Hydroxymethylation and cyanoethylation of nitroimidazoles

A series of nitroimidazoles were subjected to hydroxymethylations under a variety of conditions. Hydroxymethylation of 1-(2-hydroxyethyl), 1-(2-acetoxyethyl), and 1-(2-chloroethyl) substituted 5-nitroimidazoles with paraformaldehyde in dimethyl sulfoxide yielded the respective 2-hydroxymethyl analogs (5–7). However, attempts to hydroxymethylate 1-(2-hydroxyethyl), 1-(2-acetoxyethyl), 1-(2-cyanoethyl) substituted 4-nitroimidazoles and 1-(2-hydroxyethyl)-2-nitroimidazole were unsuccessful. Treatment of 1-(2-acetoxyethyl)-5-nitro-2-imidazolecar-baldehyde(10) with hydroxylamine-O-sulfonic acid afforded a mixture of corresponding 2-carbonitrile (12) and 2-(N-hydroxy)carboximidamide (13). Hydrolysis of 10 with ethanolic hydrochloric acid yielded 8-ethoxy-5,6-dihydro-3-nitro-8H-imidazo[2,1-c] [1,4]oxazine (11) which, on subsequent reaction with hydroxylamine-O-sulfonic acid, afforded 1-(2-hydroxyethyl)-5-nitroimidazole-2-(N-hydroxy)carboximidamide (15). Reaction of 4(5)-nitroimidazole with chloropropionitrile produced a mixture of the isomeric 1-(2-cyanoethyl) substituted 4- and 5-nitroimidazoles. Treatment of 2,4(5)-dinitroímidazole with chloropropionitrile afforded a mixture of 4(5)-chloro-5(4)-nitroimidazole and 1-(2-cyanoethyl)-4-nitro-5-chloroimidazoIe. Reaction of nitroimidazoles with acrylonitrile in the presence of Triton B yielded the corresponding 1-(2-cyanoethyl) substituted derivatives.     

Synthesis of 4-aroyl-5-nitro-1H-imidazoles and 4-aroyl-5-aminoimidazoles

The reaction of α-(aryl)-4-morpholineacetonitriles (masked aroyl anion equivalents) with N-protected 4(5)-bromo-5(4)-nitro-1H-imidazoles gave 4-aroyl-5-nitroimidazoles which were reduced to afford 4-aroyl-5-aminoimidazoles.     

SRN1 and oxidative addition reactions of nitroimidazole anions

The anions of 2- and 4(5)-nitroimidazoles react with aliphatic substituted nitro compounds and p-nitrobenzyl chloride by a S_RN1 mechanism, or by oxidative addition to the anion of 2-nitropropane, to yield 1-alkyl-2-(or 4-)-nitroimidazoles.     

Synthesis of 7-methyl-6-(nitroimidazolyl)thiopurines

We have studied the reactions of 7-methyl-6-thiopurine with 5(4)-halo-4(5)-nitroimidazoles and 6-chloro-7-methylpurine with sodium and ammonium salts of 5-mercapto-4-nitroimidazoles. We have obtained a series of 7-methyl-6-(nitroimidazolyl)thiopurines not previously described in the literature.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 217–220, February, 2000.     

Synthesis of 2-Substituted 7-Methyl-6-(nitroimidazolyl)thiopurines

2-Substituted 7-methyl-6-(nitroimidazolyl)thiopurines have been synthesized by the reaction of 2-chloro(phenylamino, cycloalkylamino)-7-methyl-6-thiopurines with 5(4)-halo-4(5)-nitroimidazoles and the reaction of 2,6-dichloro-(6-chloro-2-dimethylamino)-7-methylpurines with sodium or ammonium salts of 5(4)-mercapto-4(5)-nitroimidazoles.     

