Reaction of 3-(o-chlorobenzylidene)-2,4-dioxopentanoic acid with hydroxylamine hydrochloride. Revised structure tor azeto[3,2-d]isoxazoline

Reaction of 3-(o-ehlorobenzylidene)-2,4-dioxopentanoic acid (1) with hydroxylamine hydro-chloride in acetic acid gave 5-(o-chlorophenyl)-3-methyl-4-(α-hydroxyimino)isoxazolineglyo-xylic acid (5) and 3-(o-chlorobenzylidene)-4-hydroxyimino-2-oxopentanoic acid (2) in 57% and 7% yields. Pyrolysis of 5 afforded 5-(o-chlorophenyl)-3-methylisoxazole-4-carbonitrile (8), cis- and trans-5-(o-chlorophenyl)-3-methylisoxazoline-4-carbonitriles (9,10), and 5-(o-chloro-phenyl)-3-methylisoxazoline-4-carboxamide (11).     

Synthesis of the 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril and related compounds

The 3-methyl and 4-methyl derivatives of 3-amino-3,4-dihydro-1-hydroxycarbostyril were synthesized by the reductive cyclization of α-methyl-β-(o-nitrophenyl)alanine and α-amino-β-(o-nitrophenyl)butyric acid hydrohalides, respectively, under conditions of catalytic hydrogenation in acidic solution. The free bases of the latter two o-nitroaromatic amino acids were also catalytically hydrogenated under neutral conditions to yield the respective α-methyl-β-(o-aminophenyl)alanine and α-amino-β-(o-aminophenyl)butyric acid which were converted to the corresponding lactams, 3-methyl- and 4-methyl-3-amino-3,4-dihydrocarbostyrils. α-Methyl-β-(o-nitrophenyl)alanine was obtained by acid hydrolysis of 5-methy)-5-(o-nitrobenzyl)hydantoin which was prepared by treatment of o-nitrophenylacetone with potassium cyanide and ammonium carbonate. α-Amino-β-(o-nitrophenyl)butyric acid was synthesized by condensation of α-bromo-o-nitroethylbenzene with diethyl acetamidomalonate, followed by acid hydrolysis of the condensation product. The 4-methylated compounds were obtained as synthetic mixtures of two diasteromeric racemates in nearly the same amounts as shown by nmr spectral analysis. Unlike the demethylated parent compound, 3-amino-3,4-dihydro-1-hydroxycarbostyril, neither the 3-methyl nor 4-methyl analog was found to possess any antibacterial activity.     

o-Acetylaminophenylglyoxylic Acid Anil and Its Derivatives

1-Acetyl- and 1-benzoyl-2- and -3-phenyliminooxoindolines were synthesized. o-(Acetylamino)phenylglyoxylic acid anil was prepared from 1-acetyl-3-phenylimino-2-oxoindoline. More stable o-(acetylamino)phenylglyoxylanilide anil can be prepared not only from o-(acetylamino)phenylglyoxylanilide but also from an ester or chloride of o-(acetylamino)phenylglyoxylic acid anil. o-(Acetylamino)phenylglyoxylothiosemicarbazide was prepared from o-(acetylamino)phenylglyoxylic acid anil and from the corresponding anilide.     

Ortho effects–I: Fragmentation mechanisms in some ortho-substituted nitroarenes

The mass spectra of o-nitrobenzoic acid, o-nitroanisole, o-nitrosobenzoic acid, o-nitrobenzamide, o-nitrobenzyl alcohol and o-nitrosobenzaldehyde have been studied. Fragmentation mechanisms are proposed for the above compounds; their elucidation was aided by isotopic labeling with D and O¹⁸. Two ‘ortho-effects’ are discussed; one involving H atom transfer between substituents and the other migration of an atom or group to a charge carrying vacant ortho position. The importance of nitro to nitrite conversion in molecular and fragment ions is discussed.     

