Synthesis and stereochemistry of highly crowded N-benzylpiperidones

A series of N-benzylated 3,5-diakyl-2,6-diarylpiperidin-4-ones 4–8 were conveniently synthesized in significant yields of 68–88% by N-benzylation of the corresponding 2,6-diaryl-3,5-dimethylpiperidin-4-ones 1–3 using different benzyl bromides. Initially, the new piperidone 2,6-bis(4-ethoxyphenyl)-3,5-dimethylpiperidin-4-one 3 was synthesized by the condensation of 1:1:2 M ratio of 3-pentanone, ammonium acetate and para-ethoxybenzaldehyde in ethanolic medium. All the synthesized new compounds 3–8 were characterized by their analytical and spectral (IR, ¹H and ¹³C NMR) interpretations. The stereochemistry of the new piperidone 3 was elucidated as chair conformation with an equatorial orientation of all substituents, suggested by its vicinal couplings from ¹H NMR spectrum. To investigate the impact on piperidone stereochemistry as well as NMR chemical shifts, all the N-benzylated products 4–8 were compared with their corresponding precursors, and as a result, it is clearly established that all the synthesized N-benzyl piperidones exist in the chair conformation with an equatorial orientation of all the substituents at C-2, C-3, C-5, C-6 and N. Contrary to the probability all N-benzylated compounds retain the same conformation and configuration as their precursors, however, a remarkable change on the chemical shifts are observed. For the further unambiguous confirmation of stereochemistry, the 1-benzyl-3,5-dimethyl-2,6-diphenylpiperidin-4-one 4 was examined by single-crystal X-ray diffraction. The compound 4, C₂₆H₂₇NO, crystallized in a P-1 space group under triclinic system with unit cell dimensions a, b, c (Å) and α, β, γ (°) of 10.156(2), 11.002(2), 11.348(4) and 116.74(4), 100.81(3), 100.17(3), respectively.     

Fluorinated piperidine iminosugars and their N-alkylated derivatives: Synthesis,conformational analysis,immunosuppressive and glycosidase inhibitory activity studies

The fluorinated piperidine iminosugars 2a-4a and their N-octyl and N-decyl derivatives 2b,c-4b,c were synthesized from d-mannose/d-xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2/3, either ²C₅ or ⁵C₂, was assigned based on the ¹H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N-alkylated fluorinated d-manno-iminosugars 3b/4b were found to be better immunosuppressive agents (IC₅₀?=?5–6?μM) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β-glucosidase (IC₅₀?=?4–8?μM). The N-alkyl-iminosugars 4b-c were found to be moderate inhibitors of α-glucosidase (yeast) and α-galactosidase (coffee beans), respectively.     

Synthesis,spectral properties and conformational preferences of macrocyclic compounds containing 2,5-dithio-1,3,4-thiadiazole subunits

The syntheses of macrocyles 1–6, containing 2,5 - dithio - 1,3,4 - thiadiazole subunits connected by 1,2-, 1,3- and 1,4-bis(methylene)benzenes, as well as of the appropriate open-chain model compounds 7–12 are described. Structure proofs were afforded by their mass and ¹H NMR spectra. Different decompostion processes upon electron-impact are ascertained for compounds 1–12, depending on the position of the bridges and ortho substitution; therefore, the mass spectra can provide a sensitive diagnostic tool for structure elucidation of positional isomers. The NMR spectral data of macroycyles 1–6, coupled with those of the corresponding open-chain derivatives 7–12, indicate that the preferred conformations are determined primarily by the size and shape of their ring systems. Furthermore, variable-temperature NMR studies on intraannularly methyl substituted macrocyles 3 and 6 provide evidence that the 20-membered mesityl derivative 3 adopt the saddle-shape conformation (IV) (the energy barrier for the restricted rotation of methylene bridges if found to be ΔG^≠= 13.8 kcal/mole at + 5°), while the duryl groups in the 22-membered macrocycle 6 are free rotating even at ?60°.     

