Four-membered Heterocyclic Rings Research Articles

Energetic materials with fluorinated four-membered heterocyclic ring: 3,3′-difluoroazetidine (DFAZ) salts

Fluorine atoms and four-membered rings form 3,3′-difluoroazetidinium (DFAZ) salts, which have a better detonation property than ammonium dinitramide (ADN).

Design and synthesis of novel antineoplastic agents inspired from marine bromopyrrole alkaloids.

Azetidin-2-one, a β -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.

Cover Picture: Binding Energies of the π-Stacked Anisole Dimer: New Molecular Beam-Laser Spectroscopy Experiments and CCSD(T) Calculations (Chem. Eur. J. 18/2015)

The unravelling of new fundamental information, the intersection between laser experiments and quantum calculations, with results that will lead to a better description of the structure of biomolecules and nanomaterials is the inspiration behind the cover. In their Full Paper on page 6740 ff., M. Becucci, P. Hobza et al. report on their developments in the experimental measurement of binding energies in π–π stacked complexes, complemented by theoretical calculations. The unravelling of new fundamental information, the intersection between laser experiments and quantum calculations, with results that will lead to a better description of the structure of biomolecules and nanomaterials is the inspiration behind the cover. In their Full Paper on page 6740 ff., M. Becucci, P. Hobza et al. report on their developments in the experimental measurement of binding energies in π–π stacked complexes, complemented by theoretical calculations. Sensing Nitroaromatics In their Concept article on page 6656 ff., S. Shanmugaraju and P. S. Mukherjee detail the adaptability of self-assembled molecular architectures for sensing nitroaromatic explosives. The observed reasonable sensitivity of self-assembled metallacycles/cages is owing to their π-electron-richness and intrinsic porous structures, which eventually accommodate electron-poor nitroaromatics through multiple supramolecular interactions. The synthetic simplicity and easy functionalization make self-assembled supramolecular architectures promising sensor materials.1 Pyridoazacarbazoles A facile and efficient synthetic route to a four-membered heterocyclic ring system, hitherto unknown to literature, is described. Utilizing commercially available building blocks in an elegant base-catalyzed one-pot procedure leads to novel 5,6-dihydro-11H-pyrido[3,2-i]-1-azacarbazoles with promising anticancer properties in only one step. More details of this chemistry and the formation mechanisms are given in the Communication by B. Clement and co-workers on page 6668 ff.1 G-Quadruplexes Duplex DNA formation allows the predictable construction of nanomaterials with a large number of potential applications. Additionally, duplexes and quadruplexes may be combined to form predictable supramolecular structures. In their Full Paper on page 6732 ff., J.-L. Mergny et al. show how classical duplex DNA can guide the strand polarity of a quadruplex motif in a duplex–quadruplex substrate.1

Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake

Lobelane analogs that incorporate a central piperidine or pyrrolidine moiety have previously been reported by our group as potent inhibitors of VMAT2 function. Further central ring size reduction of the piperidine moiety in lobelane to a four-membered heterocyclic ring has been carried out in the current study to afford novel cis-and trans-azetidine analogs. These azetidine analogs (15a–15c and 22a–22c) potently inhibited [3H]dopamine (DA) uptake into isolated synaptic vesicles (Ki⩽66nM). The cis-4-methoxy analog 22b was the most potent inhibitor (Ki=24nM), and was twofold more potent that either lobelane (2a, Ki=45nM) or norlobelane (2b, Ki=43nM). The trans-methylenedioxy analog, 15c (Ki=31nM), was equipotent with the cis-analog, 22b, in this assay. Thus, cis- and trans-azetidine analogs 22b and 15c represent potential leads in the discovery of new clinical candidates for the treatment of methamphetamine abuse.

