Synthesis and properties of pyrazole carbaldehyde bis(2-hydroxyethyl)-dithioacetal hydrochlorides*

A simple method has been developed for the synthesis of water-soluble pyrazole derivatives, namely 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles hydrochlorides, by the reaction of a series of pyrazole carbaldehydes with 2-mercaptoethanol in the presence of trimethylchlorosilane. When treated with aqueous ammonia solution the pyrazole-4-carbaldehydes bis(2-hydroxyethyl)dithioacetal hydro-chlorides are converted to the 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazole free bases.     

Electrosynthesis of 4-bromosubstituted pyrazole and its derivatives

Electrosynthesis of 4-bromosubstituted pyrazole and its derivatives was carried out by bromination of initial pyrazoles on Pt anode in NaBr aqueous solutions under the conditions of diaphragm galvanostatic electrolysis. A donor substituent (Me or Et) in pyrazole ring was shown to promote to the bromination process, while an acceptor substituent (NO₂ or COOH) does not produce a significant effect to this process. Thus, the yield of 4-bromosubstituted derivatives from bromination of 3,5-dimethylpyrazole, 1,5-dimethylpyrazole, 3-nitropyrazole, pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-3-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 1-ethylpyrazole-5-carboxylic acid, and 1-methylpyrazole-3,5-dicarboxylic acid amounted 70, 94, 88, 89, 84, 78, 89, and 84%, respectively.     

A facile synthesis of certain 4- and 4,5-disubstituted 1-β-d-ribofuranosylpyrazoles

A number of pyrazole ribonucleosides, structurally related to AICA riboside and ribavirin have been prepared and evaluated for their biological activity in vitro. Deisopropylidenation of 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 6 ) with aqueous trifluoroacetic acid gave 5-amino-1-(β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 7 ). Conventional transformation of the carbonitrile function of 7 gave the AICA riboside congener ( 2 ) and related 5-amino-1-(β-D-ribofuranosyl)-pyrazoles ( 8–10 ). Acetylation of 7 at low temperature gave the versatile intermediate 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 15 ). Non-aqueous diazotization of 15 with isoamylnitrite in dibromomethane or diiodomethane gave the corresponding C₅-bromo 13 and C₅-iodo 16 derivatives. Compounds 13 and 16 were subsequently transformed into 5-bromo-1-(β-D-ribofuranosyl)pyrazole-4-carboxamide ( 11 ) and the 5-iodo analog 25 . However, a similar nonaqueous diazotization of 15 in dichloromethane afforded the deaminated product 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 22 ). Treatment of 22 with ammonium hydroxide/hydrogen peroxide gave the ribavirin congener 1-(β-D-ribofuranosyl)pyrazole-4-carboxamide ( 18 ). Similar treatment of 22 with hydrogen sulfide in pyridine or hydroxylamine in ethanol gave the 4-thiocarboxamide 19 and 4-carboxamidoxime 20 derivatives, respectively. Catalytic hydrogenation of 20 afforded 1[β-D-ribofuranosyl)pyrazole-4-carboxamidine ( 21 ). These pyrazole nucleosides are devoid of any significant antiviral or antitumor activity in vitro.     

Pyrazolo[1,5-d]triazines-1,2,4. I. Dérivés pyrazoliques

Pyrazole hydrazides and hydrazines were synthesized from pyrazole-5-carboxylic acid, 4-bromopyrazole-5-carboxylic acid and pyrazole-5-carboxaldehyde. The 5-pyrazolyloxadiazoles and 5-pyrazolylthiadiazoles were obtained by cyclising the pyrazole hydrazides with phosphorus oxychloride and tetraphosphorus decasulphide. Cyclisations in 1,2-dihydro-1-oxo- (or l-thioxo)pyrazolo[1,5-d]-1,2,4-triazines were eventually observed. The structures were assignated by nmr.     

