Degenerate thermal isomerizations of bicyclo[3.1.1]hept‐2‐ene: strategy and analysis

Bicyclo[3.1.1]hept‐2‐ene was first prepared and well identified in 1972. In 1974, the degenerate thermal isomerization involving 1‐d‐ and 3‐d‐bicyclo[3.1.1]hept‐2‐ene was approached successfully, as one of the two deuterium‐labeled structures was selected, heated, and equilibrated. There has been no further study of this degenerate isomerization. Here, a detailed outline of reaction trajectories for d₂‐labeled bicyclo[3.1.1]hept‐2‐enes is given that will establish the four independent kinetic parameters needed for 20 linking paths between six d₂‐species. The use of racemates, eliminating chiral separations and dissections, provides degenerate isomerization paths providing this method with general utility. Copyright © 2014 John Wiley & Sons, Ltd.     

A novel synthesis of highly substituted imidazo[1,5-a]pyrazine derivatives by 3-CR/2-CR sequence

By combining a three-component reaction of 2, 3-diaminomaleonitrile, ketones and isocyanides with a subsequent reaction of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives obtained from isocyanide-based three-component reaction with various alkyl and aryl isocyanates or isothiocyanates can be assembled a new class of highly substituted imidazo[1,5-a]pyrazine derivatives.     

A novel three-component reaction for the synthesis of 3-aryl-4H-benzo [1,4] oxazin-2-amine

A high yielding and fast method for the synthesis of 3-aryl-4H-benzo [1,4] oxazin-2-amine via one-pot, three component reaction of an aromatic aldehyde, isocyanide and o-aminophenol using p-toluene sulfonic acid as a catalyst is described.     

Cycloaddition of 2′-azidoethyl glycosides to fullerene[C60] under ultrasonic irradiation

The reactions of fullerene[C₆₀] with 2′-azidoethyl 2,3,4,6-tetra-O-acetyl-α-d-mannopyranoside (2a) and 2′-azidoethyl 2,3,4,6-tetra-O-acetyl-β-d-galactopyranoside (2b) under ultrasonic irradiation cause the cycloaddition of 2′-azidoethyl glycosides to fullerene[C₆₀] and lead to d-glycosyl fullerene[C₆₀] derivatives 3a and 3b, respectively. The glycosyl fullerene[C₆₀] derivatives were characterized by ¹H and ¹³C NMR, UV–vis, FAB-MS, FT-IR spectra and were a 1:1 glycoside fullerene [C₆₀]-adduct.     

A diversity oriented, microwave assisted synthesis of N-substituted 2-hydro-4-amino-pyrido[2,3-d]pyrimidin-7(8H)-ones

A protocol for the synthesis of N-substituted 2-hydro-4-amino-pyrido[2,3-d]pyrimidin-7(8H)-ones (11) is described. Thus, the formylation of a 2-aminopyridone 12 in 85% formic acid/Ac₂O, proceeding via in situ cyclization to the intermediate formamide 13, affords the corresponding 2-hydro-4-oxo-pyridopyrimidine 14, which is converted to a 4-chloro-pyridopyrimidine 15 upon treatment with POCl₃. The subsequent transformation to the title compounds is carried by treatment with the corresponding amine in MeOH under microwave irradiation conditions.     

A combined experimental and theoretical study of the alkylation of 3,5‐dithioxo‐[1,2,4]triazepines

The chemo‐ and regioselective alkylation reactions of 3,5‐dithioxo[1,2,4]triazepine 1 in a basic medium with α,ω‐dibromoalkanes 2a – c , Br(CH₂)_nBr (n = 1–3), are studied experimentally and theoretically. These alkylations, which occur at the thioxo sulfur atom in position 5, afford mainly 5‐bromomethylthio‐2,7‐dimethyl‐ 2,3‐dihydro‐ 4H[1,2,4]triazepin‐3‐one 3 for n = 1, 6,8‐dimethyl‐5‐thioxo‐2,3,4,5‐tetrahydro‐6H[1,3]thiazolo[4,5‐d][1,2,4]triazepine 4 for n = 2 and 7,9‐dimethyl‐6‐thioxo‐2,3,4,5,6,7‐hexahydro[1,3]thiazino [4,5‐d][1,2,4]triazepine 5 for n = 3. Theoretical calculations have been carried out at the B3LYP/6‐31G* and B3LYP(benzene)/6‐311+G*//B3LYP/6‐31G* levels, in order to rationalize the experimental observations. Both chemo‐ and regio‐selectivities of the alkylation reactions are analyzed. Copyright © 2008 John Wiley & Sons, Ltd.     

Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines: An example of cyclization-assisted cleavage

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 12 by cyclization-assisted cleavage from resin is reported. The procedure starts by solid supporting an ,-unsaturated acid 8 to the Wang resin 13 by using DCC and 4-DMAP in THF. The resulting ,-unsaturated ester 14 is converted to the Michael adduct by treatment with malononitrile in NaOMe/THF. Such Michael addition constitutes the first example of a Michael reaction with malononitrile in solid-phase. Finally, the Michael adducts 15 are treated with an amidine system in MeOH to yield the corresponding pyridopyrimidines 12. Compounds 12 present three diversity centers R1, R2 and G. Having validated the chemistry on solid support, a 40-membered combinatorial library was obtained using this protocol.     

Diastereoselective synthesis of fused [1,3]thiazolo[1,3]oxazins and [1,3]oxazino[2,3-b][1,3]benzothiazoles

An efficient diastereoselective synthesis of 7-ethyl 5,6-dialkyl 7H-[1,3]thiazolo[2,3-b][1,3]oxazin-5,6, 7-tricarboxylates and 2-ethyl 3,4-dialkyl 2H-[1,3]oxazino [2,3-b][1,3]benzothiazole-2,3,4-tricarboxylates via reaction of thiazole and benzothiazole with dialkyl acetylenedicarboxylates in the presence of ethyl pyruvate is described.     

Quenching of Pyrene Fluorescence by Calix[4]arene and Calix[4]resorcinarenes

Interactions involving calixarene and its derivatives are of major importance due to their widespread applications as unique hosts. Fluorescence from a common probe pyrene is used to study interactions involving calix[4]resorcinarene [1a] and its tetra-morpholine derivative [1b] in 1 M aqueous NaOH. These compounds efficiently quench the pyrene fluorescence. A comparison with the fluorescence quenching behavior of N-methylmorpholine clearly indicates the presence of long-range interactions involving 1a and 1b; the interactions are specific to the calixarene molecular framework. This is not the case for a tetra-nitro-substituted calix[4]arene [2b], an electron/charge acceptor quencher, as p-nitrophenol also shows similar interactions with pyrene. Effectiveness of cesium as the quencher of pyrene fluorescence is reduced in the presence of electron/charge donating 1b; fluorescence enhancement is observed upon addition of cesium as the concentration of 1b is increased in the solution. The role of calixarene framework in interactions involving such compounds is established.     

Efficient Construction of Pyrazolo[1,5-a]pyrimidine Scaffold and its Exploration as a New Heterocyclic Fluorescent Platform

An efficient, fast and facile pyrazolo[1,5-a]pyrimidine synthetic protocol has been established by the condensation of aminopyrazoles with 1,3-dicarbonyl components in AcOH/H₂SO₄ system. The pyrazolo[1,5-a]pyrimidine sulfides were selectively oxidized to the sulfones via a temperature-controlled stepwise oxidative fashion. The correlation between the substitution patterns of these pyrazolo[1,5-a]pyrimidines and their fluorescent spectroscopic properties were further examined, which provided the fundamentals for their potential applications in the development of new fluorescent probes. Red-shifts were easily achieved by the incorporation of unsaturated groups at the 5- and 7-positions, which suggested an approach for synthesizing long wavelength pyrazolo[1,5-a]pyrimidine dyes. The fluorescent spectroscopic properties were found to be sensitive to the hydroxy-containing and carbonyl-containing media such as alcohol and acetone, which helps to confirm the promising perspectives of further investigations in this area.     

Mass Spectral Fragmentation Patterns of Some Substituted 10,Ll-Dihydro-5H-Dibenzo[A,D] Cycloheptene-5-One and 9,10-Dihydro-4H-Benzo [4,5]Cyclohepta[1,2-B]Thiophene-4-One

Electron impact mass spectra of some substituted 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one and 9,10-dihydro-4H-benzo[4,5] cyclohepta[1,2-b] thiophene-4-one have been recorded and the identity of various ions in the mass spectra established. Substituted dibenzosuberones (2-6) exhibit one main fragmentation route, which include the elimination of the tropolone molecule from the dibenzosuberone fragment cation. Their monothiophene analogues(7-11) exhibit characteristic CO elimination from the molecular ion and formation of corresponding naphtho[1,2-b]thiophene radical cation which after elimination of CS or HCS from the thiophene nuclei give rise to the benzotrophyne radical cation.     

Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 15 is reported. The procedure started by solid supporting a p-hydroxybenzaldehyde 8 to the Wang resin by using the Mitsunobu protocol. The resulting aldehyde 17 was treated with a substituted acid methyl malonate 10 to afford the corresponding alpha, beta-unsaturated ester 18, which was converted to the Michael adduct 21 by reaction with malononitrile. Cyclization of 21 with an amidine system 13 yielded the solid supported pyridopyrimidine 22, which afforded the corresponding 2-substituted 4-aminopyrido[2,3-d]pyrimidine 15 upon treatment with TFA:DCM. Compounds 15 present three diversity centers R1, R2 and R3. Having validated the chemistry on solid support, a 32-membered combinatorial library was obtained using this protocol.     

Ultrasound-promoted catalyst-free one-pot four component synthesis of 2H-indazolo[2,1-b]phthalazine-triones in neutral ionic liquid 1-butyl-3-methylimidazolium bromide

A catalyst-free one-pot four component methodology for the synthesis of 2H-indazolo[2,1-b]phthalazine-triones under ultrasonic irradiation at room temperature using 1-butyl-3-methylimidazolium bromide, [Bmim]Br, as a neutral reaction medium is described. A broad range of structurally diverse aldehydes (aromatic aldehydes bearing electron withdrawing and/or electron releasing groups as well as heteroaromatic aldehydes) were applied successfully, and corresponding products were obtained in good to excellent yields without any byproduct.     

Studies on the adsorption of arsenic on calix[6]arene

p‐tert‐butyl calix[6]arene (PTC6) was synthesized and characterized by solid‐ and liquid‐state NMR and LC‐MS techniques. The adsorption of arsenite and arsenate on calix[6]arene under different pH conditions and adsorbate doses was studied. The maximum adsorption of arsenic species on calix[6]arene was observed around neutral pH and the adsorption density of As (III) was higher than that of As (V). The adsorption of neutral H₃AsO₃ and negatively charged H₂AsO molecules on calix[6]arene was attributed to the condensation reaction between hydroxyl groups of PTC6 and arsenic species. The complexation of arsenite with phenolic oxygen was confirmed by solid‐state ¹³C NMR CP‐MAS. Exo attack mechanism was proposed to describe the interaction of arsenous and arsenic acid molecules with PTC6. The specific interaction between calix[6]arene and arsenic species was further substantiated by zeta‐potential (ζ‐potential) measurements and free energy of adsorption. The free energy of adsorption ( ) estimated from Stern–Grahame equation was found to be 25 kJ/mole for As (III) and 19 kJ/mole for As (V). Copyright © 2010 John Wiley & Sons, Ltd.     

[13C]Aminopyrine and [13C]Caffeine Breath Test: Influence of Gender,Cigarette Smoking and Oral Contraceptives Intake

Abstract

The [¹³C]aminopyrine breath test ([¹³C]ABT) measures the global activity of cytochrome P450 in vivo and is a sensitive indicator of liver metabolic dysfunction. The present study aims to determine whether gender and cigarette smoking influence the results of [¹³C]ABT as well as to confirm the effect of oral contraceptive steroids (OCS) intake on this metabolic test. Hundred and ten healthy subjects, including men and women, smoker and non-smoker, women taking OCS or not, were phenotyped for CYP1A2 using the [¹³C]caffeine breath test and underwent a [¹³C]ABT. Both tests showed large inter-individual variations in accordance with that of CYP450 liver content. [¹³C]ABT was sensitive enough to point out a significant induction or inhibition related to cigarette smoking habits or OCS. The combined effect of smoking and OCS resulted in an overall unchanged metabolic activity. Consequently, the impact of the studied conditions on the [¹³C]ABT parameters must be considered by clinicians or clinical investigators.     

Unsymmetrical dyes derived from 7,8‐dihydrobenzo[c,d]furo[2,3‐f]indole

On the basis of the 7,8‐dihydrobenzo[c,d]furo[2,3‐f]indole nucleus, a number of unsymmetrical carbocyanines as well as styryl dyes have been synthesized and their absorption spectra have been measured. Starting from the deviations of long‐wavelength maxima, the value of electron‐donor ability D has been estimated for the heterocycle under study and a number of dye end groups have been ranked by their electron‐donor properties. Experimental inferences are supported by the quantum chemically calculated bond length alternations and energy levels for the dyes concerned. Copyright © 2009 John Wiley & Sons, Ltd.     

