Substituent effects on the tautomer ratios between the hydra-zone imine and diazenyl enamine forms in 3-(arylhydra-zono)methyl-2-oxo-1,2-dihydroquinoxalines. Correlation of the hammett constants σp with the tautomeric equilibrium constants KT

The 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 1a-e and 2a-i showed tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in dimethyl sulfoxide media. The sub-stituent effects on the tautomer ratios of A to B in compounds 1a-e and 2a-i were studied by the nmr spec-troscopy. The electron-donating or electron-withdrawing p-substituents R¹ in compounds 2a-i represented a tendency to increase the ratios of the tautomer A or the tautomer B , respectively, exhibiting the linear correlation of the Hammett constants σ_p (-0.17 to +0.78) with the tautomer ratios of A to B or the tautomeric equilibrium constants K_T. However, the presence of the ester group R² in compounds 1a-e induced the exclusive existence of the tautomer A regardless of the nature of the p-substituents R¹. In the tautomeric thermodynamic study, the elevating temperature increased the ratios of the hydrazone imine tautomer A in compounds 2a-i . The tautomeric thermodynamic parameters ΔG°, ΔH° and ΔS° were derived from the van't Hoff plots for compounds 2a , b , h , i , wherein the entropy term dominated the free-energy difference between the A and B tautomers.     

Tautomerism of aza cycles: I. Structure of 3(5)-butylsulfanyl-5(3)-methyl(phenyl)-1H-1,2,4-triazole tautomers in crystal. Preference of the 3-RA-5-RD-1H-tautomer of 3(5)-mono-and 3,5-disubstituted 1,2,4-triazoles

The X-ray diffraction study of potentially tautomeric 3(5)-butylsulfanyl-5(3)-methyl-1H-1,2,4-triazole and its 5(3)-phenyl-substituted analog showed that these compounds in crystal have the structure of 3-butylsulfanyl-5-methyl(phenyl)-1H-tautomers. Analysis of our experimental and published data indicated that 3(5)-monosubstituted 1,2,4-triazoles and 3,5-disubstituted derivatives having nonequivalent substituents in crystal as exist as a tautomer in which the electron-acceptor substituent (R_A) occupies the 3 position, while the electron-donor substituent (R_D) resides in the 5 position, i.e., as 3-R_A-5-R_D-1H-1,2,4-triazoles. Symmetric 3,5-disubstituted 1,2,4-triazoles could give rise to tautomeric equilibrium between the 1H-and 2H-structures even in crystal.     

On the tautomerism of pyrazolones: the geminal J[pyrazole C-4,H-3(5)] spin coupling constant as a diagnostic tool

The tautomerism of pyrazolones unsubstituted at position 3(5) has been investigated by ¹³C- and ¹H NMR spectroscopic methods. Apart from chemical shift considerations and NOE effects the magnitude of the geminal ²J[pyrazole C-4,H3(5)] spin coupling constant permits the unambiguous differentiation between 1H-pyrazol-5-ol (OH) and 1,2-dihydro-3H-pyrazol-3-one (NH) forms. Whereas 1H-pyrazol-5-ols and 2,4-dihydro-3H-pyrazol-3-ones (CH-form) exhibit ²J values of approximately 9-11 Hz, in 1,2-dihydro-3H-pyrazol-3-ones this coupling constant is considerably reduced to 4-5 Hz. This can be mainly attributed to the removal of the lone-pair at pyrazole N−1 in the latter due to protonation or alkylation. According to the data obtained, 2-substituted 4-acyl-1,2-dihydro-3H-pyrazol-3-ones exist predominantly as pyrazol-5-ols in CDCl₃ or benzene-d₆ solution, whereas in DMSO-d₆ also minor amounts of NH tautomer may contribute to the tautomeric composition. 2,4-Dihydro-2-phenyl-3H-pyrazol-3-one (1-phenyl-2-pyrazolin-5-one) exists in benzene-d₆ solely in the CH-form, in CDCl₃ as a mixture of CH and OH-form, whereas in DMSO-d₆ a fast equilibrium between OH and NH isomer (with the former far predominating) is probable. For 11 compounds, including neutral and protonated molecules, we have calculated at the B3LYP/6-311++G** level, the ²J(¹H,¹³C) coupling constants which are in good agreement with those measured experimentally.     