1,2,3-benzotriazines. I. The synthesis of some benzimidazo [1,2-c][1,2,3]-benzotriazines and naphth[1′,2,(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine

A number of substituted benzimidazo[1, 2-c][1,2,3]benzotriazines were prepared by the diazotization of the appropriate 2-(o-aminophenyl)benzimidazoles. Diazotization of 2-(o-aminophenyl)naphth[1,2-d]imidazole yielded a new heterocyclic ring system. Various methods of preparation of 2 - (o-aminophenyl)benzimidazoles were investigated. The condensation of o-phenylenediamines with anthranilic acids, in the presence of polyphosphoric acid, provided a convenient route to 2-(o-aminophenyl)benzimidazoles but in several cases the products were contaminated with considerable amounts of 6-(o-aminophenyl)benzimidazo[1,2 -c]quinazolines. 2 - (o-Aminophenyl)benzimidazoles were also obtained by the catalytic hydrogenation of 2-(o-nitrophenyl)benzimidazoles which resulted from the condensation of an o-phenylenediamine with an o-nitrobenzaldehyde in ethanol, nitrobenzene or acetic acid. When the condensation was carried out in nitrobenzene, small amounts of 2-(o-aminophenyl)benzimidazoles were also formed. The Weidenhagen synthesis, which involves the reaction of an aromatic diamine with an aldehyde in the presence of copper acetate and subsequent decomposition of the cuprous salt of the benzimidazole, yielded 2-(o-aminophenyl)benzimidazoles instead of the expected 2-(o-nitrophenyl)benzimidazoles when the decomposition was carried out in ethanol. When the cuprous salt was treated with hydrogen sulfide in dilute hydrochloric acid, a mixture of amino- and nitrobenzimidazoles resulted. The ultraviolet and infrared spectra of all the compounds prepared were examined.     

Competition Between Intra- and Intermolecular Hydrogen Bonding: o-Anisic Acid⋅⋅⋅Formic Acid Heterodimer

Four conformers of the heterodimer o-anisic acid–formic acid, formed in a supersonic expansion, have been probed by Fourier transform microwave spectroscopy. Two of these forms have the typical double intermolecular hydrogen-bond cyclic structure. The other two show the o-anisic acid moiety bearing a trans-COOH arrangement supported by an intramolecular O−H⋅⋅⋅O bond to the neighbor methoxy group. In these conformers, formic acid interacts with o-anisic acid mainly through an intermolecular O−H⋅⋅⋅O hydrogen bond either to the O−H or to the C=O moieties, reinforced by other weak interactions. Surprisingly, the most abundant conformer in the supersonic expansion is the complex in which the o-anisic acid is in trans arrangement with the formic acid interacting with the O−H group. Such a trans-COOH arrangement in which the intramolecular hydrogen bond dominates over the usually observed double intermolecular hydrogen bond interaction has never been observed previously in an acid–acid dimer.     

Synthesis of (o-Carborane-1,2-diyl)dipropanoic Acid and Its Derivatives

Hydrolysis of 1,2-bis(cyanoethyl)-o-carborane easily available by cyanoethylation of o-carborane gives (o-carborane-1,2-diyl)dipropanoic acid. The corresponding acid dichloride, diamide, dianilide, dibenzophenone, and diol were prepared from it by typical procedures.     

1,2,3-benzotriazines. II. Reactions of benzimidazo[1,2-c][1,2,3]benzotriazines and naphth[1′,2′(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine

A number of methyl- and halogeno-substituted benzimidazo[1,2-c][1,2,3]benzotriazines were subjected to a series of hydrolytic cleavages in acid media. The reactions of these compounds with dilute sulfuric acid yielded 2-(o-hydroxyphenyl)benzimidazoles. Concentrated hydrochloric acid produced a mixture of 2-(o-chlorophenyl)- and 2-(o-hydroxyphenyl)benzimidazoles. Hydrogen chloride in ethanol caused the formation of 2- phenylbenzimidazoles contaminated with small amounts of 2 - (o-chlorophenyl)benzimidazoles. The benzimidazo[1,2-c][1,2,3]benzotriazines underwent the Sandmeyer reaction to form 2-(o-chlorophenyl)- and 2-(o-bromophenyl)benzimidazoles in excellent yields. These reactions illustrated the behavior of these 1,2,3-triazines as internal diazonium compounds. Naphth[1′,2′(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine behaved similarly. Bromination of some benzimidazo[1, 2 - c][1,2,3]benzotriazines in aqueous medium yielded bromine-substituted [1,2-c][1,2,3]benzotriazines.     

Preparation of Nicotinic Acid from Oxidation of 3-Picoline with Oxygen Under Catalysis of T（o-Cl）PPMn

The oxidation of 3-picoline to nicotinic acid took place efficiently in an ethanol solution with 02 as the oxidant under the catalysis of T（o-Cl）PPMn at 40--150 ℃ and 0.5--3.0 MPa oxygen pressure. The influences of temperature, oxygen pressure, reaction time, concentration of 3-picoline, concentration of sodium hydroxide, and concentration of T（o-Cl）PPMn catalyst, etc. on the production of nicotinic acid were investigated. The results show that T（o-Cl）PPMn presented excellent catalytic activity in the oxidation Of 3-pieoiine to nicotinic acid and the yield of nicotinic acid varied greatly with the reaction temperature, oxygen pressure, T（o-Cl）PPMn concentration, etc.     

Mutual viscosity and NMR spin-lattice relaxation time in some benzoic acids

Experimental values of the NMR spin-lattice relaxation time (T ₁) of o-aminobenzoic acid, p-aminobenzoic acid, o-chlorobenzoic acid, p-chlorobenzoic acid and 2,4-dinitrobenzoic acid and mutual viscosity (η₁₂) of o-chlorobenzoic acid, m-chlorobenzoic acid and p-chlorobenzoic acid have been reported. The experimental values of T ₁ have been correlated with the calculated value of T ₁ obtained using different equations of dielectric relaxation time (τ). It is concluded from this comparative study that Murty's equation is a better representation of the dielectric relaxation phenomenon. It is also concluded that the mutual viscosity (η₁₂) is a better substitute for the resistance to the rotation of the individual solute molecule.     

Mass spectrometry in structural and stereochemical problems—CCXXIII:ortho interactions of nitro groups

The mass spectra of C¹³ labeled o- nitrobenzoic acid and o-nitrobenzaldehyde were studied. Earlier proposed fragmentations involving group migration to a charge-carrying vacant ortho position were verified. A completely unexpected interaction in o- nitroanisole was uncovered by O¹⁸labeling.     

Synthesis of 2-Substituted Benzimidazoles, Benzoxazoles, and Benzothiazoles from Arylsulfonyl(thio)propionitriles

The reaction of nitriles and of methyl imino ester hydrochlorides of arylsulfonyl(thio)propionic acids with o-phenylenediamine, o-aminophenol, and o-aminothiophenol has been studied. A series of new 2-substituted benzazoles has been synthesized containing arylsulfonyl(thio)propionic acid fragments.     

Synthesis and properties of 3-chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils and related heterocyclic compounds

3-Chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils were synthesized by the catalytic hydrogenation of the α-chloro- and α,4-dichloro-β-(o-nitrophenyl)propionic acids in strong acidic solution over platinum-on-carbon sulfided catalyst. However, the catalytic hydrogenation of α-bromo-β-(o-nitrophenyl)propionic acid yielded 3,4-dihydro-1-hydroxycarbostyril under the same experimental conditions. The 3-chloro-3,4-dihydro-1-hydroxycarbostyril and the α-chloro-β-(o-nitrophenyl)propionic acid underwent facile dehydrochlorination in mild alkaline solution to give 1-hydroxycarbostyril and o-nitrocinnamic acid, respectively. Selective reduction of 3-chloro-3,4-dihydro-1-hydroxycarbostyril and 1-hydroxycarbostyril to the corresponding lactams, 3-chloro-3,4-dihydrocarbostyril and carbostyril, was effected by catalytic hydrogenation in hydrochloric acid over platinum black catalyst. The structures of the substituted carbostyril derivatives were correlated with their proton nmr spectra.     

