Chemistry of thienopyridines. XXXIII. Synthetic routes to 5- and 7-substituted thieno[3,2-b]pyridines from the N-oxide

Thieno[3,2-b]pyridine ( 1 ) is oxidized to N-oxide 1a by means of m-chloroperoxybenzoic acid (83%). Compound 1a forms adducts with hydrogen chloride and picric acid and gives ring substitution alpha or gamma to the heteronitrogen atom. Thus, 1a plus nitric and sulfuric acids produces the 7-nitro-N-oxide 1m (63%), or plus phosphorus oxychloride gives a mixture of 5-chloro and 7-chloro ( 1j ) derivatives of 1 . Compound 1m is convertible into a variety of other derivatives of 1 , viz. 7-chloro-N-oxide, 1j , 7-bromo-N-oxide, 7-nitro and 7-amino. 5-Cyano- 1 , formed from 1a , is, in turn, transformed into a methyl imidate (93%), cyclic amidines, and a 5-tetrazolyl- 1 (91%). These results confirm the prediction that 1a , thieno[2,3-b]pyridine-4-oxide and quinoline 1-oxide should exhibit closely similar (i.e. analogous) chemical reactions.     

Nitration of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide with other aromatic substitutions. Isolation and mutagenicity of an α-nitropyridine N-oxide

Treatment of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide ( 2 ) with fuming nitric acid afforded 3-nitro-5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide ( 3 ), an example of formation of an α-nitropyridine N-oxide derivative by nitration of N-oxides. Further reaction of 3 resulted in deoxygenation giving 3-nitro-5,6,7,8-tetrahydro-5,8-methanoisoquinoline ( 4 ). No aromatic nitration was observed by similar treatment of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline ( 1 ) or 5,6,7,8-tetrahydroisoquinoline N-oxide ( 11 ). Some other aromatic substitutions with 1 and 2 were caried out to obtain mainly the 3-substituted derivatives. Significant mutagenicity of 3 is briefly reported.     

Three new binuclear copper(II) complexes with isonicotinic acid N-oxide: syntheses,crystal structures and properties

Three new copper(II) complexes with isonicotinic acid N-oxide (HL) and 1,10-phenanthroline (phen) as ligands, [Cu(L)(phen)(H₂O)]₂(NO₃)₂···2H₂O (1), [Cu(L)(phen)(H₂O)]₂(ClO₄)₂···2H₂O (2), and [Cu(L)(phen)Br]₂- [Cu(L)(phen)(H₂O)]₂Br₂···6H₂O (3) have been synthesized and structurally characterized. The structures of all three complexes feature a Cu₂ dimer formed by two Cu(II) ions interconnected by two bridging ligands. Each copper(II) ion has a distorted square pyramidal coordination geometry with elongated axial coordination by an aqua ligand or halogen anion. The isonicotinic acid N-oxide anion is bidentate, being coordinated to two Cu(II) ions through its N-O oxygen and one of its carboxylate oxygen atoms. Magnetic susceptibility measurements show a Curie–Weiss paramagnetic behavior characteristic of one unpaired electron for a copper(II) ion for all three complexes.     

Ion radicals. XIII. Spectroscopic and cryoscopic characterization of ions and ion radicals from phenothiazine and N-methylphenothiazine in sulfuric acid solutions

The formation and interconversion of the N-methylphenothiazine cation radical and the N-methylphenothiazine dication from both N-methylphenothiazine and N-methylphenothiazine S-oxide in sulfuric acid solutions have been demonstrated with e.s.r. and absorption spectroscopy. Cryoscopic measurements have shown that in slightly aqueous sulfuric acid N-methylphenothiazine S-oxide is converted to the N-methylphenothiazine dication and, analogously, phenothiazine 5-oxide is converted to the protonated phenazathionium ion (the phenothiazine dication).     