Alkaloids of NIRAM,natural dye from Polygonum tinctorium,and their anti-inflammatory activities

Phytochemical investigation of EtOH extract of NIRAM, natural dye from Polygonum tinctorium, resulted in the purification of nine alkaloid compounds (1–9) including four new compounds (1–4). Structures of these new compounds were elucidated by 1D and 2D NMR (¹H and ¹³C NMR, ¹H–¹H COSY, ¹H–¹³C HSQC, ¹H–¹³C HMBC), IR, UV, HR-ESI-MS, and ECD spectra. Isolated compounds (1–9) were tested for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells. Compounds 1–3, 5, and 7 showed potent NO production inhibitory activities, with IC₅₀ values of 3.88–22.87 μM.     

The synthesis of some new imidazole and triazole derivatives: crystal Structure and DFT-TDDFT investigation on electronic structure

A series of new N′-3-(1H-imidazol-1-yl)propylcarbamoyl-4-halogenebenzo hydrazonate (3a–b) were obtained by reaction Ethyl 2-((4-halogene phenyl) (ethoxy) methylene) hydrazinecarboxylate (1) and N-(3-aminopropyl)imidazole (2) at 120–140 °C. Compounds (4a–b) were obtained by the reaction compound 1 and N-(3-aminopropyl)imidazole (2) at 160–180 °C. The structures of compounds 3,4 have been inferred through UV–Vis, IR, ¹H/¹³C NMR, mass spectrometry, elemental analyses, and X-ray crystallography. DFT level 6-31G (d) calculations provided structural information. The electronic structure of compound 3a has been studied by DFT level 6-31G (d) calculations using the X-ray data. The results are accordance with X-ray data.     

DBU induced formation of 8-bromoguanosine dimer with three hydrogen bonds between the GG− base pairs

Upon hemideprotonation of 8-bromoguanosine (8-BrG) at the N1 position, induced by DBU, the adduct [8-BrG][8-BrG]^?[DBU–H]⁺ was formed. Slow evaporation of the 8-BrG methanol solution, in the presence of 0.5 equiv of DBU, yielded two polymorphic structures (1 and 2), where a neutral [8-BrG] (A) and N1 deprotonated, anionic 8-bromoguanosine [8-BrG]^? (B) were joined together through three intermolecular hydrogen bonds involving O6, N1 and C2–NH₂ sites. Such pairing gave planar GG^? dimers as the basic motif of crystal packing in both polymorphs. Both neutral and deprotonated guanosine molecules in the structure of 1 had the ribose units in a syn conformation. In the structure of polymorph 2, the N1 deprotonated guanosine molecule (B) retained the syn glycosidic conformation, while the non-deprotonated guanosine molecule (A) adopted the natural anti conformation of the ribose unit with respect to the nucleobase. Ribose rings revealed different puckering; only those of deprotonated molecules 1B and 2B possessed the usual C2′-endo envelope conformation. Crystal packing in both structures was guided by the highly complex H-bonded pattern. The CSD was searched for related structures, which are discussed with reference to polymorphs 1 and 2. ¹H and ¹³C NMR spectroscopic evidence is provided showing that the three H-bonded adduct [8-BrG][8-BrG]^?[DBU–H]⁺ was also formed in the highly H-bond competitive DMSO solution.     

Conformational analysis of 3-(substituted benzo[b]furan-2-yl)-γ-aminobutyric acid,new GABAB ligands,by 1H NMR in D2O

The conformations of 3-(substituted benzo[b]furan-2-yl)-GABA (1–4) in solution (D₂O) are estimated from high-resolution (400 MHz) ¹H NMR coupling data. Conformations and populations of conformers are calculated by means of a modified Karplus-like relationship for the vicinal coupling constants and are compared with X-ray crystallographic investigations. ¹H NMR spectral analysis evidences how 1–4 keep also in solution the preferred g⁻ conformation around the C3C4 bond as found in the solid state while a partial rotation is set up around the C2C3 bond.     

