Pyrimido[5,4-b]quinolines. II. Reactions at the heterocyclic ring-carbon and nitrogen atoms

10-Chloro-7,8-dimethylpyrimido[5,4-b]quinolin-2,4(1H,3H)dione (I) was unreactive toward ammonia but it reacted with 2 molecules of n-butylamine, presumably via Dimroth-type ring-opening and closure, to give the N₃-butyl, N₁₀-butylamino derivative (IV). In similar reactions of 10-chloro-2,4-dimethoxy-7,8-dimethylpyrimido[5,4-b]quinoline (II) only the 4-meth-oxyl was displaced by either ammonia or n-butylamine. Alkyllithium reagents also displaced the 4-methoxyl as well as added to the 3,4 double bond of II to yield the corresponding gem-dialkyl substituted (C₄) derivatives; the C₁₀ chlorine remained unreactive. 2,4-Dimethoxy-7,8-di-methylpyrimido[5,4-b]quinoline-10-one (III) could be alkylated only in the form of the thallium salt. Treatment of the benzyl derivative of III with methylmagnesium bromide led only to the displacement of the 4-methoxyl by a methyl group.     

Similarities and differences between bis[2‐(bromomethyl)phenyl] diselenide,bis[2‐(chloromethyl)phenyl] diselenide and bis[2‐(hydroxymethyl)phenyl] diselenide

The title compounds, C₁₄H₁₂Br₂Se₂, (I), C₁₄H₁₂Cl₂Se₂, (II), and C₁₄H₁₄O₂Se₂, (III), feature a diselenide bridge between two o‐benzyl bromide [in (I)], two o‐benzyl chloride [in (II)] or two o‐benzyl alcohol units [in (III)]. In the molecular structure of (I) and in both independent molecules of (II), close contacts are observed between the halogen centres and the diselenide unit. In the case of modification (IIIa), strong hydrogen bonds between the –OH groups dominate, whereas the molecular structures of modification (IIIb) and bis{2‐[(dimethylamino)methyl]phenyl} diselenide, C₁₈H₂₄N₂Se₂, (IV), are comparable with those of (I) and (II). A correlation between the strength of the contacts and the angle between the benzene planes and the Se—Se units is found.     

Anion and Cavity Effects on the Complexation Behavior of Di-Aza-Benzo-Crown-Ether Calix[4]arene towards Zn(II) Ions

A novel compound, 25, 27 - N,N - di - ((2 -ethoxy)benzyl)butylenediamine - p - tert- butylcalix[4]arene, 1, has beensynthesized by reducing its Schiff base derivative. Inclusion studies by¹H-NMR spectroscopy in a mixed solvent (CD₃OD/CDCl₃) of25,27-N,N-di-((2-ethoxy)benzyl)propylenediamine-p-tert-butylcalix[4]arene,2, and 1 with Zn(II) ions, where counter anions are Cl^-, Br^-, I^- and NO ₃ ^- ,show that both ligands can bind Zn(II) to a different extent depending onthe counter anions and the cavity size of the ligands. The stabilityconstants of ZnX₂–1 (ZnX₂-2) complexes where X = Cl^-, Br^-, I^- and NO ₃ ^- are 1.4 ± 0.1 (1.6 ± 0.1), 1.7 ± 0.1 (1.9 ±0.1), 2.2 ± 0.1 (2.7 ± 0.1) and 4.7 ± 0.1 (6.0 ±0.1), respectively. The calix[4]arene unit of the ligand 2 was found to havea structural change from cone to partial cone conformation upon binding toZnCl₂, ZnBr₂ and ZnI₂.     

