Radical carbonylation/reductive cyclization for the construction of tetrahydrofuran-3-ones and pyrrolidin-3-ones

Beta-hydroxyalkyl aryl chalcogenides obtained by regioselective ring-opening of epoxides with benzeneselenolate or -tellurolate were found to undergo efficient hetero-Michael addition when treated with ethyl propiolate. Subsequent carbonylation/reductive cyclization of the resulting vinylogous carbonates in the presence of AIBN/TTMSS and carbon monoxide (80 atm) afforded 2,5-disubstituted tetrahydrofuran-3-ones, predominantly as cis isomers (cis/trans = 4/1-9/1). Starting from a polymer-supported diaryl diselenide, the methodology was also successfully extended to solid-phase synthesis. Vinylogous carbamates prepared by hetero-Michael addition of aziridines to electron-deficient alkynes were regioselectively ring-opened with benzeneselenolate from the sterically least hindered side. Radical carbonylation/reductive cyclization of the resulting N-vinyl-beta-amino-alkyl phenyl selenides afforded 2,5-disubstituted pyrrolidin-3-ones, predominantly as cis isomers (cis/trans = 3/1-12/1).     

Synthesis of 5-methoxylated 3-pyrrolin-2-ones via the rearrangement of chlorinated pyrrolidin-2-ones

The reaction of N-substituted 4-methyl-2-pyrrolidinones or 4-diethoxyphosphoryl analogues, carrying at least two chlorine atoms between the C(3) and C(6) carbons, with alkaline methoxide in methanol afforded the corresponding 5-methoxylated 3-pyrrolin-2-ones, useful adducts for the preparation of agrochemicals or medicinal compounds.     

Preparation of 1,5-disubstituted pyrrolidin-2-ones

1,5-Disubstituted pyrrolidin-2-ones 18a-g, 19a-h, and 20a-f were synthesized in good to excellent yields via the nucleophilic substitution of 5-(benzotriazol-1-yl)-1-substituted-pyrrolidin-2-ones 9 with allylsilanes, organozinc reagents, and phosphorus compounds. Compounds 9 and 5-(benzotriazol-2-yl)-1-substituted-pyrrolidin-2-one isomers 10 are readily prepared in total 70-84% yields from 2, 5-dimethoxy-2,5-dihydrofuran (7), primary amines 8, and benzotriazole; 9 and 10 react identically with nucleophiles.     

Functional group interaction in the fragmentation of protonated 2,7-octanedione

The fragmentation of 2,7-octanedione, induced by chemical ionization with methane as a reagent gas (CI (CH₄)), is shown to be extensively governed by the interaction of the two carbonyl groups. Tandem mass spectrometry reveals that a sequential loss of H₂O and C₂H₄O from the [M + H]⁺ ion competes with sequential loss of H₂O and C₆H₁₀, and that both processes occur via the same [MH - H₂O]⁺ intermediate. This intermediate is likely to be formed via intramolecular gas-phase aldol condensation and subsequent dehydration. The resulting C(1) protonated 1-acetyl-2-methylcyclopentene structure readily accounts for the observed further decomposition to CH₃C?O⁺ and 1-methylcyclopentene (C₆H₁₀) or, alternatively, to [C₆H₉]⁺ (e. g. 1-methylcyclopentenylium) ions and acetaldehyde (C₂H₄O). Support for this mechanistic rationale is derived from deuterium isotope labelling and low-energy collision-induced dissociation (CID) of the [MH - H₂O]⁺ ion. The common intermediate shows a CID behaviour indistinguishable by these techniques from that of reference ions, which are produced by gas-phase protonation of the authentic cyclic aldol or by gas-phase addition of an acetyl cation to 1-methylcyclopentene in a CI (CH₃COOCH₃) experiment.     

The substituent effect in the fragmentation of phenylcyclohexanols

All the main fragmentation pathways undergone by trans-4- and trans-2-p-substituted phenylcyclohexanols have been studied, and the ionic abundances have been correlated with the σ constants. This analysis shows that electron withdrawing substituents, increasing the fraction of molecular ions having sufficient energy to decompose, favour all fragmentations. However, along with this ‘non-specific’ substituent effect, there is a ‘specific’ effect, in the opposite sense, increasing the formation of the [M—59]⁺ and [M—85]⁺ ions with increasing electron releasing power of the substituents. The loss of water, although it is almost exclusively a 1,4 elimination in the case of trans phenyl cyclohexanols, is not specifically influenced by the substituents.     

3-aryl-2-isoxazolines: Electron-impact fragmentation and substituent effects

The mass spectra were investigate of six 3-aryl-2-isoxazolines, and three main fragmentation pathways were found to occur through loss of 28 and 30 a.m.u. The losses of 28 (C₂H₄)and 30 (CH₂O) are seen as competitive mass spectrometric retro-1,3-dipolar cycloaddition processes. These reactions are also repeated successively, and take place in different ions either following the degradation of the substituent or the attack of the benzene ring. The substituents in the para position influence both these reactions and also the attack upon the rings. A quantitative study has been carried out on the effect of the substituent on the [M-28] reaction, which can be interpreted in terms of the first ionisation energies. These terms are linearly intercorrelated, for the compounds under examination, with the Hammett type σ-constants.     

