Synthesis, Characterization and Antiproliferative Activity of 1,2-Naphthoquinone and Its Derivatives

In the present study substituted 1,2-naphthoquinones were synthesized, purified and characterized by spectroscopic studies (UV, FT-IR, ¹H NMR, ¹³?C NMR and elemental analysis). These compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G₂ for liver sarcoma_, MG-63 for osteosarcoma and MCF-7 for human breast cancer). The cells were dosed with these ortho-naphthoquinone derivatives at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay with doxorubicin as positive control. Significant anticancer activities were observed in vitro for some members of the series, and compounds 1,2-naphthoquinone 2-thiosemicarbazone (3), 1,2-naphthoquinone-2-semicarbazone (4), 4-amino-1,2-naphthoquinone 2-thiosemicarbazone (7) and 4-amino-1,2-naphthoquinone-2-semicarbazone (8) are active cytotoxic agents against different cancer cell lines with IC₅₀ values in the range of 5.73?C17.67???M. The obtained data suggested that better anticancer activity was linked with introduction of thiosemicarbazone and semicarbazone moiety in 1,2-naphthoquinone ring system. Outcomes of experimentation also reveal that incorporation of amino group in 1,2-naphthoquinone moiety contributes positively for cytotoxic action of compounds. Docking experiments showed a good correlation between their calculated interaction energies with the topoisomerase-II and the observed IC₅₀ values of all these compounds.     

Reactions of azulenes with 1,2-diaryl-1,2-ethanediols in methanol in the presence of hydrochloric acid: comparative studies on products, crystal structures, and spectroscopic and electrochemical properties

Although reaction of guaiazulene (1a) with 1,2-diphenyl-1,2-ethanediol (2a) in methanol in the presence of hydrochloric acid at 60 °C for 3 h under aerobic conditions gives no product, reaction of 1a with 1,2-bis(4-methoxyphenyl)-1,2-ethanediol (2b) under the same reaction conditions as 2a gives a new ethylene derivative, 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (3), in 97% yield. Similarly, reaction of methyl azulene-1-carboxylate (1b) with 2b under the same reaction conditions as 1a gives no product; however, reactions of 1-chloroazulene (1c) and the parent azulene (1d) with 2b under the same reaction conditions as 1a give 2-[3-(1-chloroazulenyl)]-1,1-bis(4-methoxyphenyl)ethylene (4) (81% yield) and 2-azulenyl-1,1-bis(4-methoxyphenyl)ethylene (5) (15% yield), respectively. Along with the above reactions, reactions of 1a with 1,2-bis(4-hydroxyphenyl)-1,2-ethanediol (2c) and 1-[4-(dimethylamino)phenyl]-2-phenyl-1,2-ethanediol (2d) under the same reaction conditions as 2b give 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene (6) (73% yield) and (Z)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1-phenylethylene (7) (17% yield), respectively. Comparative studies of the above reaction products and their yields, crystal structures, spectroscopic and electrochemical properties are reported and, further, a plausible reaction pathway for the formation of the products 3-7 is described.     

Micelles catalyzed one pot regio- and chemoselective synthesis of benzo[a]phenazines and naphtho[2,3-d]imidazoles ‘in H2O’

An efficient, novel, and concise one pot regio- and chemoselective synthesis of benzo[a]phenazines (4) and naphtho[2,3-d]imidazoles (8) has been accomplished in excellent yields by nucleophilic substitution reaction of 2,3-dichloro-1,4-naphthoquinone (1) with o-phenylenediamine (2) and benzamidines (7) respectively ‘in H₂O’ using base and micelles (SDS) as catalyst. Analog reaction of 2,3-dichloro-1,4-naphthoquinone (1) with 2-aminobenzenethiol (9) under identical conditions led to formation of a mixture of benzo[b]phenothiazine (10), benzo[a]phenothiazine (11), and benzo[a]-1,4-benzothiazino-3,2-phenothiazine (12) in 17%, 23%, and 57% yields, respectively.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

Untersuchungen an diazoverbindungen und aziden—XLV: Elektrophile diazoalkansubstitution an phosphoryldiazomethanen mit thiapyryliumsalzen