Synthesis and optical properties of conjugated N,N-dimethyl and thienyl end-capped 2,5-(arylethynyl)thiophene oligomer structures

End-capped (N,N-dimethylaminophenyl) and 2′-thienylethynyl 2,5-thiophene oligomer structures were synthesized by heterocoupling between the terminal acetylenes such as: p-(N,N-dimethylaminophenyl)ethyne (3) [or 1-(p-(N,N-dimethylaminophenyl)-2-p-(ethynylphenyl)ethyne, 4]; p-(β-ethenyl-2′-thienyl)phenylethyne (E-9) [or p-(β-ethynyl-2′-thienyl)phenylethyne, 11], and 2,5-diiodothiophene, catalyzed by the Cl₂Pd(PPh₃)₂/CuI system, in good to excellent yields. The 2,5-di[(3′,5′-di(trimethylsilylethynyl)phenyl]_x-1-ethynyl]thiophene oligomers were prepared by heterocoupling between 3′,5′-di[(trimethylsilylethynyl)phenyl]_x-1-ethyne (n = 0-2) terminal acetylenes and 2,5-diiodothiophene, in excellent yields. The terminal acetylenes were efficiently prepared by a specific protection-deprotection methodology. All the ethynylphenyl compounds obtained show fluorescence radiation emission, with a bathochromic shift of the wavelength that increases with the chain conjugation.     

Through-space electronic interactions of [2.2]metacyclophane benzyl cations

The hydrolysis of 8-bromomethyl[2.2]metacyclophanes 3 to the corresponding 8-hydroxymethyl derivatives 4 was carried out in 83% aqueous dioxane solution at 25°C. Substituent effect through space on the rate of the hydrolysis of bromomethyl groups attached on the opposite aromatic ring was first found in this investigation. Interestingly, the introduction of the substituents at the internal position 16 tends to enhance the hydrolysis reaction rate 10–100 times. It was found also that the stabilization by both the direct through-space cation-π-interaction and the interaction through the intra-annular 8,16-position are possible in the [2.2]metacyclophane 8-benzyl cations. The good correlation with log(K/K_H) and σ_p ⁺ was observed for the hydrolysis of internally unsubstituted 5-bromomethyl[2.2]MCPs 7, in which the direct through-space cation-π-interactions are not possible. TiCl₄ and Nafion-H, a perfluorinated resinsulfonic acid, catalysed Friedel-Crafts benzylation of benzene and substituted benzenes with 8-bromomethyl- and 8-hydroxymethyl[2.2]metacyclophanes to afford 8-benzyl[2.2]metacyclophanes is described. A high substrate and positional selectivity were observed in the present benzylation reaction quite different from those obtained from the benzyl bromide and benzyl alcohol. The benzyl cation intermediate stabilized by the through-space electronic interaction among the opposite benzene ring was first demonstrated in the benzylation of [2.2]metacyclophane systems. The mild and selective transannular reaction attributable to the highly strained character of [2.2]metacyclophane skeleton and the increased stabilization of the 5-benzyl cation intermediate arising from the electronic interactions among the opposite benzene ring through the intra-annular 8,16-positions was also observed.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthetic and structural study of 4-phosphacyclohexanones and 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones

The synthesis of bicyclic phosphorus–nitrogen (PN) compounds containing the rigid bicyclo[3.3.1]nonan-9-one framework was attempted using the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. Three different isomers of 4-tert-butyl-2,6-di(methoxycarbonyl)-3,5-bis(p-dimethylaminophenyl)-4-phosphacyclohexanone were obtained from the Michael addition reaction of tert-butylphosphine with 2,4-di(methoxycarbonyl)-1,5-bis(p-dimethylaminophenyl)penta-1,4-dien-3-one. The reaction of the all-equatorial isomer with methylamine and formaldehyde produced the bicyclic PN compound 7-tert-butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-dimethylaminophenyl)-3-methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one. The identical Mannich reaction of the enol tautomer also yielded the same product, as well as the PN compound 4-tert-butyl-6-methoxycarbonyl-5-(p-dimethylaminophenyl)-2-methyl-2-aza-4-phosphacyclohexanone and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate. The newly synthesised 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one PN compound adopts a chair–chair conformation both in solution and the solid state.     

Reaction of 4-(N,N-Dimethylaminophenyl)magnesium Bromide with Palladium Tetrakis(triphenylphosphine)

The influence of reaction conditions on catalyzed by Pd(PPh₃)₄ cross-coupling of 4-N,N-dimethylaminophenylmagnesium bromide with 4-bromobenzonitrile in tetrahydrofuran was investigated. The yield of the product of the catalytic process, 4-N,N-dimethylamino-4'-cyanobiphenyl, and of the main product of noncatalytic process, 4-N,N-dimethylaminophenyl 4'-bromophenyl ketone, is mainly governed by the order of introduction of reagents and catalyst into the reaction zone. Experimental observations and analysis of side products suggested conclusions on the processes resulting in deactivation of the catalyst.     

