V. O. Kozminykh

Synthesis and Antimicrobial Activity of 2-(2,4-Dinitrophenylhydrazono)-4-oxobutanoic Acids and Related 3-Bromo Derivatives

As is known, aroylpyruvic acids (I) react with amines under mild conditions with the formation of 2-amino derivatives of 4-aryl-4-oxo-2-butenoic acids [1 – 10]. The interaction of aroylpyruvic acids and their esters with some arylhydrazines leads to biologically active deriativers of 1,5-diarylpyrazolo-3-carboxylic acids [2, 3]. Preliminary data on the interactions of acylpyruvic acids with 2,4-dinitrophenylhydrazine were recently reported in [11 – 15]. It was established that acylpyruvic (2-hydroxy-4oxo-2-butenoic) acids (Ia – Ij) react with 2,4-dinitrophenylhydrazine with the formation of 2-(2,4-dinitrophenylhydrazono)-4-oxobutanoic acids (IIa – IIj). Bromination of these products leads to 3-bromo-2-(2,4-dinitrophenylhydrazono)4-oxobutanoic acids (IIIa – IIIf ) (see scheme below). Compounds IIa – IIj and IIIa – IIIf appear as yellow or yellow-orange crystalline substances, which are soluble in DMSO and acetic acid, sparingly soluble in ethanol and benzene, and insoluble in water. The IR spectra of compounds II and III indicate that the reaction products in the crystalline state occur in the form of hydrazones (IIx, IIIx), with the absorption bands of carboxy carbonyl groups observed at = 1670 – 1717 cm – . The H NMR spectra of acids IIa – IIj display doublet signals due to C3H2 protons at = 3.88 – 4.60 ppm and the signals of NH groups in the hydrazine moiety at = 8.85 – 11.35 ppm, which correspond to the IIx and IIy forms. The H NMR spectra of brominated derivatives III (R = Ar) exhibit no signals from methylene protons, but display doublet signals from CH methine protons at = 5.89 – 6.53 ppm corresponding to the IIIx and IIIy forms. The proposed structures of compounds II were also confirmed by the data of mass spectrometry. These compounds cannot have an isomer structure of type IV, since the mass spectra contain intense peaks of the R–C O ions which can appear only upon fragmentation of the structure of type II. This is also indirectly confirmed by the easy heterocyclization of acids II into lactones V. As is known [6, 16], dehydration of 4-aryl-2-[(1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)amino]-4-oxo-2-buten oic acids in the presence of acetic anhydride leads to 4-[(5-aryl-2-oxo-2,3-dihydrofuran-3-ylidene)amino]-1,5-di methyl-2-phenyl-1H-pyrazol-3-ones. No products of cyclization could be isolated from 2-arylamino derivatives of 4-aryl-4-oxo-2-butenoic acids dehydrated under such conditions. We have established for the first time that acids IIa – IIc and IIf – IIi exhibit cyclization under the action of acetic anhydride with the formation of previously unreported furan-2,3-dione 3-(2,4-dinitrophenyl)hydrazones (Va – Vg). Compounds Vb – Vg (R = Ar) cannot be obtained via the direct reaction of 5-aryl-furan-2,3-diones with 2,4-dinitrophenylhydrazine because this interaction yields aroylpyruvic acid (2,4-dinitrophenyl)hydrazides (VI) [14, 15]. Compounds Va – Vg appear as bright red crystalline substances, which are stable on storage, decompose on boiling, and are insoluble in DMSO, acetic acid, ethanol, benzene, and many other solvents. The IR spectra of lactones Va – Vg contain no absorption bands (present in the spectra of initial acids II) due to the stretching vibrations of carboxy groups, but exhibit the characteristic bands at 1786 – 1808 cm – 1 due to the lactone carbonyl groups conjugated with 3-hydrazone units. The H NMR spectra of compounds V contain the signals from CH methine protons in the region of = 6.29 ppm (R = tert-Bu) or 7.08 – 7.20 ppm (R = Ar). The yields and physicochemical characteristics of compounds II, III, and V are given in Table 1, the data of IR and H NMR spectroscopy are presented in Table 2, and the mass spectra are described in the experimental part below. The

Substituted Amides and Hydrazides of Acylpyruvic Acids. Part 9. Synthesis, Antimicrobial and Analgesic Activity of Substituted 4-Aryl-3-halogen-2,4-dioxobutanoic Acid Amides

As is known, aroylpyruvic acid esters (Ix, Iy) and amides (IIx, IIy) exhibit a broad spectrum of pharmacological properties, including anticonvulsant [2 – 4], antiinflammatory [2, 5], analgesic [2, 5, 6], and antimicrobial [3, 5, 7] activity, at a low toxicity [2 – 6]. It was reported that halogenation of aroylpyruvic acid esters (I) leads to the formation of 3-substituted halogen derivatives (III) not enolized at the -dicarbonyl fragment. In comparison with the initial acid esters (I), the 3-halogen-substituted analogs (III) exhibit higher bacteriostatic [8, 9] and analgesic [10] activity. According to our data, chlorination of some aroylpyruvic acid arylamides II leads (with preparative yield) to the formation of biologically active 4-aryl-2,4-dioxo-3-chlorobutanoic acid amides (IV, Hal = Cl) [11]. In continuation of our previous investigations of the biological activity of halogen-containing amides IV, we have reacted substituted aroylpyruvic acid amides II with bromine and chlorine under mild conditions, isolated a series of new 4-aryl-3-halogen2,4-dioxobutanoic acid amides (IVa – IVo) [12 – 14], and studied their pharmacological properties. Compound R R Hal

Synthesis, Antimicrobial, and Analgesic Activity of 4-Aryl-2-N-morpholino-4-oxo-2-butenoic Acids