Two Molecular Hybrids Based on Typical or Decorated Poly-Keggin-Anion Chains: Syntheses, Structures, and Proton-Conductivities

Two proton-conductive molecular hybrids were constructed by introducing protonated water clusters, alkaline-earth metal ions and [PMo₁₂O₄₀]^3? anions in the gallery of H-bonding networks based on isonicotinic acid N-oxide. Single-crystal X-ray diffraction analyses at 293?K revealed that two complexes crystallized in the orthorhombic space group Pnnm, exhibited very close unit cell parameters, and presented similar three-dimensional hydrogen-bonded networks with large one-dimensional (1D) channels. Interestingly, typical or decorated poly-Keggin-anion chains are formed in the 1D channels. Surprisingly, the proton conductivities of two complexes in the temperature range of 85?C100?°C under 98% RH conditions reached good proton conductivities of 10^?3?S?cm^?1. A possible mechanism of the proton conduction was proposed according to the experimental results.     

1H NMR studies of solvent and substituent effects on strong intramolecular hydrogen bonds

Chemical shifts of H-bonded protons in tetrabutylammonium hydrogen maleate and 14-substituted picolinic acid N-oxides have been measured in a number of dry solvents, of different activity, in order to distinguish between symmetrical single minimum and asymmetrical hydrogen bonds. In tetrabutylammonium hydrogen maleate the resonance was observed at 20.70 ppm and its was independent of the nature of the solvent used. The chemical shift value of picolinic acid N-oxide varies with the solvent. These observations suggest that the hydrogen bond is symmetrical in tetrabutylammonium hydrogen maleate but that it is asymmetrical in picolinic acid N-oxide. The chemical shifts of substituted picolinic acid N-oxides were correlated with σ_p, σ_m and Δ_pK_a. The substituent and solvent effects are compared and the position of the intramolecular H-bonded protons in picolinic acid N-oxides are estimated and discussed.     

Reaction of γ-picoline N-oxide with ketenimines in the presence of organic acids: Preparation of α-acyloxyamides

A synthesis of a-acyloxyamides is described which utilizes the reaction of 7-picoline N-oxide and various organic acids with diphenylketene N-p-tolylimine.     

Elimination of carbon monoxide by electron impact on quinoline N-oxide,carbostyril and 8-hydroxyquinoline

Under electron impact, the molecular ions of quinoline N-oxide, carbostyril and 8-hydroxyquinoline lose carbon monoxide giving a fragment ion C₈H₇N (m/z 117), which was shown by collision-activated dissociation in each case to have the structure of the molecular ion of indole. Its formation from 8-hydroxyquinoline requires an unusual rearrangement. Isoquinoline N-oxide loses HCN rather than CO and gives a fragment which has the structure of the molecular ion of benzofuran. When the first three compounds were subjected to flash vacuum pyrolysis, quinoline N-oxide at 500–700°C gave carbostyril and indole was detected by gas chromatography/mass Spectrometry. At 900°C carbostyril and 8-hydroxyquinoline both gave indole in small amounts, detected by gas chromatography/mass Spectrometry.     

Mass spectra of some 2-, 3-, and 4-pyridinecarboxylic acids. Further evidence of a N-H interaction for loss of carbon dioxide

Mass spectra of 3-acetamido-, 3-methoxy-, and 4-methoxy-2-pyridinecarboxylic acids, 2,6-pyridinedicarboxylic acid, 4-nitro-2-pyridinecarboxylic acid N-oxide, 2-chloro- and 2-nitro-x-pyridinecarboxylic acids (X = 3 and 5), 2-chloro- and 2-nitro-4-pyridinecarboxylic acids, and 4-pyridinecarboxylic acid are reported. The 2-pyridinecarboxylic acids lost carbon dioxide (M-44) as has been reported. The 3-pyridinecarboxylic acids showed no definite trend in fragmentation; however, the 4-pyridinecarboxylic acids lost OH (M-17) first. This change in fragmentation pat-tern is due to an interaction of the ring nitrogen and carboxyl group in the 2-pyridinecarboxylic acids which is not present in the 4-pyridinecarboxylic acids.     

A novel hydrogen-bonding N-oxide–sulfonamide–nitro N—H…O synthon determining the architecture of benzenesulfonamide cocrystals

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₅H₄N₂O₃·C₆H₆N₂O₄S, and 4-chlorobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₆H₆ClNO₂S·C₅H₄N₂O₃, are stabilized by N—H…O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N—H…O(N-oxide) and N—H…O(nitro) bridges. We present here a more detailed analysis of the N-oxide–sulfonamide–nitro N—H…O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.     