Novel organotin antibacterial and anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(p-N,N-dimethylaminophenyl) fulvene (1b) and 6-(3,4-dimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to tin with SnCl₄ to yield tetra-substituted bis(cyclopentadienyl)tin dichloride complexes (3a–c). Further reaction with tin tetrachloride yielded the benzyl-substituted derivatives bis-[(p-methoxybenzyl)cyclopentadienyl] tin(IV) dichloride (4a), bis-[(p-N,N-dimethylaminobenzyl)cyclopentadienyl] tin(IV) dichloride (4b), and bis-[(3,4-dimethoxyphenyl)cyclopentadienyl] tin(IV) dichloride (4c). Preliminary antibacterial tests were carried out using the Kirby–Bauer disk-diffusion method, in which 4a–c showed little to no activity against the Gram-negative bacterium Escherichia coli, but medium activity against Gram-positive bacteria (MRSA, MSSA). In addition, the organotin complexes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values. Compound 4c showed no cytotoxic activity, while 4a and 4b were found to have IC50 values of 15 and 205 μM, respectively.     

[5]Ferrocenophane based ligands for stereoselective Rh-catalyzed hydrogenation and Cu-catalyzed Michael addition

A series of homochiral [5]ferrocenophane based N/P, N/S, N/Se, Se/P and P/P ligands was prepared from (R)-N,N-dimethylamino[5]ferrocenophane. These ligands were tested in the Rh-catalyzed hydrogenation of dimethyl itaconate and in Cu-catalyzed Michael addition of Et₂Zn to cyclohex-2-enone. The best results in terms of conversion and enantioselectivity in the Rh-catalyzed hydrogenation provided bis(diphenylphosphine) ligand 2h (100% conversion and 95% ee) and aminophosphine 2a in the Cu-catalyzed conjugate addition (100% conversion 84% ee). The enantioselectivity of the Rh-catalyzed hydrogenation of methyl 2-acetamidoacrylate was lower (41% ee).     

Asymmetric hydrosilylation of prochiral ketones in the presence of N-benzyl-N-methylephedrinium halometallates

N-benzyl-N-methylephedrinium hexachloroplatinate(IV), bromotrichlororhodate(III), and dibromodichlorozincate(II) have been synthesized by reacting (—)-N-benzyl-N-methylephedrinium bromide with K₂PtCl₆, RhCl₃ · 4H₂O and ZnCl₂, respectively. The above halometallates have been found to catalyse the asymmetric hydrosilylation of acetophenone and 3-acetylpyridine with diphenylsilane. The hydrosilylation of 3-acetylpyridine in the presence of (—)-N-benzyl-N-methylephedrinium zincate followed by silyl ether hydrolysis gives 1-(3-pyridyl)ethanol in ca 50% optical yield.     

Regioselective N-alkylation of imidazo[4,5-b]pyridine-4-oxide derivatives: an experimental and DFT study

Regioselectivities were determined for N-alkylations of imidazo[4,5-b]pyridine-4-oxide and 2-methyl-imidazo[4,5-b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K₂CO₃ in DMF as a base. Experimental attempts have shown that N-1/N-3 ratios slightly varied according to the substitution on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has shown first that this N-benzylation reaction passed through a S_N2 mechanism. Moreover, regioselectivity of N-benzylation has appeared essentially governed by ‘steric approach control’. It explained that opposite N-1/N-3 ratios were obtained with imidazo[4,5-b]pyridine-4-oxide and its 2-methyl-substituted analog. Finally, regioselectivities slightly varied with the nature of benzyl halide.     