Theoretical study of mechanism of cycloaddition reaction between 2,2-dimethyl(2-germavinylidene) [(CH3)2Ge=C:] and formaldehyde

The mechanism of the cycloaddition reaction between singlet 2,2-dimethyl(2-germavinylidene) [(CH3)2Ge=C:] and formaldehyde has been investigated with CCSD(T)//MP2/6-311G** method. From the potential energy profile, it could be predicted that the reaction has two competitive dominant reaction pathways. The first pathway consist of the transfer of formaldehyde oxygen π-electrons to the 2p unoccupied orbital of the C: atom in 2,2-dimethyl(2-germavinylidene) with a formation of intermediate which then isomerizes to a four-membered heterocyclic ring carbene (Ge and O in the 1,3-position). The second pathway is a direct [2 + 2] cycloaddition reaction in which the interaction of two π-bonds in 2,2-dimethyl(2-germavinylidene) and formaldehyde generates another four-membered heterocyclic ring carbene (Ge and O in 1,2-position). Because of the unsaturated property of the C: atom in the two four-membered heterocyclic ring carbenes, the two four-membered heterocyclic ring carbenes could further react with formaldehyde, generating two spiro-heterocyclic ring compounds.

Mechanisms and Kinetics for the Thermal Decomposition of 2-Azido-N,N-Dimethylethanamine (DMAZ)

To gain insight into the mechanisms and kinetics of 2-azido-N,N-dimethylethanamine's (DMAZ's) thermal decomposition postulated reaction paths were simulated with ab initio and density functional theory quantum chemistry models. Four reaction types were modeled: (i) spin-allowed and spin-forbidden paths involving N-N(2) bond fission and nitrene formation, (ii) HN(3) elimination with the formation of (dimethylamino)ethylene, (iii) N-N(2) bond fission with the formation of molecules with three- or four-membered heterocyclic rings, and (iv) simple scission of C-H, C-N, and C-C bonds. The geometries of stationary points of the reactions were obtained with a MPWB1K/6-31+G(d,p) model. To locate and model the geometries of minimum energy intersystem crossing points for triplet nitrene formation and isomerization, unrestricted broken spin symmetry calculations were performed. Employed to model an analogous path for methyl azide's decomposition, this approach was found to yield results similar to those obtained with a CASSCF(10,8)/aug-cc-pVDZ model. Of the four reaction types studied, N-N(2) bond fissions with singlet or triplet nitrene formation were found to have the lowest barriers. Barriers for paths to cyclic products were found to be 2-4 kcal/mol higher. Kinetic rate expressions for individual paths were derived from the quantum chemistry results, and spin-allowed nitrene formation was found to be dominant at all temperatures and pressures examined. The expression 2.69 × 10(9) (s(-1))T(1.405) exp(-39.0 (kcal/mol)/RT), which was derived from QCISD(T)/6-31++G(3df,2p)//MPWB1K/6-31+G(d,p) results, was found to be representative of this reaction's gas-phase rate. Adjusted on the basis of results from self-consistent reaction field models to account for solvation by n-dodecane, the expression became 1.11 × 10(9) (s(-1))T(1.480) exp(-37.6 (kcal/mol)/RT). Utilizing this result and others derived in the study, a model of the decomposition of n-dodecane-solvated DMAZ was constructed, and it generated simulations that well-reproduce previously published measured data for the process.

An Update on the Synthesis of β-Lactams

Because the renewed interest of β – lactams in organic and medicinal chemistry, research in this field continues in producing new appealing progresses. This review tries to call the attention on synthetic aspects related to the generation of the four-membered heterocyclic ring, published in the last few years, with special accent in stereoselective synthetic approaches. The compendium will cover methods for achieving diastereo- and enantioselectivity during [2+2] cycloadditions, with the Staudinger reaction still as the first choice method, but also important achievements have been published for the imine-enolate condensation, the carbonylative cycloaddition, and the Kinugasa reaction. Significant success was also obtained in the synthesis of innovative 2-azetidinones through the formation of a single bond. In this respect, the C3-C4 bond formation, through intramolecular cyclization of linear epoxy or halo derivatives, and the carbenoid C-H insertion are among the most effectively exploited procedures. In addition, the adaptation of most procedures to solid-phase methodologies has facilitated the generation of molecular diversity based on the β – lactam skeleton. Keywords: β-lactams, 2-azetidinones, stereoselective synthesis, chiral auxiliaries, chiral catalysts, memory of chirality