As is known, aroylpyruvic acids (I) attach amines under mild conditions at the carbonyl group in position C with the formation of substituted 2-amino-4-aryl-4-oxo-2-butenoic acids [1 – 7]. Previously, it was reported that 2-cyclohexylamino, some 2-arylamino, and 2-heterylamino-4-aryl-4oxo-2-butenoic acids exhibit moderate antimicrobial [6] and analgesic activity [6, 7]. In continuation of the search for biologically active substances among substituted 2-amino-4-aryl-4-oxo-2-butenoic acids, we have synthesized a series of 4-aryl-2-N-morpholino-4-oxo-2-butenoic acids (IIa – IIf ) via interaction of aroylpyruvic acids (Ia – If ) with morpholine [8]. Compounds IIa – IIf appear as colorless crystalline substances, which are soluble in DMSO, sparingly soluble in ethanol and benzene, and insoluble in water.

1,3,4,6-tetracarbonyl systems. Part 8. Synthesis and antimicrobial activity of 2(5)-halogenated derivatives of 1,3,4,6-tetracarbonyl compounds

A series of 1,6-disubstituted 2,5-dibromohexan-1,3,4,6-tetraones and 2,2,5,5-tetrahalogenohexan-1,3,4,6-tetraones have been obtained by the treatment of 1,6-disubstituted hexane-1,3,4,6-tetraones with bromine and chlorine. Bromination of (4Z)-6-aryl-3,4-dihydroxy-6-oxohexa-2,4-dienamides led to (2Z,4E)-2-aminocarbonyl-6-aryl-5-bromo-3,4-dihydroxy-6-oxohexa-2,4-dienoates and 6-aryl-2,5-dibromo-3,4,6-trioxohexanamides in preparative yield. The proposed structures of the reaction products were confirmed by IR, UV, 1H and 13C NMR, and mass spectrometry. The bacteriostatic activity and acute toxicity of the synthesized compounds have been studied.

Reaction of 2-(2-oxoethylidene)furan-3(2H)-ones with isopropylidenehydrazides of aromatic carboxylic acids: Synthesis of 3-hydroxy-3-(2-oxoethyl)-2,3-dihydropyridazin-4(1H)-ones

Abstract3-Hydroxy-3-(2-oxoethyl)-6-phenyl-2,3-dihydropyridazin-4(1H)-ones were obtained by the reaction of methyl 3-oxo-5-phenylfuran-2(3H)-ylideneacetate or 2-[2-(4-chlorophenyl)-2-oxoethylidene]-5-phenylfuran-3(2H)-one with benzoic or p-nitrobenzoic isopropylidenehydrazides. Equilibrium C(5)H and C(5)H2 tautomeric forms were detected in solutions of the 4-chlorophenyl derivatives in DMSO-d6.

Substituted Amides and Hydrazides of Acylpyruvic Acids. Part 10. Synthesis, Antimicrobial and Analgesic Activity of 4-Aryl-2-arylamino-4-oxo-2-butenoic Acid Arylamides

As is known, aroylpyruvic acid amides exhibit a broad spectrum of pharmacological properties, including antimicrobial [2 – 7], antiinflammatory [6, 7], analgesic [3 – 7], and anticonvulsant [5] activity, with low toxicity [2, 3, 5 – 7]. It was reported [8 – 10] that aroylpyruvic acid arylamides (I) are capable of adding aromatic amines at the carbonyl group in position 2 under mild conditions with the formation of 4-aryl-2-arylamino-4-oxo-2-butenoic acid arylamides (II). However, the biological activity of such arylamides remain unstudied. In order to fill this gap and in continuation of the search for new biologically active compounds, we have synthesized a series of 4-aryl-2-arylamino-4-oxo-2-butenoic acid arylamides (IIa – IIh) [11, 12] using reactions of aroylpyruvic acid arylamides (Ia – Ie) with aromatic amines and studied some pharmacological properties of the obtained compounds. The yields and physicochemical characteristics of compounds IIa – IIh are presented in Table 1. The proposed structures were confirmed by the results of IR and H NMR spectroscopy measurements (Tables 1 and 2). The IR spectra of compounds II (except for IIc) display absorption bands at = 1673 – 1711 cm – , assigned to the stretching vibrations of amide carbonyl and ester groups, and a broad absorption band at 1551 – 1644 cm – , which is characteristic of the NH-chelate cycle. The H NMR spectra of compound IIb, as well as the spectra of the initial amides I, contain a marker signal from CH methine protons of the Z-enamine form (IIZ) at = 6.65 – 6.76 ppm. In addition, these spectra display the signals from two geminal protons of the C3H2 group ( = 4.49 – 4.56 ppm) corresponding to the minor X-imine form (IIX). The spectra of compounds IIa and IId – IIh exhibit no signals of the IIX form, which is indicative of complete enolization in these compounds (in good agreement with the known data [10]). In addition, the spectra of compounds IIa, IIb, and IId showed the presence of E-form (IIE) characterized by the signal of methine proton CH at = 6.22 – 6.56 ppm.

Dioxobutanoic and 2-Arylamino-4-oxo-butenoic Acids

As is known, halogenation of esters and amides of aroylpyruvic acids (I) leads to the formation of 3-halogensubstituted derivatives (II) [1 – 6]. In contrast to the initial esters and amides, derivatives II possess bacteriostatic [1, 2, 4, 6, 7] and analgesic [3, 6, 8] properties at a relatively low toxicity [6]. Halogenation of acylpyruvic acids (III) and their 2-imino derivatives (2-arylamino-4-oxo-2-butenoic acids, IV) has never been studied, except for the bromination of cynnamoylpyruvic acid (whereby bromine is attached at the double bond of the styryl unit) [9].