The pyrolysis of azetidine: Shock-tube kinetics similarities and contrasts with two analogs

The kinetics of decomposition of azetidine {(CH₂)₃N(SINGLEBOND)H)} was measured using single-pulse shock-tube techniques, over the temperature range 855–1100 K, in high argon dilution. These data confirm and extend an earlier investigation that utilized the very low-pressure pyrolysis method. A brief survey of many reports regarding the interesting features of azetidine is presented. In two appendices the thermodynamic and kinetic data on trimethylene sulfide, oxide, and immine are intercompared. New ab-initio calculations are cited for the parent species and their fragmentation products. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 185–191, 1998.     

Ultrasound assisted,synthesis of N-(7-(R)-2-oxa-8-azabicyclo[4.2.0]octan-8-yl)isonicotinamide derivatives and their biological evaluation

In this study, new series of azetidine derivatives were synthesized ( 4a-n ) from isoniazide ( 1 ), Aromatic aldehydes ( 2a-n ), dihydropyran ( 3 ) using SnCl₂ catalyst, via one pot multicomponent reaction/cycloaddition reaction. The synthesized azetidine derivatives were characterized by IR, ¹H NMR and ¹³C NMR and have been screened for antimicrobial, antituberculosis and anti-inflammatory activities. In relation to Staphylococcus aureus (ATCC 25923) promising antibacterial activity was shown, compounds 4e and 4k , followed by compounds 4h , 4n , 4f , 4g and 4l . The synthesized azetidine derivatives, 4a , 4e , 4j and 4m (with zone 12 mm) displayed antituberculosis activity. But its lower potential than, the standard streptomycin (with zone 18 mm). Further 4d compound alone displayed similar activity.     

Azetidine,pyrrolidine and hexamethyleneimine at 170 K

The crystal structures of the cyclic amines azetidine (C₃H₇N), pyrrolidine (C₄H₉N) and hexamethyleneimine (homopiperidine, C₆H₁₃N), of the series (CH₂)_nNH, with n = 3, 4 and 6, respectively, have been determined at 170 K, following in situ crystallization from the melt. These structures provide crystallographic data to complete the homologous series of cyclic amines (CH₂)_nNH, for n = 2–6. Azetidine and pyrrolidine contain chains propagating along 2₁ screw axes, in which the molecules are linked by co-operative N—H...N hydrogen bonds. Azetidine has two molecules in its asymmetric unit, while pyrrolidine has only one. Hexamethyleneimine contains tetrameric hydrogen-bonded rings formed about crystallographic inversion centres, with two molecules in its asymmetric unit. The observation of crystallographically distinct molecules in the hydrogen-bonded chains of azetidine and cyclic hydrogen-bonded motifs in hexamethyleneimine is consistent with expectations derived from comparison with monoalcohols forming chains or rings by co-operative O—H...O hydrogen bonds. The next member of the cyclic amine series, heptamethyleneimine, forms a cubic plastic phase on cooling from the melt.     

Phototransformations of azetidine radical cations stabilized in freonic matrices

It has been established that transformations of azetidine radical cations observed in freonic matrices under the action of light with λ = 436 nm (T = 77 K) are associated with C-N bond cleavage which corresponds to the cyclic form yielding a mixture of open distonic C-centered radical cations of the following structure: ·CH₂CH₂CH=NH ₂ ⁺      

Theoretical determination of molecular structure and conformation: Part X. Geometry and puckering potential of azetidine, (CH2)3NH,combination of electron diffraction and ab initio studies

Restricted Hartree—Fock calculations on 21 planar and puckered conformers of azetidine have been done employing a split valence basis augmented by d functions. Complete geometry optimizations have been performed for eight conformers. In this way the puckering potential of azetidine is explored over the range ?40° < ø (puckering angle) < 40°, for both sp³ and sp² hybridization of the nitrogen atom. In its equatorial form, azetidine is slightly more puckered than cyclobutane. This is because of a decrease of van der Waals' repulsion between H atoms. Charge effects lead to destabilization of the axial forms. There is only moderate coupling between puckering and methylene group rocking. Previously published electron diffraction (ED) data are reinvestigated using vibrational corrections and information from the ab initio calculations. On the basis of this MO constrained ED (MOCED) analysis a puckering angle φ = 35.1(1.8)° is found. Observed r_g and r_e bond distances are compared with ab initio values.     

Synthesis of spirocyclopropyl γ-lactams by tandem intramolecular azetidine ring-opening/closing cascade reaction: synthetic and mechanistic aspects

The scope and limitations of a novel intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams from azetidines in high regio- and stereoselectivity is reported. The key step of the process is a S_N2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and TEA. This study is a very rare example of nucleophilic ring-opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkylation or the use of N-electron-withdrawing groups. Application of this process to 2-azetidinone system led to a complete change in reactivity and provide 6-aza-bicyclo[3.2.0]heptane derivatives via an unprecedented Mukaiyama aldol-like reaction involving an ester acceptor and a silyl imidate.     

