(II) coordination environment, yielding new chiral Ni­(II) complexes. The main advantage of the application of electrochemical techniques is the possibility of precise control of the concentration of a base and its in situ reaction with the complex. This opens up the possibility to carry out further functionalization of the anionic adduct formed in Michael addition via a successive <i>one-pot</i> reaction with the other electrophile. A one-pot cascade reaction of electrochemically deprotonated Ni­(II) glycinate with (<i>E</i>)-2-nitroethenylbenzene and the successive interaction with benzyl chloride or dimethyl sulfate allowed a new oxime-containing Ni­(II) complex to be obtained, which might be considered as an important synthon. All complexes were reliably characterized using HRMS and ¹H and ¹³C NMR (including 2D techniques); an adduct with (2<i>E</i>)-1,3-diphenylprop-2-en-1-one was also characterized by X-ray diffraction studies and CD spectrum. The manner of stereocontrol in the Michael addition of electrochemically deprotonated Ni­(II) glycinate was shown to be different for terminal 2,2- and for 1,2-disubstituted alkenes. In the case of the 1,2-disubstituted alkene both stereocenters are already formed in the first reaction step, which is reversible and thermodynamically controlled. The second step (protonation of the anion) is fast and irreversible, and it does not influence the stereochemical result of the reaction. In contrast to the previous case, only one stereocenter is formed in the first thermodynamically controlled step for terminal alkenes, whereas the configuration of the second stereocenter is determined by a kinetically controlled protonation step

Three-Component Heterocyclization of <i>gem</i>-Bromofluorocyclopropanes with NOBF₄: Access to 4‑Fluoropyrimidine <i>N</i>‑Oxides

Novel three-component heterocyclization involving <i>gem</i>-bromofluorocyclopropanes, nitrosyl tetrafluoroborate, and a molecule of the solvent (nitrile) yielding previously unknown fluorinated pyrimidine <i>N</i>-oxides is described. A two-step synthetic approach to 4-fluoropyrimidine <i>N</i>-oxides from alkenes under mild conditions is developed using this reaction. Mechanistic aspects of the heterocyclization are discussed

Chiral Nickel(II) Binuclear Complexes: Targeted Diastereoselective Electrosynthesis

Ni­(II) complexes containing (<i>S</i>)-<i>o</i>-[<i>N</i>-(<i>N</i>-benzylprolyl)­amino]­benzophenone as an auxiliary chiral moiety in the form of a Schiff base with α-amino acids (α-amino acid = glycine, alanine, dehydroalanine; <b>Gly-Ni, Ala-Ni</b>, and <b>Δ-Ala-Ni</b>) were subjected to various types of electrochemical activation (oxidation, reduction, and a treatment with electrogenerated base), affording regio- and diastereoselective synthesis of novel types of binuclear Ni­(II) complexes via C–C coupling. New compounds were fully characterized by HRMS, MALDI-TOF, CD, and ¹H and ¹³C NMR (including two-dimensional techniques) spectroscopy; two complexes were characterized by X-ray diffraction analysis. The structures of the novel complexes obtained via electrosynthesis completely match the predictions (made from preliminary voltammetric investigations of the starting complexes as well as from DFT estimations of the energy and symmetry of their frontier molecular orbitals) about the nature of chemical transformations which may follow the electron transfer steps. Electrochemical oxidation of <b>Gly-Ni</b> and <b>Ala-Ni</b> allows access to new dimeric complexes linked via benzophenone moieties in the Ni­(II) coordination environment. These new binuclear Ni­(II) complexes are of interest as chiral redox mediators for both oxidative and reductive transformations, since they exhibit quasi-reversible electrochemical behavior (their reduced and oxidized forms are stable, at least on the time scale of cyclic voltammetry). Three other binuclear Ni­(II) complexes which were obtained via reductive dimerization of the <b>Δ-Ala-Ni</b> complex, via nucleophilic addition of electrochemically deprotonated <b>Gly-Ni</b> to <b>Δ-Ala-Ni</b>, and via oxidative electrochemical dimerization of deprotonated <b>Gly-Ni</b> are of interest as convenient precursors for the stereoselective preparation of diamino dicarboxylic acids HO­(O)­CCH­(NH₂)­(CH₂)_<i>n</i>(NH₂)­CHC­(O)­OH (<i>n</i> = 2–0), since the obtained binuclear Ni­(II)–Schiff base complexes can be easily disassembled using aqueous HCl in methanol