Ring transformation reactions of C-nucleosides: Facile synthesis of pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]triazine C-nucleosides

1,3-Dimethyluracil ( 1 ), a versatile synthon for the synthesis of various heterocycles, reacted readily with 3-aminopyrazoles 2 in sodium ethoxide to give pyrazolo[1,5-a]pyrimidines 3 . Under similar conditions, 3-aminopyrazole C-nucleosides 4 and the synthon 1 gave a mixture of pyrazolo[1,5-a]pyrimidine C-nucleosides, which was separated on a silica gel column. Attempts to remove the protecting groups yielded pyranose derivative 10 . Another synthon 1,3-dimethyl-5-azauracil and 3-aminopyrazoles 12 gave pyrazolo[1,5-a]triazines 13 . In a similar reaction with 3-aminopyrazole C-nucleosides 4 gave the corresponding pyrazolo[1,5-a]-triazine C-nucleosides 14 and 15 .     

Mass Spectral Fragmentation Patterns of 11-(o- and p-R-Anilino)-5H-dibenzo[b,e][1,4]diazepines. IV

The mass spectral fragmentation patterns of eleven 11-(o- and p-R-anilino)-5H-dibenzo[b,e][1,4]diazepines obtained by electron impact have been studied. All the spectra analyzed contain molecular ions, which are base peak for para isomers and the principal fragmentation routes takes place either from the molecular ion, or from (M⁺ - 1) ion. There are, however, some deviations from the general fragmentation pattern in the case of 1,4-dibenzodiazepines with o-amino and p-methoxy substituents caused by direct interaction of these groups with the dibenzodiazepine ring.     

Ortho,Effects in organic molecules on electron impact: X—unusual ortho effects of the methyl group in o-picolinotoluidide

The mass spectrum of o-picolinotoluidide gives rise to three major fragments at m/z 184, m/z 169 and m/z 168, corresponding to the loss of CO from the molecular ion followed by the loss of ?H₂ and ?H₃ by independent pathways. It has been shown that the ortho methyl group and the nitrogen of the pyridine ring in the 2-position are involved in the formation of these three major fragments observed in the mass spectrum of o-picolinotoluidide. The mass spectrum of 2-(o-toluidino) pyridine, the molecular ion of which can resemble the [M? CO]⁺ ion in o-picolinotoluidide, also shows loss of CH₃ and NH₂ radicals from the molecular ions. Based on these observations coupled with the high resolution data, the mass analysed ion kinetic energy spectrometry and high voltage scans of these fragments in both the compounds, two mechanistic pathways have been proposed for the formation of these ions in o-picolinotoluidide.     

The high-resolution mass spectra of aliphatic aldehydes

The mass spectra of the C₃ to C₉ n-alkanals and a number of branched aldehydes have been obtained at a resolution sufficient to resolve the O? CH₄ doublets. From the resolved spectra, a study of metastable transitions, and the spectrum of one deuterium-labelled alkanal, (n-hexanal-2,2-d₂) the major fragmentation reactions have been elucidated. Of particular interest are the γ-cleavage reaction, leading to [C₃H₅O]+ in the n-alkanals, which proceeds both by a simple cleavage and by cleavage preceded by hydrogen interchange, and the loss of C₂H₄, which involves loss of the C₂ and, probably C₃, carbons.     

Electron impact induced fragmentation of some 7-(o- and p-R-benzylidene)-3-(o- and p-R-phenyl)-3,3a,4,5,6,7-hexahydro-2H-indazoles. I

The mass spectral fragmentation patterns of ten 7-(o- and p-R-benzylidene)-3-(o- and p-R-phenyl)-3,3a,4,5,6,7-hexahydro-2H-indazoles, I, obtained by electron impact have been studied. All the spectra analyzed contain molecular ions and the principal fragmentation routes take place either from the molecular ion, or from (M⁺-1) ion. Likewise, our investigation of the mass spectra of these compounds revealed interesting relationships between the substitution pattern in the framework of I and the fragmenation pathways.     

A facile synthesis of 8-(β-D-ribofuranosyl)-4-thioxo-3H-pyrazolo[1,5-a]-1,3,5-triazine and its α-anomer

A versatile intermediate 2 for C-nucleoside synthesis was treated with thiosemicarbazide to obtain thiosemicarbazone 6 , which was then converted to 3-aminopyrazol-2N-thiocarboxamide derivatives 7 and 8 by the reaction of 6 and sodium ethoxide. 4-Thioxo-4H-pyrazolo[1,5-a]-1,3,5-triazine C-nucleosides 11 and 12 were obtained by the ring closure reaction of 7 and 8 with triethyl orthoformate. Brief treatment of 11 and 12 with 10% methanolic hydrogen chloride afforded C-nucleosides 4 and 13 , respectively, without anomerization. Identification of compounds 4 and 13 was made on the basis of ¹H nmr and uv spectra, as well as chemical conversion to known compounds with established configurations. Model compounds were also synthesized in order to confirm the heterocyclic moieties.     