Crystal and molecular structure of 1-azabicyclo[3.2.0]heptane-1-methyl chloride

The structure of the compound, 1-azabicyclo[3.2.0]heptane-1-methyl chloride has been determined by a single crystal x-ray diffraction study. The compound crystallizes in space group C_mcm with four formula weights in a unit cell of dimensions a = 8.53, b = 10.30, c = 9.27 ± .01 Å. The molecular cations fit in large holes between the chloride anions and consequently are disordered about the cation positions. The five-membered ring portion is non-planar and bears a strong resemplance to other five-membered rings in bicyclic-fused compounds. The azetidine portion of the molecule is planar. The basic fused ring structure is contrasted to that found in penicillin salts. A final value of R = 0.10₆ for the 305 independent reflections was obtained.     

Azetidine‐Containing Alkaloids Produced by a Quorum‐Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa

Pseudomonas aeruginosa displays an impressive metabolic versatility, which ensures its survival in diverse environments. Reported herein is the identification of rare azetidine‐containing alkaloids from P. aeruginosa PAO1, termed azetidomonamides, which are derived from a conserved, quorum‐sensing regulated nonribosomal peptide synthetase (NRPS) pathway. Biosynthesis of the azetidine motif has been elucidated by gene inactivation, feeding experiments, and biochemical characterization in vitro, which involves a new S‐adenosylmethionine‐dependent enzyme to produce azetidine 2‐carboxylic acid as an unusual building block of NRPS. The mutants of P. aeruginosa unable to produce azetidomonamides had an advantage in growth at high cell density in vitro and displayed rapid virulence in Galleria mellonella model, inferring functional roles of azetidomonamides in the host adaptation. This work opens the avenue to study the biological functions of azetidomonamides and related compounds in pathogenic and environmental bacteria.     

Green Synthesis of 1‐(1,2,4‐Triazol‐4‐yl)spiro[azetidine‐2,3′‐(3H)indole]‐2′,4′(1′H)‐diones as Potential Insecticidal Agents

One pot green synthesis of 1‐(1,2,4‐triazol‐4‐yl)spiro[azetidine‐2,3′‐(3H)‐indole]‐2′,4′(1′H)‐diones was carried out by the reaction of indole‐2,3‐diones,4‐amino‐4H‐1,2,4‐triazole and acetyl chloride/chloroacetyl chloride in ionic liquid [bmim]PF₆ with/without using a catalyst. It was also prepared by conventional method via Schiff's bases, 3‐[4H‐1,2,4‐triazol‐4‐yl]imino‐indol‐2‐one. Further, the corresponding phenoxy derivatives were obtained by the reaction of chloro group attached to azetidine ring with phenols. The synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and FAB mass) data. Evaluation for insecticidal activity against Periplaneta americana exhibited promising results.     

β-lactams from azetidine carboxylates. A synthesis of (1-3-ana,the nucleus of the nocardicins

A synthesis of ($\text{+}$)-3-ANA is described involving oxidative decarbonylation of an azetidine carboxylic ester.     

CBS-4 ab initio results on the formation and stability of N-aminoazetidine radical cation and derivatives

Experimental evidence has recently indicated the role of substituted azetidine radical cations in the electron ionization (EI) mass spectrometric fragmentation of N,N-dimethylhydrazone derivatives of 5- and 6-unsaturated straight-chain aldehydes. Although the 2+2 cycloaddition of ethylene and methyleneamine to form neutral azetidine has a very high energy barrier and is only mildly exothermic, CBS-4 ab initio calculations show that formation of the proposed radical-cation intermediate is strongly exothermic with a low barrier. Further calculations show that the general energetics remain essentially unchanged even when substituents of the type present in the mass spectrometric studies are included. These calculations demonstrate that the proposed new mass spectral fragmentation mechanism is both thermodynamically and kinetically feasible.     

Divergent total synthesis of penaresidin B and its straight side chain analogue

The divergent synthesis of penaresidin B and its straight side chain analogue was accomplished by constructing an azetidine ring via S_N2 type cyclization of protected 2,3-syn-3,4-syn-4-amino-1,3-dihydroxyhept-6-en-2-yl mesylate and late-stage introduction of an alkyl side chain via olefin cross-metathesis of 4-allylazetidine with readily available terminal alkenes. This synthetic route would be useful to synthesize penaresidin side chain analogues.     