Synthesis,characterization and biological activity of Hg(II), Fe(III) complexes with 1,3,4-oxadiazole, 1,2,4-triazole derivatives from L-methionine

Four novel heterocyclic1,3,4-oxadiazole, 1,2,4-triazole derivatives, namely: 5-[1-amino-3-(methylsulfanyl)propyl]-1,3,4-oxadiazole-2(3H)-thione (4), 4-amino-5-[1-amino-3-(methylsulfanyl)propyl]-4H-1,2,4-triazole-3-thiol (5), 1-amino-3-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-5-thiol (7), and 5-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-3-thiol (9) have been synthesized from l-methionine and characterized by different spectroscopic techniques (FT-IR, UV–Vis, ¹H NMR, ¹³C NMR and MS). Complex formation with Hg⁺⁺ and Fe⁺⁺⁺ ions were formed from the four heterocyclic 4, 5, 7 and 9. The antimicrobial activities for synthetic intermediates and final four products were assisted using paper disk diffusion method against Gram-negative bacteria: Escherichia coli, Pseudomonas aeroginosae and Gram-positive bacteria: Staphylococus aureus 25923, Staphylococus aureus 43300 and showed variant activity against some of the microorganisms tested.     

Synthesis of enantiomerically pure spiro-cyclopropane derivatives containing multichiral centers

A novel chiral source, 5-(R)-[(1R,2S,5R)-(−)-menthyloxy]-3-bromo-2(5H)-furanone (5a), was obtained in 46% yield with d.e.≥98% from the epimeric mixture of 5-(l-menthyloxy)-3-bromo-2(5H)-furanone (5a+5b) obtained via the bromination of an epimeric mixture of 5-(l-menthyloxy)-2(5H)-furanone (3a+3b) followed by the elimination of hydrogen bromide. The asymmetric reaction of 5a with a nucleophilic alcohol afforded enantiomerically pure spiro-cyclopropane derivatives containing four stereogenic centers, 9a–9e, in 50–68% yield with d.e.≥98%. The enantiomerically pure compounds 9a–9e were identified on the basis of their analytical data and spectroscopic data, such as [α]_D²⁰, UV, IR, ¹H NMR, ¹³C NMR, MS and elementary analysis. The absolute configuration of the chiral spiro-cyclopropane compound 9a was established by X-ray crystallography.     

A series of ruthenium(II) organometallic complexes incorporating pyridine-2-carboxylato ligand: Detailed spectroscopic and computional studies

The reaction of Ru(κ2C,O-RL)(PPh3)2(CO)Cl, 1 with excess sodium salt of pyridine-2-carboxylic acid (Napic) furnishes the complexes of the type Ru(κ1C-RL)(PPh3)2(CO) (pic), 2(R) with excellent yield (κ2C,O-RL is C6H2O-2-CHNHC6H4R(p)-3-Me-5, κ1C-RL is C6H2OH-2-CHNC6H4R(p)-3-Me-5 and R is Me, OMe, Cl). The chelation of pic is attended with the cleavage of Ru–O and Ru–Cl bonds and iminium–phenolato→imine–phenol prototropic shift. The 1 ​→ ​2 conversion is irreversible and the type 2 species are thermodynamically more stable than the acetate, nitrite and nitrate complexes of 1. The spectral (UV–vis, IR, 1H NMR) and electrochemical data of the complexes are reported. In dichloromethane solution the complexes display one quasi–reversible RuIII/RuII cyclic voltammetric response with E1/2 in the range 0.72–0.80 ​V vs. Ag/AgCl. The crystal and molecular structure of Ru(κ1C-MeOL)(PPh3)2(CO)(pic)∙CH3CN is reported which revealed distorted octahedral RuC2P2NO coordination sphere. The pairs (P, P), (C, O) and (C, N) define the three trans directions. The electronic structures of the complexes are also scrutinized by density functional theory (DFT) and time–dependent density functional theory (TD–DFT) calculations.     

Novel colorimetric chemosensors containing pyridine moiety for detection of some cations in water and crops samples: Design,synthesis, and evaluation

This investigation deals with synthesis of some novel chemo sensors for identifying cations in drinking water and agricultural crops. This takes place via interaction of 2,5-dioxo-1,2,3,4-tertrahydropyridine-3-carbonitrile (3) and 2-thioxo-5-oxo-1,2,3,4-tertrahydropyridine-3-carbonitrile (4) with Cu^II and Co^II. The novel compounds' structures have been examined using spectrum data (IR, ¹H NMR, ¹³C NMR, and MS) as well as elemental and physical studies. Complexation behaviors of Compounds 3 and 4 as organic ligands were predicted, discussed, and calculated via Density-Functional Theory (DFT) and Colorimetric investigation. The newly synthesized receptors 3 and 4 showed selective colormetric sensing capability for some cations by color shifting from colorless to pale violet in a nearby ideal aqueous solution enabling naked eye identification and quantitative determination of cooper (Cu^II) and cobalt (Co^II) metal ion.     