Microwave promoted improved regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones by radical cyclisation

In this work, two new effective methodologies have been adopted for the preparation of 5-(2′-bromobenzyloxy)pyrimidine-2,4-diones 6(a–k). In the first methodology, 5-hydroxy uracils 4(a–f) were alkylated with 2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl bromide 5b under phase transfer catalysis condition using lithium hydroxide/tetrabutyl ammonium bromide in N,N-dimethylformamide at 45 °C, and in the second method, the microwave irradiation (MWI) protocol has been exploited by mixing 5-hydroxy uracils 4(a–f) with 30 % excess of 2-bromobenzyl bromide 5a or 2-bromo-5-methoxy benzyl bromide 5b. A catalytic amount of TBAB and potassium carbonate was added and irradiated in an open Erlenmeyer flask in a microwave oven for 3–12 min. The tributyltin hydride-mediated radical cyclisation of 6(a–k) was carried out under MWI to generate 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones 7(a–k) in 80–89 % yield, and the reaction time was shortened compared to the previously reported conventional radical cyclisation method.     

Tributyltin(IV)[3‐(3′,5′‐dimethylphenylamido)propanoate] as a potent HCV inhibitor,its delivery study,controlled release and binding sites using CTAB as a standard cell membrane

Gaussia luciferase assay was used to measure the anti‐hepatitis C (anti‐HCV) potency of tributyltin(IV)[3‐(3′,5′‐dimethylphenylamido)propanoate] in infected Huh 7.5 cells (human hepatocellular cell). Interaction of the organotin(IV) complex with cetyl N,N,N‐trimethylammonium bromide (CTAB) micelles was studied using UV–visible and steady‐state florescence spectroscopy. The anti‐HCV study showed a log IC₅₀ value of 0.96 nm for the complex. The complex–CTAB interaction parameter showed that partition of the complex from bulk water to the CTAB micelle was a spontaneous process, and the red shift in visible spectra of the complex confirmed its increased solubility into micelles. Copyright © 2013 John Wiley & Sons, Ltd.     

Stereocontrolled synthesis of 3-amino-2-hydroxyalkyl diphenylphosphine oxides mediated by chiral azetidinium salts and epoxyamines

The stereocontrolled synthesis of amino hydroxyalkyl diphenylphosphine oxides has been achieved starting from (2S,3S)-N,N-dibenzyl-3-hydroxy-2-methylazetidinium bromide or (1R),[1′(S)-(dibenzylamino)ethyl]oxirane. The regioselective ring opening of both heterocyclic systems at the less substituted carbon atom with phosphorus nucleophiles proceeded with full stereochemical integrity.     

Synthesis and crystal structure of the first dinuclear zinc complex containing 1,4,7-triazacyclononane and biological properties of the protonated ligand

Abstract

A new binuclear complex, [Zn₂L₂Cl₄]·2H₂O {L?=?N-aldehyde-N-(4-(benzyloxy)benzyl)-1,4,7triazacyclononane}, was synthesized and characterized by X-ray, elemental analysis, infrared and electronic spectroscopy, and mass spectrometry. The central ion is bridged by the L and lies in a tetrahedral configuration with Zn···Zn distance of 6.283 Å. The complex crystallizes in the triclinic space group Pī. ESI-MS of the complex indicates that the protonated ligand HL⁺ is the active species. The interaction of HL⁺ with calf thymus–DNA (CT–DNA) and bovine serum albumin (BSA) was studied by means of various spectroscopic methods, which revealed that HL⁺ could interact with CT–DNA through groove-binding mode and could quench the intrinsic fluorescence of BSA in a static quenching process. DNA–cleavage experiments indicate that HL⁺ exhibits efficient DNA–cleavage activity in the presence of H₂O₂, hydroxyl radical (HO^?) may serve as the major cleavage active species, and the pseudo-Michaelis–Menten kinetic parameters (K_cat, K_M, V_max); 2.47?h^?1, 2.70?×?10^?4 M and 6.68?×?10^?4 Mh^?1.     

Short-chain model studies on emission properties of poly(9-vinylphenanthrene-co-p-N,N-dimethylaminostyrene): Exciplex quenching and subsequent formation of another fluorescent exciplex

The emission properties of 1-(4-dimethylaminophenyl)-3-(9-phenanthryl)propane, Ph(CH₂)₃ DMA, and 1,3-di-(9-phenanthyrl)propane, Ph(CH₂)₃Ph, were studied in comparison with those of poly(9-vinylphenanthrene-co-p-N,N-dimethylaminostyrene). Ph(CH₂)₃DMA showed an intense intramolecular exciplex fluorescence in dioxane. Ph(CH₂)₃Ph did not exhibit a clear intramolecular excimer fluorescence. The quenching of the intramolecular exciplex by several electron acceptors was studied. As a result moderate electron acceptors, such as cyanobenzene, methyl benzoate, and acrylonitrile, selectively quenched the intramolecular exciplex, and in the case of cyanobenzene the subsequent formation of another fluorescent exciplex was observed. The results were discussed in terms of the reduction potentials of electron accepting quenchers.     

