Synthesis of novel O-alkylbenzochromeno-1,5-benzodiazepinones. Study of the N–H····N and CO····HN hydrogen bonding interactions with 2-aminopyridines

A series of novel 6-(O-alky)lbenzochromeno-1,5-benzodiazepin-2-ones 4a–c was prepared through the condensation between the [1]benzopyrano[4,3-c][1,5]benzodiazepin-7(8H)one 1 and a series of alkylalcohols. Scaffold 4 exhibited interesting hydrogen-bonding interaction with 2-aminopyridine derivatives. The so obtained self-assembled systems 5 were fully characterized by 1D/2D-NMR techniques and mass spectrometry. The hydrogen-bonding interaction was supported by IR and Raman spectroscopy and by ¹H NMR titration experiments, and was confirmed by an X-ray crystal structure analysis.     

Synthesis of helical shaped 1,1′-bibenzo[c]phenanthrene-2,2′-diol (HEBPOL) derivatives by reduction of helical quinones

A new class of helical shaped bi-phenol (1,1′-bibenzo[c]phenanthrene-2,2′-diol; HEBPOL) type derivatives 2a–g were synthesized from quinone derivatives using the conventional 5% Pd-C catalytic reduction process. We obtained excellent yields for all of the 2a–g derivatives. The HEBPOLs were characterized by different analytical techniques including FTIR, ¹H NMR, ¹³C NMR, MS and X-ray crystallography.     

Regioselective synthesis of o-triazolyl-1,5-benzodiazepin-2-ones and o-isoxazolyl-1,5-benzodiazepin-2-ones via copper-catalyzed 1,3-dipolar cycloaddition reactions

A series of novel O-triazolyl-1,5-benzodiazepin-2-ones 6a–o and O-isoxazolyl-1,5-benzodiazepin-2-ones 7a–o was synthesized via a Cu(I)-catalyzed 1,3-dipolar alkyne–azide coupling reaction of N-substituted-1,5-benzodiazepine–alkyne derivatives 3a–c with various aromatic azides 4a–e and nitrile oxides 5a–e, respectively. The chemical structures of synthesized compounds were determined using ¹H NMR, ¹³C NMR, heteronuclear multiple bond correlation (HMBC), high-resolution mass spectra, as well as elemental analysis and was further confirmed by an X-ray diffraction analysis for compound 7d.     

The stereochemistry of isoquinoline Reissert compounds: a unique platform for observation of steric and electronic interactions

Isoquinoline Reissert compounds (2-acyl-1,2-dihydroisoquinaldonitriles) with either 3-H (1) or 3-CH₃ (2) substituents and various N-acyl groups have been examined in detail by ¹H and ¹³C NMR spectroscopy and X-ray crystallography. In all cases the trans amide conformation, with reference to the carbonyl oxygen and the 3-position of the isoquinoline ring, predominates in solution. In the solid state the nitrile moieties are pseudo-axial and the amides exist almost exclusively in the trans form, except for the case of 2-isobutyryl-3-methyl-1,2-dihydroisoquinaldonitrile (2c), which exists exclusively as the cis amide form in the solid state. In N-aroyl 3-CH₃ compounds with two ortho-aroyl substituents both amide isomerism and hindered aryl/carbonyl rotation are observed by ¹H NMR spectroscopy. In other N-aroyl derivatives only hindered aryl/carbonyl rotations are observed by NMR and in N-alkanoyl compounds amide isomerism is observable only at very low temperatures. X-ray crystallography reveals the two rotamers in the solid state in four cases of ortho-substituted benzoyl compounds; with one exception, the rotamer with the larger ortho-aroyl substituent syn to the pseudo-axial cyano group is favored. Unusual solubility and reactivity patterns observed with these compounds are rationalized in terms of the interplay between steric and electronic factors.     

Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using Weinreb amide

A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9 having a Weinreb amide at the 5-position, is prepared by the sequential Staudinger/aza-Wittig/cyclization reactions of (E)-tert-butyl{3-azido-2-[methoxy(methyl)carbamoyl]allyl}carbamate (E)-10. The transformation of the Weinreb amide of 9 to an acyl group proceeds smoothly by a substitution reaction using aryllithiums or alkyllithiums in the presence of a catalytic amount of BF₃ etherate, affording 7 in good to high yield. The N-protecting group of 7 can be easily removed to obtain N-unsubstituted 2-amino-5-acyldihydropyrimidines 8, and the derivatives are observed as a single isomer in ¹H NMR spectroscopy. All dihydropyrimidines in this study were hitherto unavailable and difficult to synthesize by conventional methods.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Synthesis,characterization and antimicrobial activity of novel sulphapiperazine containing arylazopyrazoles