Nachbargruppeneffekte bei der Massenspektrometrischen Fragmentierung von Amino-benzylalkoholen

The fragmentation behaviour of a series of substituted aminobenzylacohols has been investigated by means of high and low resolution mass spectroscopy, metastable defocusing and deuterium labelling. o-, m- and p-Isomers exhibit characteristic fragmentation patterns that are of considerable diagnostic value in the structure determination of this class of compounds.     

Mass spectrometry of β-keto aldehydes: Novel hydroxyl transfer reactions

The mass spectral fragmentation of 2,3-diaryl-3-oxo-1-propanals has been investigated by low electron energy, metastable defocusing and shift techniques. The o-nitro group strongly interacts with α-cleavage reactions of the carbonyl group. The cyclization/elimination processes, accompanied by oxygen and hydroxyl transfer in the mass spectra of o-nitro-β-keto aldehydes, are preceded by hydrogen abstraction by the nitro group.     

Hydrogen migration in the electron impact induced retro diels-alder fragmentation of N-aryl-4H-5,7a-epoxyisoindolines

The electron impact induced fragmentations of the C-5 unsubstituted and 5-methyl N-aryl-4H-5,7a-epoxyisoindolines (where aryl is pheny, p-tolyl, p-methoxyphenyl, o-methoxyphenyl and p-chlorophenyl) were investigated. The fragmentation patterns deduced were supported by exact mass measurements of prominent ions and by deuterium labelling. The retro Diels-Alder fragmentation turned out to be a predominant process in all the compounds investigated. In the mass spectra of the 5-methyl N-aryl-4H-5,7a-epoxyisoindolines hydrogen migration preceding fragmentation occurred. From the mass spectrum of the specifically deuterated compound it was concluded that the transferred hydrogen originates exclusively from the 5-methyl group.     

The mass spectra and ionization potentials of the neutral fragments produced during the electron bombardment of aromatic compounds

A mass spectrometer equipped with a dual ionization chamber ion source has been used to characterize directly the neutral species produced in the dissociative ionization of gases by electron impact. Neutral fragment mass spectra have been obtained for the electron ionization and fragmentation of benzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene and isotopically labeled toluene. The neutral fragment mass spectra correlate well with the structures of the molecules. The abundant species in the neutral fragment mass spectra also correlate reasonably well with the abundant complementary positive ions of the normal mass spectra. Ionization potentials have been determined for the abundant neutral species produced. Where comparisons with values reported elsewhere are possible, the agreement is usually within ±0.2 eV or less.     

Heterocyclic derivatives of naphthalene-1,8-dicarboxylic anhydride. Part I. Nitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones

Condensation of o-phenylenediamine with 2-, 3- and 4-nitronaphthalene-1,8-dicarboxylic anhydrides gives, in each case, an isomer mixture. Separation of the mixtures into the six isomeric mononitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones is described and the isomers characterised in respect of previously reported data on some isomers; ir and mass spectrum data are reported, the latter showing fragmentation ions which may be used in characterising dyes based on this chromophore. Other new derivatives of 7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-one are also described.     

Synthesis of pseudo-C-nucleosides from β-formyl-α,β-unsaturated ester bearing a β-furanosidic moiety

Abstract  

Pseudo-C-nucleosides have potential biological activity, and an efficient synthesis of new pseudo-C-nucleosides has been developed via the reaction of a β-formyl-α,β-unsaturated ester bearing a β-sugar moiety with hydrazines in neutral and acidic conditions. The preparation of the β-formyl-α,β-unsaturated ester was accomplished by oxidation of the secondary hydroxyl group of 3-O-benzyl-1,2-O-isopropylidene-α-d-glucofuranose, followed by elongation of its carbon chain with (ethoxycarbonylmethylene)triphenylphosphorane and oxidation of the hydroxymethyl group.     

Mass spectrometry in structural and stereochemical problems–CXCIII: On the combined hydroxyl and water loss in nitrophenylhydrazones

The mass spectrum of valeraldehyde o-nitrophenylhydrazone displays only a low intensity peak (3% relative abundance) corresponding to the loss of 35 mass units from its molecular ion contrary to data previously published. Mention is also made of the fragmentation of 5-nonanone 2,4-dinitrophenylhydrazone in view of a recent challenge to a published rationalization for the electron impact promoted fragmentation for this compound.     

