Quantum chemical studies of azoles 3. Thermodynamic stabilities of neutral molecules and intermediates formed in electrophilic substitution of azoles containing three or four heteroatoms

Density functional theory quantum chemical calculations of thermodynamic stabilities in the gas phase and in water were carried out for 1,3,4-oxadiazole and 1,3,4-thiadiazole, 1,2,4-1H-triazole and 1,2,4-4H-triazole, 1,2,3,4-1H-tetrazole and 1,2,3,4-2H-tetrazole molecules, and for cationic and bipolar (carbenoid) intermediates formed by these molecules in electrophilic substitution reactions (with proton as model electrophile) and the results obtained are compared. Differences in the chemical behavior of pairs of isomeric 1H- and 4H-1,2,4-triazoles and 1H- and 2H-tetrazoles are analyzed.     

2-Nitroguanidine derivatives: XI. Reactions of <Emphasis Type="Italic">N</Emphasis>′-nitrohydrazinecarboximidamide and 2-methylidene-<Emphasis Type="Italic">N</Emphasis>′-nitrohydrazinecarboximidamide with glyoxal

The reaction of glyoxal with N′-nitrohydrazinecarboximidamide (1-amino-2-nitroguanidine) in the presence of sodium hydroxide at a molar ratio of 1 : 1 : 1 gave N′-nitro-2-(2-oxoethylidene)hydrazinecarboximidamide as a mixture of syn and anti isomers, whereas at a reactant ratio of 1:2:2 N′-nitro-2-[(5-nitroamino-2H-1,2,4-triazol-3-yl)methyl]hydrazinecarboximidamide and 3-nitroamino-4,5-dihydro-1,2,4-triazin-5-ol were formed. N′-Nitro-2-(2-oxoethylidene)hydrazinecarboximidamide reacted with N′-nitrohydrazinecarboximidamide in boiling ethanol to give N′-nitro-2-[(5-nitroamino-2H-1,2,4-triazol-3-yl)methyl]hydrazinecarboximidamide, while in glacial acetic acid 2,2′-(ethane-1,2-diylidene)bis(N′-nitrohydrazinecarboximidamide) was obtained. The latter was also formed in the reaction of glyoxal with N′-nitrohydrazinecarboximidamide in acetic acid at room temperature. The reaction of 2-methylidene-N′-nitrohydrazinecarboximidamide with glyoxal led to the formation of 3-nitroimino-2,3,4-5-tetrahydro-1,2,4-triazine-5-carbaldehyde or 1-(methylideneamino)-2-(nitroimino)imidazolidine-4,5-diol, depending on the conditions.     

Hetero-Diels–Alder Reaction of Aroylpyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalinetriones with Styrene

Hetero-Diels–Alder reaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with styrene afforded diastereoisomeric (5R*,6aR*)- and (5S*,6aR*)-3,5-diaryl-5,6-dihydropyrano[4′,3′:2,3]pyrrolo[1,2-a]-quinoxaline-1,2,7(8H)-triones.     

Synthesis and reactions of 3-(3-ethoxycarbonyl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)propenic acid

The reaction of ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carboxylate with the malonic acid led to the formation (2E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-4-yl)propenic acid. In reactions of this acid chloride with 4-amino-5-aryl(hetaryl)-4H-1,2,4-triazole-3-thiols were obtained ethyl 4-[(E)-2-{3-aryl(hetaryl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl}ethenyl]-1-phenyl-1H-pyrazoe-3-carboxylates, with 5-aryltetrazoles, ethyl 4-[(E)-2-(5-aryl-1,3,4-oxadiazol-2-yl)-ethenyl]-1-phenyl-1H-pyrazole-3-carboxylates, with 1-(2-hydroxy-3,5-dimethylphenyl) followed by the Baker-Venkataraman rearrangement and the cyclization, ethyl 4-[(E)-2-(6,8-dimethyl-4-oxo-4Hchromen-2-yl)ethenyl]-1-phenyl-1H-pyrazole-3-carboxylate.     

Synthesis of Pyrano[4′,3′:2,3]pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalines by Reaction of Aroylpyrroloquinoxalines with Alkyl Vinyl Ethers

Thermally induced [4 + 2]-cycloaddition of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with alkyl vinyl ethers afforded mixtures of diastereoisomeric (5S*,6aR*)- and (5R*,6aR*)-5-alkoxy-3-aryl-5,6-dihydropyrano[ 4′,3′: 2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-triones.     

