Synthesis and biological activity of new hybrids compounds derived from benzofuroxanes and polyene antibiotics

Hybrid compounds based on 4,6-dichloro-5-nitrobenzofuroxan, 7-chloro-4,6-dinitrobenzofuroxan, 5,7-dichloro-4,6-dinitrobenzofuroxan, and polyene antibiotics (amphotericin B and nystatin) have been prepared for the first time. They have exhibited biological activity comparable to that of starting antibiotics. Activity of the compound derived from 5,7-dichloro-4,6-dinitrobenzofuroxan and nystatin towards Trichophyton mentagrophytes is 4 times higher than that of nystatin.     

Synthesis and investigation of antimicrobial activity of compounds derived from benzo[C][1,2,5]oxadiazole-1-oxides and phenolates

(Di)chloro(di)nitrobenzofuroxans form substitution products involving carbon atoms with phenolates in isopropyl alcohol medium. In the case of 4,6-dinitro-5,7-dichlorobenzofuroxan, besides replacement of one chlorine atom and the formation of C-bonded product, we observed the hydrolysis of the second chlorine and replacement of it by hydroxyl group. Products of reaction of 4,6-dichloro-5-nitrobenzofuroxan with phenolates display excellent antimicrobial activity and have dual action, both against bacteria and fungi.     

Reactions of 5,7-Dichloro-4,6-dinitrobenzofuroxane and -furazane with Triphenylphosphine

Reactions of 5,7-dichloro-4,6-dinitrobenzofuroxane and 5,7-dichloro-4,6-dinitrobenzofurazane with triphenylphosphine proceed through a nucleophilic aromatic substitution of chlorine and nitro groups in the sixmembered ring of the heterocycles. The structure of the phosphorylation products was established from the IR, ³¹P NMR, and mass spectra and from XRD and elemental analysis. Schemes of the routes of the phosphorylation are discussed.     

Synthesis of 5,7-dichloro-2H-1-benzopyran-2-ol

The reaction of 4,6-dichloro-2-(methylthiomethoxy)cinnamaldehyde ( 3 ) or 4,6-dichloro-2-hydroxycinnamaldehyde ( 5 ) with mercuric chloride in hot aqueous acetonitrile gave 5,7-dichloro-2H-1-benzyopyran-2-ol ( 4 ) in good yield.     

Structural Revision and Elucidation of the Biosynthesis of Hypodoratoxide by 13C,13C COSY NMR Spectroscopy

Feeding of (2,3,4,5,6‐¹³C₅)mevalonolactone to the fungus Hypomyces odoratus resulted in a completely labeled sesquiterpene ether. The connectivity of the carbon atoms was easily deduced from a ¹³C,¹³C COSY spectrum, revealing a structure that was different from the previously reported structure of hypodoratoxide, even though the reported ¹³C NMR data matched. A structural revision of hypodoratoxide is thus presented. Its absolute configuration was tentatively assigned from its co‐metabolite cis‐dihydroagarofuran. Its biosynthesis was investigated by feeding of (3‐¹³C)‐ and (4,6‐¹³C₂)mevalonolactone, which gave insights into the complex rearrangement of the carbon skeleton during terpene cyclization by analysis of the ¹³C,¹³C couplings.     

Synthesis and Characterization of Some Ruthenium Mixed-Ligand Complexes

The complexation reaction of trans-[RuCl₂(Dpte)₂] (Dpte – (diphenylthio)ethane) with mixed diimine ligands 2,2"-bipyridine, pyridylquinoline, 4,6-dichloro-2-(2-pyridyl)pyrimidine, 4,6-dichloro-5-methyl-2-(2-pyridyl)pyrimidine, and 4,6-dichloro-5-phenyl-2-(2-pyridyl)pyrimidine produces new Ru(II) mixed-ligand complexes. These complexes exhibit maximum photo- and chemical stability and high absorptivity. The above complexes have been characterized using IR, ¹H and ¹³C NMR, electronic absorption spectroscopy, and elemental analysis.     