The effect of column characteristics on the minimum analyte concentration and the minimum detectable amount in capillary gas chromatography. Part II: The stationary phase film thickness

For a typical narrow bore (50 μm) and wide bore (320 μm) capillary column the effects of increased stationary phase film thickness (d_f) on the minimum detectable amount, Q_o, as well as on the minimum analyte concentration, C_o, are described. In treating the effect of an increased film thickness, two approaches can be followed; either the separation temperature is kept constant, resulting in larger values of the capacity ratio, k, or the column temperature is increased such as to keep k constant. For normalized chromatographic conditions the effects of both approaches on the minimum plate height, optimum carrier gas velocity, and required plate number are described, finally yielding expressions for Q_o and C_o for both mass flow and concentration sensitive detectors. At constant temperature, C_o always increases with the film thickness for mass flow sensitive detectors (e.g. FID). Wide bore thin film columns offer the lowest value of C_o attainable. For concentration sensitive detectors (e.g. TCD), C_o is affected neither by column diameter nor by film thickness. The Q_o–d_f plot for constant temperature shows a minimum, suggesting an optimum film thickness for mass flow sensitive as well as concentration sensitive detectors. The corresponding capacity ratio has a value between 0.5 and 1.5. At elevated temperatures (k constant) in combination with mass flow sensitive detectors, again an optimum film thickness exists, corresponding to a minimum value of C_o. For constant capacity ratio Q_o always increases with the film thickness for both types of detectors. As indicated above, in some situations the lowest values of C_o and Q_o are obtained at an increased film thickness, the effect being marginal. As an initial guideline, for the daily practice of capillary gas chromatography with respect to minimum values of C_o and Q_o, the use of thin film columns is to be preferred.     

A One-Pot Approach to Novel Pyridazine C-Nucleosides

The synthesis of glycosides and modified nucleosides represents a wide research field in organic chemistry. The classical methodology is based on coupling reactions between a glycosyl donor and an acceptor. An alternative strategy for new C-nucleosides is used in this approach, which consists of modifying a pre-existent furyl aglycone. This approach is applied to obtain novel pyridazine C-nucleosides starting with 2- and 3-(ribofuranosyl)furans. It is based on singlet oxygen [4+2] cycloaddition followed by reduction and hydrazine cyclization under neutral conditions. The mild three-step one-pot procedure leads stereoselectively to novel pyridazine C-nucleosides of pharmacological interest. The use of acetyls as protecting groups provides an elegant direct route to a deprotected new pyridazine C-nucleoside.     

Variantes de mycosides caracterisees par des residus glycosidiques substitues par des chaines acyles–I: Spectres de masse des mycosides G′ et A′ peracetyles

Mass spectra of peracetylated mycosides G′ and A′ are characterised by rearranged oxonium ions, corresponding to deoxysugars which have lost an acyl chain by fragmentation in the mass spectrometer. The main carboydrate constituent of mycoside G′ is a deoxysugar with one acyl chain and a methyl group. Mycoside A′ contains deoxysugars with one acyl chain and 0, 1 or 2 methyl groups. Deoxysugars with no acyl chains and one (G′, A′) or two (A′) methyl groups are also present. The mass spectra indicate that the acyl chains might be of the mycolic type: Peaks which might correspond to a fragmentation on both sides of the methyl branching are present and the CH⁺˙?C? C₂₂H₄₅ fragment, found in the spectrum of paracetylated mycoside A′ is characteristic of the branched chain. The highest peaks (m/e 1072 and 1100) in the spectrum of paracetylated mycoside A′ can be due to a mycolic chain after loss of acetic acid, methanol and H (l) on loss of acetic acif and H (m). The nature and abundance of the mycocerosic acids which esterify the aglycones can be deduced from the same spectra, as well as the structure of these aglycones which has been established previously by degradation and mass spectrometry. In order of decreasing abundance, C₂₇ and C₂₄ mycocerosic acids are present in mycoside G′, and C₂₉, C₃₂, C₃₂, C₃₀ and C₂₇ mycocerosic acids are found in mycoside A′.     