Electronic absorption spectra of some nicotinamides and nicotinic acids. Molecular orbital treatment

The electronic absorption spectra of the position isomers nicotinamide and isonicotinamide, nicotinic acid, and isonicotinic acid were investigated, together with the spectra of thionicotinamide, N-methyl nicotinamide and nicotinic acid N oxide. Apparent differences in the spectra of the position isomers were interpreted in terms of the torsion angle between the planes of the molecule, the height of the barrier to internal rotation, and the results of molecular orbital (MO) calculations. The largest perturbation effect was observed in the case of thionicotinamide whereas the smallest effect was observed in the case of nicotinic acid N oxide. MO calculations have indicated the existence of overlapping transitions. The observed transitions proved to be π-π* transitions, none of the n-π* was observed. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 64 : 689–701, 1997     

The deoxydative substitution reactions of nicotinamide and nicotinic acid N-oxides by 1-adamantanethiol in acetic anhydride

The reaction of nicotinamide N-oxide with 1-adamantanethiol in acetic anhydride yielded a mixture of 2-and 6-(1-adamantylthio)nicotinamides (49%, in the ratio of 24:1) and 2-, 5-, and 6-(1-adamantylthio)nicotino-nitriles (18%, in the ratio of 79:1:20). From a reaction of nicotinic acid N-oxide with 1-adamantanethiol, there was isolated 2-(1-adamantylthio)nicotinic acid as the only sulfide in 23% yield. Carbon? sulfur bond cleavage took place when 2-(1-adamantylthio)nicotinic acid, or the corresponding amide or nitrile, were boiled with concentrated hydrochloric acid to furnish 2-mercaptonicotinic acid and 1-chloroadamantane, quantitatively. The reaction of nicotinamide N-oxide alone in acetic anhydride at 135° formed N-acetyl-2-hydroxynicotinamide (61%), 2-hydroxynicotinonitrile (0.5%) and N,N-diacetyl-2-acetoxynicotinamide (0.8%).     

Interaction of cellulose with amine oxide solvents

Cellulose I, mainly as ramie or as Avicel microcrystalline cellulose, has been monitored by optical microscopy and by ¹³C CPMAS NMR, over the course of its dissolution in hot N-methylmorpholine N-oxide solvent. Its interaction with the near-solvent N-ethylmorpholine N-oxide and related non-solvents has also been investigated. NMR shows that N-methylmorpholine N-oxide partly converts crystalline cellulose I into amorphous solid cellulose. The changes in chemical shift imply increased flexibility at the glycosidic bonds. In contrast, N-ethylmorpholine N-oxide converts cellulose I to cellulose III_I, without dissolution. Microscopy shows that the ramie fibres swell laterally, and at least some also shorten longitudinally, during dissolution. Model studies using methyl--d-glucopyranose show no evidence from ¹³C chemical shifts for different modes of binding with different solvents. However, N-methylmorpholine N-oxide binds more strongly to methyl--d-glucopyranose in DMSO than does N-ethylmorpholine N-oxide, whereas N-ethylmorpholine N-oxide binds better to H₂O. Also, ¹³C T ₁ values for aqueous cellobioside show increasing rotational freedom of the –CH₂OH sidechains as N-methylmorpholine N-oxide is added. Together, these observations imply the initial penetration of solvents and near-solvents between the molecular cellulose sheets. Subsequently, N-methylmorpholine N-oxide breaks H-bonds, particularly to O-6, just sufficiently to loosen individual chains and then dissolve the sheets.     

On the synthesis of thieno[3,2-c]quinoline N-oxide and thieno-[3,2-C]isoquinoline N-oxide. The nmr spectra of the six isomeric thieno-fused quinoline and isoquinoline N-oxides

The synthesis of the two remaining isomeric monothieno-analogues of phenanthridine N-oxide, thieno-[3,2-c]quinoline N-oxide and thieno[3,2-c]isoquinoline N-oxide, is described. The ¹H and ¹³C nmr spectra of all six isomeric thieno-fused quinoline and isoquinoline N-oxides are discussed.     

