Synthesis of benzoxazoles from imino esters I. 2-Alkyl(aryl)-substituted benzoxazoles

It is found that condensation of esters of iminocarboxylic and iminoperfluorocarboxylic acids with o-aminophenol is a convenient general method for preparing 2-alkyl, 2-perfluoroalkyl, and 2-aryl substituted benzoxazoles. Hydrochlorides of esters of iminocarboxylic acids react smoothly with o-aminophenol even at room temperature. Condensation of esters of iminoperfluorocarboxylic acids, whose hydrochlorides are unstable, is suitably carried out in the presence of an equimolecular quantity of the corresponding perfluorocarboxylic acid. 2-Alkyl(aryl) substituted benzoxazoles can also be obtained by heating o-aminophenol with esters of iminocarboxylic acids in the form of free bases. Esters of iminoperfluorocarboxylic acids also react similarly. Under similar conditions diesters of bisiminocarboxylic and bisiminoperfluorocarboxylic acids and o-aminophenol give, -di(benzoxazolyl-2) alkanes, and, -di(benzoxazolyl-2) perfluoroalkanes respectively.The synthetic part of the work was communicated at the conference on Heterocycles in Organic Synthesis, Kiev, June 1964. For a preliminary communication see [1].     

Condensation of aldehydes and ketones

The alkaline condensation of β-aceto-and β-propionaphthalenes with furfural has given, respectively, 2-(α-furfuryl)-1, 3-di(β-naphthoyl)-propane and 3-(α-furyl)-2,4-di(β-naphthoyl)pentane; both δ-diketones have also been obtained by the Michael condensation. Under more severe conditions, two molecules of furfural condense with three molecules of β-acetonaphthalene to form 2, 4-di(α-furyl)-1, 3, 5-tri(β-naphthoyl)pentane. Under similar conditions, benzaldehyde exhibits only a feeble capacity for triketone condensation with β-acetonaphthalene. The condensation of β-propionaphthalene with furfural has given the new compound furylidenepropionaphthalene. It has been shown that both under the conditions of the improved Chichibabin pyridine synthesis and under the conditions of the Leuckhardt reaction, 3-(α-furyl)-1, 3-di(β-naphthoyl)propane gives 4-(α-furyl)-2, 6-di(β-naphthyl)pyridine.     

Synthesis of substituted disulfonyl-containing polycyclic azines with the bridgehead nitrogen atom. Effects of the structure of 3-substituted pyridinium ylides on the regioselectivity of their reactions with <Emphasis Type="Italic">E</Emphasis>-1,2-di(alkylsulfonyl)-1,2-dichloroethenes

Heating the substituted pyridinium and isoquinolinium salts with E-1,2-di(alkylsulfonyl)-1,2-dichloroethenes in either chloroform or acetone in the presence of three-fold excess of Et₃N gave high yields of substituted 1,2-di(alkylsulfonyl)indolizines and 1,2-di(alkylsulfonyl) pyrrolo[2,1-a]isoquinolines, respectively. Effects of the structure of 3-substituted pyridinium ylides on the regioselectivity of their reaction with E-1,2-di(alkylsulfonyl)-1,2-dichloroethenes were revealed. It was shown that the presence of electron-releasing and electron-withdrawing substituents in the pyridinium ylide favors the formation of 8-substituted and 6-substituted 1,2-(dialkylsulfonyl)indolizines, respectively.     

Silica sulfuric acid catalyzed synthesis of benzoxazoles,benzimidazoles and oxazolo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridines under heterogeneous and solvent-free conditions

A simple, rapid and efficient method for the preparation of benzoxazoles, benzimidazoles and oxazolo[4,5-b]pyridines from the reaction of orthoesters with o-aminophenols, o-phenylenediamine and 2-amino-3-hydroxypyridine in the presence of silica sulfuric acid under heterogeneous and solvent-free conditions is reported. The significant features of this method are short reaction times, high yields of the products, mild reaction conditions, solvent free reaction, cheapness, non-toxicity and reusability of the catalyst.     