Synthesis of novel pyrrolidin-2-ones: γ-aminobutyric acid cyclic analogues

Some new N-substituted pyrrolidin-2-ones, cyclic analogues of baclofen and of 3-(5-methoxybenzo-[b]furan-2-yl)-γ-aminobutyric acid, have been prepared and characterized, starting from 4-(4-chlorophenyl)-pyrrolidin-2-one and 4-(5-methoxybenzo[b]furan-2-yl)pyrrolidin-2-one.     

Mass spectral fragmentation pattern of 3-methyl-4-arylaminomethyleneisoxazol-5-ones

The mass spectral fragmentation patterns of 3-methyl-4-arylaminomethyleneisoxazol-5-ones obtained by electron impact have been elucidated. The base peaks are due to the molecular ions. The main fragmentation routes involve loss of H, OH, H₂O, CO₂ and COOH from the molecular ions as well as rupture of the exocyclic CH-NH bond.     

Synthesis of pyrrolidin-3-ones from dihydropyran precursors via spiro-N,O-acetals

2,2-Disubstituted pyrrolidin-3-ones are prepared in three steps from simple dihydropyran derivatives; the key spiro-N,O-acetal intermediate is a useful N-sulfonylketoiminium ion precursor. This route represents a formal synthesis of the indolizidine alkaloid core, with potential application to pyrrolizidines and quinolizidines.     

A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.     

Synthesis of some 3-cyano-2-methylquinolin-4-ones

The condensation of ethyl 2-cyano-3-ethoxycrotonate with various anilines gave the corresponding anilinocrotonates which were cyclized in refluxing Dowtherm “A” to give the title quinolones.     

Synthesis of functionalized pyrrolidin-2-ones and (S)-Vigabatrin from pyrrole

Starting from pyrrole, the novel 3,4-didehydropyrohomoglutamate 8 or (ent)-8 can be efficiently synthesized in up to 91% ee, which can be utilized as a versatile building block toward functionalized pyrrolidin-2-ones. Moreover, (ent)-8 can be readily converted to (S)-Vigabatrin, being an irreversible inhibitor for GABA-T, which is used as adjunctive therapy in patients that suffer from epilepsy.     

Electron-impact fragmentation of some secondary aliphatic nitramines. Migration of the nitro group in heterocyclic nitramines

The mass spectra of a series of nitramines, including the explosives RDX and HMX, are reported. The nature of the major fragment ions is established by labeling with ¹⁵N or¹³C and by high resolution mass spectrometry. Electron-impact-induced fragmentation pathways including the migration of the nitro group in the heterocyclic nitramines, RDX and HMX, are postulated.     

The thermal fragmentation of 1,3,4-diathiazol-2-ones

Thermal expulsion of carbon oxusulphide from 1,3,4-dithiazol-2-ones in the presence of DMAD affords nitrile sulphide-derived dimethyl isothiazole-4,5-dicarboxylates.     

Influence of substituent groups at the 3‐position on the mass spectral fragmentation pathways of cephalosporins

The structural fragment ions of nine cephalosporins were studied by electrospray ionization quadrapole trap mass spectrometry (Q‐Trap MSⁿ) in positive mode. The influence of substituent groups in the 3‐position on fragmentation pathway B, an α‐cleavage between the C7? C8 single bond, coupled with a [2,4]‐trans‐Diels‐Alder cleavage simultaneously within the six‐membered heterocyclic ring, was also investigated. It was found that when the substituent groups were methyl, chloride, vinyl, or propenyl, fragmentations belonging to pathway B were detected; however, when the substituents were heteroatoms such as O, N, or S, pathway B fragmentation was not detected. This suggested that the [M–R₃]⁺ ion, which was produced by the bond cleavage within the substituent group at the 3‐position, had a key influence on fragmentation pathway B. This could be attributed to the strong electronegativity of the heteroatoms (O, N, S) that favors the production of the [M–R₃]⁺ ion. Moreover, having the positive charge of the [M–R₃]⁺ ion localized on the nitrogen atom in the 1‐position changed the electron density distribution of the heterocyclic structure, which prohibits a [2,4]‐reverse‐Diels‐Alder fragmentation and as a result fragmentation pathway B could not occur. The influence of the substituent group in the 3‐position was determined by the intensity ratio (e/d) of ions produced by fragmentation pathway A, a [2,2]‐trans‐Diels‐Alder cleavage within the quaternary lactam ring, including the breaking of the amide bond and the C6? C7 single bond (ion d), and fragmentation pathway B (ion e). The results indicate that the electronegativity of the substituent group was a key influencing factor of pathway B fragmentation intensity, because the intensity ratio (e/d) is higher for a chlorine atom, a vinyl, or a propenyl group than that of a methyl group. This study provided some theoretical basis for the identification of cephalosporin antibiotics and structural analysis of related substances in drugs. Copyright © 2010 John Wiley & Sons, Ltd.