Synthesis of heterocycles from arylation products of unsaturated compounds: XVIII. 5-Arylfuran-2-carboxylic acids and their application in the synthesis of 1,2,4-thiadiazole, 1,3,4-oxadiazole,and [1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazole derivatives

Arylation of furan-2-carboxylic acid or its methyl ester with arenediazonium chlorides in the presence of copper(II) chloride gave the corresponding 5-arylfuran-2-carboxylic acids or methyl 5-arylfuran-2-carboxylates. 5-Arylfuran-2-carbonyl chlorides reacted with potassium thiocyanate and then with 5-methyl-1,2-oxazol-3-amine to give 5-aryl-N-[3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl]furan-2-carboxamides as a result of recyclization of intermediate isoxazolylthiourea derivatives. The reactions of 5-arylfuran-2-carbonyl chlorides with 5-(2-furyl)-1H-tetrazole involved opening of the tetrazole ring with elimination of nitrogen molecule and led to the formation of 2-(5-arylfuran-2-yl)-5-(2-furyl)-1,3,4-oxadiazoles. 3-Substituted 6-(5-arylfuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles were obtained by condensation of 5-arylfuran-2-carboxylic acids with 5-substituted 4-amino-4H-1,2,4-triazole-3-thiols in phosphoryl chloride.     

Synthesis and antimicrobial activity of novel fused [1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indole derivatives

Synthesis of new fused systems of triazino[5,6-b]indole starting with preparation of 3-amino[1,2,4]-triazino[5,6-b]indole 1 by reaction of isatin with 2-aminoguanidinium carbonate in boiling acetic acid is presented [1]. Intermediate compound 1 reacted with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine and gave new heterotetracyclic nitrogen systems, such as 3-(N ²-guanidinylimino)indole-2(1H)-one 2, 3-(N-ethoxycarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 3, 3-(N-ethoxymethyleneamino)-4H-[1,2,4]-triazino[5,6-b]indole 4, 3-(hydrazinothiocarbonylamino)-4H-[1,2,4]triazino[5,6-b]indole 5, respectively. N-(1,3-dioxoindene-2-ylidene)-4H-[1,2,4]triazino[5,6-b]indol-3-amine 6 was synthesized by reaction of compound 1 with aldehyde, ethyl chloroformate, triethyl orthoformate, and ninhydrine. New fused indole systems, pyrimido[2′,1′:3,4][1,2,4]triazino[5,6-b]indol-3(4H)-one 8, 9, 11, 12 and 1H-imidazo[2′,1′:3,4][1,2,4]triazino-[5,6-b]indol-2(3H)-one 10, were synthesized in the reaction of the intermediate 1 with bifunctional compounds. Structures of the products were elucidated from their elemental analysis and spectral data (IR, ¹H and ¹³C NMR and mass spectra). Antimicrobial activity of some synthesized compounds was tested.     

Alkylation of 1,2,4-triazole-3-thiols with haloalkanoic acid esters

Alkylation of 4,5-disubstituted 4H-1,2,4-triazole-3-thiols with methyl chloroformate and ethyl chloroacetate chemoselectively afforded the corresponding S-alkyl derivatives, whereas the alkylation of 5-benzyl-4-phenyl-4H-1,2,4-triazole-3-thiol with methyl 3-bromopropanoate gave an inseparable mixture of S- and N-alkylation products. Hydrazinolysis of S-(5-benzyl-4-phenyl-4H-1,2,4-triazol-3-yl) methyl carbonothioate involved anomalous cleavage with formation of the initial 4,5-disubstituted 1,2,4-triazole and methyl hydrazinecarboxylate.     

Reaction of Imidazoles and Triazoles with 1-(Benzotriazol-1-yl)-2-iodoethanone

Reactions of 2-methyl-1H-imidazole, 1H-benzimidazole, 4H-1,2,4-triazole, and 1H-benzotriazole with 1-(1H-benzotriazol-1-yl)-2-iodoethan-1-one in the absence of a base gave the corresponding N-mono- and N,N′-disubstituted derivatives. 4H-1,2,4-Triazole-3-thiol reacted with 1-(1H-benzotriazol-1-yl)-2-iodoethan-1- one to afford 1-([1,3]thiazolo[2,3-c][1,2,4]triazol-5-yl)-1H-benzotriazolium triiodide.     

