Mechanistic investigation on 2-aza-spiro[4,5]decan-3-one formation from 1-(aminomethyl)cyclohexylacetic acid (gabapentin)

The intramolecular cyclization of the amino acid gabapentin has been studied in the pH range 2.24-11.15 at 80 °C in buffered solutions and constant ionic strength, and monitoring the progress of the process by fluorimetric method and proton NMR spectroscopy. From the profile of log k₀ versus pH two different acid-base equilibria are involved. The maximum rate is observed above pH 9.80 and the minimum rate has been measured between pH 5.15 and 6.21. The pK_a1 and pK_a2 have been determined by potentiometric titration to be 3.72 and 9.37, respectively. The buffer effect and the solvent kinetic isotopic effect suggest that the reaction is subject to general acid and general base catalysis. The process is sensitive to the gabapentin concentration (pH 10.45) and the pseudo-first order rate constant decrease with increasing the reagent concentration above 5.50×10⁻² M.     

Claisen rearrangement induced by low-energy collision of ESI-generated, protonated benzyloxy indoles

The Claisen rearrangement is a well-known process occurring in condensed phase. In the gas-phase protonated allyl phenyl ethers, propargyl phenyl ethers, and N-allyl aniline produced by positive ion chemical ionization undergo Claisen rearrangement. This reaction has been observed even in the case of odd-electron molecular ions. Phenyl allenyl ether molecular ions actually undergo Claisen rearrangement, producing intense [M - CO](+*) ions. In this investigation, the behavior of protonated benzyloxy indole and some of its derivatives, obtained in electrospray conditions, is described. Low-energy MS/MS experiments carried out on [M + H](+) species show CO loss and an unexpected water loss: both can be justified only by the occurrence of Claisen rearrangement. Deuterium labeling experiments confirm this mechanism. The influence of different substituents in the indole moiety is discussed.     

Asymmetric synthesis of (−)-bissetone via a highly enantioselective hetero-Diels–Alder reaction

We demonstrate a new approach for the asymmetric synthesis of bissetone. The key reaction is the highly enantioselective hetero-Diels–Alder cycloaddition of triene 3 with ethyl glyoxylate catalyzed by readily available BINOL–Ti complexes. The HDA cycloadduct 4 was then transformed in five steps into O-protected bissetone (8) and its C5-epimer in good yield.     

Preparation and Mechanism of Solvolysis of N-Hydroxy-α-oxobenzeneethanimidoyl Chloride,a 2-(Hydroxyimino)-1-phenylethan-1-one Derivative: Molecular Structure of α-Oxo-oximes (=α-(Hydroxyimino) Ketones)

Acid-catalyzed methanolysis of N-hydroxy-α-oxobenzeneethanimidoyl chloride ( 1 ), a 2-(hydroxyimino)-1-phenylethan-1-one derivative obtained in one step from acetophenone, leads to a constant ratio of methyl α-oxobenzeneacetate ( 2 ) and methyl α-(hydroxyimino)benzeneacetate ( 3 ). ¹³C(α) Labelled [¹³C]- 1 affords ¹³C(α) labelled [¹³C]- 3 , thus discarding the hypothesis of its formation via 1,2-arene migration. The reported sequence opens a novel approach to phenylglyoxylic and mandelic acid esters (=α-oxobenzeneacetic and α-hydroxybenzeneacetic acid esters), from acetophenone. The molecular structures of 1 and 3 were determined by X-ray structure analysis and compared with previously reported crystallographic data of α-oxo-oximes (=α-(hydroxyimino) ketones) 4 and 6 – 8 . The unique stereoelectronic characteristics of the α-oxo-oxime moiety are discussed. All α-oxo-oximes share the following structural characteristics: (E)-configuration of the oxime C=N−OH bond (i.e. OH and C=O trans), the s-trans conformation of the oxo and imino moieties about the C(α)-C(=NOH) single bond, and intermolecular H-bonding. They differ from the isostructural β-diketone enols by the absence of resonance-assisted intramolecular H-bonding.     

Conversion of bis(trichloromethyl) carbonate to phosgene and reactivity of triphosgene, diphosgene, and phosgene with methanol(1)

Triphosgene was decomposed quantitatively to phosgene by chloride ion. The reaction course was monitored by IR spectroscopy (React-IR), showing that diphosgene was an intermediate. The methanolysis of triphosgene in deuterated chloroform, monitored by proton NMR spectroscopy, gave methyl chloroformate and methyl 1,1, 1-trichloromethyl carbonate in about a 1:1 ratio, as primary products. The reaction carried out in the presence of large excess of methanol (0.3 M, 30 equiv) was a pseudo-first-order process with a k(obs) of 1.0 x 10(-)(4) s(-)(1). Under the same conditions, values of k(obs) of 0.9 x 10(-)(3) s(-)(1) and 1.7 x 10(-)(2) s(-)(1) for the methanolysis of diphosgene and phosgene, respectively, were determined. The experimental data suggest that, under these conditions, the maximum concentration of phosgene during the methanolysis of triphosgene and diphosgene was lower than 1 x 10(-)(5) M. Methyl 1,1,1-trichloromethyl carbonate was synthesized and characterized also by the APCI-MS technique.     

Oxidative decarboxylation of cyclohexane monocarboxylic acid III. Initiated oxidation

A mechanism is suggested for the oxidative decarboxylation of cyclohexane monocarboxylic acid initiated by decomposition of H₂O₂. The process is a non-branching chain reaction. Cyclohexanone and cyclohexanol form in termination reactions.