New derivatives of 4-quinaldinol

The reactions of 1, 1, 3-trichloro-1-propene and also 1, 1, 1-trichloro-2-propene with acetoacetic ester gave α-(γ, γ-dichlorallyl)acetoacetic ester (I). In the reactions with aniline and o- and p-toluidines, the corresponding α-(γ, γ-dichloroallyl)-β-arylamino-crotonic esters were produced, thermal cyclization of which gave 2-methyl-3-(γ, γ-dichloroallyl)-4-hydroxyquinoline (II) and its 6CH₃- (III) and 8CH₃- (IV) homologs. With phosphorus oxychloride, II–IV gave the corresponding 4-chloro-substituted quinolines (V–VII); with concentrated sulfuric acid, II–VII were converted into the corresponding β-quinolinylpropionic acids VIII–XIII.     

Reactions of halogen metal alkoxides

The study of the thermal stability of halogen-magnesium alkoxy-carbinolates was continued. The data obtained led to the development of procedures for the synthesis of esters of α-oxo and of α-hydroxy-acids containing the thienyl radical. An intramolecular hydrogen bond between the sulfur atom and the hydrogen of the hydroxyl group in esters of (5-bromothienyl-2)glycolic acid was revealed. The presence of this bond was confirmed by infrared spectroscopic data and by the results of the investigation of the esters of (thienyl-3)- and (4-bromothienyl-3)glycolic acids.     

Basicity of Highly Substituted β-Octaalkyl-<Emphasis Type="Italic">meso</Emphasis>-aryl- and -<Emphasis Type="Italic">meso</Emphasis>-thienyl Porphyrins

5-Phenyl-, 5,15-diphenyl-5,15-di(thiophen-2-yl)-, and 5,10,15,20-tetraphenyloctaalkyl-21H,23H-porphyrins in benzene–acetic acid mixtures are moderate bases (pK–0.27 to–2.48). There is no simple correlation between the basicity constants and any electronic or geometric structure parameter of their molecules due to the contributions of three factors to the basicity: distortion of the planar structure in highly substituted macrocycles and their protonated forms, positive charge delocalization over the conjugated bond system, and electronic effects of substituents.     

Some derivatives of α-pyrone-3-carboxylic acid and its homologs

Saponification of the appropriate 3-carbethoxy-α-pyrones gives α-pyrone-3-carboxylic acid and its homologs, further converted via their acid chlorides to the substituted amides of the acids.     

Monofluoro-substituted azomethine ylides in fluorocarbene reactions with imines. Synthesis and transformations of monofluoroaziridines

N-Arylmethylene and N-benzhydrylideneamines react with fluorocarbene yielding fluoro-substituted azomethine ylides that undergo 1,3-π-cyclization into aziridines. Generation of fluoroylides in the presence of dipolarophiles (dimethyl maleate or dimethyl acetylenedicarboxylate) led to the reaction of 1,3-dipolar cycloaddition resulting in substituted 2-pyrrolines or pyrroles. 2-Fluoroaziridines, products of N-alkyl-N-benzhydrylideneamines 1,3-π-cyclization, in the presence of acid catalysts suffer isomerization into α-fluoroimines and 1,3-disubstituted indoles.     

Synthesis,Structure, and Biological Activity of Products of Reactions of 3,4-Dioxohexane-1,6-dioic Acid Esters with 2-Aminophenol

Bioactive derivatives of 1,4-benzoxazine have been prepared via reactions of 3,4-dioxohexane-1,6- dioic (ketipic) acid esters with 2-aminophenol. (2'Z)-2,2'-(2-Hydroxy-2H-1,4-benzoxazin-2-yl-3-ilidene)diacetic acid esters or (2Z)-[2-oxo-2H-1,4-benzoxazin-3(4H)-ylidene]acetic acid esters can be formed depending on the conditions. The structures of the products of dialkyl ketipate esters reactions with 2-aminophenol were determined by means of X-ray diffraction. It has been demonstrated that the prepared compounds exhibit antimycotic activity against test cultures of plant pathogenic fungi (Fusauium sp., Alternarium sp., and Bipolaris soraciniana).     