Investigation of the structure of and the properties of the potentially tautomeric 1,2,3,4-tetrahydro-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazine-1,4-diones in the gaseous and aqueous phases using the AM1 semi-empirical method

Potentially tautomeric 1,2,3,4-tetrahydro-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazine-1,4-diones and their fixed tautomeric forms have been studied in order to predict their tautomeric equilibrium constants and pK_a values using semi-empirical AM1 quantum-chemical calculations at the SCF level in the gas phase and in aqueous solution. Hydroxy-oxo forms were found to be more stable than dioxo and dihydroxy forms. The results obtained from the tautomeric equilibria and basicity calculations are in good agreement with experimental data.     

Spectaline and iso-6 cassine,two new piperidin 3-ol alkaloids from the leaves of cassia spectabilis

From the leaves of an african leguminosae: Cassia spectabilis DC, we have isolated two unprecedented piperidin 3-ol alkaloids. By spectral data, their structures were elucidated as follows (+)Spectaline(l): 2(S)-methyl 6(R)-(13'-oxotetradecyl)piperidin 3(S)-ol and (-)iso-6-cassine(2) 2(R)-methyl 6(R)-(11'-oxodecyl) piperidin 3(R)-ol.     

Azoles and azines. 62. Structure of 2-aryl-1,3-oxazine-4,6-diones

¹H,¹³C NMR, IR, and UV spectra have been studied for solutions of a number of potentially tautomeric 2-aryl-1,3-oxazine-4,6-diones and their 5-methyl substituted analogs with variation of substituent at the para position of the benzene ring, as well as compounds with a fixed structure that simulates possible tautomeric forms. The data have been compared with the results of quantum chemical calculations carried out in SSO MO LCAO approximation by the CNO, CNDO/2, and MPNDO/3 methods. In DMSO and THF solution the test compounds exist predominantly as 2-aryl-4-hydroxy-6H-1,3-oxazin-6-ones. The para substituent in the benzene ring does not affect the composition of the tautomer mixture significantly.For Communication 61, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 386–394, March, 1987.     

Antileishmanial Effects of Acetylene Acetogenins from Seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae) and Semisynthetic Derivatives

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-yn-19′-enyl)butanolide (1) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-ynyl)butanolide (2), from the seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae). Using an ex-vivo assay, compound 1 showed an IC₅₀ value of 29.9 μM against the intracellular amastigote forms of Leishmania (L.) infantum, whereas compound 2 was inactive. These results suggested that the terminal double bond plays an important role in the activity. This effect was also observed for the semisynthetic acetylated (1a and 2a) and eliminated (1b and 2b) derivatives, since only compounds containing a double bond at C-19 displayed activity, resulting in IC₅₀ values of 43.3 μM (1a) and 23.1 μM (1b). In order to evaluate the effect of the triple bond in the antileishmanial potential, the mixture of compounds 1 + 2 was subjected to catalytic hydrogenation to afford a compound 3 containing a saturated side chain. The antiparasitic assays performed with compound 3, acetylated (3a), and eliminated (3b) derivatives confirmed the lack of activity. Furthermore, an in-silico study using the SwissADME online platform was performed to bioactive compounds 1, 1a, and 1b in order to investigate their physicochemical parameters, pharmacokinetics, and drug-likeness. Despite the reduced effect against amastigote forms of the parasite to the purified compounds, different mixtures of compounds 1 + 2, 1a + 2a, and 1b + 2b were prepared and exhibited IC₅₀ values ranging from 7.9 to 38.4 μM, with no toxicity for NCTC mammalian cells (CC₅₀ > 200 μM). Selectivity indexes to these mixtures ranged from >5.2 to >25.3. The obtained results indicate that seeds of Porcelia macrocarpa are a promising source of interesting prototypes for further modifications aiming at the discovery of new antileishmanial drugs.     