Inherently Emissive Puromycin Analogues for Live Cell Labelling

Puromycin derivatives containing an emissive thieno[3,4-d]-pyrimidine core, modified with azetidine and 3,3-difluoroazetidine as Me₂N surrogates, exhibit translation inhibition and bactericidal activity similar to the natural antibiotic. The analogues are capable of cellular puromycylation of nascent peptides, generating emissive products without any follow-up chemistry. The 3,3-difluoroazetidine-containing analogue is shown to fluorescently label newly translated peptides and be visualized in both live and fixed HEK293T cells and rat hippocampal neurons.     

A pair-excitation MCSCF calculation based on CNDO/INDO approximation I

Second-order multiconfigurational self-consistent field (MCSCF ) calculation has been programmed on the basis of CNDO /INDO molecular orbital bases, in which the configuration space employed is restricted within pair-excitations. Test calculations have been carried out for 17 small molecules. All the MCSCF ground states of these molecules have been successfully converged to their respective optimal states by employing a simple weighting scheme. This procedure provides a great savings in computer time. The MCSCF calculation on azetidine required only 27 min on a HITAC M-680H. The MCSCF energies of HF, F₂, and BH show improved behaviors up to large atomic distances (～7au).     

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.     

Efficient synthesis of azetidine through N-trityl- or N-dimethoxytritylazetidines starting from 3-amino-l-propanol or 3-halopropylamine hydrohalides

Efficient synthetic routes for the preparation of azetidine starting from commercially available 3-amino-l-propanol or 3-halopropylamine hydrohalides are reported. First, the appropriate N-trityl- or N-dimethoxy-trityl protected tosyloxy- or halopropylamines were prepared. These precursors were then cyclized into the N-trityl- or N-dimethoxytritylazetidines. The N-protecting groups were removed in the presence of perchloric acid giving the hydrogen perchlorate salt of azetidine. The latter compound was transformed into its free base using a strong base under anhydrous conditions. The relatively expensive 4,4′-dimethoxytrityl chloride and less expensive trityl chloride used in these synthetic procedures were recycled in good yields. Azetidine hydrogenperchlorate can be used to prepare N-substituted azetidines without the need to isolate the free azetidine.     

Mass spectra of azetidines

The mass spectra of azetidine, 2-methylazetidine, 2-phenylazetidine, methylene-bis-azetidines, their N-halo- and N-tosyl derivatives, 2-phenylazetine as well as N,N-dimethylmethane sulphonamide, N,N-dimethyl and N,N-diethyl- p-toluene sulphonamides have been investigated. The fragmentation of azetidine derivatives via the open form of the molecular ion is discussed.     

Synthesis of heterocyclic bioregulators and semiochemicals

Chemistry and biology of oxygen heterocycles as insect pheromones are reviewed referring to exo-brevicomin, disparlure, japonilure and olean. Synthesis of koninginin A, a microbial metabolite, is discussed. Two azetidine alkaloids, penaresidin A and penazetidine A, were synthesized.     

Solvent‐free cycloaddition reaction of 3‐indolylimines with chloroacetyl chloride under microwave irradiation

Solvent‐free approach is developed for the rapid synthesis of spiro[azetidine‐indoles] 6a–g on basic alumina supported potassium carbonate (K₂CO₃–Al₂O₃) from the cycloaddition reaction of indolylimines 3 and chloroacetyl chloride 4 as synthons using microwaves. The procedure neither required toxic and hazardous base nor volatile solvents. 3 was synthesized in situ by the neat reaction of indole‐2,3‐diones 1 and fluorinated anilines 2 under microwave irradiation. Solvent‐free aminoalkylation of spiro compounds 6a and 6b has been carried out under microwaves. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:468–473, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10180     

Quantum chemical study of several monocyclic complex β‐lactam C‐3, C‐4, and N‐derivatives,and β‐ring model molecules

A quantum chemical study of several complex monocyclic 4‐benzoyl‐4‐phenyl‐β‐lactam derivatives was carried out using cyclobutane, azetidine, 2‐azetidinone, 1‐methyl‐2‐azetidinone, and 3‐methyl‐2‐azetidinone as model compounds. The optimum geometry was obtained for the different conformations. The planarity of the ring was discussed in terms of the influence of the substituents on the amide resonance. To better analyze the amide resonance and the activity of the β‐lactam ring, a vibrational study was also carried out. To examine the influence of solvent polarity on the carbonyl bands, the Fourier transform–infrared (FT‐IR) spectra of the β‐lactam monocyclic derivatives were recorded in CCl₄, C₆H₆, and CHCl₃ solutions. The normal vibrations of the β‐lactam ring in the model compounds were characterized and used in the analysis of the β‐ring of more complex derivatives. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002