Chemistry of the phenoxathiins and isosterically related heterocycles. XI . The synthesis and 13C-NMR spectroscopy of 2-azaphenoxathiin

The synthesis of the 2-azaphenoxathiin ring system via the intermediary 2-azaphenoxathiin 2-oxide is described. Complete assignment of the ¹³C-nmr spectrum is reported, based on the observed heteronuclear ¹H-¹³C spin-couplings of the system and calculated chemical shifts as assignment criteria. The possible relation of the chemical shift of Cα to the dehidral angle of the system is also discussed.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XV. Synthesis of 1-nitrophenoxathiin and the relation of the 13C-Nmr chemical shift of the alpha-carbon to the dihedral angle

The synthesis of the previously unreported 1-nitrophenoxathiin is described. The ¹³C-nmr spectrum of the title compound is assigned based on chemical shift additivities and ¹H-¹³C spin-coupling constants. From the observed ¹³C-nmr chemical shift of the alpha-carbon the title compound was predicted to have a molecular dihedral angle, Ø = 143.3°, based on a recently described interrelation between the alpha-carbon ¹³C-nmr chemical shift and the dihedral angle. Independent measurement of the dihedral angle in a crystallographic study has shown that there are two independent molecules contained in the assymetric unit which posess dihedral angles, Ø = 145.7 and 163.4°, the former in excellent agreement with the angle predicted by the assigned ¹³C-nmr data.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXXI. Synthesis of the 1,3-diazaphenoxathiin ring system and the relationship of the 13C-NMR chemical shift of the C-10a resonances to the molecular dihedral angle determined by X-Ray diffraction: A further investigation

Synthesis of the 1,3-diazaphenoxathiin ring system and the confirmation of its structure by ¹³C-nmr spectroscopy and X-ray crystallography are reported. Implications of the ¹³C-nmr chemical shift of the C-10a resonance and its relationship to the molecular dihedral angle are presented. The molecule crystallizes in the Pbca space group and was found to have a dihedral angle of 165.5(9)°, the structure refining to a final R-factor of T = 0.0427.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XVI. The synthesis and molecular structure of 3-azaphenoxathiin: Evidence in support of factors responsible for control of the dihedral angle

The synthesis of the 3-azaphenoxathiin ring system and its molecular structure are reported. Based on ¹³C-nmr chemical shift additivities associated with the insertion of an annular nitrogen atom and the observed ¹³C-nmr shift of Cα, the title compound was predicted to have a dihedral angle θ = 160.2°. The observed dihedral angle from the crystal structure was found to be θ = 167.07° which is in reasonably good agreement with the predicted value. It is proposed that the position of the annular nitrogen atom is solely in-control of the observed dihedral angle.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XIII. 13C-NMR spectroscopy of 1-azaphenoxathiin 10,10-dioxide. An unusual perturbation of 1H-13C coupling constants

The total assignment of the ¹³C-nmr spectrum of 1-azaphenoxathiin 10,10-dioxide is reported based on the utilization of additivity correlations for the conversion of sulfide to sulfone linkages. Although the benzenoid portion of the molecule obeyed standard additivity correlations, substantial deviation in additivity behavior was observed in the pyridyl portion of the molecule. Examination of the ¹H-¹³C spin-coupling constants showed a perturbation of the primary one bond (¹J_CH) couplings of the C-2 and C-4 carbons.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXXII . The synthesis of 2-azathianthrene and selected analogs

The synthesis of 2-azathianthrene ([1,4]benzodithiino[2,3-c]pyridine), the only remaining monoazathianthrene yet to be reported, is described. Attempts at the direct condensation of disubstituted pyridines with the dianion of 1,2-dimercaptobenzene were generally unsuccessful requiring that the alternative condensation of the dianion with disubstituted pyridine 1-oxides be employed. The title compound was characterized by physical means including ¹³C-nmr spectroscopy. One analog, 4-nitro-2-azathianthrene was also studied by X-ray crystallographic means; the molecule crystallized with two molecules in the asymmetric unit P2₁/n, a = 20.712(3), b = 7.8109(13), c = 13.720(2)Å, β = 107.880(11)°, Z = 8, the data refined to a final R = 0.051 for 3061 reflections. Dihedral angles between the planes of the phenyl rings were 135.00(13) and 132.52(13)° for the two independent molecules contained in the crystal. Close non? bonded S ?O intramolecular contacts were observed in both molecules between the sulfur and nitro-group oxygens. Both nitro groups are twisted out of the plane of the pyridine ring and are oriented at angles of 28.75 and 38.82° respectively.     