Synthesis,Structure, and Antimicrobial Activity of the Reaction Products of Chloronitro-Substituted Benzofurazanes and Benzofuroxanes with Morpholine

New amination reactions of morpholine with a series of chloronitro-substituted benzofurazanes and -furoxanes were studied. The reactions of morpholine with 5,7-dichloro-4,6-dinitrobenzofuroxane and 4-chloro-5-nitro- and 5-chloro-4-nitrobenzofurazanes gave products of the aromatic nucleophilic substitution of the chlorine substituents in the nitrogenous heterocycles. The composition and structure of the products were established by chemical, physical, and physicochemical methods. The reaction of morpholine with 4,6-dinitrobenzofuroxane gave a stable Meisenheimer σ-complex, the structure of which was assessed by X-ray diffraction analysis. The synthesized compounds showed high antibacterial and antimycotic activities toward pathogenic human and animal microflora.     

Reaction of dichloronitrobenzofuroxanes with amines and their derivatives

Reactions of 4,6-dichloro-5,7-dinitrobenzofuroxane and 4,6-dichloro-5-nitrobenzofuroxane with some aliphatic amines were studied. In the reaction of 4,6-dichloro-5,7-dinitrobenzofuroxane with 2,2-dimetoxyethylmethylamine the monosubstituted product was formed for the first time. In the reactions of 4,6-dichloro-5-nitrobenzofuroxane with amines substitution only of one chlorine atom takes place.     

The Structure of New Host Molecules that form Channel Inclusion Compounds

1,3-Benzenediamine,N,N′-bis(4,6-dichloro-1,3,5-triazine-2-yl) and 1,3,5-Triazine,2,2′-[2-methyl-1,3-phenylenebis(oxy)] bis(4,6-dichloro) were synthesized as host molecules. The inclusion compound of 1,3-Benzenediamine,N,N′-bis(4,6-dichloro-1,3,5-triazine-2-yl) crystallizes in the monoclinic crystal system in space group C2/c. The host molecule occupies the space group 2-fold special position and packed in the crystal lattice in such a manner as to leave channels running along the c axis of a rectangular cross-section. It crystallizes with two molecules of acetone that are hydrogen bonded to the amino nitrogen atoms. Molecules of 1,3,5-Triazine,2,2′-[2-methyl-1,3-phenylene bis(oxy)]bis(4,6-dichloro) are packed in the crystal in such a manner as to leave channels of a trapezoid cross-section that are running along the a axis. Guest molecules such as metanol, ethanol, and ethyl acetate can be used to fill the channels. The crystal structures of two inclusion compounds are described.     

Nucleophilic substitution reactions of 2,4,6-tris(trinitromethyl)-1,3,5-triazine. 2. interaction of 2,4,6-tris(trinitromethyl)-1,3,5-triazine with primary amines and hexamethyldisilazane

2-R-amino-4,6-bis (trinitromethyl)-1,3,5-triazines have been synthesized, and their structures have been established. Dynamic¹³C NMR spectroscopy has been used to measure the rotational barriers of the tertbutylamino group around the C₍₂₎-NHBu-t bond in 2-(tert-butylamino)-4,6-dichloro-1, 3, 5-triazine and 2-(tertbutylamino)-4,6-dimethoxy-1,3,5-triazine. X-ray diffraction was used to investigate the structure of 2-(tertbutylamino)-4,6-bis (trinitromethyl)-1,3,5-triazine. From the results obtained in this work it has been concluded that the bond between the NHBu-t group and the triazine ring has a partial double-bond character.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from ] Khimiya Geterotsikiicheskikh Soedinenii, No. 5, pp. 679–688 May, 1995. Original article submitted March 7, 1995.     

Sorption–Chromatographic Determination of Aniline, 4-Chloroaniline, and 2,5-Dichloroaniline in Air

Conditions were found for the chemisorption preconcentration of aniline, 4-chloroaniline, and 2,5-dichloroaniline from air using tubes packed with silica gel with immobilized 4-chloro-5,7-dinitrobenzofurazan and for the subsequent HPLC determination with diode-array detection. The maximum analyte recoveries (98, 90, and 75% for aniline, 4-chloroaniline, and 2,5-dichloroaniline, respectively) were achieved at a 2-cm thickness of the adsorbent layer (silica gel with a grain size of 0.1–0.3 mm impregnated with 3 wt % 4-chloro-5,7-dinitrobenzofurazan), an aspiration rate of 0.6–0.8 L/min, and an aspirated air volume of 10 L. Taking into account a tenfold preconcentration of analytes after the desorption, the detection limit for aniline is equal to 0.0007 mg/m³.     

