Synthesis and anticonvulsant activity of some novel 3-aminoquinazolines

A number of novel 3-aminoquinazolines were obtained via two synthetic pathways. In the first method o-aminobenzoylhydrazines were prepared either by reacting an isatoic anhydride and a hydrazine or by reacting o-nitrobenzoic acid with a hydrazine, followed by catalytic reduction. Subsequent cyclization with an appropriate orthoester provided 3-aminoquinazolines and 2-methyl-3-aminoquinazolines. The second pathway involved condensation of o-aminoacetophenone with a hydrazine to form hydrazones which were reduced to aminohydrazines and cyclized as above to yield 4-methyl-3-aminoquinazolines and 2,4-dimethyl-3-aminoquinazolines. The title compounds were evaluated in mice in MES and sc Met seizure models for anticonvulsant activity, and in the rotorod test for neurotoxicity. They were generally toxic. However, 4-methyl-3-(N-piperidino)-3,4-dihydroquinazoline hydrochloride exhibited activity comparable to that of methaqualone.     

Synthesis and Structure-Photophysics Evaluation of 2-N-Amino-quinazolines: Small Molecule Fluorophores for Solution and Solid State

2-N-aminoquinazolines were prepared by consecutive S_NAr functionalization. X-ray structures display the nitrogen lone pair of the 2-N-morpholino group in conjugation with the electron deficient quinazoline core and thus representing electronic push-pull systems. 2-N-aminoquinazolines show a positive solvatochromism and are fluorescent in solution and in solid state with quantum yields up to 0.73. Increase in electron donor strength of the 2-amino substituent causes a red-shift of the intramolecular charge transfer (ICT) band (300–400 nm); whereas the photoluminescence emission maxima (350–450 nm) is also red-shifted significantly along with an enhancement in photoluminescence efficiency. HOMO-LUMO energies were estimated by a combination of electrochemical and photophysical methods and correlate well to those obtained by computational methods. ICT properties are theoretically attributed to an excitation to Rydberg-MO in SAC-CI method, which can be interpreted as n-π* excitation. 7-Amino-2-N-morpholino-4-methoxyquinazoline responds to acidic conditions with significant increases in photoluminescence intensity revealing a new turn-on/off fluorescence probe.     

Enantiopure Double‐Helical Phenylene Ethynylene Cyclophynes with the 2,2′‐Binaphthyl Template

New types of enantiopure compounds were synthesized to gain better insight into the structural features of phenylene ethynylene cyclophynes. Besides the previously obtained meta‐substituted arylene ethynylenes, 1 , ortho‐connected phenylene ethynylene units were incorporated to give cyclophynes with ortho/meta and ortho/ortho connection modes, 2 and 3 . Furthermore, a diphenylethyne component was also accommodated in 4 . Both ab initio calculations and NMR spectra suggest a large amount of strain for 2 but less strain for 3 and 1 a , the latter having the smallest ring size among cyclophynes with the meta/meta connection mode. The CD spectra of 2 and 3 showed a characteristic shoulder at around 340 nm, similar to the case of 1 a . This implies that the aromatic acetylene bonds cross over each other in the double‐helical structure. These results indicate that chirality information is useful for probing the persistency of molecular shape.     

Anionic polymerization of o‐substituted styrene derivatives: Control of reactivity and stereochemistry by aminomethyl group

Ortho‐substituted styrenes, such as 2‐(N,N‐dimethylaminomethyl)styrene ( 1 ), 2‐(1‐pyrrolidinylmethyl)styrene ( 2 ), and 2‐[(S)‐2‐(1‐pyrrolidinylmethyl)‐1‐pyrrolidinylmethyl]styrene ( 3 ), were synthesized, and the effects of the ortho‐substituents on the polymerizability and stereoregularity of the obtained polymers using the anionic method were examined. The bulkiness and coordination of the ortho‐substituted amino groups to the counter cation significantly affected the polymerizability and stereochemistry of the obtained polymers. The anionic and radical polymerizations of 2 with a less hindered ortho‐substituent afforded polymers in good yields, whereas those of 1 and 3 resulted in lower yields. The anionic polymerization of 3 bearing an optically active diamine derivative at the ortho‐position with n‐butyllithium in toluene at 0 °C gave a polymer with a high stereoregularity and stable regular conformation based on the stereoregular backbone structure. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4088–4094, 2000     

Reactions of N- and C-Alkenylanilines: I. Synthesis of Anilides and Amidines from ortho-Alkenyl(cycloalkenyl)anilines and Their Transformations

N-Acetyl- and N-formyl-ortho-alkenyl(cycloalkenyl)anilines were synthesized. Their reaction with P2O5 or PCl5 afforded quinolines. By reaction of the ortho-alkenyl(cycloalkenyl)anilines with 1-methylimino- or 1-phenylimino-1-chloroethanes amidines were obtained that were cyclized in the polyphosphoric acid. The reaction with the polyphosphoric acid of amidines prepared from alkenylanilines and 1-methylimino-1-chloroethane gave rise to 3-methyl-3,4-dihydroquinazolines; on replacing in the substrate methylimine group for phenylimine one the yield of quinazoline decreased.     