Mannich reaction of benzotriazole (1), ethyl-4-amino benzoate (2) and formaldehyde in ethanol afforded 4-(1H)-benzotriazoyl methyl amino benzoate (3), which on treatment with hydrazine hydrate results in the 4-(1H)-benzotriazoyl methyl amino benzoyl hydrazide (4). This compound on condensation with pre-prepared various ethyl-2-substituted phenyl hydrazono-3-oxobutyrates (6a–h), furnished 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) methyl amino) benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl) phenyl) hydrazono)-1H-pyrazol-5(4H)-ones (7a–h). All these compounds (7a–h) were characterized by spectral studies. The compounds showed significant antimicrobial activity against various bacteria and fungi.     

Chiral solvating properties of (S)-1-benzyl-6-methylpiperazine-2,5-dione

In CDCl₃ solution, enantiopure (S)-1-benzyl-6-methylpiperazine-2,5-dione (S)-1a formed diastereomeric CO⋯H–N hydrogen-bonded associates with racemic (RS,Z)-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b, (RS)-tert-butyl pyroglutamate (RS)-2c and (RS)-N-benzoylalanine methyl ester (RS)-2d. This resulted in splitting (doubling) of the characteristic signals in the ¹H NMR and ¹³C spectra of racemic compounds 2a–d in the presence of 1 equiv of (S)-1a. The formation of hydrogen-bonded dimers in CDCl₃ solution was studied by ¹H NMR, ¹³C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, (S)-1a and 2a–c. On the other hand, a slightly different binding mode was proposed for association of (S)-1a with alaninamide (RS)-2d. Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert-butyl pyroglutamate 2c were re-determined by ¹H NMR in the presence of (S)-1a in CDCl₃. The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of (S)-1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.     

Novel pyrimidine and its triazole fused derivatives: Synthesis and investigation of antioxidant and anti-inflammatory activity

In the present study, we have carried out the synthesis of novel dihydropyrimidinecarbonitrile (1a–c), its dimethylated adduct (2a–c), and hydrazine derivative (3a–c) of 2a–c and its triazole fused derivatives (4a–c, 5a–c and 6a–c). The structure of newly synthesized compounds was confirmed by IR, ¹H NMR, mass spectral data and elemental analysis. Further the novel derivatives were investigated for their in vitro antioxidant and anti-inflammatory activity. The results revealed that some of the tested compounds showed potent antioxidant and anti-inflammatory activity. The mass spectral pattern of 6a has been investigated in order to elucidate the structure.     

Efficient synthesis of new oxindol-based heterocyclic entities via indolin-2-one derivatives

New series of oxindol-based heterocyclic entities (2–11) have been designed and synthesized using indolin-2-one derivatives as key materials (1a–d). The chemical structures of the new synthesized compounds were characterized by FTIR, ¹HNMR, ¹³CNMR, MS spectroscopy and elemental analyses. Three of the newly synthesized compounds were tested for anticancer activity in the National Cancer Institute (NCI) against human panel breast cancer cell line MCF7, from the in vitro assays compound 6c presented promising anti-cancer activity using Doxorubicin as a reference. Compound 6c could be a lead compound for discovery of new anticancer agent.     

One-step,stereoselective synthesis of octahydrochromanes via the Prins reaction and their cannabinoid activities

Novel, functionalized octahydrochromane derivatives were synthesized in a single step via the Prins reaction. Enantiomerically pure (+)-isopulegol was reacted with benzaldehyde to stereoselectively yield the corresponding octahydro-2H-chromen-4-ol derivative containing five stereocenters. A total of 10 compounds were synthesized by altering the enantiomer of isopulegol and the substituted benzaldehyde, and the resulting enantiopure octahydrochromanes were screened in vitro against the cannabinoid receptor isoforms CB1 and CB2. Compounds containing an olefin at the C4 position [(+)-3c, (?)-3c, (?)-7c, (?)-9c and (?)-11c] of the octahydrochromane scaffold were found to exhibit reasonable displacement of [³H] CP55,940 from the CB receptors, whereas the corresponding hydroxy analogs [(+)-3a, (+)-3b, (?)-3a, (?)-3b and (+)-5a] had very little or no effect.     

