Synthesis and Reactions of Some Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives with a Thiophene Ring as Analgesic, Anticonvulsant, and Antiparkinsonian Agents

A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimidinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition, they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the corresponding Schiffs base and imide derivatives. Diazotization of amides gave thienotriazinone derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone derivatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding thioethyl- or thioglycolic acid pyrimidinone derivatives.The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene®, Carbamazepine®, and Benzotropene® as reference drugs.     

Synthesis and Reactions of Some Fused Oxazinone,Pyrimidinone, Thiopyrimidinone,and Triazinone Derivatives with a Thiophene Ring as Analgesic,Anticonvulsant, and Antiparkinsonian Agents

Summary. A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimidinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition, they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the corresponding Schiffs base and imide derivatives. Diazotization of amides gave thienotriazinone derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone derivatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding thioethyl- or thioglycolic acid pyrimidinone derivatives.The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene®, Carbamazepine®, and Benzotropene® as reference drugs.Received January 23, 2003; accepted (revised) March 17, 2003 Published online September 15, 2003     

Transition-metal-free O-, S-, and N-arylation of alcohols, thiols, amides, amines, and related heterocycles

A new protocol for the Ullmann-type arylation process of different aromatic heterocycles without any transition-metal catalyst, implying the use of a combination of an excess of potassium hydroxide and dimethyl sulfoxide, is described. The reaction can be performed between a broad range of starting nucleophiles including phenol, alcohols, amines, nitrogen-containing five-membered systems such as pyrazoles, imidazoles, and indoles, and amides with haloarenes, iodide and bromide derivatives giving the best results, the possible pathway involving the in situ generation of the corresponding benzyne intermediate. When the reaction was performed with 2-iodoaniline and either carboxamides or isothiocyanato derivatives, the corresponding benzoazole derivatives were obtained.     

Chemo-, regio-, and enantioselective Pd-catalyzed allylic alkylation of indolocarbazole pro-aglycons

[reaction: see text] Monosubstituted isomerically pure indolopyrrolocarbazole precursors have been prepared via palladium-catalyzed asymmetric allylic alkylation methodology, employing both achiral cyclopentenyl electrophiles and chiral glycal derivatives. Chemoselective allylation of (bis)indole lactam pro-aglycon 3 allows access to N-distally substituted indolopyrrolocarbazole derivatives; glyoxamide precursor 14 provides entry into N-proximally substituted derivatives.     

Synthesis and characterization of monomers and polymers of acrylated phosphonate esters derived from glycerol,D-mannitol,D-sorbitol,pentaerythritol, and dipentaerythritol

Phosphonic acid ester derivatives of glycerol, D -mannitol, D -sorbitol, pentaerythritol, and dipentaerythritol have been synthesized by transacetalation reactions with diethyl 2,2-diethoxyethylphosphonate. These phosphonated derivatives of polyols and carbohydrates have been esterified to from the corresponding methacrylates. All these compounds have been characterized on the basis of their elemental analysis and spectroscopic (infrared including FT–IR, ¹H-, ¹³C-, ³¹P-NMR, and mass) methods. Transacetalation reactions with dialkyl 2,2-dialkoxyethylphosphonate lead to the synthesis of 1,3-dioxane derivatives in the case of D -mannitol, pentaerythritol, and dipentaerythritol, whereas a mixture of both 1,3-dioxane and 1,3-dioxolane derivatives is obtained with D -sorbitol and glycerol. The methacrylates of phosphonylated polyol derivatives show the capacity to dissolve and interact with metal salts such as bismuth bromide and uranyl nitrate. Some of the polymers obtained from these monomers have been characterized on the basis of their spectral and thermal (differential scanning calorimetry) properties.     

Synthesis, identification, and benzene solubility of the piperidine, pyrrolidine, and morpholine derivatives of fullerene C60

Synthesis of the piperidine, pyrrolidine, and morpholine derivatives of fullerene C₆₀ and their identification by electronic and IR spectroscopy were reported. The solubility of these derivatives in benzene at temperatures from 20 to 80°C was studied.     