Metalation of t-butyl sulfoxides,sulfones and sulfonamides of pyridazine and pyrazine. Metalation of diazines. XX

In the pyridazine series, the use of tert-butylsulfinyl and tert-butylsulfonyl as ortho directing groups for metalation has been tested. Various functionalized products were obtained in good yields. In the case of 3-tert-butylsulfinyl-6-methoxypyridazine, the metalation was regioselective in ortho to the sulfinyl group. The metalation of 2-tert-butylsulfinyl and 2-tert-butylsulfonylpyrazine gave low to moderate yields. Synthesis of diazinesulfonamides were improved and the metalation of N-tert-butylsulfonamidopyrazine was achieved.     

Synthesis of fused pyrimidines with N‐, S‐heterocyclic moieties by double‐annelation reaction

A variety of tri‐ and tetracyclic hetero systems were obtained by reaction of heteroaromatic ortho‐aminoesters or ortho‐aminonitriles with iminothioether, yielding double‐annelation of a thiazolo[3,2‐a]‐pyrimidine, pyrimido[2,l‐b]thiazine, imidazo[1,2‐a]pyrimidine, and pyrimido[1,2‐a]pyrimidine moieties in a one‐pot process.     

Synthesis of C-2 Unsubstituted Furanonaphthoquinones

Four C-2 unsubstituted naphtho[2,3-b]furan-4,9-quinones were prepared via the corresponding phthalides obtained by directed ortho-metalation-based route.     

Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol

A series of 2-isobornylphenol derivatives containing aminomethyl groups either at ortho-(monoderivatives) or ortho- and para-positions (bis-derivatives) relative to the hydroxy group of phenol moiety was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro models. It was demonstrated that Mannich bases containing an n-octylaminomethyl group are significantly exceeding both starting 2-isobornylphenol and the standard antioxidant, 2,6-di-tert-butyl-4-methylphenol, by their ability to inhibit H₂O₂-induced erythrocyte hemolysis.

     

A LFER Kinetic Study of The Reaction of 5‐Substituted Orotic Acids with Diazodiphenylmethane

Linear free energy relationships (LFER) were applied to the kinetic data for the reaction of 5‐substituted orotic acids, series 1 , with diazodiphenylmethane (DDM) in N,N–dimethylformamide and compared with results obtained for 2‐substituted benzoic acids, series 2 . The correlation analysis of the kinetic data with σ substituent parameters was carried out using SSP (single substituent parameter) methods. From the sign and value of proportinality constant ρ, lower sensitivity to the substituent effect was obtained in series 1 , 0.876, than in the series 2 , 1.877. Evaluation of substituent “ortho‐effect” was performed using the Charton model, which includes the steric substituent parameter, and Fujita and Nishioka's model, which describes the total ortho‐effect as contribution of ordinary polar effect, the ortho‐steric and ortho‐polar effects. Results of correlations, obtained by using the Charton model, showed highest contribution of the polar effect, 0.861 vs. 2.101, whereas the steric effect is of lowest significance, 0.117 vs. 0.055, for series 1 and 2 , respectively. Also, a low negative value of coefficient with the steric effect, –0.08, obtained from the Fujita–Nishioka model indicated low steric effect, influencing a decrease of the reaction rate in series 1 . The structural and substituent effects were also studied by using the density functional theory method, and together with kinetic data, it gave a better insight into the influence of the effect of both geometry and substituent on the π?electron density shift induced reactivity of investigated acids.     

Cyclocondensation reaction of a 1,5-diketone with 1,2-diamines

Reaction of 2-acetonyl-4,5-dimethoxy-3′-chlorobenzophenone (1) with ethylenediamine afforded the imidazo[2,1-a]isoquinoline 2, whereas 6-(3-chlorophenyl)-8,9-dimethoxybenzo[b]phenazine (3) and naphthol 4 were obtained with ortho-phenylenediamine.     

QSPR study on pK<Subscript>a</Subscript> values of N-methoxy-polynitroaniline derivatives

A QSPR study is presented for acidities of thirteen N-methoxy-polynitroaniline derivatives. Hammett σ values are known for meta and para substituents, and in the present study values are introduced for ortho-substituents in these N-methoxy-polynitroaniline derivatives. Hammett σ values for ortho-substituents in these N-methoxy-polynitroaniline derivatives were obtained by multiplying para values with 0.65.     

Application of the ortho-lithiation-cyclization strategy to N-benzyl-and N-phenethylamine derivatives

The ortho-lithiation-cyclization of iodinated N,N-diacylphenethylamines provides a convenient method for the preparation of 2-(2-acetoamidoethyl)acetophenones and 2-(2-benzamidoethyl)benzophenones, which could be easily transformed into dihydroisoquinolines. By contrast, the N-ethylamino, N-acetylamino, and N-trimethylsilylamino moieties studied as ortho-directing groups provide poor assistance to the metalation of N-benzyl- and N-phenemylamines and the corresponding isoindolone or isoquinolone derivatives are obtained in low yields.     