Disulfide bond cleavage in TEMPO-free radical initiated peptide sequencing mass spectrometry

The gas‐phase free radical initiated peptide sequencing (FRIPS) fragmentation behavior of o‐TEMPO‐Bz‐conjugated peptides with an intra‐ and intermolecular disulfide bond was investigated using MSⁿ tandem mass spectrometry experiments. Investigated peptides included four peptides with an intramolecular cyclic disulfide bond, Bactenecin (RLC RIVVIRVC R), TGF‐α (C HSGYVGVRC ), MCH (DFDMLRC MLGRVFRPC WQY) and Adrenomedullin (16–31) (C RFGTC TVQKLAHQIY), and two peptides with an intermolecular disulfide bond. Collisional activation of the benzyl radical conjugated peptide cation, which was generated through the release of a TEMPO radical from o‐TEMPO‐Bz‐conjugated peptides upon initial collisional activation, produced a large number of peptide backbone fragments in which the S? S or C? S bond was readily cleaved. The observed peptide backbone fragments included a‐, c‐, x‐ or z‐types, which indicates that the radical‐driven peptide fragmentation mechanism plays an important role in TEMPO‐FRIPS mass spectrometry. FRIPS application of the linearly linked disulfide peptides further showed that the S? S or C? S bond was selectively and preferentially cleaved, followed by peptide backbone dissociations. In the FRIPS mass spectra, the loss of ?SH or ?SSH was also abundantly found. On the basis of these findings, FRIPS fragmentation pathways for peptides with a disulfide bond are proposed. For the cleavage of the S? S bond, the abstraction of a hydrogen atom at C_β by the benzyl radical is proposed to be the initial radical abstraction/transfer reaction. On the other hand, H‐abstraction at C_α is suggested to lead to C? S bond cleavage, which yields [ion ± S] fragments or the loss of ?SH or ?SSH. Copyright © 2011 John Wiley & Sons, Ltd.     

Mass spectrometric studies–VI: Aziridines

The mass spectra of C-alkylaziridines show that generally β-cleavage is the most important fragmentation, although α-cleavages also occur as do γ-, and δ- and ?-cleavages in appropriate examples. A surprising rearrangement of the β-cleavage ions has been explained as the result of a four-centre cyclization followed by fragmentation. Other decompositions occur via transannular cleavages with and without hydrogen transfer. α-Cleavage appears to be the most important fragmentation of N-alkylaziridines. N-Phenylaziridine shows very marked 1,2-phenyl-migration before fragmentation.     

Derivatives of 3′-Azidothymidine with 6-Cyanopyridone as Base or as Phosphoramidate Ester and their Antiretroviral Activity

Strongly pairing ethynylpyridone C-nucleosides are attractive surrogates for thymidine in oligonucleotides. Exploratory work on the antiviral activity of 3′-azidothymidine (AZT) derivatives with ethynylpyridone as base had identified strong lipophilicity as a limiting factor. Two strategies are being pursued to overcome this issue. In order to make the base more polar, the ethynyl group has been replaced with a cyano group, leading to a cyanopyridone C-nucleoside, whose eleven-step synthesis is reported here, together with the synthesis of a 3′-azido-2′,3′-dideoxynucleoside derivative. The base pairing with adenine in a DNA duplex was studied by UV melting analysis of a self-complementary hexamer containing the 6-cyano-2′-deoxynucleoside instead of thymidine. A melting point increase of 2 °C compared to the unmodified control was found. The other strategy employs a phosphoramidate prodrug design with less lipophilic amino acid esters. Here, anti-HIV test of the alaninyl and prolinyl methyl esters of AZT gave promising results in cell culture experiments, increasing the selectivity index up to 5.8-fold for the III_B strain and up to 5-fold for the ROD strain of the virus, as compared to the parent nucleoside. These findings help to design the next generation of pyridone C-nucleosides with potential applications as antivirals.     

Comparison of collisional activation spectra of some positive ions produced both by charge reversal of negative ions and by decomposition of positive ions

The charge reversal collision induced decomposition mass analyzed ion kinetic energy spectrum of allyl anion has been compared with the collision induced dissociation mass analyzed ion kinetic energy spectrum of allyl cation and found to be identical except for the presence of +2 ions formed by charge stripping in the spectrum of the [C₃H₅]⁺ ion. Likewise, the collision induced dissociation mass analyzed ion kinetic energy charge reversal spectrum of [CH₃Se]^? has been compared with the collision induced dissociation mass analyzed ion kinetic energy spectrum of [CH₃Se]⁺ and found to be identical. A study of the pressure dependence of the collision induced dissociation mass analyzed ion kinetic energy spectrum of [C₃H₅]⁺ and [C₃H₅]^? showed increasing fragmentation with increasing collision gas pressure, and suggests that a greater mean number of collisions converts more energy to internal modes in the collision induced dissociation mass analyzed ion kinetic energy experiment even at low pressures.