Electrophilic diazoalkane substitution of the phosphoryl diazomethanes 2a–2e with 2,6-di-tert-butylthiapyrylium-tetrafluoroborate (1) yields the 4-(diazomethyl)-4H-thiapyranes 3a–3e; the olefin 5 is formed as by-product in all cases. The μ-allylpalladium chloride catalyzed decomposition of 3a and c leads via a 1,2-H-shift to the 4-methylen-4H-thiapyranes 6a and b; competing 1,2-C-migration, which should afford the thiepines 7, could not be observed. The 4-methylen-4H-thiapyranes are characterized by addition of perchloric acid (6a→8) and 4-phenyl-1,2,4-triazolin-3,5-dione (6a,b→9a,b). Corresponding substitution reactions with 2,4,6-triphenylthiapyrylium-perchlorate (10) at 3a–3c in so far take an unusual way as the bis(6H-pyrrolino[1,2-b]pyrazoles) 11a–11c are formed instead of (diazomethyl)-4-(or 2)H-thiapyranes. The constitution of the heterobicycles is established by X-ray structure analysis of 11c.     

Zum verhalten von mono- und diolefinen gegenüber thallium(III)trifluoracetat

Cis-butene-2 yields with Tl(III)trifluoroacetate by cis-addition of two trifluoroacetoxygroups the bis-2,3-trifluoroacetate 1a of the mesobutane diol, whereas the trans-butene-2 affords the bis-2,3-trifluoroacetate of the racemic threo-compound as expected 2a. Cyclohexene is transformed by Tl(III)trifluoroacetate to the cyclotrimeric form 3a of cyclopentylaldehyde. Cis-cyclooctene is oxidized to trifluoroacetate 4a of cyclooctene-1-ol-3. The homoallylic alcohol 5 (cyclohexene-1-ol-4) suffers a remarkable—but not unexpected—fragmentation to Z-trifluoroacetoxy-hexene-4-al-55a. By treating the conjugated dienes cyclohexadiene and cyclopentadiene with this reagent only cis-addition of two trifluoroacetoxygroups takes place under formation of the mixture of cis-1,4-bis-trifluoroacetoxy-cyclohexene-2(8a) and cis-1,2-bis-trifluoroacetoxy-cyclohexene-3(8b) on the one and cis-1,4-bis-trifluoroacetoxy-cyclopentene-2(9a) plus cis-1,2-bis-trifluoroacetoxy-cyclopentene-3(9b) on the other side. 1,3-Butadiene and 2,3-dimethyl-butadiene are transformed under solely 1,2-addition of the trifluoroacetoxygroups to the bis-trifluoroacetoxy compounds 6a and 7a.     

Etude des petits cycles—XXVIII : Regression de cycle generale de cyclobutanols—I. Halohydrines-1,2, diols-1,2 et epoxydes correspondants

Methods for preparing 2-bromo and 2-tosyloxy cyclobutanols (1a and 1b) and 1,2-cyclobutanediols (6, 7, 8, 10 and 11), starting from 2-oxocyclobutanol 5 and 1,2-cyclobutanedione 9, have been studied. The cyclobutanols 1a and 1b undergo ring contraction in basic media while the 1,2-cyclobutanediols contract in acidic media or on heating. This ring contraction, reported previously for epoxycyclobutanes, affords cyclopropyl aldehydes or ketones in high yields.     

Synthesis of sulfur-substituted quinolizidines and pyrido[1,2-a]azepines by ring-closing metathesis

Sulfur-substituted quinolizidines and pyrido[1,2-a]azepines (7) can be prepared by ring-closing metathesis (RCM) of 4-(phenylthio)-1,2,5,6-tetrahydropyridin-2-ones (6) bearing terminal alkenyl groups at both N-1 and C-6 positions, which are obtained from 3-(phenylthio)-3-sulfolene (1) in four steps. Some synthetic transformations of 2-(phenylthio)-1,6,9,9a-tetrahydroquinolizin-4-one (7a) and 2-(phenylthio)-1,6,9,10,10a-pentahydropyrido[1,2-a]azepin-4-one (7d) are also reported.     