Synthesis and a-glucosidase inhibitory activity of chrysin,diosmetin,apigenin,and luteolin derivatives

Several derivatives have been synthesized from chrysin, diosmetin, apigenin, and luteolin, which were isolated from diverse natural plants. The a-glucosidase inhibitory activity of these compounds was evaluated. The glucosidase inhibitory activity of all derivatives(IC50 24.396 mmol/L) was higher compared with that of the reference drug, acarbose(IC50= 563.601 40.492 mmol/L), and 1-deoxynojirimycin(IC50= 226.912 12.573 mmol/L). O30,O7-Hexyl diosmetin(IC50= 2.406 0.101 mmol/L)was the most potent inhibitor identified. These compounds showed a higher inhibitory ability compared with their precursors except the luteolin derivatives. In general, the inhibitory activity of the synthetic derivatives was enhanced with long alkyl chains at positions 30, 40 and 7 of the flavonoid.     

Derivative of alpha,beta-dicyanostilbene: convenient precursor for the synthesis of diphenylmaleimide compounds, E-Z isomerization, crystal structure, and solid-state fluorescence

A convenient and efficient procedure was developed for preparing 3,4-diaryl-substituted maleimides through the improved synthesized diaryl-substituted fumaronitrile. The synthesis of diphenyl-substituted fumaronitrile derivatives from phenylacetonitrile compounds was analyzed and improved. We found the stoichiometry of the sodium methoxide and the concentration of the starting material, phenylacetonitrile derivatives, were crucial for the high yield and easy purification of the products. Particularly, bis(4-bromophenyl)fumaronitrile, bis(3-trifluoromethylphenyl)fumaronitrile, and bis(4-methoxyphenyl)fumaronitrile were isolated in good yields of 70-90% by simple suction filtration. In addition, (1)H NMR provided compelling evidence that the E-Z isomerization was involved in the formation reaction of the maleimide compounds from either fumaronitrile or maleonitrile derivatives. Single-crystal X-ray structures of these three fumaronitrile derivatives, the first three of the kind, were obtained, revealing the nonplanar molecular structure. We ascribe the strong solid-state fluorescence of these diphenylfumaronitrile derivatives to the nonplanar structure that inhibits the close packing of the molecule aggregation and thus the fluorescence quenching.     

Preparation of trinitroethyl-substituted secondary amides of carboxylic,carbonic, and sulfonic acids

Conclusions Methods were proposed for the synthesis of the previously unknown N-trinitroethyl derivatives of the secondary amides of carboxylic, carbonic, and sulfonic acids by reacting the N-chloromethyl derivatives of the secondary amides with either trinitromethane salts or the methoxymethyl derivatives of the secondary amides with trinitromethane.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2146–2148, September, 1981.     

Synthesis,Electrochemistry, and Hydrolysis of Anthraquinone Derivatives

Anthraquinone (AQ) derivatives, including members of the anthraquinone imide (AQI) family, have been synthesized to afford good candidates for electron-transfer studies in DNA. Electron-withdrawing groups on the AQ ring give a less negative reduction potential, as desired. As expected, the AQI derivatives have less negative reduction potentials than AQ derivatives. The AQI ring system has a half-life for hydrolysis of about 75 min in a 3:7 MeCN and 0.005 M K₂CO₃ in MeOH.     

Phosphorylation of 3',4',5,7-Tetramethyldihydroquercetin

3',4',5,7-Tetramethyldihydroquercetin was phosphorylated with phosphorous acid derivatives, and similar results were obtained with phosphorochloridites and phosphoramidites. The PIII derivatives obtained were subjected to oxidation. The structures of the products were determined by NMR spectroscopy.     

Preparation of derivatives of 5-,6-, and 8-hydroxy-2-aminoanthracene

Three phenolic derivatives of 2-aminoanthracene have been prepared as their diacetyl derivatives by Bucherer-type amination of appropriately substituted anthracenes.     

Synthesis of some polyureas based on diamino derivatives of bis-1, 3, 4-oxadiazole

Ortho-, meta, and para-nitrobenzoyl derivatives of the dihydrazides of succinic, glutaric, adipic, and azelaic acids are prepared, from which are obtained nitro and amlno derivatives of bis-1,3,4- diazole. Various conditions for synthesizing these compounds are investigated. A series of polyureas is obtained by reacting diamino derivatives of bis-1,3,4-oxadiaole with diisocyanates, and some of their properties are investigated.     