New synthesis of 2-nitroimidazoles

1-Triphenylmethylimidazoles are treated with n-butyllithium in tetrahydrofuran at 0° to form the 2-lithio derivatives. The latter species react with n-propyl nitrate to give l-trityl-2-nitroimidazoles which, after acid hydrolysis, provide the corresponding 2-nitroimidazoles. 2-Nitroimidazole was obtained from imidazole in overall yields of 27–35% 4-methyl-2-nitroimidazole was obtained in 40% overall yield from 4-methyl-imidazole. Imidazole-4,5-dicarboxylic acid was converted, in several steps, to l-tritylimidazole-4-methanol, and the latter compound was transformed into 2-nitroimidazole-4-methanol in an overall yield of 18%. Protection of the hydroxymethyl function was found to be unnecessary during carbanion formation and nitration. Attempts to nitrate 1-methylimidazole or 1-methoxymethylimidazole by the same procedure failed.     

Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds

Investigation into Sonogashira reaction on 5-iodo-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds had been developed by introducing an iodo atom at the C-5 position of the imidazole ring of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile compounds. Specifically, 5-iodo-1-(4-iodophenyl)imidazole-4-carbonitrile compound had shown double Sonogashira coupling reactions with two differently substituted iodine along with the formation of two other compounds where an unusual coupling product with self-aggregation property was obtained. In other cases, monocoupling had been observed together with another compound where iodine atom present at C5 position of imidazole was replaced by hydrogen atom.     

Reglochemistry in Electrophilic Reactions of Propanedlthio-Substituted Allylic Anions Influenced by the γ-Substituents

The dienyl anion 1f, generated from metallation of 2-(1,3-pentadienyl)-1,3-dithianc with n-BuLi in THF, reacted exclusively at the C-1 position (α-site) with alkylating agents and ketones, but it showed some tendency toward the C-3 position (γ-site) in the reactions with benzyl bromide and aliphatic aldehydes. No reaction at the C-5 position (?-site) was observed in any studied case. Examination of the related propanedithio-substituted allylic anions having various γ-substituents revealed that the regiochemistry was remarkably influenced by the γ-substituents and the attacking electrophiles. The electronic effect according to the principle of hard and soft acids and bases is proposed to account for the observed regiochemistry, while the steric factor was minor. Two trienes, obtained by alkylations of the dienyl anion 1f with 4-bromo-1-butene and 5-pentenyl methanesulfonate, were applicable to intramolecular Diels-Alder reactions to give bicyclic compounds.     

Synthesis of substituted 5-bromomethyl-4-nitroimidazoles and use for the preparation of the hypoxia-selective multikinase inhibitor SN29966

5-Bromomethyl-4-nitroimidazoles have utility as bioreductive trigger precursors for the preparation of hypoxia-selective prodrugs. Here we describe an efficient two-step synthesis of 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole, a preferred precursor, employing an N-bromosuccinimide mediated radical bromination. Use of this precursor to prepare SN29966, a promising hypoxia-selective irreversible pan-ErbB inhibitor is reported along with the preparation of four other prodrug candidates. 5-Bromomethyl-4-nitroimidazole analogues bearing electron-donating and electron-withdrawing substituents at the N-1 and C-2 positions are also described.     

Investigations on imidazoles 99. Synthesis and some conversions of esters of 4-nitro-5-imidazolylmalonic,-acetoacetic, and-cyanoacetic acids

Some esters of 1-alkyl(1,2-dialkyl)-4-nitro-5-imidazolylmalonic,-acetoacetic, and-cyanoacetic acids have been synthesized by the reaction of 5-chloro(bromo)-1-alkyl(1,2-dialkyl)-4-nitroimidazoles with ethyl esters of carboxylic acids indicated. Some conversions of the compounds obtained have been studied, including ketone and acid decomposition, synthesis of derivatives at the COOH and CO groups, and hydrogenation to 4-aminoimidazole derivatives.For Part 98 see [1].Center for Drug Chemistry, All-Russian Research Institute for Pharmaceutical Chemistry, Moscow 119815. Novokuznetsk Research Institute for Pharmaceutical Chemistry, Novokuznetsk 654034, Russia. Zaporozhye State Medical University, Zaporozhye 330074, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 54–60, January, 1999.     

Synthesis of 2-amino-6-(nitroimidazolyl)thiopurines

We have synthesized a series of novel 2-amino-6-(nitroimidazolyl)thiopurines by reaction of thioguanine with 1-alkyl(1,2-dialkyl)-5-chloro-4-nitro-, 2-alkyl(1,2-dialkyl)-5-bromo-4-nitro-, and 1-alkyl(1,2-dialkyl)-4-chloro-5-nitroimidazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 221–224, February, 2000.     