Reaction of <Emphasis Type="Italic">o</Emphasis>-Quinones in Cyclohexane Solutions with Alkyl Radicals Generated by Solution γ-Irradiation

The structures of products formed in reactions of tert-butylated o-quinones with alkyl radicals were determined by ¹H and ¹³C NMR and two-dimensional ¹H-¹H NOESY spectroscopy, and also by gas chromatography-mass spectrometry. The major products formed upon γ-irradiation of deaerated solutions of 4-tert-butyl-1,2-benzoquinone and 3,5-di-tert-butyl-1,2-benzoquinone in cyclohexane are monoalkyl ethers and products of addition to the C=C bond. In the case of 4-tert-butyl-1,2-benzoquinone, these are products of mixed O-C and C-C alkylation; the adduct formed by addition of the cyclohexyl radical to the C=C bond in 3,5-di-tert-butyl-1,2-benzoquinone gives an unsymmetrical dimer whose structure was proved by single-crystal X-ray diffraction.     

Study of the reaction of 3,6-di-<Emphasis Type="Italic">tert</Emphasis>-butyl-<Emphasis Type="Italic">о</Emphasis>-benzoquinone with organozinc and organocadmium compounds

The effect of substituents in the reactions of 3,6-di-tert-butyl-о-benzoquinone with organozinc and organocadmium compounds, leading to three types of products: 3-alkyl-6-tert-butyl-о-benzoquinones, 4-alkyl-3,6-di-tert-butyl-о-benzoquinones, and 2-alkoxy-(or 2-phenoxy)-3,6-di-tert-butylphenols. Correlation analysis gave evidence to show that the first- and second-type products are formed by nucleophilic 1,2- and 1,4-addition, while substituted phenols result from single-electron transfer.     

Structure and Reactivity of Bicyclo[2.2.1]hept-2-ene-<Emphasis Type="Italic">endo</Emphasis>-5,<Emphasis Type="Italic">endo</Emphasis>-6-dicarboxylic (endic) Acid Hydrazide

Establishing of the structure of hydrazinolysis product obtained from bicyclo[2.2.1]hept-2-ene-endo-5, endo-6-dicarboxylic (endic) acid was performed by preparation of the compound under alternative conditions followed by comparison of the characteristics and spectral parameters of the resulting substances, and also by quantum-chemical calculations by the density functional method of the chemical shifts in ¹H and ¹³C NMR spectra of different reaction products. The X-ray diffraction analysis of the hydrazide was also carried out. The compound obtained was assigned a structure of N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide. The products were prepared by its reactions with arylsulfonyl chlorides, benzoyl chlorides, m-tolyl and p-toluene-sulfonyl isocyanates, phenyl isothiocyanate, with o-nitrobenzaldehyde, and oxiranes (1,2-epoxycyclohexane and 2,3-epoxypropylcarbazole). The aromatic sulfonamides, carboxamides, and ureas were epoxidized by performic acid obtained in situ from the formic acid and hydrogen peroxide. Products of [3+2]-cycloaddition of aryl azides to the strained double bond in the N-aminobicyclo[2.2.1] hept-2-ene-endo-5,endo-6-dicarboximide and its derivatives. The structures of compounds obtained were confirmed by their IR, 1H and 13C NMR spectra.     

Chemistry of Acyl(imidoyl)ketenes: IX. Synthesis and Thermolysis of 3-Aroyl-8-chloro-1,2-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones

Reactions of 3-Z-aroylmethylene-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-ones with oxalyl chloride afford 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones and Z-3-(2-aryl-2-chlorovinyl)-6-chloro-2H-1,4-benzoxazine-2-ones. Aroyl(imidoyl)ketenes generated by decarbonylation of pyrrolobenzoxazinetriones undergo dimerization through [4+2]-cycloaddition to form 4-aroyl-3-aroyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)-1H, 5H-pyrido[2,1-c][1,4]benzoxazine-1,5-diones.     

3-Methylidene-2,4-dioxo-4-pentafluorophenylbutanoates in the Synthesis of Heterocycles

3-Ethoxy- and 3-arylaminomethylidene-2,4-dioxo-4-pentafluorophenylbutanoates undergo cyclization by the action of hydrazine hydrate and phenylhydrazine to give ethyl 4-pentafluorobenzoylpyrazole-5-carboxylates. The reaction of 3-ethoxymethylidene-2,4-dioxo-4-pentafluorophenylbutanoate with o-phenylene-diamine leads to formation of 3-[2-(2-aminophenylamino)-1-pentafluorobenzoylethenyl]-1,2-dihydroquinoxa-lin-2-one. 3-Arylaminomethylidene-2,4-dioxo-4-pentafluorophenylbutanoates react with o-phenylenediamine to afford 3-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinolin-3-yl)-1,2-dihydroquinoxalin-2-ones and/or 3-(2-arylamino-1-pentafluorobenzoylethenyl)-1,2-dihydroquinoxalin-2-ones.     