Acidity trends in alpha,beta-unsaturated sulfur, selenium, and tellurium derivatives: comparison with C-, Si-, Ge-, Sn-, N-, P-, As-, and Sb-containing analogues

The gas-phase acidity of CH3-CH2XH (X=S, Se, Te), CH2=CHXH (X=S, Se, Te) and PhXH (X=S, Se) compounds was measured by means of Fourier transform ion cyclotron resonance mass spectrometry. To analyze the role that unsaturation plays on the intrinsic acidity of these systems, a parallel theoretical study, in the framework of the G2 and the G2(MP2) theories, was carried out for all ethyl, ethenyl (vinyl), ethynyl, and phenyl O-, S-, Se-, and Te-containing derivatives. Unsaturated compounds are stronger acids than their saturated analogues, because of the strong pi-electron donor ability of the heteroatoms that contributes to a large stabilization of the unsaturated anions. Ethynyl derivatives are stronger acids than vinyl compounds, while phenyl derivatives have an intrinsic acidity intermediate between that of the corresponding vinyl and ethynyl analogues. The CH2=CHXH vinyl compounds (enol-like) behave systematically as slightly stronger acids than their CH3-C(H)X (keto-like) tautomers. Vinyl derivatives are stronger acids than ethyl compounds, because the anion stabilization attributable to unsaturation is greater than that undergone in the neutral compounds. Conversely, the enhanced acidity of the ethynyl derivatives with respect to the vinyl compounds is due to two concomitant effects, the stabilization of the anion and the destabilization of the neutral compound. The acidities of ethyl, vinyl, and ethynyl derivatives containing heteroatoms of Groups 14, 15, and 16 of the periodic table are closely related, and reflect the differences in electronegativity of the CH3CH2-, CH2=CH-, and CH[triple chemical bond]C- groups.     

Synthesis,Photophysical and Electronic Properties of Mono-, Di-, and Tri-Amino-Substituted Ortho-Perylenes,and Comparison to the Tetra-Substituted Derivative

We synthesized a series of new mono-, di-, tri- and tetra-substituted perylene derivatives with strong bis(para-methoxyphenyl)amine (DPA) donors at the uncommon 2,5,8,11-positions. The properties of our new donor-substituted perylenes were studied in detail to establish a structure-property relationship. Interesting trends and unusual properties are observed for this series of new perylene derivatives, such as a decreasing charge transfer (CT) character with increasing number of DPA moieties and individual reversible oxidations for each DPA moiety. Thus, (DPA)-Per possesses one reversible oxidation while (DPA)₄-Per has four. The mono- and di-substituted derivatives display unusually large Stokes shifts not previously reported for perylenes. Furthermore, transient absorption measurements of the new derivatives reveal an excited state with lifetimes of several hundred microseconds, which sensitizes singlet oxygen with quantum yields of up to 0.83.     

Photoinduced activation of molecular oxygen by various porphyrins,bis-porphyrins,phthalocyanines, pyridinoporphyrazins,and their metal derivatives

Aerobic irradiation of tetraphenylporphyrins, phthalocyanines, tetra-t-butylphthalocyanines, tetracarboxylphthalocyanines, tetrapyridinoporphyrazins and some of their metal derivatives with visible light (λ > 420 nm) give singlet oxygen by energy transfer and oxygen superoxide by electron transfer, but some of their Cu, Zn of Pt derivatives are efficient quenchers for superoxide formation.     

Synthesis of 1,2-Diazol-4-sulfonamides, 1,2,4- and 1,2,5-Oxadiazol-3-sulfonamides, 1,2,3-Triazol-4-sulfonamides, and Pyrimidine-5-sulfonamides starting from Cyanomethanesulfonyl Chloride