Hydrogen‐bonded supramolecular motifs in 2‐amino‐4,6‐dimethoxypyrimidinium picrate and pyrimethaminium picrate dimethyl sulfoxide solvate

In the crystal structures of 2‐amino‐4,6‐dimethoxypyrimidinium 2,4,6‐trinitrophenolate (picrate), C₆H₁₀N₃O₂⁺·C₆H₂N₃O₇⁻, (I), and 2,4‐diamino‐5‐(4‐chlorophenyl)‐6‐ethylpyrimidin‐1‐ium (pyrimethaminium or PMN) picrate dimethyl sulfoxide solvate, C₁₂H₁₄ClN₄⁺·C₆H₂N₃O₇⁻·C₂H₆OS, (II), the 2‐amino‐4,6‐dimethoxypyrimidine and PMN cations are protonated at one of the pyrimidine N atoms. The picrate anion interacts with the protonated cations through bifurcated N—H...O hydrogen bonds, forming R₂¹(6) and R₁²(6) ring motifs. In (I), Z′ = 2. In (II), two inversion‐related PMN cations are connected through a pair of N—H...N hydrogen bonds involving the 4‐amino group and the uncharged N atom of the pyrimidine ring, forming a cyclic hydrogen‐bonded R₂²(8) motif. In addition to the pairing, the O atom of the dimethyl sulfoxide solvent molecule bridges the 2‐amino and 4‐amino groups on both sides of the paired bases, resulting in a self‐complementary …DADA… array of quadruple hydrogen‐bonding patterns.     

The behaviour of perchloro-3,4-dimethylenecyclobutene,-pentafulvene and- pentafulv-alene under electron-impact

The mass spectra of 1,2-dichloro-3,4-bis(dichloromethylene)cyclobutene (IV) and of hexachloropentafulvene (II) have been studied. Compound IV cannot be an intermediate in the formation of II from octachloro-1,2-dimethylenecyclobutane (III) under electron-impact, as previously suggested. In the mass spectra of II and IV the species [C₆]⁺ and [C₅]⁺ occur, obviously through cleavage of the semicyclic C-C bond. The mass spectrum of pentachlorofulvalene (VI) shows strikingly that successive elimination of an even number of CI atoms is preferred over that of an odd number of CI atoms; probably corresponding C-CI bonds in the two rings are broken simultaneously. Amongst the fragments, the species [C₁₀]⁺ and [C₇]⁺ and possibly also [C₈]⁺ and [C₉]⁺ have been observed.     

Sorption-chromatographic determination of hydrazine and its substituted derivatives in air

Working conditions were found for the chemisorption preconcentration of hydrazine, phenylhydrazine, and 1,1-dimethylhydrazine from air with tubes containing silica gel with immobilized 4-chloro-5,7-dinitrobenzofurazan and the subsequent determination by high-performance liquid chromatography with diode array detection. A recovery of 98% (hydrazine), 90% (phenylhydrazine), and 97% (1,1-dimethylhydrazine) is attained at a thickness of the sorbent layer of 2 cm, an aspiration rate of 0.2–0.8 L/min, and a volume of aspirated air of 10 L. Silica gel with a particle size of 0.1–0.3 mm impregnated with 4-chloro-5,7-dinitrobenzofurazan (2 wt %) was used as the sorbent. The detection limits of compounds without regard for preconcentration after their desorption are 0.01 (hydrazine), 0.017 (1,1-dimethylhydrazine), and 0.015 mg/m³ (phenylhydrazine).     

