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%.     

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.     

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.     

Nitropyrazoles 16. The use of methoxymethyl group as a protecting group for the synthesis of 4-methyl-3-nitro-5-R-pyrazoles

4-Methyl-3,5-dinitropyrazole prepared by nitration of 1,4-dimethylpyrazole readily reacts with methoxymethyl chloride and methyl vinyl ketone in acetonitrile in the presence of a base giving 1-methoxymethyl-4-methyl-3,5-dinitropyrazole and 4-methyl-3,5-dinitro-1-(3-oxobutyl)pyrazole, respectively. The action of the thioglycolanilide anion on 4-methyl-3,5-dinitro-1-(3-oxobutyl)pyrazole results only in the removal of 1-protecting group and the formation of 2-[(3-oxobutyl)thio]acetanilide, while the action of anionic S-nucleophiles on 1-methoxymethyl-4-methyl-3,5-dinitropyrazole leads to the substitution products of the 5-NO₂ group in which the methoxymethyl group can be removed by acid hydrolysis.     

Alkylating nucleosides. 3. The reaction of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide

Bromination of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide gave the corresponding 4-bromo-3,5-dimethylpyrazole, 3-methyl-5-(bromomethyl)pyrazole and 4-bromo-3-methyl-5-(bromomethyl)pyrazole nucleosides. Structural assignments were made on basis of analytical and ¹ H nmr spectral data. All of the bromomethylpyrazole nucleosides described showed cytostatic activity against HeLa cell sultures.     

Electrosynthesis of 4-chloro derivatives of pyrazole and alkylpyrazoles

Electrosynthesis of 4-chloro-substituted derivatives of pyrazole and its alkyl derivatives is carried out via the chlorination of original pyrazoles on a Pt anode in aqueous NaCl solutions under conditions of galvanostatic diaphragm electrolysis. The efficiency of this process is shown to depend on the structure of starting pyrazoles, particularly, the donor-acceptor properties of substituents, the position of the latter in the pyrazole ring, and the concomitant contribution of side reactions. Thus the yield of 4-chlorosubstituted products at the chlorination of pyrazole, 3,5-dimethylpyrazole, 1,5-dimethylpyrazole, and 3-nitropyrazole is 68, 92, 53, and 79%, respectively. By the example of 1,5-dimethylpyrazole, the possibility of electrochemical chlorination to the side chain of pyrazoles was demonstrated.     

Studies With Pyrazol-3-Carboxylic Acid Hydrazide: The Synthesis of New Pyrazolyloxadiazole and Pyrazolyltriazole Derivatives

A simple and versatile method for the synthesis of pyrazol-3-yl-1,3,4-oxadiazole, pyrazol-3-yl-1,2,4-triazole, (1,5-diphenylpyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)pyrazole, and (1,5-diphenylpyrazol-3-yl)-(5-hydroxy-3-metheyl-1-carbonyl)pyrazole derivatives from 1,5-diphenylpyrazole-3-carboxylic acid hydrazide has been developed.     

Synthesis of New Fused and Spiro Heterocyclic Systems from 3,5‐Pyrazolidinediones

4‐Bromo‐1‐phenyl‐3,5‐pyrazolidinedione 2 reacted with different nucleophilic reagents to give the corresponding 4‐substituted derivatives 3–8 . The cyclized compounds 9–11 were achieved on refluxing compounds 3 , 4 or 6_a in glacial acetic acid or diphenyl ether. 4,4‐Dibromo‐1‐phenyl‐3,5‐pyrazolidinedione 12 reacted with the proper bidentates to give the corresponding spiro 3,5‐pyrazolidinediones 13–15 , respectively. The 4‐aralkylidine derivatives 16_a‐c , were subjected to Mannich reaction to give Mannich bases 17_a‐c‐22_a‐c , respectively. 4‐(p‐Methylphenylaminomethylidine)‐1‐phenyl‐3,5‐pyrazolidinedione 23 or 4‐(p‐methylphenylazo)‐1‐phenyl‐3,5‐pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and N,S‐acetals to give pyrano[2,3‐c]pyrazole, pyrazolo[4′,3′:5,6]pyrano[2,3‐c]pyrazole, spiropyrazole‐4,3′‐pyrazole and spiropyrazole‐4,3′‐[1,2,4]triazolane derivatives 24–34 , respectively.     

