1,1-Dihalo-2-benzycyclopropanes in reaction with nitrous acid

Interaction of 1,1-dichoro and 1,1-dibromo-2-benzylcyclopropanes with nitrous acid generated in situ was studied. It was shown that both nitration of the aromatic ring and heterocyclization of 1,1-dihalo-2-benzylcyclopropanes take place. Heterocyclization is initiated by opening of the cyclopropane ring in the reaction with nitrosyl cation. The nature of halogen atom in the cyclopropane ring affects the regioselectivity of the reactions.     

Synthesis of some N-substituted 4,5-dihydro-7,8-dirnethoxybenzothiazepin-3-one 1,1 -dioxides

Reaction of ethyl 3,4-dimethoxyphenylpropionale with chlorosulfonic acid yielded 2-carbo-elhoxyethyl-3,4-dimelhoxybenzene sulfochloride, which was converted to 2-earboethoxyethyl-3,4-dimethoxybenzcnesulfonamides by the action of ammonia or substituted aromatic amines. Alkaline hydrolysis of these sulfonumide esters furnished the corresponding acids. The reaction of acids with phosphorus pentachloride resulted in the key intermediates, the ehloroearboxycthyl-3,4-dimethoxybenzenesulfonamides. The latter was cyelized to N-substituted 4,5-dihydro-7,8-dirnelhoxybenzothizepine-3 -one 1, 1-dioxide. Reactions of benzolhiazepinonc ring and nrnr specttra are described.     

Enolate ions as beta-activators of ortho-metalation: direct synthesis of 3-aminoindenones

beta-Ketonitriles derived from a Claisen condensation of benzoate esters with alkyl- or phenylacetonitriles lead to 3-aminoindenones in the presence of excess LDA. This new reaction is also applicable to pyridine carboxylic esters. All of the 3-aminoindenones and their aza analogues can be hydrolyzed by acid to give the corresponding 1,3-indandiones. The mechanism of the reaction falls into the directed-ortho-metalation class in which the initial enolate ion of the keto-nitrile directs self-metalation at an ortho position. The new anion then cyclizes onto the nitrile group to generate an aminoindenone. Surprisingly the simplest member of the series, benzoylacetonitrile, does not undergo cyclization. Mechanistic isotope studies revealed that this substance preferentially and directly forms a dianion on the side chain, which is not further deprotonated at the ortho position of the aromatic ring.     

Synthesis and reactions of esters of 3-cyano-2-OXO-5,6-tri(tetra)methylene-1,2-dihydroisonicotinic and 2-amino-3-Ethoxycarbonyl-5,6-tri(tetra)-methyleneisonicotinic acids

Esters of 3-cyano-2-oxo-5, 6-tri (tetra)-methylene-1, 2-dihydroisonicotinic and 2-amino-3-ethoxycarbonyl-5, 6-tri (tetra)methyleneisorticotinic acids have been obtained by the reaction of 2-oxocyclopentyl(hexyl)glyoxylic acid esters with malonic acid derivatives. Boiling the esters containing a tetramethylene ring with 75% sulfuric acid gave hydrolysis of the ester and cyano groups to carboxyl with subsequent decarboxylation at the 3 position and the formation of 2-oxo-5, 6-tetramethylene-1, 2-dihydroisonicotinic acid (2-oxo-1, 2, 5, 6, 7, 8-hexahydroquinoline-4-carboxylic acid).Perm Pharmaceutical Institute, Perm, 614000. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 370–373, March, 1996. Original article submitted July 10, 1995, revision submitted December 26, 1995.     

2-Indolyl ketone synthesis

The preparation of 2-indolyl alkyl ketones by reductive cleavage of a β-keto sulfone or by the reaction of 1-chloro-2-propanone (chloroacetone) with a 2-aminobenzoic acid derivative is described. The β-keto sulfone intermediates are prepared by condensation of the carbanion of dimethyl sulfone and indole-2-carboxylic acid esters. Lack of reactivity of several 2-aminobenzoic acids in the 1-chloro-2-propanone process is related to the presence of electron-withdrawing substituents in the aromatic ring.     

Transformations of bis(2-chloroethyl) arylphosphonites in the presence of haloacetic acid esters

The reaction of aryl(dichloro)phosphines with (2-chloroethoxy)trimethylsilane in the presence of haloacetic acid esters was studied with the goal of developing a new method for the synthesis of ethyl [(2-chloroethoxy)(4-dimethylaminophenyl)phosphoryl]acetate. The effect of various factors, such as substituent in the para position of the aromatic ring in the initial aryl(dichloro)phosphine, halogen nature in haloacetic acid ester, and chloro(trimethyl)silane, on the reaction course was analyzed.     