Parallel and automated library synthesis of 2-long alkyl chain benzoazoles and azole[4,5-<Emphasis Type="BoldItalic">b</Emphasis>]pyridines under microwave irradiation

Summary A versatile route to 40-membered library of 2-long alkyl chain substituted benzoazoles (1 and 2) and azole[4,5-b]pyridines (3 and 4) via microwave-assisted combinatorial synthesis was developed. The reactions were carried out in both monomode and multimode microwave oven. With the latter, all reactions were performed in high-throughput experimental settings consisting of an 8×5 combinatorial library designed to synthesize 40 compounds. Each step, from the addition of reagents to the recovery of final products, was automated. The microwave-assisted N-long chain alkylation reactions of 2-alkyl-1H-benzimidazole (1) and 2-alkyl-1H-benzimidazole[4,5-b] pyridines (3) were also studied.     

Comparison of two dosage regimens of the substrate for the [13C]methacetin breath test

The [¹³C]methacetin breath test ([¹³C]MBT) – a valuable non-invasive tool dedicated to the assessment of the liver metabolic capacity – still needs standardisation. The aim of this study was to check whether currently used dosage regimens of [¹³C]methacetin provide concordant [¹³C]MBT results in subjects with an atypical body constitution. Healthy volunteers: low body mass<55 kg (eight women), and high body mass>95 kg (eight large body frame men) were recruited. They underwent [¹³C]MBT on separate days, taking in random order [¹³C]methacetin: a fixed 75 mg dose (FX75), or a 1 mg kg^?1 body mass-adjusted dose (BMAD). Samples of expiratory air for ¹³CO₂ measurement were collected over 3 h. The maximum momentary ¹³C elimination in breath air occurred earlier and was higher following BMAD than with FX75 in the low body mass females (T _max 14.6±1.0 min vs. 22.1±2.4 min, p=0.019; D _max 41.9±2.9 % dose h^?1 vs. 36.6±3.6 % dose h^?1, p=0.071). In the high body mass men, T _max remained unchanged, whereas D _max was slightly higher with BMAD compared to FX75 (21.5±3.2 min vs. 23.0±3.0 min; 38.5±2.9 % dose h^?1 vs. 32.3±2.5 % dose h^?1). It is concluded that in subjects with a body constitution outside the general population average, the dosage of the substrate may affect some results of the [¹³C]MBT. The dosage-related differences appear, however, to be insignificant if the result of the [¹³C]MBT is reported as a cumulative ¹³C recovery in breath air.     

Theoretical studies on [2 + 2 + 2] reaction mechanisms of three ethynes. More accurate estimation of activation energy

The mechanisms of the [2 + 2 + 2] cycloaddition reaction of three ethyne molecules were studied by ab initio molecular orbital and density functional methods. The transition states range from that of the concerted mechanism with D_3h symmetry to that of the stepwise mechanism with C₂ symmetry. The transition state structure and the activation energy depend on the basis set and computational method employed in the analysis. The activation energy barrier was determined to be in the range of 36–44 kcal/mol. The activation energy determined by various methods corresponds to the interaction energy, which is related to the electron correlation energy. The best estimation of the activation energy barrier is 41.6 kcal/mol, achieved from the relation between the interaction energy and the activation energy. Copyright © 2013 John Wiley & Sons, Ltd.     

[2.2.2]Paracyclophane as a receptor for the cesium cation in the gas phase

By using electrospray ionisation mass spectrometry, it was proven experimentally that the cesium cation (Cs⁺) forms with [2.2.2]paracyclophane (C₂₄H₂₄) the cationic complex [Cs(C₂₄H₂₄)]⁺. Further, applying quantum chemical calculations, the most probable structure of the [Cs(C₂₄H₂₄)]⁺ complex was derived. In the resulting complex with a symmetry very close to C₃, the ‘central’ cation Cs⁺, fully located in the cavity of the parent [2.2.2]paracyclophane ligand, is bound to all three benzene rings of [2.2.2]paracyclophane via cation–π interaction. Finally, the interaction energy, E(int), of the considered cation–π complex [Cs(C₂₄H₂₄)]⁺ was found to be ?73.2 kJ/mol, confirming the formation of this fascinating complex species as well. This means that [2.2.2]paracyclophane can be considered as a receptor for the Cs⁺ cation in the gas phase.