Specificity of the reaction of β-carboxyvinyl(triphenyl)phosphonium chloride with azoles

Reactions of pyrazole, 3,5-dimethylpyrazole, 1,2,4-triazole, 5-aminotetrazole, and imidazole with β-carboxyvinyl(triphenyl)phosphonium chloride in boiling acetonitrile are accompanied by elimination of azole with formation of the initial salt and elimination of triphenylphosphine to give the corresponding azole hydrochloride and α-azolyacrylic acid. In all cases, ethylenebis(triphenylphosphonium) dichloride was formed, and the reactions with the most nucleophilic 3,5-dimethylpyrazole and imidazole also led to their adducts with α-azolylacrylic acid. In the reactions of pyrazole and 3,5-dimethylpyrazole with β-carboxyvinyl-(triphenyl)phosphonium chloride at room temperature, the conesponding addition products were isolated in almost quantitative yield.     

Some heterocyclic sulfonyl chlorides and derivatives

The syntheses of 4- and 5-chlorosulfonylfuran-2-carboxylic acid (Ia,IIa), 4-chlorosulfonylfuran-2-carboxamide (Ib), 3,5-dimethylpyrazole and isoxazole-4-sulfonyl chlorides (IIIa,IVa) and 2,4-dimethylthiazole-5-sulfonyl chloride (Va) are described. The sulfonyl chlorides were converted into a range of amides, hydrazides and azides. Condensation of the sulfonohydrazides with β-dicarbonyl compounds, gave the corresponding β-ketohydrazones (VII), which, with the exception of the derivatives (VIIe,f,g,i), were converted to the sulfonylpyrazoles (VIII). The structures and spectral data of these compounds are briefly discussed. The reaction of the sodio derivative of acetylacetone with thiophene-2-sulfonyl chloride (VIc) gave 3-(thiophene-2-sulfonyl)pentane-2,4-dione (XII), which with hydrazine gave 4-(thiophene-2-sulfonyl)-3,5-dimethylpyrazole (XIII). However, the analogous reaction with thiophene-2-sulfonohydrazide (VIa) failed to give the expected 1,4-bisthiophenesulfonylpyrazole.     

N-Dimethoxyphenylation of highly basic pyrazoles during undivided electrolysis

The reactions of pyrazole, 3,5-dimethylpyrazole, and its 4-nitro derivatives with 1,4-dimethoxybenzene during undivided amperostatic electrolysis in MeCN (CH₂Cl₂) were studied. The basicity of the medium, which depends on the solvent nature, the nature and concentration of pyrazole and the acid-base properties of additives, and the amount of electricity passed determine the yield and relative content of the target products, viz., 1,4-dimethoxy-2-(pyrazol-1-yl)benzenes (1) and 1,4-dimethoxy-1,4-di(pyrazol-1-yl)cyclohexa-2,5-dienes (2). The process occurs mainly through the interaction of the nonionized solvato complex of pyrazole with the 1,4-dimethoxybenzene radical cation and affords radical intermediates structurally similar to compounds 1 and 2. The key stage of the process determining the 1 : 2 ratio is the rearrangement of the intermediately produced 1,4-dimethoxy-1-(pyrazol-1-yl)arenonium cation to the 1-(pyrazol-1-yl)-2,5-dimethoxyarenonium cation.     