Tuning the electronic properties of Fe2(μ-arenedithiolate)(CO)6−n(PMe3)n (n = 0, 2) complexes related to the [Fe–Fe]-hydrogenase active site

Complexes [Fe₂(μ-S₂Ar)(CO)₆] (S₂Ar) = benzene-1,2-dithiolate (1a) toluene-3,4-dithiolate (2a), 3,6-dichloro-1,2-benzenedithiolate (3a), quinoxaline-2,3-dithiolate (7a) have been prepared to investigate the electronic effect that different bridging arenedithiolate ligands have on the appended Fe₂(CO)₆ sites. Dinuclear complexes [Fe₂(μ-S₂Ar)(CO)₄(PMe₃)₂] (1–3,7)b and mononuclear complexes [Fe(S₂Ar)(CO)₂(PMe₃)₂] (1–3,7)c were synthesized from their parent hexacarbonyl complexes (1–3,7)a. IR spectroscopic, crystallographic and electrochemical analyses show that an increase of the electron-withdrawing character (where quinoxaline-2,3-dithiolate > 3,6-dichloro-1,2-benzenedithiolate > 1,2-benzenedithiolate ≥ toluene-3,4-dithiolate) of the bridging ligand leads to a decreased electron density at the iron centers, which yield a milder reduction potential and higher eCO stretching frequencies. This effect is coherent for all of the investigated complexes. Electrocatalytic proton reduction by complex 3a (with trifluoromethanesulfonic acid) was evidenced by cyclic voltammetry. As a result of the milder reduction potential of 3a itself, proton reduction that is promoted by 3a proceeds at a potential that is milder than that for the 1a-catalyzed process.     

Photochemical cyclodehydrogenation of Lewis acid-conjugates of azobenzenes

Irradiation of the conjugate acids of azobenzene (1a) with Lewis acids like anhydrous AlCl₃, anhydrous SnCl₄ and anhydrous FeCl₃ in 1,2-dichloroethane results in cyclodehydrogenation to benzo[c]cinnoline (2a). The formation of benzidine (3a) along with 2a suggests that the reaction is a photochemical disproportionation. The absorption spectra of the conjugate acids in 1,2-dichloroethane reveal that inversion of the n → π* and π → π* singlet state energies occurs on complexation of the azo nitrogen with the Lewis acid. Irradiation of the Lewis acid-conjugates of 2-methylazobenzene (1b), 2,2′-dimethylazobenzene (1c), 4,4′-dimethylazobenzene (1d) and 4-chloroazobenzene (1e) also results in cyclodehydrogenation.     

Preparation and emission spectra of polymeric 1,2-diketones

Monomers of the methacrylate type, viz. 1-[4-(2-methacroyloxyethoxy)phenyl] propandione-1,2 (7a) and 1-phenyl-2-[4-(2-methacroyloxyethoxy)phenyl] ethandione-1,2 (7b) having the 1,2-dicarbonyl chromophore in the side-chain, were synthesized. The soluble homopolymer of monomer 76 and copolymers of both monomers 7a and 7b with styrene and methyl methacrylate were prepared by radical polymerization in solution. The absorption and emission spectra of a model compound and the homopolymer showed that the 1,2-dicarbonyl chromophore behaved as an isolated unit. No fluorescence was observed for the model compound or the homopolymer in emission spectra of poly(methyl methacrylate)-doped films. Phosphorescence of low- and high-molecular carbonyls was quenched by ferrocene in solution. Comparison of Stern-Volmer constants indicates partial steric hindrance of energy transfer for high-molecular donor.     

Photochemistry—xiii: The photokomerization of pyridazine 1 ,2-dioxides: formation of 3a,6a-dihydroisoxazolo[5,4-d]isoxazole

Products, generated from a photolysis of 1,2-dioxides (1) of unsubstituted (a), 3-Me-(b), 4-Me-(c), 3,6-diMe (d), 3-Ph-(e), 3-Me-6-Ph-(f) and 3,6-diPh-(g) pyridazines, have been investigated.Dioxides (1a–g) afforded 3a,6a-dihydroisoxazolo[5,4-d]isoxazoles (2a-g). Dioxides (1e and 1g) afforded 3-phenylisoxazole(7) besides 2. The structure of 2a was examined by X-ray crystallography.The compound 2d was also obtained by oxidation of the hexa-3-ene-2,5-dione dioxime. A mechanism generating those products has been speculated.     

Catalyst-free tandem Michael addition-cyclization reactions in aqueous media for the synthesis of benzimidazo[1,2-a]pyrimidinone derivatives

The catalyst-free reactions of Baylis-Hillman alcohols (1a-i) with 2-aminobenzimidazole (2) in THF-H₂O (1:4) were developed for the convenient and greener synthesis of benzimidazo[1,2-a]pyrimidinone derivatives (3a-i). The pesticidal activities of 3a-i were examined to investigate a new biological activity of the imidazo[1,2-a]pyrimidinone-type compounds.     