Proton and carbon nuclear magnetic resonance study on some n- and o-acyl derivatives of monohydroxypyridines

Comparative study on the proton and carbon NMR spectra for a series of $\text{N}$- and $\text{O}$-acyl substituted monohydroxypyridines (C₅H₄NO$\text{R}$: $\text{R}$=-H, -CHO, -COCH₃, -COC(CH₃)₃, -COCF₃, -COC₆H₅, -SO₂CH₃, -SO₂C₆H₄CH₃ is reported. p]Characteristic ¹H, ¹³ NMR and IR spectral features allow simple and unambiguous distinction between the isomeric $\text{N}$- and/or $\text{O}$-acyl-derivatives of 2-, 3- and 4-hydroxypyridines, so that both forms can clearly be identified when tautomeric equilibria occur, since the tautomerism rate is slow on the NMR time scale     

Substituent effects on the tautomer ratios between the hydrazone imine and diazenyl enamine forms in side-chained quinoxalines

The 3-(arylhydrazono)methyl-2-oxo-1,2-dihydroquinoxalines 9–11 were synthesized by the reaction of the quinoxalines 6–8 with various p-substituted benzenediazonium salts. Compounds 9–11 showed the tautomeric equilibria between the hydrazone imine A and diazenyl enamine B forms in dimethyl sulfoxide media. The substituent effect on the tautomer ratios of A to B was studied by the nmr spectroscopy to clarify that the presence of the ester group R² on the hydrazone carbon and electron-donating p-substituent R¹ on the side chain benzene ring exhibited a tendency to increase the ratios of the tautomer A .     

Vinylamine—XII : Untersuchungen zur substituentenabhängigkeit der imin-enamin-tautomerie an β-aryl-vinylaminen

The equilibria of imine-enamine tautomeric compounds 3–6 have been determined by NMR spectroscopy. With exception of the 4-nitro group, the influence of the substituents R² is represented by the Hammett σ-values. The same is true for the cis-trans-isomerism of 3E–5E. It is shown that the trans-enamine is stabilized by electron-withdrawing substituents R². Slopes and intercepts of the regression lines depend largely on the substituents on nitrogen or α-carbon. The enamine isomer is favored by an aryl substituent in the α-position.     

Probes for narcotic receptor mediated phenomena. Part 31: Synthesis of rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol, and azocine-8-ol, the ortho-c and the para-c oxide-bridged phenylmorphan isomers

Two of the 12 possible oxide-bridged phenylmorphans, were synthesized, rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol (7) (the ortho-c compound), and rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-8-ol (8) (the para-c compound). Single-crystal X-ray diffraction studies indicated that the dihedral angle between the least squares planes through the phenyl ring and the atoms C₁, C_11a, C₁₂, and C₃ in the piperidine ring in both 7·CHCl₃ and 8·HBr was 6.9°. The C₁₂-C_6a-C_6b-C_10a torsion angle was found to be 139.3° for both compounds. The angular relationship between the phenolic ring and the piperidine ring in phenylmorphans that interact with specific opioid receptors as agonists or antagonists is of considerable theoretical interest.     