New structural forms in molecular metal phosphonates: novel tri- and hexanuclear zinc(II) cages containing phosphonate and pyrazole ligands

The reaction of ZnCl(2) with tert-butylphosphonic acid and 3,5-dimethylpyrazole in the presence of triethylamine as a hydrogen chloride scavenger affords a trinuclear molecular zinc phosphonate [Zn(3)Cl(2)(3,5-Me(2)Pz)(4)(t-BuPO(3))(2)]. The structure of this compound contains a planar trizinc assembly containing two bicapping mu(3) [t-BuPO(3)](2-) ligands and terminal pyrazole and chloride ligands. In contrast an analogous reaction of ZnCl(2) with phenylphosphonic acid and 3,5-dimethylpyrazole affords a hexanuclear zinc phosphonate [Zn(6)Cl(4)(3,5-Me(2)PzH)(8)(PhPO(3))(4)]. The six zinc centers are arranged in a chairlike conformation. The four phosphonates in this complex also act as bridging tripodal mu(3) [RPO(3)](2-) ligands.     

The molecular structure and chemical reactivities of the condensation products of o-substituted benzylidenacetylacetone with hydrazine dihydrochloride

Reaction of o-nitrobenzylideneacetylacetone ( 1a ) with hydrazine dihydrochloride in methanol gave 4-(α-methoxy-o-nitrobenzyl)-3,5-dimethylpyrazole hydrochloride ( 4a ), whose structure was unambigously confirmed by an X-ray crystallographic analysis, via 4-(o-nitrobenzylidene)-3,5-dimethylisopyrazole ( 2a ). Compound 2a was synthesized by condensation of 1a with hydrazine dihydrochloride in acetonitrile. Analogously the corresponding o-chloro derivatives ( 2b, 4b ) were obtained. These were converted to N-methyl ( 6b ) and N-acetyl ( 7a,b ) derivatives and the behaviors on bromination and pyrolysis were investigated.     

Haloperoxidase‐like Compounds: Synthesis,Structure and Properties of Two New Oxidovanadium‐Poly(pyrazolyl)borate‐Carboxylate Complexes

Two new oxidovanadium (IV) complexes: TpVO(L₁) ( 1 ) and Tp*VO(pzH*)(L₂) ( 2 ) [Tp = hydrotris(pyrazolyl)borate, HL₁ = 5‐methyl‐1H‐pyrazole‐3‐carboxylic acid, Tp* = hydrotris(3,5‐dimethylpyrazolyl)borate, pzH* = 3,5‐dimethylpyrazole, HL₂ = 5‐phenyl‐1H‐pyrazole‐3‐carboxylic acid] have been synthesized and characterized by elemental analysis and IR spectroscopy. The single‐crystal structures of the complexes shows that the vanadium ion is in a distorted octahedral environment with a N₄O₂ donor set in each complex. Additionally, hydrogen bonding interaction exits in both complexes. Interestingly, the molecules of 1 are held together to form a 1D hydrogen bonded polymer along the b axis, whereas complex 2 is a hydrogen bonded dimer. In addition, the catalytic activities of complexes 1 and 2 in bromination reactions in phosphate buffer with phenol red as a trap were evaluated primary by UV/Vis spectroscopy. Furthermore, ab initio calculations of complexes 1 and 2 were performed.     

Synthesis of Adamantane Derivatives. XVIII. On the Bromination of 1- and 3-Homoadamantanecarboxylic Acids. an Improved Synthesis of L-Bromomethyladamantane-3-Carboxylic Acid and Some Derivatives Thereof

Although the ionic bromination of adamantane and its derivatives has been well established,² direct bromination of homoadamantane derivatives seems not to be strdied extensively.³ We wish to report the bromination of 1- (IIb) and 3-homoadaman-tanecarboxy acid (IIa), which provided an improved preparative method for 1-bromomethy ladamantane-3-carboxylic acid (III).     

Synthesis of 1-Aryl-1H-pyrazolecarbonitriles and related derivatives

The synthesis of 1-aryl-5-cyano-1H-pyrazole-4-carboxylic acid, ethyl esters 1 is described. Subsequent chemistry led to relatively simple and unique pyrazole derivatives. Most important of these are 1-aryl-5-(aminocarbonyl)-1H-pyrazole-4-carboxylic acids 2, which are chemical hybridizing agents in wheat and barley. The regioselective hydrolysis of 1-(3-chlorophenyl)-1H-pyrazole-4,5-dicarboxylic acid, dimethyl ester (7b) and subsequent chemistry is also described.     