Electrosynthesis of pyrazole-4-carboxylic acids by oxidation of 4-formylpyrazoles on NiO(OH)-electrode in aqueous alkaline solution

Electrochemical oxidation of di- and trisubstituted 4-formylpyrazoles on a Ni-anode in aqueous alkali led to the formation of the corresponding pyrazole-4-carboxylic acid in 60–90% yields. The yields of the target products depend on position of substituent in the pyrazole ring and are decreased in the following sequence of substituent at position 1 Me > Et > Ph, as well as when the aqueous medium was replaced with aqueous alcohol (50% Bu^tOH). Oxidation of 4-formylpyrazoles containing Me groups at the carbon atoms of the pyrazole ring led, to monoacids and also pyrazoledicarboxylic acids in small (1.5–14%) amounts; the latter were the oxidation products of the aldehyde and the Me groups.     

Efficient iodination of structurally varying pyrazoles in heterophase medium

A synthesis of 4-iodo-substituted pyrazoles by iodination of pyrazole and its derivatives in the heterophase (H₂O/CHCl₃ (CCl₄)) medium with the system KI-KIO₃ in the presence of H₂SO₄ additives was accomplished. The yields of 4-iodo-substituted pyrazoles in the iodination of pyrazole, 3,5-dimethylpyrazole, pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-3-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 3-nitropyrazole, 1-methyl-3-nitropyrazole, 1-methylpyrazole, 1-ethylpyrazole, and 1-isopropylpyrazole were within 80–97%, whereas in the case of 3-nitropyrazole-5-carboxylic acid it was 32%.     

A new synthesis of 1,5-dihydropyridazino[3,4-b]quinoxalines and 2-(pyrazol-4-yl)quinoxalines

The reaction of 6-chloro-2-(l-methylhydrazino)quinoxaline 1-oxide 3 with acetylenedicarboxylates gave the 8-chloro-1-memyl-1,5-dihydropyridazino[3,4-b]quinoxaline-3,4-dicarboxylates 4a,b and 2-(pyrazol-4-yl)quinoxaline 1-oxides 5a,b . The formation of compounds 4a,b would follow the 1,3-dipolar cycloaddition reaction, subsequent 1,2-hydrazino migration, and then dehydrative cyclization, while the production of compounds 5a,b would proceed via the addition of the hydrazino group to acetylene-dicarboxylate leading to the construction of a pyrazole ring, followed by rearrangement of the pyrazole ring. Compounds 5a,b were deoxidized with phosphoryl chloride/N,N-dimethylformamide to change into the 4-(quinoxalin-2-yl)pyrazole-3-carboxylates 8a,b .     

Microwave versus ultrasound assisted synthesis of some new heterocycles based on pyrazolone moiety

Different pyrazolone derivatives were prepared by microwave irradiation and ultrasound assisted methods besides the traditional ones. They were used for synthesis of some derivatives of spiropiperidine-4,4′-pyrano[2,3-c]pyrazole, dihydropyrano[2,3-c]pyrazole, pyrazole-4-carbothioamide, 4-(2-oxo-1,2-diphenylethylidene)-1H-pyrazol-5(4H)-one, azopyrazole, arylmethylenebis-1H-pyrazol-5-ol and araylidene-1H-pyrazol-5(4H)-one via reactions with different reagents applying the ultrasound method in some cases.     

Electrosynthesis of 4-iodopyrazole and its derivatives

Electrosynthesis of 4-iodo-substituted pyrazoles has been accomplished by iodination of the corresponding precursors on a Pt-anode in aqueous solutions of KI under conditions of the diaphragm galvanostatic electrolysis. Efficiency of the process depends on the donor-acceptor properties of substituents and their positions in the pyrazole ring. Thus, iodination of pyrazole, 3,5-dimethylpyrazole, 3-nitropyrazole, 1-methylpyrazole, 1,3-dimethylpyrazole, pyrazole-3(5)-carboxylic acid or methyl esters furnished 4-iodo derivatives in 57, 86, 2, 5, 35, 30, and 40% yields, respectively.     