Unsymmetrical mononuclear and insoluble polynuclear oxo-vanadium(IV) Schiff-base complexes

Unsymmetrical and symmetrical mononuclear and insoluble polynuclear oxo-vanadium(IV) Schiff-base complexes were prepared and characterized. The complexes [VO(5-x-6-y-Sal)(5-x′-6-y′-Sal)en)] (where x, x′ = H, Br and y, y′ = H, OMe) were obtained in monomeric form while for x or x′ = NO₂ polymers were produced. In the case of [VO(5-x-6-y-Sal)(5-x′-6-y′-Sal)pn)] with a six-member N–N chelating ring, oxo-vanadium(IV) complexes were polynuclear. The tetradentate N₂O₂-Schiff-base ligands are coordinated in the equatorial plane of oxo-vanadium(IV). Electrochemical and spectroscopic data (UV–Vis and IR) suggest importance of coordination geometry and the substiuents on phenyl rings and the bridge group. Electron density of the vanadium center decreases by the electron-withdrawing groups on the ligand while electron density on vanadium increases via σ-donation of phenolic oxygen.     

Antifilarial and antimalarial agents. Basically substituted 10-aminobenzo[b] [1,5] naphthyridines, 10-Aminobenzo[b] [1,5] naphthyridine N-Oxides,and 8-Amino-1,5-naphthyridines

Various 2-alkoxy 7-chloro-10-[[[(dialkylamino)alkyl]amino]]benzo[b][1,5]naphthyridines (XI) and N-oxides (XV, XVII, XVIII, XXII), 4-[(2-alkoxy-7-chlorobenzo[b][1,5]naphthyridin-10-yl)-amino]-α-(diethylamino)-o-cresol derivatives (XII-XIV, XXI) and N-oxides (XIX, XX, XXV), 2-butoxy-8-[[[(dialkylamino)alkyl]amino]]-1,5-naphthyridines (XXVIa and b), and 2-butoxy-8–[[3-[(diethylamino)methyl]-p-anisidino]]-1,5-naphthyridine (XXVII) were synthesized for antifilarial and antimalarial evaluation. The compounds were obtained in 13–91% yield by the condensation of 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridines, 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridine 5-oxides, and 2-butoxy-8-chloro-1,5-naphthyridine with the appropriate diamine in phenol, or by perbenzoic acid oxidation of the parent 10-amino-7-chlorobenzo-[b][1,5] naphthyridines in chloroform. Among them, eight compounds killed adult Litomosoides carinii in gerbils when administered in daily gavage doses of 25–400 mg./kg. for 5 days. Azacrine 5-oxide (XVII), the most active compound, was equipotent with amodiaquine (1a), azacrine (IX), and quinacrine 10-oxide (VI). Twelve substances were active orally against Plasmodium berghei in mice at doses ranging from 3.8–155 mg./kg./day for 6 days. 7-Chloro-10-[[-3-[(diethylamino)-methyl]-p-anisidino]]-2-methoxybenzo[b][1,5]naphthyridine 5-oxide dihydrochloride (XX) was approximately 12 times as potent as quinine against P. berghei, but was highly cross-resistant with chloroquine (IV). Structure-activity relationships are discussed.     

Complexation of (N, N-diethylthiocarbamoylmethyl) diphenylphosphine sulfide with silver nitrate. The structure of the [Ag{Ph2P(S)CH2C(S)NEt2}2]NO3 complex

(N, N-Diethylthiocarbamoylmethyl)diphenylphosphine sulfide, Ph₂P(S)CH₂C(S)NEt₂, forms a distorted tetragonal bisligand complex [AgL₂]NO₃ with Ag⁺. The stability constant of the complex in acetonitrile was estimated by spectrophotometry (logK=3.7). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 846–852, April, 1997.