Syntheses of Diamino-dideoxylyxose Derivatives using Acylnitroso Dienophiles

N-Acylnitroso derivatives 6 which were prepared by in-situ oxidation of the corresponding hydroxamic acids 5 reacted instantaneously and in high yields with dihydropyridine 4 . The Diels-Alder adducts 8 were formed regiospecifically with the acylnitroso dienophiles 6a–c , whereas the dienophiles 6d–f gave mixtures of both regioisomers 7 and 8 . These and some other results [2] were best explained by the FMO theory. The Diels-Alder adducts 7 and 8 gave the corresponding ‘anti’-cis-glycols when reacted with OsO₄/N-methylmorpholine N-oxide. Hydrogenolysis of the N–O bond followed by peracetylation led to the expected aminolyxose derivatives 14 and 16 . A similar sequence, using 4 and the hydroxamic-acid derivative 18 of (+)-D-mandelic acid led, with a poor asymmetric induction, to a mixture of the expected optically active aminolyxose compounds 19A / 19B .     

On the possibility of isolating diazirine N-oxides

Ab initio molecular orbital calculations at the 6-31G level predict that diazirine N-oxide is more stable with respect to its constituent fragments, singlet CH₂ and N₂O₂, than diazirine is with respect to singlet CH₂ and N₂. In view of these results and the many diazirines which have been reported, it is suggested that it may be possible to detect a suitably substituted diazirine N-oxide.     

Nitrogen-15 nuclear magnetic resonance spectroscopy. Pyridine N-oxides and quinoline N-oxides

The noise-decoupled nitrogen-15 NMR spectra of ten pyridine N-oxides and two quinoline N-oxides have been obtained at the natural-abundance level by high-resolution NMR spectroscopy. Substituents at the 4-ring position of pyridine N-oxide, capable of resonance interaction with the N-O moiety, give fairly large shifts in the expected directions. Spectra taken in dimethyl sulfoxide solution give 5–20 ppm and 33–55 ppm downfield shifts with respect to the solutions of the same substances in 2,2,2-trifluoroethanol and trifluoroacetic acid. Solvent influences are discussed in terms of hydrogen bonding and protonation of the N-oxide oxygen. Carbon-13 chemical shifts and one-bond carbon-hydrogen coupling constants of some substituted pyridine N-oxides are reported and discussed.     

Studies on complexes of metal(II) carboxylates with donor molecules,part III. Complexes of cobalt(II) alkanoates with aromatic amineN-oxides

Summary Cobalt(II) propionate and n-butyrate react with pyridineN-oxide, 3-methylpyridineN-oxide and quinolineN-oxide in methanol to give solid [Co(O₂CR)₂ · L]₂ complexes which have been shown by elemental analysis, conductance, molecular weight, magnetic and spectral studies to be octahedral, binuclear, carboxylate bridged species. The complexes exhibit low magnetic moments at room temperature.     

Variation in coordination modes of aromatic N-oxides in lanthanum(III) coordination polymers

Two new coordination polymers of lanthanum(III) benzoate having pyridine N-oxide and 4,4′-bipyridyl-N,N′-dioxide as ancillary ligands are synthesized and characterized. Different binding modes of the N-oxide are demonstrated; pyridine N-oxide binds as a bridging ligand, whereas 4,4′-bipyridyl-N,N′-dioxide is monodentate.     

A Dansyl Amide N-Oxide Fluorogenic Probe Based on a Bioorthogonal Decaging Reaction

A smart fluorescence “turn-on” probe which contained a dansyl amide fluorophore and an N-oxide group was designed based on the bioorthogonal decaging reaction between N-oxide and the boron reagent. The reaction proceeds in a rapid kinetics (k₂=57.1±2.5 m ⁻¹ s⁻¹), and the resulting reduction product showcases prominent fluorescence enhancement (up to 72-fold). Time dependent density functional theoretical (TD-DFT) calculation revealed that the process of photoinduced electron transfer (PET) from the N-oxide moiety to the dansyl amide fluorophore accounts for the quenching mechanism of N-oxide. This probe also showed high selectivity over various nucleophilic amino acids and good biocompatibility in physiological conditions. The successful application of the probe in HaloTag protein labeling and HepG2 live-cell imaging proves it a valuable tool for visualization of biomolecules.