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole,pyrazole and/or pyridine ring systems

A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4-aminobenzohydrazide as link-bridge. The synthetic strategy of nicotinonitrile-thiazole analogues involves cyclization of the precursor N-phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2-((4-(pyrazole-1-carbonyl)phenyl)amino)-nicotinonitrile derivatives 9–10 . The 2-((4-(4-thiazolylidene-pyrazole-1-carbonyl)-phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6-amino-4-aryl-3,5-dicyano-2-oxo-1-(4-substitutedbenzamido)-pyridines 19 were synthesized by Knoevenagel condensation N′-(2-cyanoacetyl)-benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile-thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.     

Synthesis of pyrazole derivatives as potential bioisosteres of thromboxane-synthetase inhibitors

A series of ω-carboalkenyl pyrazole derivatives have been synthesized as potential thromboxane-synthetase inhibitors considering the close bioisosteric relationship between the pyrazole ring and other heteroaromatic carboalkenyl compounds exhibiting inhibitory activity. (E)-7-(1-Phenylpyrazol-4-yl)hept-2-enoic acid (4b) were prepared in 28% overall yield from its minor bis-homologue, (E)-5-(1-phenylpyrazol-4-yl)pent-2-enoic acid (4a) , obtained from 4-formyl-1-phenylpyrazole (6) in 17% overall yield. Compounds 4a, 4b, 7, 8 and 13 were screened for their ability to inhibit the in vitro rabbit blood platelet aggregation induced by collagen using the Born test. Among the active compounds 4a exhibited an important inhibition at 1 μM concentration.     

Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.     

Iodonium derivatives of heterocyclic compounds

A method for the preparation of phenyliodonium derivatives of pyrazoles was developed. The reaction of pyrazole and 3,5-dimethyl- and 3,5-diphenylpyrazoles with phenyl iodosoacetate in the presence of p-toluenesulfonic acid gives pyrazole-4-phenyliodonium tosylates, which are converted to pyrazole-4-phenyliodonium betaines on treatment with alkali. The tosylates are converted to pyrazole-4-phenyliodonium chlorides, bromides, and iodides by exchange reactions, and pyrazole-4-phenyliodonium fluorides and borofluorides are obtained by reaction of the betaines with hydrofluoric and fluoboric acids. The ionization constants for a number of phenyliodonium derivatives of pyrazoles were calculated on the basis of the electronic absorption spectra. The 4-phenyliodonium grouping increases the acidity of pyrazoles by 4.5–5 orders of magnitude.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 245–248, February, 1973.     

Unsaturated lactones

New, biologically active pyrazole derivatives containing an unsaturated -lactone ring were obtained by condensation of 2-(1-etboxycarbonyl-1,3-diketopropyl)-2-buten-4-olides with phenylhydrazine and hydrazine hydrate. A number of transformations of the resulting pyrazole-3-carboxylic acid esters were realized.See [1] for communication XXXIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1611–1614, December, 1978.     

Design,synthesis and insecticidal activities of novel 1-substituted-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives

A series of novel 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives(6a–6n, 7a, 7b, and 8a-8f)were synthesised by placing the amide bond at the 4-position of the pyrazole ring. These derivatives differed from the structure of chlorantraniliprole analogues with the amide bond at the 5-position of the pyrazole ring. Preliminary bioassay results revealed that a few title compounds exhibited good insecticidal activities against lepidopteran pests, such as Plutella xylostella, Mythimna separate, Heliothis armigera, and Ostrinia nubilalis. Some title compounds also elicited broad-spectrum insecticidal activities against dipterous insects including Culex pipiens pallens after altering the amide position. Similar to pyrazole-5-carboxamide analogues, compounds 6b and 6e showed 100% insecticidal activity against P. xylostella, C. pipiens pallens, and M. separate at concentrations of 200, 2, and 200 mg/m L, respectively.This finding suggested that 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives are potential alternative insecticides for management of agriculture pests.     