Determination of atorvastatin and metabolites in human plasma with solid-phase extraction followed by LC–tandem MS

The aim of the present study was to develop a chromatographic method for the analysis of atorvastatin, o- and p-hydroxyatorvastatin (acid and lactone forms) in human plasma after administration of atorvastatin at the lowest registered dose (10 mg) in clinical studies. Sample preparation was performed by solid-phase extraction and was followed by separation of the analytes on an HPLC system with a linear gradient and a mobile phase consisting of acetonitrile, water and formic acid. Detection was achieved by tandem mass spectrometry operated in the electrospray positive ion mode. Validation of the method for the compounds for which reference compounds were available (acid forms of atorvastatin, o- and p-hydroxyatorvastatin) showed linearity within the concentration range (0.2–30 ng/ml for atorvastatin acid and p-hydroxyatorvastatin acid, and 0.5–30 ng/ml for o-hydroxyatorvastatin acid) (r²0.99, n=5 for all analytes). Accuracy and precision (evaluated at 0.5, 3 and 30 ng/ml for atorvastatin, p-hydroxyatorvastatin and 1, 3 and 30 ng/ml for o-hydroxyatorvastatin) were both satisfactory. The detection limit was 0.06 ng/ml for atorvastatin and p-hydroxyatorvastatin, and 0.15 ng/ml for o-hydroxyatorvastatin. The method has been successfully applied in a clinical study where atorvastatin, o- and p-hydroxyatorvastatin (both acid and lactone forms) could be detected in a 24-h sampling interval after administration of the lowest registered dose of atorvastatin (10 mg) for one week.     

Chemiluminescence determination of <Emphasis Type="Italic">o</Emphasis>-chlorobenzylidenemalonic acid dinitrile in extracts

A chemiluminescence method was developed for determining o-chlorobenzylidenemalonic acid dinitrile (o-CBMA DN) in extracts. The method is based on chemiluminescence developed in a strong alkaline solution upon the interaction between 3-aminophthalic hydrazide (luminol) with the superoxide radical formed in the reaction of atmospheric oxygen activated by hemin with the products of the alkaline hydrolysis of o-chlorobenzylidenemalonic acid dinitrile and with the products of their condensation with p-nitrobenzaldehyde. The luminescence intensity of luminol was proportional to the concentration of o-CBMA DN in the range 1 × 10⁻⁶−1 × 10⁻¹ mg/mL. The determination limit for o-CBMA DN was (1 ± 0.3) × 10⁻⁶ mg/mL (p = 95%, n = 5, RSD = 29%) at 293 K.     

DPPH (= 2,2‐Diphenyl‐1‐picrylhydrazyl = 2,2‐Diphenyl‐1‐(2,4,6‐trinitrophenyl)hydrazyl) Radical‐Scavenging Reaction of Protocatechuic Acid Esters (= 3,4‐Dihydroxybenzoates) in Alcohols: Formation of Bis‐alcohol Adduct