Chemistry of the phenoxathiins and isosterically related heterocycles. IX.N-oxidation on the 13C-nmr chemical shifts and coupling constants of the 1-azaphenoxathiin system

The synthesis of 1-azaphenoxathiin N-oxide is described. Total assignment of the ¹³C-nmr spectrum and the effects of the N-oxide moiety on the chemical shifts and ¹H-¹³C spin couplings constants are described and compared to the parent 1-azaphenoxathiin system. The potential for the use of N-oxidation induced changes in ¹³C-nmr chemical shifts and ¹H-¹³C coupling constants as an assignment criterion is also discussed.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XVIII. The synthesis, 1H- and 13C-NMR Spectroscopy of benzo[b]-1,4,9-triazaphenoxathiin

The first synthesis of a triazaphenoxathiin system, benzo[b]-1,4,9-triazaphenoxathiin, is reported. Attempts directed toward the total assignment of the ¹³C-nmr spectrum of the title compound failed to produce an unequivocal assignment. The carbons of the benzo-portion of the molecule could not be unequivocally assigned at 25.2 MHz but were subgrouped into permutable pairs of resonances on the basis of relaxation times, a result of the antisotropic reorientation of the molecule. Further attempts to complete the ¹³C-nmr assignment at 100 MHz by selective on-resonance decouplings in the 400 MHz ¹H-nmr spectrum were also unsuccessful because of similarities in the chemical shifts of the benzo-protons. Complete ¹H-nmr chemical shifts and homo-nuclear spin-coupling constants were obtained using the PANIC program.     

Chemistry of the phenoxathiins and isosterically related heterocycles. X. Correlation of the dihedral angles of phenoxathiin analogs with the 13NMR chemical shifts of the sulfur bearing la carbon

The observation of a linear relationship between the ¹³C-nmr chemical shifts of the C-la carbon and the dihedral angle in a series of phenoxathiin analogs is reported. Presently available data, although limited, is presumed to be indicative of a more general behavior which has not been previously recognized or utilized. Extension of this observation to include other sulfur containing tricyclic systems may be expected to provide a useful means for the preliminary estimation of dihedral angles from solution ¹³C-nmr measurements after suitable parameterization.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXIII . 1-azathianthrene: First reported synthesis of a monoazathianthrene and the investigation of the 13C-NMR spectrum using two-dimensional NMR techniques

The reaction of the dianion of 3-mercaptopyridin-2(1H)-thione with 2-chloronitrobenzene in N,N-dimethylformamide leads to the formation of 1-azathianthrene, the first reported mono-aza analog of the thianthrene ring system. A partial assignment of the ¹³C-nmr spectrum of the title compound is reported, the assignment based on chemical shift arguments, spin-lattice (T₁) relaxation times and ¹H-¹³C spin coupling constants. Amplitude modulated two-dimensional Fourier transform (AM2DFT) techniques were employed for the acquisition of the heteronuclear spin-coupling constants.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XII. Synthesis of diazaphenoxathiin analogs: 1,9-Diazaphenoxathiin and 1,7-diazaphenoxathiin

The synthesis of the first diazaphenoxathiins, 1,9-diazaphenoxathiin and 1,7-diazaphenoxathiin, are described. Complete assignments are made for the ¹³C-nmr spectra of these compounds based on additivity correlation and ¹H-¹³C spin-coupling constants. The isolation and confirmation of the structure of 2-[2′(-3′-nitropyridylthio)]-3-[2″-(3″-nitropyridyloxy)] pyridine using ¹³C-nmr and appropriate model compounds is also discussed. A preliminary evaluation of spontaneous motor depression in mice showed a substantial difference between the observed activities of the two diazaphenoxathiins reported. The possibility of the observed difference being associated with the relative positions of the annular aza-substitutions is discussed.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XVII. First synthesis of a benzoxathiinopyridazine and the determination of structure by 13C-NMR: 1-Methoxy-3,4-diazaphenoxathiin

The reaction of 5-methoxy-3,4-dichloropyridazine with the disodium salt of o-mercaptophenol leads to the formation of 1-methoxy-3,4-diazaphenoxathiin as the sole product of the reaction. The structure of the isolated product was confirmed by ¹³C-nmr spectroscopy, with the development of arguments to discriminate the isolated compound from 4-methoxy-1,2-diazaphenoxathiin, the other product possible in this reaction. Mechanistic considerations in the formation of the isolated product are discussed.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XIV. Total assignment of the 13C-Nmr spectrum of pyrrolo[3,2,1-kl]phenothiazine

Total assignment of the ¹³C-nmr spectrum of the novel tetracyclic phenothiazine, pyrrolo[3,2,1-kl]phenothiazine is described. Assignments were determined from model systems, ¹H-¹³C spin-coupling behavior in conjunction with selective excitation techniques and spin-lattice (T₁) relaxation measurements. The anisotropic reorientation of this ring system via a principal axis passing through the center of the molecule, which provides a qualitative basis for signal discrimination, is also discussed.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXXIII . The influence of intramolecular sulfur-nitro group interactions on the reactivity at sulfur