Electrosynthesis of 4-chloropyrazolecarboxylic acids

4-Chlorosubstituted pyrazolecarboxylic acids were synthesized via chlorination of the corresponding acids at the Pt anode in NaCl aqueous solutions under conditions of divided galvanostatic electrolysis. The efficiency of the process depends on the structures of the initial pyrazolecarboxylic acids, particularly, on the donor-acceptor properties of the substituents and on their position in the pyrazole ring. The yields of the 4-chlorosubstituted products of chlorination of pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 1-methyl-pyrazole-3-carboxylic acid, 1-ethylpyrazole-3-carboxylic acid, and 1-methyl-3-nitropyrazole- 5-carboxylic acid are 92, 93, 69, 80, and 4%, respectively.     

Synthesis of a tritium-labeled, fipronil-based, highly potent, photoaffinity probe for the GABA receptor

3-[4-[1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazolo]]-3-(trifluoromethyl)diazirine is a fipronil-based (i.e. fiprole), high-affinity probe for the GABA receptor. For synthesis of the tritium-labeled version of this trifluoromethyldiazirinylfiprole ([(3)H]TDF) the required intermediate, 3-[4-[1-(2,6-dichloro-3-iodo-4-trifluoromethylphenyl)-5-iodopyrazolo]]-3-(trifluoromethyl)diazirine, was prepared in 10 steps from pyrazole and 3,5-dichloro-4-fluorobenzotrifluoride. One of the key transformations was lithiation and subsequent iodination of the 4-(2,2,2-trifluoro-1-hydroxyethyl)pyrazole intermediate. The last step involved reduction of the diiodofiprole with tritium, Pd/C, and triethylamine in ethyl acetate and afforded [(3)H]TDF with a specific activity of 15 Ci/mmol and 99% radiopurity.     

新型螺[色烯并(2,3-c)吡唑-4,1’-异苯并呋喃]-3’-酮类化合物的合成及光学性能研究

在酸催化及脱水作用下,以2-(4-二丁基氨基-2-羟基苯甲酰基)苯甲酸或2-(4-二乙基氨基-2-羟基苯甲酰基)苯甲酸和吡唑啉酮为原料,通过Knoevenagel缩合和脱水反应,合成了一系列新型螺[色烯并(2,3-c)吡唑-4,1’-异苯并呋喃]-3’-酮类化合物.考察了反应物配比、催化剂、温度和时间等因素对反应的影响,初步探究了所合成化合物在不同pH、溶剂中的光学性能,其中1-(4-氯苯基)-7-(二乙基氨基)-3-甲基-1H,3’H-螺[色烯并[2,3-c]吡唑-4,1’-异苯并呋喃]-3’-酮(1e)和1-(4-氯苯基)-7-(二丁基氨基)-3-甲基-1H,3’H-螺[色烯并[2,3-c]吡唑-4,1’-异苯并呋喃]-3’-酮(1j)有潜力作为强酸强碱的pH指示剂.     

Diazabicycloalkanes with nitrogen atoms in bridgehead positions 20. Synthesis of naphtho[2,3-b]-1,4-diazabicyclo[2.2.2]octene

Reaction of 2-acetamido-3-bis(2-hydroxyethyl)aminonaphthalene with phosphorus oxychloride leads to the formation of 2-methyl-1-(2-chloroethyl)naphtho[2,3-d]imidazole, while reaction with hydrobromic acid gives naphtho[23-b]-1,4-diozabicyclo[2.2.2]octane in 13% yield. The yield of the latter can be increased to 45% by exchange of the hydroxyl groups in the starting material by chlorine and by deacetylation.For Communication 19, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 97–100, January, 1991.     

Synthesis and properties of 1-(2-hydroxyethyl)tetrazole

The heterocyclization of monoethanolamine with ethyl orthoformate and sodium azide in acetic acid was studied. It was shown that the reaction proceeds through a step involving the formation of a disubstituted formamidine and leads to the production of 1-(2-hydroxyethyl)tetrazole in high yield. A method for the purification of 1-(2-hydroxyethyl)tetrazole by complexing with cupric chloride was developed, and its physicochemical properties and some chemical transformations were investigated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1422–1424, October, 1985.