6,6′-Bis(1,5-diazabicyclo[3.1.0]hexane)

The interaction of 1,3-diaminopropane with glyoxal and NaOCl in water at pH 9.5–10.5 afforded the previously unknown 6,6′-bis(1,5-diazabicyclo[3.1.0]hexane). According to X-ray diffraction data, both bicyclic fragments of the title compound adopt a boat conformation. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 623–625, March, 1999.     

Diastereoselective synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes

A general method was developed for the synthesis of substituted 1,3,6-triazabicyclo[3.1.0]hexanes via intramolecular aminomethylation of the NH group of the diaziridine ring by the reactions of 3-aminomethyl-1,3-dimethyldiaziridine with aliphatic, aromatic, and heteroaromatic carbonyl compounds. These reactions with aldehydes proceeded diastereoselectively to form mixtures of two racemates, viz., 1R*,2R*,5R*,6R* and 1R*,2S*,5R*,6R*, in a ratio of (3—20) : 1, the predominant diastereomer being isolated in all cases. The reactions with symmetrical ketones gave rise exclusively to the (1R*,5R*,6R*) racemate. The predominant diastereomer 1R*,2R*,5R*,6R*-2-(2-bromothien-5-yl)-1,3,6-triazabicyclo[3.1.0]hexane crystallized as a conglomerate. The structure of one of its enantiomers was established by X-ray diffraction analysis.     

Molecular structure of 6-cyclopropyl-1,5-diazabicyclo[3.1.0]hexane: gas phase electron diffraction and theoretical study

The molecular structure and conformational composition of 6-cyclopropyl-1,5-diazabicyclo[3.1.0]hexane were determined by gas phase electron diffraction and quantum chemical calculations. The gas phase electron diffraction data were well reproduced for the mixture of two conformers with anti-boat and gauche-boat mutual ring orientation having 15 and 85% relative abundance, respectively. The standard enthalpy of formation of substance under study was calculated using atomization reactions, yielding value of 307.9 ± 3.3 kJ mol^-1 in gas phase.     

Synthesis and properties of 7,7-dichloro-3,4-benzobicyclo[4.1.0]heptane, its tricarbonylchromium complexes, and isomeric 7-chloro-3,4-benzobicyclo[4.1.0]heptanes

The reaction of Cr(CO)₆ with 7,7-dichloro-3,4-benzobicyclo[4.1.0]heptane gave the correspondingexo- andendo-chromium tricarbonyl complexes in a ratio of 4.5:1. The structures of the resulting compounds were established by NMR spectroscopy, mass spectrometry, and X-ray structural analysis. Reduction of dichlorobenzobicycloheptane and its chromium tricarbonyl complexes with LiAlH₄ affordedexo- andendo-7-chloro-3,4-benzobicyclo[4.1.0]heptanes in a 3.5:1 ratio. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 720–724, April, 1998.     

Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N′-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK_a of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74±0.05, which is 1.3 pK_a units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules.     

Stereocontrolled approach to 1-azabicyclo[4.1.0]heptanes: application to the synthesis of trans-2,6-disubstituted piperidines

Stereocontrolled synthesis of a 1-azabicyclo[4.1.0]heptane is achieved by formation of an NH aziridine from the corresponding 1,2-azido alcohol and subsequent intramolecular conjugate addition onto a tethered α,β-unsaturated ester. Regioselective ring opening of the product at C-7 by heteroatom based nucleophiles yields trans-2,6-disubstituted piperidines in moderate to good yields.     

One-pot assembly of 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes from alkyl aryl(hetaryl) ketoximes, acetylene, and aliphatic ketones: a new three-component reaction

A new three-component reaction between alkyl aryl(hetaryl)ketoximes, acetylene, and aliphatic ketones in the superbasic systems KOH/DMSO and LiOH/CsF/DMSO (70-90 °C, initial acetylene pressure 13-15 atm, 5-60 min) affords novel 4-methylene-3-oxa-1-azabicyclo[3.1.0]hexanes in yields of up to 75%. Using KOH/DMSO, the side products of the reaction are O-vinylketoximes and 2-aryl(hetaryl)pyrroles, while with LiOH/CsF/DMSO, the reaction proves to be selective, only minor amounts of the corresponding alkyl aryl(hetaryl) ketones being detectable.     