Synthesis, characterization, and cyclometalation studies of benzo[1,2-h: 5,4-h′]diquinolines with palladium and platinum

Benzo[1,2-h: 5,4-h′]diquinoline(1a) represents a new family of tridentate NCN pincer ligand. We report the synthesis of the parent ligand (1a) and its derivatives (1b R = Me, 1c R = t-Butyl, 1d R = Phenyl). The ligands were characterized by ¹H and ¹³C NMR, as well as mass spectral analysis, and X-ray structural determination. They readily undergo cyclometalation with LiPdCl₄, Pd(OAc)₂, and K₂PtCl₄ to form the cyclometalated Pd(NCN)Cl (2a-c, 3a), and Pt(NCN)Cl (4a) pincer complexes. These complexes have been characterized through NMR, and mass spectrometry. PdNCNCl (2a) structure was determined by single crystal X-ray diffraction. Complex 2a has shown to catalyze the Heck coupling reaction between bromobenzene and n-butylacyrlate in NMP at 140 °C, TON of 2506 were observed.     

The mechanism of the rearrangement of 1-benzyl-1,2-dihydroisoquinolines: some criticisms answered

The rearrangement of 2-methyl-1,2-dihydropapaverine (1a) to the corresponding 2-methyl-3-benzyl-3,4-dihydroisoquinolinium ion (3a) has been shown to be a second order rate process with an unusually high entropy of activation. These data, together with an analysis of the orbital symmetry requirements, have been shown to be consistent with the previously proposed double exchange mechanism for this reaction.     

The first synthesis and X-ray structures of polyfluorinated 1,2-, 2,3- and 2,4a-dihydro-1,3-diazafluorenes

Acetic acid-catalyzed condensation of 2-amino-3-(1-imino-2,2,2-trifluoroethyl)-1,1,4,5,6,7-hexafluoroindene (1b) with acetone and cyclopentanone gives 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-2,3-dihydro-1,3-diazafluorene (2a) and 5,6,7,8,9,9-hexafluoro-4-trifluoromethyl-2,3-dihydro-1,3-diazafluorene-2-spiro-1′-cyclopentane (3a) together with small amounts of 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-1,2-dihydro-1,3-diazafluorene (2b) and 5,6,7,8,9,9-hexafluoro-4-trifluoromethyl-1,2-dihydro-1,3-diazafluorene-2-spiro-1′-cyclopentane (3b), respectively. When acted upon by (CH₃)₂SO₄ compounds 2, 3 were converted into corresponding fluorine-containing 1-methyl-1,2-dihydro-1,3-diazafluorenes 6, 7. 4a-Chloro-5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-2,4a-dihydro-1,3-diazafluorene (8) has been synthesized by the interaction of compound 2 with SOCl₂. Solution of compound 2 as well as 8 in CF₃SO₃H-CD₂Cl₂ generated 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-1,2,3,4-tetrahydro-1,3-diazafluorene-4-yl cation (2c). The structures of compounds 2, 3, 6-8 have been determined by single crystal X-ray diffraction.     

Autoxidation of terpenic aldehydes—I

The autoxidation reaction of diterpenic 4-axial-aldehyde torulosal (1b) has been studied. Naturally occurring 4-hydroxy-nor-diterpenes have been proved to be artefacts arising in the autoxidation of the corresponding 4-aldehyde. Hydroperoxides (1d) and (2d), the main autoxidation products of 1b, have also been postulated as intermediates in the formation of 4-hydroxy-nor-diterpenes (1a and 2a).     

Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride

Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC₅₀) of 2.7 × 10⁻⁴ and 1.9 ×  10⁻⁴ M, respectively, were observed.     

Synthesis,structures and photophysical properties of (o-carboranyl)-(pyridyl)methanols

The reaction of o-carboranyllithium with two equiv. of 2-pyridinecarboxaldehyde affords 1-[(hydroxy)(pyridyl)methyl]-o-carborane (1) and 1,2-bis[(hydroxy)(pyridyl)methyl]-o-carborane (2), which have been characterized by IR and NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction. Compound 2 exhibits interesting polymorphism (monoclinic 2a and triclinic 2b). The solid state structures of the new carboranes feature intermolecular and intramolecular hydrogen bonding interactions involving all the N and O atoms, leading to one dimensional (1, 2b) or two-dimensional (2a) supramolecular structures. The photoluminescence of 1 and 2b was investigated in the solid and solution states at room temperature, respectively.