Synthesis of new 1-(3,4-dimethylphenyl)-1,5-dihydropyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4-one derivatives

New substituted pyrazolo[3,4-d]pyrimidin-4-ones have been synthesized as a result of a series of transformations including hydrolysis of ethyl 5-amino-1H-pyrazole-4-carboxylates, cyclization of the carboxylic acids thus obtained to pyrazolo[3,4-d][1,3]oxazin-4(1H)-ones, and treatment of the latter with substituted anilines. The final pyrazolo[3,4-d]pyrimidin-4-one derivatives can also be synthesized from 5-(arylamido)-1H-pyrazole-4-carboxylic acids in the presence of a catalytic amount of anhydrous zinc(II) chloride.     

Cloning and Characterization of the Gene Encoding Alpha-Pinene Oxide Lyase Enzyme (Prα-POL) from <Emphasis Type="Italic">Pseudomonas rhodesiae</Emphasis> CIP 107491 and Production of the Recombinant Protein in <Emphasis Type="Italic">Escherichia coli</Emphasis>

The alpha-pinene oxide lyase (Prα-POL) from Pseudomonas rhodesiae CIP107491 belongs to catabolic alpha-pinene degradation pathway. In this study, the gene encoding Prα-POL has been identified using mapping approach combined to inverse PCR (iPCR) strategy. The Prα-POL gene included a 609-bp open reading frame encoding 202 amino acids and giving rise to a 23.7 kDa protein, with a theoretical isoelectric point (pI) of 5.23. The amino acids sequence analysis showed homologies with those of proteins with unknown function from GammaProteobacteria group. Identification of a conserved domain in amino acid in positions 18 to 190 permitted to classify Prα-POL among the nuclear transport factor 2 (NTF2) protein superfamily. Heterologous expression of Prα-POL, both under its native form and with a histidin tag, was successfully performed in Escherichia coli, and enzymatic kinetics were analyzed. Bioconversion assay using recombinant E. coli strain allowed to reach a rate of isonovalal production per gramme of biomass about 40-fold higher than the rate obtained with P. rhodesiae.     

Researches ok heterocyclic rings containing nitrogen and sulfur II. Orotylamino acids,their esters,and salts of orotic acid with amines

Esters of orotylamino acid are synthesized by reacting orotyl chloride with glycine andα- andβ-alanine esters. Orotylamino acids are prepared by reducing the benzyl ester of orotylglycine, or by reacting orotyl chloride with sodium salts of amino acids. A series of salts of orotic acid are prepared by reacting orotic acid with amines.     

Synthesis of dihydrocoumarin carbamate derivatives

The condensation at room temperature in the trifluoroacetic acid of para- and meta-hydroxy-substituted methylphenylcarbamate with cinnamic acids or their esters containing electron-donor substituents in the benzene ring yielded dihydrocoumarins with a carbamate function attached to C⁶ or C⁷. Under similar conditions the methyl(2-hydroxyphenyl)carbamate, cinnamic acids or their esters containing electron-acceptor substituents or electron-donor substituents in the ortho-position of the benzene ring are not involved into the condensation.     