Synthesis of 5-(4,6-dimethyl-2-pyrimidinyl)-1,3,4-oxadiazole-2-thione and its alkylation,aminomethylation, and acylation

The reaction of the hydrazide of 4,6-dimethyl-2-pyrimidinecarboxylic acid with potassium ethylxnthate gave 5-(4,6-dimethyl-2-pyrimidinyl)-1,3,4-oxadiazole-2-thione. The alkylation of this product in an alkaline medium proceeds at the sulfur atom, while the aminomethylation and acylation proceed at the nitrogen atom. The major criterion for the structure of the S- and N-derivatives is the chemical shift of C₍₂₎ in the 1,3,4-oxadiazole ring in the ¹³C NMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700–705, May, 1993.     

Hydrogen‐bonding and π–π inter­actions in 2‐amino‐4,6‐dimethyl­pyrimidinium salicylate

In the crystal structure of the title compound, C₆H₁₀N₃⁺·C₇H₅O₃⁻, the asymmetric unit contains four crystallographically independent 2‐amino‐4,6‐dimethyl­pyrimidinium and salicylate ions (Z = 8). In each of these, one of the pyrimidine N atoms is protonated, and the carboxyl­ate group of the salicylate ion inter­acts with the pyrimidine group through a pair of N—H⋯O hydrogen bonds, forming an R₂²(8) motif. The pyrimidine cations also form base pairs via a pair of N—H⋯N hydrogen bonds (involving the amino group and the unprotonated ring N atom), forming another R₂²(8) motif. Three such R₂²(8) motifs, fused together, constitute a closed cyclic aggregate, and the linking of these aggregates, arranged in consecutive layers, can be analysed in terms of off‐face stacking inter­actions.     

High-performance liquid chromatography of 5,7-dinitrobenzofurazan and nitrobenzodifurazan derivatives of aromatic amines

The retention times of 5,7-dinitrobenzofurazan and nitrobenzodifurazan derivatives of aromatic amines in reversed-phase high-performance liquid chromatography on a column filled with Hypersil ODS correlate with the acidity constants of these derivatives in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) and with the σ constants of substituents in the aromatic nucleus. Procedures were developed for the determination of aniline, N-methylaniline, N,N-dimethylaniline, and N-ethylaniline as their 5,7-dinitrobenzofurazan and nitrobenzodifurazan derivatives with detection limits of 70 μg/mL. The procedures can be used for the analysis of reaction mixtures in the synthesis of these substituted amines.     

2,4‐Diamino‐5‐(1‐naphthyl)‐3,5‐diaza‐1‐azoniaspiro[5.5]undeca‐1,3‐diene chloride

The title salt, C₁₈H₂₂N₅⁺·Cl^?, is a member of a new series of lipophilic 4,6‐di­amino spiro‐s‐triazines which are potent in­hib­itors of di­hydro­folate reductase. The protonated triazine ring deviates from planarity, whereas the cyclo­hexane ring adopts a chair conformation. A rather unusual hydrogen‐bonding scheme exists in the crystal. There is a centrosymmetric arrangement involving two amino groups and two triazine ring N atoms, with graph‐set R(8) and an N?N distance of 3.098 (3) Å, flanked by two additional R(8) systems, involving two amino groups, a triazine ring N atom and a Cl^? anion, with N?Cl distances in the range 3.179 (2)–3.278 (2) Å. Furthermore, the Cl^? anion, the protonated triazine ring N atom and an amino group form a hydrogen‐bonding system with graph‐set R(6).     

Extraction-chromatographic determination of hydrazine in natural water as a 5,7-Dinitrobenzofurazan derivative using diode-array detection

The conditions for the derivatization of hydrazine withp-dimethylaminobenzaldehyde and 4-chloro-5,7-dinitrobenzofurazan, extraction preconcentration of derivatives from natural water, and HPLC determination of the toxicant with diode-array detection were studied. The 5,7-dinitrobenzofurazan derivative was quantitatively extracted from water with isoamyl alcohol and a mixture of isoamyl alcohol with methylene chloride at pH 3–4. A procedure was developed for the extraction-chromatographic determination of hydrazine in water with c_min = 0.05 Μg/L and the analytical range 0.12-60 Μg/L. The concentration of hydrazine in lake Kaban water was determined.