Structural and magnetic properties of RMn2−xFexD6 compounds (R=Y, Er; x≤0.2) synthesized under high deuterium pressure

RMn_2−xFe_xD₆ compounds were obtained by applying a deuterium pressure of several kbar to RMn_2−xFe_x compounds for x≤0.2 and R=Y, Er. These compounds are isostructural to RMn₂D₆ compounds and crystallize in a K₂PtCl₆ type structure with a random substitution of R and half the Mn atoms in the same 8c site whereas the other Mn atoms are located on the 4a site and surrounded by six D atoms (24e site). According to neutron powder diffraction analysis the Fe atoms are preferentially substituted on the 4a site. YMn_2−xFe_xD₆ compounds are paramagnetic and their molar susceptibility follows a modified Curie-Weiss law. ErMn_2−xFe_xD₆ compounds display a ferromagnetic behavior at 2 K, but their saturation magnetization (M_S∼4.0 μ_B/f.u.) is half that of their parent compounds (M_S∼8.0 μ_B/f.u.). The neutron diffraction patterns of ErMn_1.8Fe_0.2D₆ display below 13 K both ferromagnetic and antiferromagnetic short range order, which can be related to a disordered distribution of Er moments. The paramagnetic temperatures of ErMn_2−xFe_xD₆ compounds are negative and decrease versus the Fe content whereas they are positive and increase for their parent compounds.     

Substituent effects in the ring-chain tautomerism of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines

Condensation of Betti base analogue amino naphthols with substituted benzaldehydes led to 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines (3-9) which proved to be three-component (r¹-o-r²) tautomeric mixtures in CDCl₃ at 300 K. The electronic effects of the 3-aryl groups on the ratios of the ring-chain tautomeric forms at equilibrium could be described by the equation log K_X=ρσ⁺+log K_X=H. The value of the intercept was found to be strongly influenced by the steric arrangement of the 1,3-diaryl substituents.     

Substituent effects on the tautomer ratios between the enamine and methylene imine forms in side-chained quinoxalines

The p- and m-substituted 3-arylcarbamoylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxalines 3a-o showed the tautomeric equilibria between the enamine C and methylene imine D forms in dimethyl sulfoxide or dimethyl sulfoxide/trifluoroacetic acid media. The linear correlation of the Hammett σ_p and σ_m values with the log K_T values was observed in the dimethyl sulfoxide/trifluoroacetic acid (2:1) media of compounds 3a-o , wherein K_T meaned the tautomeric equilibrium constants ([D]/[C]).     

Synthesis and reactivity of 4″-phenylsulfinimine-avermectin B1 and 4′-phenylsulfinimine-avermectin B1 monosaccharide derivative

A short, efficient synthesis of 4″-(R or S)-4″-deoxy-4″-amino-4″-C substituted avermectin B₁ and 4′-(R or S)-4′-deoxy-4′-amino-4′-C substituted avermectin B₁ monosaccharide 3 and 4 has been developed through the nucleophilic addition of an organometallic reagent to an intermediate phenylsulfinimide 7. These new derivatives of avermectin B₁ exhibited potent, broad spectrum insecticidal activity.     

The substrate specificity of the heat-stable stereospecific amidase from Klebsiella oxytoca

The substrate specificity of the heat-stable stereospecific amidase from Klebsiella oxytoca was investigated. In addition to the original substrate, 3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, the amidase accepted 2-hydroxy-2-(trifluoromethyl)-butanamide and 3,3,3-trifluoro-2-amino-2-methylpropanamide as substrates. Compounds with larger side chains and compounds where the hydroxyl group was substituted with a methoxy group, or in which the CF₃ group was substituted by CCl₃, were not accepted. The biotransformation is a new synthetic route to (R)-(+)-3,3,3-trifluoro-2-amino-2-methylpropanoic acid, and its related (S)-(−)-amide, and to (R)-(+)-2-hydroxy-2-(trifluoromethyl)-butanoic acid and its related (S)-(−)-amide.     