Nitro-groups positioned ortho to thio-esters have been shown to engage in strong, non-bonded intramolecular interactions between the sulfur atom and one of the nitro-group oxygens. The effect of the sulfur-nitro group oxygen interaction on the chemical reactivity at the sulfur atom of 9-nitro-1-azaphenoxathiin is reported. Conditions which normally produce the sulfone exclusively have been shown to yield the sulfoxide with only a minimal quantity of the sulfone produced. Protracted periods of reflux are required to produce the sulfone from the sulfoxide.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XX. Assignment of the 13C-NMR spectra of phenarsazine-10-chloride and several substituted analogs. The effect of substitution on the anisotropic reorientation of the phenarsazine system

The total assignment of the ¹³C-nmr spectra of phenarsazine-10-chloride and several substituted analogs is reported. Spin-lattice (T₁) relaxation measurements have shown these systems to reorient anisotropically. In the case of the parent system and the 3-chloro substituted system, the axis of anisotropic reorientation has been shown to pass approximately through the center of the molecule. In the case of benzo[c]phenarsazine-7-chloride, the axis of anisotropic reorientation, which has been accurately defined, is shifted 23° from that in the previous cases, the shift occurring in the direction of the benzo-moiety.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXIX The crystal and molecular structure of 5-(3′-hydroxypyridyl-2′-thio)-4-nitro-1-methylimidazole

Reaction of the dianion of 3-hydroxypyridine-2(1H)-thione with 5-chloro-4-nitro-1-methylimidazole in N,N-dimethylformamide led to the formation of 5-(3′-hydroxypyridyl-2′-thio)-4-nitro-1-methylimidazole, which failed to cyclize to the desired pyrid[1,4]oxathiinoimidazole derivative. In an effort to determine why the intermediate phenolate sulfide had failed to cyclize, the crystal structure of the isolated product was determined. The structure refined to R = 0.036.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXXVII The synthesis and molecular structure of benzo[2, 3]naphtho[5, 6, 7-ij][1, 4]dithiepin and its 1-oxide

Benzo[2, 3]naphtho[5, 6, 7-ij][1, 4]dithiepin was prepared by the condensation of the disodium salt of 1, 2-dimercaptobenzene with 1-chloro-8-nitronaphthalene. The structure was established by nmr and mass spectroscopy. A small quantity of benzo[2, 3]naphtha[5, 6, 7,ij][1, 4]dithiepin 1-oxide was also isolated. The structure was initially established by mass spectrometry. The proton spectrum was totally assigned using a combination of proton zero quantum coherence (ZQCOSY) and proton-carbon heteronuclear chemical shift correlation (HC-COSY) techniques, which also allowed the unequivocal assignment of the protonated carbon resonances. An X-ray crystal structure of the 1-oxide irrefutably confirmed the structure. The crystal was triclinic and the space group was Pl, and the data refined to a final R = 0.0353. The molecule was shown to be folded about the axis passing through the two sulfur atoms with a dihedral angle of 109.00°.     

The crystal and molecular structure of phenothiazine-10-propionitrile. The effect of crystal packing on the dihedral angle of phenothiazine heterocycles

Phenothiazine-10-propionitrile, C₁₂H₈SNC₂H₄CN, crystallizes in the centrosymmetric monoclinic space group P2₁/n, with a = 5.785(1)Å, b = 15.427(3)Å, c = 14.497(4)Å, β = 92.50(1)°, Z = 4, D_meas = 1.29(1) g cm³ and D_calc = 1.28 g cm³ at 23°. Three dimensional X-ray data were collected with a manual diffractometer using MoKα (λ 0.71069Å) radiation and by multiple film Weissenberg techniques using CuKα (λ 1.5418Å) radiation. The structure was determined by Patterson and Fourier methods and refined with 519 observed reflections by full matrix least-squares methods to an R of 0.077. The dihedral angle between the two planes of the o-phenylene rings is 135.4(3)°. In the folded heterocyclic ring the C-S-C angle is 97.8(7)° and the average C? S bond is 1.76(1)Å. A comparison of this structure to that of phenothiazine-10-propionic acid shows the two chemically similar molecules have the same dihedral angles in spite of completely different solid state packing patterns.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XXII. 6,7,9-trimethyl-4-azaphenoxathiin: First reported synthesis of an analog of the 4-azaphenoxathiin ring system

The reaction of 2-chloro-3-thiocyanatopyridine with a substituted spiroepoxycyclohexadienone, which served as a masked phenol with reversed polarity, led to the first reported synthesis of an analog of the 4-azaphenoxathiin ring system. Confirmation of the structure was obtained from the assignment of the ¹³C-nmr spectrum.     

Chemistry of the phenoxathiins and isosterically related heterocycles. XIX.. The crystal and molecular structure of 1-N,N-dimethylamino-2,3-diazaphenoxathiin: An interesting product isolated from the reaction of o-mercaptophenol with 3,4,5-trichloropyridazine in N,N-dimethylformamide

The isolation of 1-N,N-dimethylamino-2,3-diazaphenoxathiin and its molecular structure as determined by X-ray crystallography are described. The existence of a potential non-bonded interaction between the lone pair of electrons of the dimethylamino group nitrogen and sulfur atom are also discussed.