New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine N-oxides with hexafluoropropene

Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N--O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1-aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.     

Traceless solid-phase synthesis of chiral 3-aryl beta-amino acid containing peptides using a side-chain-tethered beta-amino acid building block

[reaction: see text] A general method for the attachment of a chiral aromatic side-chain-containing beta-amino acid to a polymer support using a traceless silyl linkage strategy has been developed. Using this building block, solid-phase synthesis was carried out to obtain tripeptide analogues with the aromatic ring either unsubstituted or halogenated (Br, I) at the position of the silyl group. The building blocks could generate libraries of peptidomimetics or cyclic peptides containing beta-amino acids with nonpolar side chains.     

An expedient esterification of aromatic carboxylic acids using sodium bromate and sodium hydrogen sulfite

Treatment of aromatic carboxylic acids and substituted toluenes with a mixture of sodium bromate and sodium hydrogen sulfite in a two-phase system gave the corresponding esters in good yield. The intermediate α-brominated toluene was formed by the in situ generated hypobromous acid. The α-bromotoluene underwent an intermolecular nucleophilic substitution reaction with aromatic carboxylic acids present in the reaction mixture to afford the corresponding esters.     

Friedel-Crafts-Type Acylation and Amidation Reactions in Strong Brønsted Acid: Taming Superelectrophiles

In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions, not exhaustively, but mainly based on our research results. The electrophilic species involved are isocyanate cation and acylium cation, respectively, and both have a common ⁺C=O structure, which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However, aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion. Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame the superelectrophilic character.     

New synthesis of α-nitroalkyl- and α-nitroaralkylcarboxylic esters from α-nitroalkyl- and α-nitroaralkyl-2-oxazolines

2-Nitroalkyl- and 2-nitroaralkyl-2-oxazolines are readily converted, in one step, to α-nitroalkyl- and α-nitroaralkylcarboxylic esters on treatment with the appropriate alcohol and trifluoroacetic acid (TFA). The initial products of the ring cleavage are the TFA salts of the ammonioalkyl esters of α-nitroalkyl- and α-nitroaralkylcarboxylic acids. These salts undergo facile transesterification to the α-nitrocarboxylic esters on refluxing with the appropriate alcohol.     

Electrophilic Reaction of Phenyl Bis(Phenylthio) Sulfonium Cation as an Active Species for the Oxidative Polymerization of Diphenyl Disulfide

Computer modeling predicts that the methyl bis(methylthio) sulfonium cation can act as an efficient electrophile for sulfide bond formation in which the sulfur atoms at the side position of the cation react with the phenyl ring of an aromatic molecule. The electrophilic reaction mechanism of phenyl bis-(phenylthio) sulfonium cation with anisole was examined using computer simulation. The reaction between phenyl bis- (phenylthio) sulfonium cation, which is a homogeneous structure of thecation, and anisole shows the efficient formation of 4-phenylthioanisole with diphenyl disulfide as a by-product. In the oxidative polymerization of diphenyl disulfide, the formation process of polyp-phenylene sulfide) includes an elementary reaction between the phenylthio group at each side position of the phenyl bis(phenylthio) sulfonium cation and the carbon at the para position of the phenyl ring.     

Synthesis of some new benzimidazole-5(6)-carboxylic acids

The title compounds, 1,2-dialkyl-benzimidazole-5(6)-carboxylic acids 34–45 were prepared at four steps; 1) preparation of mono amide derivatives 1–11 by the reaction of methyl 3,4-diaminobenzoate and substituted phenyl or phenoxyacetic acid chlorides; 2) preparation of the methyl benzimidazolecarboxyl-ates 12–22 , with zinc chloride and dry hydrogen chloride gas; 3) alkaline hydrolysis of the esters 23–33 ; and 4) substitution of the imidazole ring with benzyl or p-fluorobenzyl bromide, in alkali medium. 2-Aryl-benzimidazole-5(6)-carboxylic acids 50–53 were prepared via the oxidative condensation of 3,4-diaminobenzoic acid and aromatic aldehydes with cupric ion.     

Vinylpyrylation of aromatic compounds

The reaction of β-ethoxyvinylpyrylium salts with aromatic compounds gives styrylpyrylium salts, which are also formed from methylpyrylium salts, ethyl orthoformate, and aromatic compounds. The previously unknown phenomenon of attack by a carbonium cation on the meta position of a benzene ring passivated by a nitro group (nitrobenzene) was detected.     