Cyclocondensation of 2,2-dichloroethenylbenzamide and its analogs with amidines and hydrogen sulfide in the presence of bases

Available chlorine-containing enamides of the general formula Cl₂C=CHNHCOR (I) easily react with benzamidine and its derivatives to give 1:1 adducts which under heating with sodium methylate transform to 2-(methoxymethyl)-4,5-diaryl-s-triazines. Reaction of compounds (I) with hydrogen sulfide in the presence of triethylamine yields a mixture of products. Only the corresponding 3,5-bis(acylaminomethyl)-1,2,4-tritiolanes were isolated from the reaction mixture in moderate yield.     

Trifluoroacetylation of 3-methyl-1<Emphasis Type="Italic">H</Emphasis>-1,2-diazaphenalenes of the naphthalene and acenaphthene series

Acylation of 3-methyl-1H-1,2-diazaphenalenes of the naphthalene and acenaphthene series with trifluoroacetic anhydride afforded the corresponding N- and C-trifluoroacetyl derivatives and dimerization products of 3-methyl-6-methoxy-1H-1,2-diazaphenalene.     

Synthesis and molecular structure of [2,3,4,5-tetrafluoro-6-(<Emphasis Type="Italic">p</Emphasis>-methoxyphenylamino)phenyl]diphenylphosphine

The reaction of (pentafluorophenyl)diphenylphosphine with C-ethoxycarbonyl-(p-methoxyphenyl) nitrile imine was used to synthesize [2,3,4,5-tetrafluoro-6-(p-methoxyphenylamino)phenyl]diphenylphosphine oxide whose reduction with trichlorosilane gave [2,3,4,5-tetrafluoro-6-(p-methoxyphenylamino)phenyl] diphenylphosphine, the first representative of tertiary ortho-arylamino-substituted arylphosphines. According to X-ray diffraction data, the principal steric characteristics of the phosphine are close to those known for triarylphosphines.     

Synthesis of <Emphasis Type="Italic">N</Emphasis>-aryl-2-methyl-4-oxo-3,4,5,6-tetrahydro-2<Emphasis Type="Italic">H</Emphasis>-2,6-methano-1,3,5-benzoxadiazocine-11-carboxamides

N-Aryl-2-methyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazocine-11-carboxamides were synthesized by three-component reactions of N-aryl-3-oxobutanamides with salicylaldehyde and urea in ethanol in the presence of NaHSO₄ as catalyst. The product structure was determined by IR and ¹H NMR spectroscopy and X-ray analysis.     

Perfluoroepoxyoxolanes in the synthesis of fluorine-containing heterocycles

Perfluoro-3,4-epoxyoxolane and 3,4-epoxy-2-trifluoromethylpentafluorooxolane readily reacted with difunctional nucleophiles via opening of the oxirane ring and subsequent heterocyclization. Their reactions with thiourea and o-phenylenediamine gave new fluorine-containing fused heterocyclic compounds, 2-amino-3a-hydroxy-4,4,6,6,6a-pentafluoro-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]thiazole and 1,1,3,3-tetrafluoro- and 1-trifluoromethyl-1,3,3-trifluoro-1,3-dihydrofuro[3,4-b]quinoxalines, respectively. The molecular and crystalline structures of the products were determined by X-ray analysis.     

Synthesis of nitrogen-containing heterocycles on the basis of 3-(4-acetylphenyl)-1-methylquinolin-2(1<Emphasis Type="Italic">H</Emphasis>)-one

The Meerwein reaction of 1-methylquinolin-2(1H)-one with 4-acetylbenzenediazonium chloride gave 3-(4-acetylphenyl)-1-methylquinolin-2(1H)-one which was brominated to 3-[4-(2-bromoacetyl)phenyl]-1-methylquinolin-2(1H)-one. The latter reacted with pyridine, 4-methylpyridine, quinoline, benzo[f]quinoline, and triphenylphosphine to afford the corresponding quaternary salts, and its reactions with thioacetamide, thiourea, 2-aminopyridine, and 2-aminopyrimidine led to the corresponding thiazole, imidazo[1,2-a]pyridine, and imidazo[1,2-a]pyrimidine derivatives containing a 2-oxoquinoline fragment. 3-(4-{2-[2-(Arylmethylidene)-hydrazinyl]-1,3-thiazol-4-yl}phenyl)-1-methylquinolin-2(1H)-ones were obtained by condensation of 3-[4-(2-bromoacetyl)phenyl]-1-methylquinolin-2(1H)-one with thiosemicarbazide and aromatic aldehydes.