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 and computational studies of some N-acyl-t(3)-isopropyl-r(2),c(6)-bis-2′-furylpiperidin-4-one oximes

Four N-acyl-t(3)-isopropyl-r(2),c(6)-bis-2′-furylpiperidin-4-one oximes 1–4 were synthesized and the high resolution ¹H and ¹³C NMR spectra have been recorded at various temperatures and analyzed. The spectra reveal the presence of two rotameric forms (syn and anti) in solution. ¹H-¹H COSY and ¹H-¹³C COSY spectra have been recorded to assist the assignment of the signals for the syn and anti isomers of 1–4. Coupling constants predict an equilibrium mixture of boat form B₁ and alternate chair form CA for 1–4. The effect of varying the substituents at nitrogen and at C(4) on the ¹H and ¹³C chemical shifts has been analyzed in detail. The molecular structures of the N-acyl derivatives 1–4 were also determined using AM1 Hamiltonian and the results have been compared to the results derived from spectral studies. Mass spectra have also been recorded for 1–4.     

Photocyclization of methyl 2-arylthio- and 2-aryloxy-acetoacetates: A facile synthesis of benzoheterocycles

A series of methyl 2-arylthio- (2) and 2-aryloxy-acetoacetates (3) have been prepared and their tautomeric equilibria have been examined by ¹H NMR spectroscopy. S-substitution at the α-position results in an increase of enol tautomer over 90%, while the O-analogues exist predominantly in the keto form (Table 1). Pyrex-filtered irradiation of 2-arylthio compounds 2a-1 in benzene-methanol (1:1) solution gives benzothiophene derivatives (6a–f, 7–10) in fair yield except for 2j and 2k, for which photocyclization does not occur and only polymer formation is observed. A similar irradiation of O-analogues 3b and 3c affords the furan derivatives 17 and 18, respectively, in rather low yield, whereas 3a in photoinert under these conditions. Regiospecificity of photocyclization is revealed by the reactions of 2-naphthyl derivatives (2h and 3c) which afford only naphto[2,1-b] isomer. A plausible reaction mechanism is also discussed.     

Übergangsmetall-substituierte phosphane,arsane und stibane: XXXVI. Diastereomere dreikernkomplexe mit verbrückenden dimethylarsino-, dimethylstibino- oder dimethylbismutino-einheiten

Interaction of the chiral organometallic Lewis bases Cp(CO)(Me₃P)Fe—EMe₂ (E = As, Sb, Bi) (1a–1c) with the norbornadiene metal complex (C₇H₈)Mo(CO)₄ yields the first examples of trinuclear complexes [Cp(CO)(Me₃P)Fe—EMe₂]₂Mo(CO)₄ (2a–2c), bearing two chiral metal atoms separated by a E—Mo—E-linkage. 2a–2c are generated as a mixture of two diastereomers (RS/SR, RR/SS), which gives rise to a resonance doubling in their ¹H and ³¹P NMR spectra. This phenomenon is not observed for the achiral, in part sterically more crowded derivatives [Cp(CO)₂Fe—SbMe₂]₂Mo(CO)₄ (4) and [Cp(CO)₂(Me₃P)Mo—EMe₂]₂Mo(CO)₄ (E = As, Sb (6a, 6b)), which excludes the existence of conformers resulting from restricted rotation about the FeE or MoE bond in the case of 2a–2c.     

Synthesis of steroid analogs of tubuloclustin,their cytotoxicity and effect on microtubules of A549 carcinoma cells

Synthesis of analogs of tubuloclustin (N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine (1)) with the colchicine fragment replaced with 2-methoxyestradiol scaffold attached via phenolic hydroxy group was described. Esters 3a–c exhibit moderate cytotoxicity (EC₅₀ = 5–6 μmol L^–1) and exert a weak effect on the microtubule network in A549 human lung carcinoma cells similar to the clustering effect of tubuloclustin and its derivatives. Conjugates 6a–c and 7a–c with the phenolic ester bond are low stable and compounds 7a–c are inactive to the microtubules of A549 cells, while compounds 6a–c cause an unusual effect of curling of the microtubules.     