Organophosphorus chemistry—V : Thermal transformation of the cyclohexylammonium salt of O-aryl N-cyclohexyl phosphoramidic acids into sym-pyrophosphates

The formation of pyrophosphates from phosphorus monoamidates was studied by TGA associated with chromatographic techniques upto 320°. Above this temperature the salts decomposed completely. Other compounds were also formed: diamidophosphoric acid aryl esters, pyrophosphorus amidic acids, cyclohexylamine, phenols and a number of minor thermoproducts. The influence of substituents attached to the aromatic ring on the over-all rate of decomposition reaction showed the order: t-Bu > Me > H > Cl. Anomalous results were found for NO₂. Second order rate constants were measured. A mechanism in two steps is suggested for the reaction investigated. Initial formation of free phosphoramidic acid as proposed by Clark appears to be unnecessary. Pyrolysis stequiometric equation was proposed.     

2-Chloroethylthiol esters of dic arboxylic acids

Mono- and bis(2-chloroethyl)thiol esters of aliphatic, aromatic, and heterocyclic dicarboxylic acids have been obtained by the reaction of the dicarboxylic acid chlorides with ethylene sulfide or 2-chloroethanethiol. The compounds were characterized by their electronic spectra.     

Thermometric titrations of amines with nitrosyl perchlorate in acetonitrile solvent

Thirteen aliphatic and four aromatic amines, namely diethylamine, triethylamine, n-propylamine, di-n-propylamine, tri-n-butylamine, isopropylamine, di-isopropylamine, n-butylamine, di-n-butylamine, tri-n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, aniline, N,N-dimethylaniline, 2-nitroaniline and 4-nitroaniline were titrated thermometrically with nitrosyl perchlorate in acetonitrile solvent. All the aliphatic amines gave very well-shaped thermometric titration curves. The calculated recovery values of the amines were very good. In comparison, the aromatic amines, aniline and N,N-dimethylaniline gave rather well-shaped titration curves, but the recovery values were fairly low. 2-Nitro- and 4-nitro anilines gave no thermometric response at all. The heats of reaction of the amines with nitrosyl perchlorate are rather high. However, the average heat of reaction of the aromatic amines is approximately two-thirds that of the average heat of the aliphatic amines. To support this method all the amines were also titrated potentiometrically and very similar results to those obtained with the thermometric method are seen. The nitrosyl ion is a Lewis acid, strong enough to titrate quantitatively aliphatic amines in acetonitrile solvent, but not strong enough to titrate aromatic amines at the required level in the same solvent.     

Synthesis of Heterocycles from the Products of Anionic Arylation of Unsaturated Compounds. 7. Products of Haloarylation of Acrylic Acid and Its Esters in the Synthesis of Benzo[b]thiophene Derivatives

3-Chloro-2-chlorocarbonylbenzo[b]thiophenes were obtained on oxidation of Meerwein reaction products, viz. 3-aryl-2-halopropionic acids and their esters, with thionyl chloride in the presence of N-benzyl-N-methylmorpholinium chloride. Disubstituted thioureas were synthesized by the reaction of these compounds with ammonium thiocyanate and aromatic amines, and were cyclized by interaction with iodoacetic acid with the formation of 4-thiazolidinone derivatives. The same cyclization in the presence of aromatic aldehydes leads to the formation of the corresponding 5-arylidene-substituted 4-thiazolidinones.     

Solid-phase synthesis of substituted 3-amino-3′-carboxy-tetrahydrocarbazoles

Two related solid-phase synthesis routes have been developed allowing the synthesis of 3-amino-3′-carboxy substituted tetrahydrocarbazole derivatives. Diversity can be introduced at the amino and carboxy functionalities and at the nitrogen and the aromatic ring of the tetrahydrocarbazole moiety. Both routes rely on Fmoc-protected 1-amino-4-oxocyclohexanone carboxylic acid as central core element. Derivatization of the carboxy function is achieved with amines, derivatization of the amino functionality is possible by reaction with alkyl halides, isocyanates, activated alcohols, sulfonic acid chlorides or carboxylic acids. The tetrahydrocarbazole scaffold is generated by Fischer indole cyclization with phenyl hydrazine derivatives, thereby introducing diversity in the aromatic moiety. N-Alkylation at the indole nitrogen with alkyl halides delivers N-substituted derivatives.     

Stereoselective synthesis of 3-alkylideneoxindoles by rhodium-catalyzed cyclization reaction of 2-alkynylaryl isocyanates with aryl- and alkenylboronic acids

The rhodium-catalyzed cyclization reaction of 2-alkynylaryl isocyanates with aryl- and alkenylboronic acids furnishes 3-alkylideneoxindoles in a stereoselective manner. The reaction allows arrangement of various substituents on the exocyclic double bond and aromatic ring with wide functional tolerance.