X-ray diffraction and quantum-chemical study of 3-(1,3-dioxolan-2-yl)-4,6-dinitrobenzo[d]isoxazole

X-ray diffraction study of the molecular structure of 3-(1,3-dioxolan-2-yl)-4,6-dinitrobenzo[d]isoxazole in the crystal, and quantum-chemical calculations of the isolated molecule demonstrated that the differences in the reactivity of the nitro groups at positions 4 and 6 are not associated with the electronic structure of the molecule but are, apparently, attributed to the properties of the corresponding ipso- complexes.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 8. Aminomethylation of 3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates as a method for the synthesis of new functionally substituted 3,7-diazabicyclo[3.3.1]nonane derivatives

Aminomethylation of 3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates upon treatment with primary amines and excess formaldehyde leads to 3,7-diazabicyclo[3.3.1]nonane derivatives. N-Methylmorpholinium 4-(2-chlorophenyl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate was obtained by the reaction of (E)-3-(2-chlorophenyl)-2-cyanoprop-2-enethioamide with 1-cyanoacetyl-3,5-dimethylpyrazole and N-methylmorpholine in acetone in quantitative yield. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2397–2400, December, 2007.     

Examination of the structure in solid state of amino analogs of 4,4′-[1,5-pentanediylbis(oxy)]bisbenzonitrile by means of X-ray diffraction, C CP/MAS NMR, and theoretical calculations

A single crystal of X-ray diffraction structures is presented for 4,4′-[1,5-(3-oxapentanediylbis(amino))]bisbenzonitrile 2 and 4,4′-[1,5-(N-methyl-3-azapentane-diylbis(oxy))]bisbenzonitrile 3. The molecular structures of these derivatives differ especially in conformations of the central linker: in 2 this linker adopts a trans/gauche conformation, whereas in 3 – a fully extended conformation. The N atoms in various positions of the aliphatic linker change dramatically the molecular packing mode of both bisnitriles. But in both cases the nitrile groups take part in intermolecular hydrogen bonds: a type of NH···N in 2 and of CH···N in 3. Various conformations of both molecules were reflected in ¹³C CP/MAS NMR spectra in solid state as single and double resonance patterns for 2 and 3, respectively. A preliminary anticancer assay against 60 cell lines of 3 reveals strong growth inhibition of leukemia, melanoma, and renal cancer cells.     

Synthesis, spectroscopic characterization, X-ray structure and DFT calculations of [Re(CO)3L2Cl] (L = 1,2,4-triazolo-[1,5-a]pyrimidine)

The paper presents a combined experimental and computational study of novel tricarbonyl complex – fac-[Re(CO)₃(tp)₂Cl] (tp = 1,2,4-triazolo-[1,5-a]pyrimidine). The compound has been characterized spectroscopically and structurally (by single-crystal X-ray diffraction). The absorption and emission spectra of the complex have been discussed on the basis of DFT and time-dependent (TD)DFT calculations.     

A new member of the calix[4]crown family:Facile synthesis and characterization of a calix[4]crown-9 cone conformer

25,27-Dipropoxy-p-tert-butylcalix[4]crown-9 cone conformer 5 was readily synthesized via an intramolecular cyclization strategy in good yields.The structures of all the new compounds involved were confirmed by NMR,ESI-MS and elementalanalyses.All of them were proved to be in the cone conformation.     

(5RS)‐6H‐Spiro[pyrazolo[1,5‐c]quinazoline‐5,4′‐thiochroman]: efficient synthesis under mild conditions,molecular structure and supramolecular assembly

Pyrazolo[1,5‐c]quinazolines are fused‐quinazoline derivatives which have been reported as potential agents against neurological disorders. The normal synthesis routes to these compounds require harsh reaction conditions, long reaction times or multistep sequences. The title compound, C₁₈H₁₅N₃S, has been prepared under very mild conditions by condensation of thiochroman‐4‐one with 5‐(2‐aminophenyl)‐1H‐pyrazole, which had itself been prepared by the reaction of hydrazine hydrate with 4‐hydroxyquinoline mediated by a brief period of microwave heating. Within the molecule in the crystal structure, the reduced pyrimidine ring adopts an envelope conformation, whereas the thiane ring adopts a half‐chair conformation. Molecules are linked into sheets by a combination of one N—H...S hydrogen bond and two independent C—H...π(arene) hydrogen bonds, which utilize the same aryl ring as the acceptor, with one C—H bond donating to each face of the ring. Comparisons are made with some related compounds.     

Oxidative Aromatization of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines: Synthetic Possibilities and Limitations,Mechanism of Destruction,and the Theoretical and Experimental Substantiation

The reaction tolerance of the multicomponent process between 3-aminoazoles, 1-morpholino-2-nitroalkenes, and aldehydes was studied. The main patterns of this reaction have been established. Conditions for the oxidation of 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines were selected. Previous claims that the 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines could not be aromatised have now been refuted. Compounds with an electron-donor substituent at position seven undergo decomposition during oxidation. The phenomenon was explained based on experimental data, electro-chemical experiment, and quantum-chemical calculation. The mechanism of oxidative degradation has been proposed.     

Studies toward the construction of substituted piperidine-2-ones and pyridine-2-ones from Baylis-Hillman adducts: discovery of a facile synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates

Studies toward the construction of functionalized piperidone derivatives from derivatives of Baylis-Hillman adducts are described. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthesis of 4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates.     