Summary. Cyanomethanesulfonyl chloride was reacted with amines yielding cyanomethanesulfonamides which could be transformed into alkoxymethylidene and aminomethylidene derivatives. The reaction of alkoxymethylidene derivatives with phenylhydrazine resulted in the formation of 5-aminopyrazol-4-sulfonamides, whereas from cyanomethanesulfonamides via the N-hydroxyamidine derivatives and their reaction with esters 1,2,4-oxadiazol-3-methanesulfonamides became accessible. Nitrosation of cyanomethanesulfonamides yielded 2-hydroxyimino derivatives which were then transformed into 2-hydroxyimino N-hydroxyamidine derivatives, and finally cyclized into 4-amino-1,2,5-oxadiazol-3-sulfonamides. On the other hand diazotation of cyanomethanesulfonamides gave the 2-arylhydrazono derivatives, which after transformation into N-hydroxyamidine derivatives gave by reaction with POCl₃ 5-amino-1,2,3-triazol-4-sulfonamides. Finally, the reaction between cyanomethanesulfonamides and formamidinium acetate opened an easy access to 4-aminopyrimidine-5-sulfonamides, which could be transformed by trialkyl orthoformiates into substituted pyrimidino[4,5-e][1,2,4]thiadiazine derivatives. All intermediates as well as transformation products of the heterocyclic systems were isolated and well characterized. Mechanisms were discussed, and the stereochemistry, when necessary and possible, was elucidated.     

Regioselective enzyme-catalyzed synthesis of sophorolipid esters,amides, and multifunctional monomers

Novel enzyme-mediated synthetic routes were developed to provide a new family of sophorolipid derivatives and glycolopid-based amphiphilic monomers. These compounds are of great interest for their potential use in immunoregulation, as well as for other biological properties. In the present work, an efficient lipase-catalyzed conversion of sophorolipid ethyl ester to (a) the 6'-monoacylated derivatives using Novozym 435, (b) 6' '-monoacylated derivatives using Lipase PS-C, (c) secondary amide derivatives using Novozym 435, and (d) 6',6' '-diacylated amide derivatives using Novozym 435 in an one-pot reaction and (e) the regioselective monoacylation of an amide derivative at the 6'- and 6' '-positions using Novozym 435 and Lipase PS-C, respectively, are described. The ethyl ester produced by esterification of the sophorolipid mixture with sodium ethoxide was subjected to acylation catalyzed by Novozym 435 in dry tetrahedrofuran (THF) with vinyl acetate and vinyl methacrylate to produce 6'-monoacylated derivatives. In contrast, Lipase PS-C catalyzed acylations of sophorolipid ethyl ester in dry THF with vinyl acetate and vinyl methacrylate to give the corresponding 6'-monoacylated derivatives. Novozym 435 mediated amidation of sophorolipid ethyl ester in dry THF with phenethylamine, tyramine, p-methoxyphenethylamine, 2-(p-tolyl)ethylamine, and p-fluorophenethylamine generated the corresponding secondary amides but not tertiary amides. The formation of diacyl derivatives of amides was achieved by their treatment with vinyl acetate and vinyl methacrylate in dry THF using Novozym 435 as catalyst. The conversion of sophorolipid ethyl ester to the same diacyl derivatives of amide (i.e., both amidation and acylation) in high yield was also demonstrated in dry THF by a one-pot reaction using Novozym 435. Furthermore, regioselective monoacylation of a sophorolipid amide at 6' and 6' ' in dry THF with vinyl acetate and vinyl methacrylate using Novozym 435 and Lipase PS-C was also demonstrated.     

Synthesis and spectroscopic properties of nickel complexes of benzo-, 1,2-naphtho-, or 2,3-naphthoannulated β-oxatetraazachlorins

The first β-oxatetraazachlorin derivatives have been synthesized starting from phthalonitrile derivatives and 5,5-dimethyl-1,3-oxazolidine-2,4-dione instead of the previously employed tetramethylsuccinonitrile. Absorption and magnetic circular dichroism (MCD) spectral properties are similar to those obtained for the corresponding tetramethyl-substituted TAC derivatives, confirming the presence of the low-symmetry aromatic structures.     

Low-valent niobium-catalyzed reduction of alpha,alpha,alpha-trifluorotoluenes

[reaction: see text] In the presence of 5 mol % of niobium(V) chloride, alpha,alpha,alpha-trifluorotoluene derivatives were reduced with lithium aluminum hydride to give toluene derivatives in good yields. Stepwise, partial reduction of bis(trifluoromethyl)benzene derivative was also demonstrated.