3-Phenylpyrazolo(4,3-c)pyridine and derivatives: structure determination

The structures of 3-phenylpyrazolo(4,3-c)pyridine (1) and 5-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo(4,3-c)pyridine (2) are determined by detailed ¹H and ¹³C NMR analysis and theoretical calculations in comparison with their N-methyl derivatives as fixed models. CNDO/2 and PPP calculations are performed on the three prototropic forms admissible for the tautomeric system 1. By comparison of the ¹³C NMR and UV spectra of 1 with those of its three fixed N-methyl derivatives and of the UV spectra calculated for the tautomers of 1 with that experimentally obtained in the range 200–450 nm, 3-phenylpyrazolo(4,3-c)pyridine (1) is established to exist entirely in the 1H tautomeric form 1A.By ¹³C NMR investigations of 5-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo(4,3-c)-pyridine (2), in comparison with its fixed 1-methyl-1H derivative 9 and other substituted pyrazoles, 2 is determined to be a mixture of the 1H- (2A) and 2H- (2B) tautomers with 2A largely predominating. The compounds investigated are described here for the first time.     

A new route for the preparation of the 22,23-dioxocholestane side chain from diosgenin and its application to the stereocontrolled construction of the 22R,23S-diol function

The new (22R,23S,25R)-3β,16β,26-triacetoxy-cholest-5-ene-22,23-diol (11a) was synthesized from diosgenin (3) through a synthetic route based on chemoselective RuO₄ oxidation of (25R)-3β,16β-diacetoxy-23-ethyl-23¹,26-epoxycholesta-5,23(23¹)-dien-22-one (9) that afforded (20S,25R)-3β,16β,26-triacetoxycholest-5-ene-22,23-dione (10) which was stereoselectively reduced using NaBH₄. Compound 9 was obtained from the known isomeric 22,26-epoxycholest-5-ene steroidal skeleton 8b by treatment with p-TsOH in toluene, amberlyst-15 or directly from diosgenin by treatment with BF₃·OEt₂/Ac₂O. Chemoselective reduction of the 23-keto group of 10, was attained using NaBH₄/ZnCl₂ at −70 °C to give 23S-14. The NMR spectra of all compounds were unambiguously assigned based on one and two dimensional experiments and the C-22 and C-23 stereochemistry in the diacetate derivative 11b, as well as the structure of epoxycholestene 9 were further established by X-ray diffraction analyses. The new route for the functionalization of the side chain of diosgenin can find application in the synthesis of norbrassinosteroid analogues.     

Synthesis of C-11 linked active ester derivatives of vitamin D3 and their conjugations to 42-residue helix-loop-helix peptides

Derivatives of vitamin D₃ carrying an 8-carbon linker at C-11 terminating in an active ester were synthesized from commercial vitamin D₃ using a disassembly-reassembly strategy. Vitamin D₃ was cleaved at the C6-C7 double bond and the ‘upper’ fragment was converted, via a series of reactions, to derivatives substituted at C-11 with an 8-carbon linker terminating in an ethyl ester. Reassembly with modified ‘lower’ fragments using Horner-Wittig olefination followed by linker ester hydrolysis and re-esterification with p-nitrophenol gave C-11 substituted p-nitrophenyl esters. These vitamin D derivatives were conjugated to 42-amino acid helix-loop-helix peptides by reaction of their p-nitrophenyl esters with lysyl side-chain amino groups on the peptides. The vitamin D—peptide conjugates, being potential specific binder candidates for vitamin D-binding protein, were characterized by mass spectroscopy and CD measurements.     

Electron impact mass spectrometry of some 6-substituted tetrazolo[1,5-c]pyrimidin-5(6H)-ones

The electron impact mass spectra of 6-methyltetrazolo[1,5-c]pyrimidin-5(6H)-one, its 7- and 8-methyl derivatives, three 8-halo derivatives and two related nucleosides are reported. On the basis of the high-resolution data and detected metastable ions, the fragmentation routes of their molecular ions are proposed. Coexistence of the tautomeric forms of the title compounds of cyclic (tetrazole) or linear (azide) structure can be suggested owing to the fragmentation pathways identified for the bases. Decomposition of the related nucleosides lies in the breaking of nucleoside bonds to produce the appropriate base and sugar fragments.