A concise,efficient and versatile synthesis of amino‐substituted benzo[b]pyrimido[5,4‐f]azepines: synthesis and spectroscopic characterization,together with the molecular and supramolecular structures of three products and one intermediate

A concise, efficient and versatile synthesis of amino‐substituted benzo[b]pyrimido[5,4‐f]azepines is described: starting from a 5‐allyl‐4,6‐dichloropyrimidine, the synthesis involves base‐catalysed aminolysis followed by intramolecular Friedel–Crafts cyclization. Four new amino‐substituted benzo[b]pyrimido[5,4‐f]azepines are reported, and all the products and reaction intermediates have been fully characterized by IR, ¹H and ¹³C NMR spectroscopy and mass spectrometry, and the molecular and supramolecular structures of three products and one intermediate have been determined. In each of N,2,6,11‐tetramethyl‐N‐phenyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepin‐4‐amine, C₂₂H₂₄N₅, (III), 4‐(1H‐benzo[d]imidazol‐1‐yl)‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, which crystallizes as a 0.374‐hydrate, C₂₁H₁₉N₅·0.374H₂O, (VIIIa), and 6,7,9,11‐tetramethyl‐4‐(5‐methyl‐1H‐benzo[d]imidazol‐1‐yl)‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₂₄H₂₅N₅, (VIIIc), the azepine ring adopts a boat conformation, but with a different configuration at the stereogenic centre in (VIIIc), as compared with (III) and (VIIIa). In the intermediate 5‐allyl‐6‐(1H‐benzo[d]imidazol‐1‐yl)‐N‐methyl‐N‐(4‐methylphenyl)pyrimidin‐4‐amine, C₂₂N₂₁N₅, (VIIb), the immediate precursor of 4‐(1H‐benzo[d]imidazol‐1‐yl)‐6,8,11‐trimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, (VIIIb), the allyl group is disordered over two sets of atomic sites having occupancies of 0.688 (5) and 0.312 (5). The molecules of (III) are linked into chains by a C—H…π(pyrimidine) hydrogen bond, and those of (VIIb) are linked into complex sheets by three hydrogen bonds, one of the C—H…N type and two of C—H…π(arene) type. The molecules of the organic component in (VIIIa) are linked into a chain of rings by two C—H…π(arene) hydrogen bonds, and these chains are linked into sheets by the water components; a single weak C—H…N hydrogen bond links molecules of (VIIIc) into centrosymmetric R₂²(10) dimers. Comparisons are made with some related compounds.     

Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR,X-ray and Photophysical Analysis §

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K₂CO₃ in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (¹H, ¹³C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.     

Three-component condensation of diethyl 2,4,6-trioxoheptanedicarboxylate with salicylaldehyde and ammonium acetate as a new method for the synthesis of the [1]benzopyrano[4,3-<Emphasis Type="Italic">b</Emphasis>]pyridine system

Three-component condensation of diethyl 2,4,6-trioxoheptanedicarboxylate with salicylaldehyde and ammonium acetate in EtOH affords 2,5-diethoxycarbonyl-5-hydroxy-4-oxo-4,4a, 5,10b-tetrahydro-1H-[1]benzopyrano[4,3-b]pyridine. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1494–1496, June, 2005.     

An efficient method for the synthesis of imidazo[1,5-a]quinoxalines from 3-acylquinoxalinones and benzylamines via a novel imidazoannulation

The reaction of 3-aroylquinoxalin-2(1H)-ones and their N-alkyl analogues with benzylamines in DMSO proceeds through an intermediate formation of N-(α-quinoxalinylbenzylydene)benzylamine, which when subjected to oxidative cyclocondensation gives imidazo[1,5-a]quinoxalines. Applying this new approach of imidazoannullation to the bis-3-aroylquinoxalines makes it possible to develop fundamentally new methods of the synthesis of bis-imidazo[1,5-a]quinoxalines with the use of different benzylamines and heteromacrocycles with the 1,3-bis(3-arylimidazo[1,5-a]quinoxalin-1-yl)benzene structural fragment when m-xylylenediamine is used.     

Benzannulation of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with chalcones and their synthetic equivalents as a method for the synthesis of tetrazolo[5,1-b]quinazolines

Derivatives of tetrahydrotetrazolo[5,1-b]quinazolines were synthesized by the reactions of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with α,β-unsaturated carbonyl compounds and their synthetic equivalents in methanol in the presence of sodium methoxide. The spontaneous or specifically target oxidation of these derivatives gives rise to aromatic tetrazoloquinazolines. The reaction pathways and mechanisms were discussed. The structures of the resulting compounds were confirmed by IR and ¹H NMR spectroscopy, mass spectrometry, and elemental analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1971–1976, September, 2008.