Deprotonation of pyrazole and its analogs by aqueous copper acetate in the presence of triethylamine

Deprotonation reactions of pyrazole and its analogs by aqueous copper acetate in benzene at room temperature in the presence of triethylamine were studied. Unlike 3,5-dimethylpyrazole, more acidic pyrazole, 5-methyl-3-trifluoromethylpyrazole, and 3,5-bis(trifluoromethyl)pyrazoles are deprotonated to give pyrazolate bridges. The structural features of the obtained compounds are discussed based on X-ray diffraction data.     

Characteristic features of the reaction of 3(5)amino-5(3)-methylpyrazole with 1-nitroanthraquinone-2-carboxylic acid

In the reaction of 3(5)-amino-5(3)-methylpyrazole with 1-nitroanthraquinone-2-carboxylic acid in sulfolane at 150°C, 2-methyl-pyrazolo[5,1-b]naphtho[2,3-h]quinazoline-5,10,13-trione is formed with an admixture of 1-aminoanthraquinone-2-carboxylic acid and 1-aminoanthraquinone. Under similar conditions, from 4-amino-1,5-dimethylpyrazole, only 1-(1,5-dimethyl-4-pyrazolylamino)anthraquinone-1-carboxylic acid is formed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1191–1192, September, 1992.     

Biological Activities of Lichen-Derived Monoaromatic Compounds

Lichen-derived monoaromatic compounds are bioactive compounds, associated with various pharmacological properties: antioxidant, antifungal, antiviral, cytotoxicity, and enzyme inhibition. However, little is known about data regarding alpha-glucosidase inhibition and antimicrobial activity. Very few compounds were reported to have these activities. In this paper, a series of monoaromatic compounds from a lichen source were isolated and structurally elucidated. They are 3,5-dihydroxybenzoic acid (1), 3,5-dihydroxybenzoate methyl (2), 3,5-dihydroxy-4-methylbenzoic acid (3), 3,5-dihydroxy-4-methoxylbenzoic acid (4), 3-hydroxyorcinol (5), atranol (6), and methyl hematommate (7). To obtain more derivatives, available compounds from the previous reports such as methyl β-orsellinate (8), methyl orsellinate (9), and D-montagnetol (10) were selected for bromination. Electrophilic bromination was applied to 8–10 using NaBr/H₂O₂ reagents to yield products methyl 5-bromo-β-orsellinate (8a), methyl 3,5-dibromo-orsellinate (9a), 3-bromo-D-montagnetol (10a), and 3,5-dibromo-D-montagnetol (10b). Compounds were evaluated for alpha-glucosidase inhibition and antimicrobial activity against antibiotic-resistant, pathogenic bacteria Enterococcus faecium, Staphylococcus aureus, and Acinetobacter baumannii. Compound 4 showed stronger alpha-glucosidase inhibition than others with an IC₅₀ value of 24.0 µg/mL. Synthetic compound 9a exhibited remarkable activity against Staphylococcus aureus with a MIC value of 4 µg/mL. Molecular docking studies were performed to confirm the consistency between in vitro and in silico studies.     

1,1-bis(3,5-dimethyl-1-pyrazolyl)- and 1-Amino-1-(3,5-dimethyl-1-pyrazolyl)-4,4-dichloro-1-buten-3-ones

Reaction of 1,1,4,4-tetrachloro-3-buten-2-one with 3,5-dimethylpyrazole gave 1,1-dichloro- 4,4-bis-(3,5-dimethyl-1-pyrazolyl)-3-buten-2-one. Treatment of the latter with amines resulted in replacement of one pyrazole ring by the amine residue with formation of the corresponding 4-amino-1,1-dichloro-4-(3,5- dimethyl-1-pyrazolyl)-3-buten-2-ones.Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 10, 2004, pp. 1557–1560.Original Russian Text Copyright © 2004 by Potkin, Petkevich, Kaberdin, Kurman.