A DFT Study on the Mechanism of the Annulation Reaction of Trichloronitroethylene with Aniline in the Synthesis of Quinoxalinone-N-oxides

The new annulation reaction of trichloronitroethylene with aniline results in the formation of a quinoxalinone-N-oxide derivative. The mechanism of this one-pot annulation reaction between trichloronitroethylene (TCNiE) and anilines has been extensively investigated with B3LYP/6-31+G** methodology. Five different paths (1-5) were proposed and modeled by using this method. These paths were compared in terms of the activation energies of their rate-determining steps and in regard to the experimental findings. Paths 3 and 5, proceeding via four-membered heterocyclic rings, were found to be the most plausible paths with activation energies of 32 and 29 kcal/mol for the rate-determining steps, respectively. The effects of substituent, solvent, temperature, and computational method on these steps were also investigated. The results showed that path 5 is the most plausible mechanism for the annulation reaction of trichloronitroethylene with aniline.

Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates

The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols, including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding beta-aryloxy amines in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to determine the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed (up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state, giving beta-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.

Theoretical study on stability and NMR chemical shifts of the diketene molecule, its isomers and their mono- and disulphur analogues

Theoretical Gibbs free energies have been determined for a set of cycloaddition products of allene with CO2, CS2 or OCS molecules, and of CH2CX with CH2CY molecule (X, Y=O, S). Each of the cycloaddition reactions leads to one or two isomeric products with four-membered heterocyclic ring. Theoretical thermochemical data suggest that the isomers in which sulphur atom is build into the four-membered ring can be easily formed in different reactions whereas formation of those with oxygen atom in the ring strongly depends on the considered reaction. Analysis of the theoretical 1H and 13C chemical shifts forms a basis for the detection of the isomer traces in reaction mixtures as well as for the elucidation of future experimental spectra.

High-Pressure Synthesis of New Aromatic Poly(diazetidinediones) by Cyclodimerization Polymerization of Aromatic Diisocyanates

New aromatic poly(diazetidinediones) having a strained four-membered heterocyclic ring structure, which we were unable to obtain by the polymerization under atmospheric pressure, were synthesized for the first time by the cyclodimerization polymerization of aromatic diisocyanates under high pressure without use of solvent or catalyst. As shown by a model compound study, aromatic monoisocyanates cyclodimerized almost quantitatively, yielding 1,3-disubstituted 1,3-diazetidine-2,4-diones at 180-200°C under 400-800 MPa for 20-40 h. Aromatic diisocyanates were converted cleanly to poly(diazetidinediones) through the cyclodimerization polymerization at 200°C under 700 MPa for 20 h

Four-membered Heterocyclic Rings from Iminophosphoranes. Preparation and reactivity of 2,4-diimino-1,3-diazetidines and related compounds

Aza Wittig-type reaction either of iminophosphoranes derived from N-aminoheterocycles or bis(iminophosphoranes) has been found to be an useful method for the synthesis of the four-membered ring 1,3-diazetidine. This account deals with the following cyclization reaction, reactivity and synthetic utility of this ring system and related compounds.

The Infrared Absorption Spectra of the Condensation Products of Formaldehyde with Hydrazine

Abstract The infrared absorption spectra of tetraformaltrisazine and formalazine have been obtained in the solid state. From a tentative assignment of the bands observed, it has been shown that a molecule of tetraformaltrisazine has the bicyclic structure proposed by Hofmann and Storm, while formalazine is a polymer with a four-membered heterocyclic ring.

Three- and four-membered heterocyclic rings

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