Protocatechuic acid esters (= 3,4‐dihydroxybenzoates) scavenge ca. 5 equiv. of radical in alcoholic solvents, whereas they consume only 2 equiv. of radical in nonalcoholic solvents. While the high radical‐scavenging activity of protocatechuic acid esters in alcoholic solvents as compared to that in nonalcoholic solvents is due to a nucleophilic addition of an alcohol molecule at C(2) of an intermediate o‐quinone structure, thus regenerating a catechol (= benzene‐1,2‐diol) structure, it is still unclear why protocatechuic acid esters scavenge more than 4 equiv. of radical (C(2) refers to the protocatechuic acid numbering). Therefore, to elucidate the oxidation mechanism beyond the formation of the C(2) alcohol adduct, 3,4‐dihydroxy‐2‐methoxybenzoic acid methyl ester ( 4 ), the C(2) MeOH adduct, which is an oxidation product of methyl protocatechuate ( 1 ) in MeOH, was oxidized by the DPPH radical (= 2,2‐diphenyl‐1‐picrylhydrazyl) or o‐chloranil (= 3,4,5,6‐tetrachlorocyclohexa‐3,5‐diene‐1,2‐dione) in CD₃OD/(D₆)acetone 3 : 1). The oxidation mixtures were directly analyzed by NMR. Oxidation with both the DPPH radical and o‐chloranil produced a C(2),C(6) bis‐methanol adduct ( 7 ), which could scavenge additional 2 equiv. of radical. Calculations of LUMO electron densities of o‐quinones corroborated the regioselective nucleophilic addition of alcohol molecules with o‐quinones. Our results strongly suggest that the regeneration of a catechol structure via a nucleophilic addition of an alcohol molecule with a o‐quinone is a key reaction for the high radical‐scavenging activity of protocatechuic acid esters in alcoholic solvents.     

Photochemical conversion of o-phenylenediamine and o-aminophenol into heterocyclics

o-Phenylenediamine is photo-oxidized to phenazine-2,3-diamine in ethanolic or aqueous hydrochloric acid solution. In acetic or propionic acid solutions it forms benzimidazole derivatives. o-Aminophenol in ethanol is photo-oxidized to 2-amino-3H-phenoxazin-3-one and two tetracyclic solvent addition products.     

Synthesis and thermal decomposition kinetics of the complexes [Sm(o‐NBA)3bipy]2·2H2O and [Sm(o‐BrBA)3bipy]2· 2H2O

Two new complexes [Sm(o‐NBA)₃bipy]₂·2H₂O ( 1 ) and [Sm(o‐BrBA)₃bipy]₂·2H₂O ( 2 ) (where o‐NBA is o‐nitrobenzoic acid, o‐BrBA is o‐bromobenzoic acid, and bipy is 2,2′‐bipyridine) were prepared and characterized by elemental analysis, IR, UV, and molar conductance, respectively. The thermal decomposition behaviors of the two complexes were investigated by means of TG–DTG and IR techniques. The thermal decomposition kinetics was studied by using advanced double equal‐double steps method, nonlinear integral isoconversional method, and nonlinear differential isoconversional method. The kinetic parameters of the second‐step process for the two complexes were obtained, respectively. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 40: 607–616, 2008     

Photolysis of ortho-Azidobenzoic Acid in Solutions and a Solid State

The photolysis of o-azidobenzoic acid in solutions, adsorbed on silica gel, and in a crystalline state was studied by IR and UV spectroscopy and thin-layer chromatography. It was found that the photolysis resulted in the formation of 2,1-benzisoxazolone (the product of intramolecular cyclization of singlet nitrenes) and anthranilic acid and o,o"-dicarboxyazobenzene (the reaction products of triplet nitrenes). The formation of 2,1-benzisoxazolone is a reversible reaction because of the secondary photolysis to singlet nitrenes, which leads to an increase in their concentration in the system.     

Selective separation of minor actinides and lanthanides using aromatic dithiophosphinic and phosphinic acid derivatives

A new extractant for the separation of actinide(III) and lanthanide(III) cations, bis(o-trifluoromethylphenyl) phosphinic acid (2) was synthesized. The synthetic route employed mirrors one that was employed to produce the sulfur containing analog bis(o-trifluoromethylphenyl) dithiophosphinic acid (1). Classic radiochemical methods and absorbance spectroscopy were used to study the coordination chemistry of the Am-dithiophosphinic acid and Am-phosphinic acid complexes.