Rhodium(III)-catalyzed [4 + 2] annulation of N-arylbenzamidines with 1,4,2-dioxazol-5-ones: Easy access to 4-aminoquinazolines via highly selective CH bond activation

A novel approach for the synthesis of 4-aminoquinazolines has been developed via rhodium(III)-catalyzed [4 + 2] annulation of N-arylbenzamidines with 1,4,2-dioxazol-5-ones. This reaction features excellent regioselectivity, broad substrate scope and high step economy, which would provide the reference for the construction of the fused 4-aminoquinazolines with biologically and pharmacologically active compounds.     

A new approach to fluorinated 4(3H)-quinazolinones

A new approach for the synthesis of fluorinated 1H-quinazolin-4-ones and 4-substituted quinazolines has been developed. 6-Fluoro-1H-quinazolin-4-ones were obtained by intramolecular cyclization of fluorine-containing S-ethyl N-benzoylisothioureas. Nucleophilic substitution reactions at positions 2 and 7, as well as alkylation at 1-position of quinazolinones were investigated. In addition, the synthesis of fluorine-containing 4-aminoquinazolines was carried out.     

Chemistry of condensed thiophenes. IV. Acetylation of phenanthro[4,5-bcd]thiophene

Treatment of phenanthro[4,5-bcd]thiophene ( 2 ) with acetyl chloride and aluminum chloride in nitrobenzene gives acetylation of positions ortho and para to the heteroatomic sulfur atom. In separate experiments, mixtures of 1- and 3-acetyl (50% yield, ratio 1.9:1) or of 1,5-, 1,7-, and 3,5-diacetyl (79% yield, ratio 3:1:1) derivatives were obtained. Isolated as isomerically pure products were the 1-acetyl and the 1,5-diacetyl compounds, as well as the oximes of the 1- and 3-acetyl derivatives. Comparison of these results is made with those reported for nitration of 2 , which also occurs ortho and para to the sulfur atom, and with nitration and acetylation of pyrene (the benzolog of 2 ) which substitutes in the corresponding positions.     

The Preparation of Substituted 1(2H)-Isoquinolinones from Dilithiated 2-Methyl-N-arylbenzamides, 2-Methyl-N-(arylmethyl)-benzamides,or 2-Methylbenzoic Acid, 2,2-Dimethylhydrazide

2-Methyl-N-arylbenzamides (N-aryl-ortho-toluamides), 2-methyl-N-(arylmethyl)-benzamides (substituted benzyl, N-benzyl-ortho-toluamides), or 2-methylbenzoic acid, 2,2-dimethylhydrazide (ortho-toluic acid, N,N-dimethylhydrazide), were dilithiated with excess lithium diisopropylamide, and the resulting polyanion-type intermediates were condensed with aromatic esters followed by acid cyclization to the 3-substituted-1(2H)-isoquinolinones (isocarbostyrils).     

Synthesis of 2-aminoquinazolines from ortho-fluoroketones

The reactions of ten ortho-fluoroketones with guanidine carbonate in N,N-dimethylacetamide were investigated as a new synthetic approach to 2-amino-4-alkyl- and 2-amino-4-arylquinazolines. The yields obtained ranged from low to moderate and were highly dependent upon the nature of the substituents on the reactant. Eight new quinazolines were elaborated in this study.     

Ruthenium‐Catalyzed Oxidant‐Free Allylation of Aromatic Ketoximes with Allylic Acetates at Room Temperature

Substituted aromatic ketoximes reacted efficiently with allylic acetates in the presence of {[RuCl₂(p‐cymene)]₂} and AgSbF₆ in 1,2‐dichloroethane at ambient temperature, providing ortho‐allyl aromatic ketoximes in a highly regioselective manner without an oxidant. In the reaction, the acetate group of allyl acetate acts as a base to activate the C?H bond of aromatics. Later, ortho‐allyl aromatic ketoximes were converted into ortho‐allyl aromatic ketones in the presence of HCl.     

A New Strategy for the Synthesis of 3-Acyl-coumarin Using Mesoporous Molecular Sieve MCM-41 as a Novel and Efficient Catalyst

3-Acyl-coumarins were obtained in high yields from ortho-hydroxybenzaldehydes and ethyl acetoacetate or ethyl benzoylacetate in acetonitrile in the presence of a catalytic amount of mesoporous molecular sieve MCM-41. 3-Acyl-coumarins were obtained in high yields from ortho-hydroxybenzaldehydes and ethyl acetoacetate or ethyl benzoylacetate in acetonitrile in the presence of a catalytic amount of mesoporous molecular sieve MCM-41.