Synthesis and spectroscopic characterization of [CoIII(salophen)(amine)2]ClO4 (amine=morpholine,pyrrolidine, and piperidine) complexes. The crystal structures of [CoIII(salophen)(morpholine)2]ClO4 and [CoIII(salophen)(pyrrolidine)2]ClO4

Three Co(III) complexes of the type [Co(salophen)(amine)₂]ClO₄, salophen=N,N′-disalicylidene-1,2-phenylendiamine dianion and amine=morpholine (1), pyrrolidine (2), and piperidine (3), have been synthesized and characterized by elemental analysis, IR, UV–Vis, ¹H, and ¹³C NMR spectroscopy. [Co(salophen)(morpholine)₂]ClO₄ (1) and [Co(salophen)(pyrrolidine)₂]ClO₄ (2) have been studied by X-ray diffraction. Compound 1 crystallizes in ribbons of complexes and perchlorates held together by weak NH⋯O and CH⋯O hydrogen bonds between morpholines and perchlorates. The latter also interconnect the chains to a 3D network. Some minor π–π interactions exist. Compound 2 crystallizes as endless chains of complexes linked by weak CH⋯O hydrogen bonds to the disordered perchlorates. The pyrrolidine moiety is turned by 90° with respect to 1 and forms intramolecular NH⋯O hydrogen bonds. The coordination polyhedra of 1 and 2 possess C_s symmetry, and the salophens are not planar in either of them.     

Dianionic complexes with hexacoordinate silicon(IV) or germanium(IV) and three bidentate ligands of the salicylato(2–) type: Syntheses and structural characterization in the solid state and in solution

Reaction of tetramethoxysilane or tetramethoxygermane with salicylic acid and morpholine (molar ratio 1:3:2) in tetrahydrofuran yielded morpholiniummer-tris[salicylato(2–)-O¹,O³]silicate(mer -5) and morpholiniummer-tris[salicylato(2–)-O¹,O³]germanate (mer-8), respectively. Treatment of tetramethoxysilane with 5-chlorosalicylic acid and piperidine (molar ratio 1:3:2) in tetrahydrofuran afforded piperidinium mer-tris[5-chlorosalicylato(2–)-O¹,O³]silicate–ditetrahydrofuran (mer-6·2THF). Triethylammonium mer-tris[3-methylsalicylato(2–)-O¹,O³]silicate (mer-7) was obtained analogously by reaction of tetramethoxysilane with three molar equivalents of 3-methylsalicylic acid and two molar equivalents of triethylamine in dichloromethane/diethyl ether. The racemic compounds mer-5, mer-6· 2THF,mer-7, and mer-8 were characterized by elemental analyses (C, H, N), single-crystal X-ray diffraction, as well as solid-state (²⁹Si) and solution(¹H, ¹³C, ²⁹Si) NMR studies. The structural characterizationwas complemented by computational studies (HF studies, TZVP level) of thefac- and mer-tris[salicylato(2–)-O¹,O³]silicatedianion. In addition, the behavior of mer-7 in solution was studied by VT ¹HNMR experiments.     

5'-Substituted 2,2'-anhydrouridines

3',5'-Di-O-acetyl-2'-halogenouridines (1a, 1c and 1d) can be partially deacetylated at C-5' by transesterification with methanol-HCl, providing the 3'-O-acetyl derivatives 2a–2c. These can be converted into the 5'-O-mesyl derivatives 3a–3c, and latter into the 5'-chloro compounds 3d-3f. All 5'-substituted 2'-halogeno compounds give the corresponding 2,2'-anhydrouridine derivatives 4a–4c on treatment with NaOMe. Structures were proved by IR and ¹H-NMR.     

A modular design of ruthenium(II) catalysts with chiral C2-symmetric phosphinite ligands for effective asymmetric transfer hydrogenation of aromatic ketones

Hydrogen-transfer reduction processes are attracting increasing interest from synthetic chemists in view of their operational simplicity. The new chiral C₂-symmetric ligands N,N′-bis-[(1S)-1-sec-butyl-2-O-(diphenylphosphinite)ethyl]ethanediamide, 1 and N,N′-bis-[(1S)-1-phenyl-2-O-(diphenylphosphinite)ethyl]ethanediamide, 2 and the corresponding ruthenium complexes 3 and 4 have been prepared and their structures have been elucidated by a combination of multi-nuclear NMR spectroscopy, IR spectroscopy, and elemental analysis. ¹H–³¹P NMR, DEPT, ¹H–¹³C HETCOR, or ¹H–¹H COSY correlation experiments were used to confirm the spectral assignments. The catalytic activity of complexes 3 and 4 in transfer hydrogenation of acetophenone derivatives by iso-PrOH has also been studied. Under optimized conditions, these chiral ruthenium complexes serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as excellent catalysts, giving the corresponding chiral alcohols in 99% yield and up to 75% ee. This transfer hydrogenation is characterized by low reversibility under these conditions.