Conformational study of α-arylethylamides of (−)-camphanic acid

The absolute conformation and configuration of diastereomeric amides (4A,B–6A,B) of (1S,3R)-camphanic acid (lactone of 1-hydroxy-2,2,3-trimethylcyclopentan-1,3-dicarboxylic acid, (−)-camphanic acid 9) with α-arylethylamines 1–3 are deduced from ¹H NMR data and MM2 calculations. The α-arylethyl group in diastereomers A and B adopt nearly opposite absolute conformations, stabilized by hydrogen bonding in the syn-oriented O–C(1)–C(6)–N–H unit, and repulsive interaction between the 1′C–Me group and the amide CO group. The absolute configuration (1′S) is assigned to the 4A–6A diastereomers, and the (1′R)-configuration to the 4B–6B diastereomers; this assignment is confirmed by the preparation of 4A and 5A from enantiomerically pure (1′S)-α-arylethylamines 1 and 2, respectively. These results also enabled the assignment of pro-R (H_R) and pro-S (H_S) protons in the benzyl derivative 7.     

UV absorption and keto–enol tautomerism equilibrium of methoxy and dimethoxy 1,3-diphenylpropane-1,3-diones

UV absorption spectra of 1,3-diphenylpropane-1,3-dione (1), its three methoxy derivatives (2–4) and its six dimethoxy derivatives (5–10) in various solvents dissolved were collected. The keto–enol tautomerism equilibrium constant was calculated with ¹H NMR. The position of the methoxy group in 1,3-diphenylpropane-1,3-dione was shown to have an influence on the molecule's UV absorption spectrum and the keto–enol tautomerism equilibrium constant. The methoxy group in the para position increases the absorption of radiation in the UV-A range. A shift to the keto form in the keto–enol tautomerism equilibrium is experienced by compounds with methoxy groups in ortho position. When two methoxy groups are present, the influence of their position is cumulative.     

Synthesis and structure of pseudotetrahedral Co(II) zwitterionic complexes: trichloro(1-methylpiperazin-1-ium-N4)cobalt(II) and trichloro(1,4-dimethylpiperazin-1-ium-N4)cobalt(II)

The pseudotetrahedral cobalt(II) zwitterionic complexes, [CoCl₃(H₂Meppz)] (1) [H₂Meppz⁺=1-methylpiperazin-1-ium cation] and [CoCl₃(HMe₂ppz)] (2), [HMe₂ppz⁺=1,4-dimethylpiperazin-1-ium cation] have been synthesized and characterized in the solid state by X-ray single crystal analysis, IR spectra, magnetic measurements and electronic spectra. In both the compounds the cobalt(II) center is coordinated in a distorted tetrahedral fashion by the three chloride ions and by one nitrogen of the piperazine ring that retains the more stable chair conformation. The distorted coordination polyhedron in complex 1 preserves the C_3v symmetry while in complex 2 it retains only the m symmetry. In complex 1, the (H₂Meppz)⁺ cation binds the Co(II) ion in the equatorial position of the piperazine ring using the unmethylated N1–H nitrogen atom that is less hindered than the methylated one. Complex 2, on the contrary, is a novelty being the first example of a Co(II) ion bound in the axial position of a piperazine ring, this produces a long Co(II)–N bond, 2.108(4) Å. Electronic spectra in the solid state are in perfect accordance with the X-ray crystallographic results indicating a C_3v symmetry for complex 1 and a C_s(m) symmetry for complex 2. These complexes present strong two-center and three-center hydrogen bonds of N⁺–H⋯Cl type.     

Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams: Promising biologically active heterocyclic scaffolds

An efficient and operationally simple strategy for the stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactam heterocycles is described. The C-3 functionalized 3-phenyl/benzylsulfonyl-β-lactams 3/3′, 5/5′ has been synthesized via Michael addition using different Michael acceptors on trans-3-phenyl/benzylsulfonyl-β-lactams 2(a–f) using K₂CO₃ as a base and acetonitrile/DMF as solvents. The reaction furnished exclusively cis-β-lactam adducts 3(a–r) using sterically less hindered Michael acceptors. Further, the effect of steric bulk and chiralilty of Michael acceptors was explored to achieve target C-3 functionalized β-lactams 3(s-u)/3′(s-u) and 5(a–c)/5′(a–c). The structural and stereochemical analysis of novel β-lactams were carried out using FT-IR, NMR (¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C COSY and ¹³C DEPT-135), elemental analysis (CHNS), mass spectrometry (EIMS and LCMS) in representative cases and single crystal X-ray crystallographic studies (3e). The cis or trans configuration of the Michael acceptor (E) at C-3 was assigned with respect to C4-H.     

Dynamic behaviour of 1,n′-disubstituted ferrocenes

1,n′-Disubstituted ferrocenes with ketone/phthalimido (2) and ketone/amine substituents (3) were synthesised and characterised by IR, ¹H NMR, ¹³C NMR, VT ¹H NMR, UV/Vis spectroscopy, mass spectrometry and cyclic voltammetry. The molecular structure of 2 was confirmed by X-ray crystal structure determination. The dynamic behaviour was experimentally studied in solution and theoretically by DFT calculations. The thermal stability of the ketone/amine derivative 3 was investigated using thermal analyses.     

Structures and conformations of 1-aryl-1,4-dihydro-3(2H)-isoquinolinones

The X-ray crystal structures of series of 1-aryl-1,4-dihydro-3(2H)-isoquinolinones (1-7) have been determined. Lactame heterocyclic ring possesses more or less deformed boat conformation in all examined structures. The aryl substituent adopts the equatorial position in the structures 1-3 and the axial one in 5-7. In the structure of 4, due to extremely flattened heterocyclic ring, aryl substituent location can be named as bisectional. In all solved structures the molecules are joined into the dimers via two N-H?O hydrogen bonds. At the same time, ¹H NMR studies in DMSO-d₆ solutions were accomplished and profound analysis of ²J, ³J, and ⁵J coupling constants have shown that in isoquinolinone system the heterocyclic ring adopts the boat conformation in all investigated compounds. The stereochemical orientations of the phenyl ring at C1 do not depend on the nature of the substituent but, exclusively, on the mode of substitution. However, three forms of undulated laktam heterocyclic ring conformation in respect of 1-aryl substituent positions were confirmed by calculation (conformational analysis).     

Configurationally and conformationally homogeneous cyclic n-aryl sulfimides—IV : Synthesis,configuration and stereochemistry of the rearrangement of 1,3-di-thiane-1-N-p-chlorophenylimides

1,3-Dithiane-1-N-p-chlorophenylimides (1,4-9) were prepared and their configuration and conformation was determined by ¹H and ¹³C NMR. The compounds were rearranged to the corresponding 2-(2'-amino-5'-chlorophenyl)-1, 3-dithianes (1U,4U,9U). The rearrangement reactions took place with ?95% stereospecifity. The mechanism of the reaction was investigated with the aid of analogs specifically deuterated at C-2.     

Cyclopericodiol and new chlorinated melleins isolated from Periconia macrospinosa KT3863

Cyclopericodiol (1) and two new chlorinated melleins (2 and 3) were isolated from Periconia macrospinosa KT3863. The results of density functional theory (DFT)-based calculations while estimating the values of the ¹³C chemical shifts and the spin coupling constants allowed to determine the relative configurations of 1 and 2. The absolute configurations of these compounds were established by comparing the experimental electronic circular dichroism (ECD) spectra with those obtained while performing time-dependent DFT calculations. Interestingly, the methyl and hydroxy groups at C3 and C4, respectively, of 2 assume an 1,2-anti-diaxial conformation due to absence of 1,3-diaxial repulsion. This conclusion was supported by the observation that 2 afforded an ECD spectrum that was almost the mirror image of that of 3. Furthermore, the theoretical spin coupling constants ³J_H-3/C1, ²J_H-3/C4, ³J_H-3/C4a, and ²J_H-3/C9 were in agreement with the heteronuclear multiple-bond correlation (HMBC) intensities of H-3 with C1, C4, C4a, and C9.