Kinetics and mechanism of benzyl <Emphasis Type="Italic">para</Emphasis>-chlorophenyl ketone oxidation

The oxidation of benzyl para-chlorophenyl ketone in chlorobenzene at 100°C occurs through the formation of short chains. Non-peroxide reaction products (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone, para-chlorobenzyl, benzaldehyde, and para-chlorobenzoic acid) are formed not only by the transformation of hydroperoxide (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone) but also (or solely) through the recombination of α-ketoperoxyl radicals with or without chain termination. α-Hydroperoxide decomposes predominantly through a heterolytic route to form para-chlorobenzoic acid and benzaldehyde. Benzaldehyde and 1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone undergo radical chain oxidation in the reaction medium to form benzoic acid (benzaldehyde), para-chlorobenzyl, and benzoic and para-chlorobenzoic acids (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone). The homolytic decomposition of α-hydroperoxy ketone and α-hydroxy-α-hydroperoxy ketone causes the self-acceleration of the process and affords 1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone or, to a lesser extent, benzaldehyde and para-chlorobenzoic acid (α-hydroperoxy ketone). para-Chlorobenzoic acid substantially accelerates the heterolytic decomposition of α-hydroxy-α-hydroperoxy ketone and the oxidation of benzyl para-chlorophenyl ketone with peroxy acids to ester according to the Baeyer-Villiger mechanism. The rate constants of the main steps of the process and kinetic parameters are calculated by solving the inverse kinetic problem.     

Five-membered 2,3-dioxo heterocycles: LVI. Reaction of 3-aroyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones with acyclic enamino ketones

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with 4-arylaminopent-3-en-2-ones and 3-amino-1,3-diphenylprop-2-en-1-ones to give substituted 4-aroyl-3-hydroxy-1-(o-hydroxyphenyl)-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-diones.     

Diastereoselective 1,3-Dipolar Cycloaddition of Nitrones to 1<Emphasis Type="Italic">H</Emphasis>-Pyrrole-2,3-diones. Synthesis of pyrrolo[3,2-<Emphasis Type="Italic">d</Emphasis>]isoxazoles

1H-pyrrol-2,3-diones react with nitrones affording substituted pyrrolо[3,2-d]isoxazoles. The structures of ethyl (3R*,3aR*,6aR*)-6-benzyl-3-(4-bromophenyl)-4,5-dioxo-2,6a-diphenylhexahydro-3aHpyrrolo[ 3,2-d]isoxazole-3a-carboxylate and dimethyl (3R*,3aR*,6aS*)-3-(4-bromophenyl)-4,5-dioxo-2,6-diphenyltetrahydro-3aH-pyrrolo[3,2-d]isoxazole-3a,6a(4H)-dicarboxylate were proved by single-crystal X-ray analysis.     

An efficient synthesis of <Emphasis Type="Italic">β</Emphasis>-methoxycarbonyl-<Emphasis Type="Italic">γ</Emphasis>-butyrolactones

β-Methoxycarbonyl-γ-butyrolactones bearing a γ-aromatic substituent were prepared via copper-catalyzed reductive aldol addition/lactonization domino reactions of ketones with α,β-unsaturated dicarboxylate esters and a silane under ambient temperature. The reaction has advantage of using readily available reagents, mild conditions and high efficiency.     

Reaction of 2-(2-Oxo-1,2-dihydro-3<Emphasis Type="Italic">H</Emphasis>-indol-3-ylidene)acetic acids esters with phenylhydrazine

2-(2-Oxo-1,2-dihydro-3H-indol-3-ylidene)acetic acids esters reacted with phenylhydrazine yielding products of the regioselective addition of the latter in the α-(C²)-position of the exo ethylene bond, (2-oxo-2,3-dihydro-1H-indol-3-yl)(2-phenylhydrazino)acetic acids esters.     

Synthesis of 6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidine-5-carboxylic acids and their methyl esters

6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylic acids and methyl 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylates were synthesized by fusion of 4-aryl-2,4-dioxobutanoic acids and their methyl esters, respectively, with 1H-tetrazol-5-amine and aromatic aldehydes. The reaction of methyl 2,4-dioxopentanoate with 1H-tetrazol-5-amine and 2-fluorobenzaldehyde in boiling acetic acid gave methyl 6-acetyl-5-hydroxy-7-(2-fluorophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-5-carboxylate.