Investigations on imidazoles 98. Reactions of nitrohaloimidazoles with amino acids

The reaction of 5-chloro(bromo)-1-methyl(1,2-dimethyl)-4-nitroimidazoles and 4-chloro-1-methyl-5-nitroimidazole with amino acids has been studied. This has enabled a series of N-(4-nitro-5-imidazolyl)- and N-(5-nitro-4-imidazolyl)-substituted amino acids to be synthesized. Esters of some of these acids have been obtained.For Part 97 see [1].Center for Drug Chemistry, All-Russian Research Institute for Pharmaceutical Chemistry, Moscow 119815. Novokuznetsk Research Institute for Pharmaceutical Chemistry, Novokuznetsk 654034, Russia. Zaporozhye State Medical University, Zaporozhye 330074, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 48–53, January, 1999.     

Simultaneous determination of three 5-nitroimidazoles in foodstuffs by differential pulse voltammetry and chemometrics

The voltammetric behaviour of three 5-nitroimidazoles,metronidazole,tinidazole and ornidazole,was investigated,and a method was developed for the simultaneous determination of these compounds,based on their reduction at a hanging mercury drop electrode(HMDE) in pH 8.95 buffer with differential pulse voltammetric(DPV) approach.Well defined voltammetric waves with peak potentials of -692,-640 and -652 mV were observed for these compounds,respectively.It is difficult to determine them individually from their mixtures without preseparation,for their voltammetric peaks overlapped seriously,so the chemometrics were used to resolve the overlapped voltammogram and quantify the mixtures.The proposed method was successfully applied to the determination of three 5-nitroimidazoles in milk and honey samples.     

Structural features of diastereomeric oxazolidin-2-ones

Model diastereomeric oxazolidinones containing various substituents at positions 3 and 5 were synthesized. Several individual diastereomers bearing methyl groups at positions 4 and 5 in cis-and trans orientations were isolated. The TLC and ¹H NMR spectroscopic data suggest that diastereomers, particularly those containing the aryl substituent at position 5, are substantially different in the physical and spectral properties. The configurations of some diastereomers were established by X-ray diffraction and NOESY spectroscopy. For these compounds, the reliable assignment of the characteristic ¹H NMR signals of individual groups was made, which provided evidence for the cis or trans orientation of the methyl groups at positions 4 and 5. The scope of the method as applied to the determination of the cis and trans isomers from their ¹H NMR spectra is discussed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 133–139, January, 2007.     

Researches on imidazoles

The effective anti-Trichomonas preparation 1-(-hydroxyethyl)-2-methyl-5-nitroimidazole(metronidazole) is synthesized, as well as its 4-nitro derivative, and a number of other 2-methylimidazole derivatives: 1-(-hydroxyethyl)-2-methylimidazole, 1-(, -dihydroxypropyl)-2-methyl-4-nitroimidazole, and nitric acid esters of 1-(-hydroxyethyl)-2-methyl -4(& 5)-nitroimidazoles.     

Synthesis and hydrolytic cleavage of 1-aryl-5-cyano-6-(2-dimethylaminovinyl)-4-oxo(thioxo)-1,4-dihydropyrimidines

1-Aryl-5-cyano-6-(2-dimethylaminovinyl)-4-oxo-1,4-dihydropyrimidines and their 4-thioxo analogs, which were prepared in three steps from cyanoacetamide and cyanothioacetamide, respectively, were subjected to hydrolysis. In aqueous AcOH, hydrolysis of N-(dimethylaminomethylene)-2-cyano-5-dimethylamino-2,4-pentadieneamide derivatives containing amino groups at position 3 afforded formylpyridones. The reaction of 2-cyano-3-dimethylaminothiocrotonamide with DMF dimethyl acetal gave rise to 3-cyano-4-dimethylamino-2-methylthiopyridine.     

Nucleotides Part XL. Synthesis and Characterization of Modified 2′–5′ Adenylate Trimers–Potential Antiviral Agents

2′–5′ Adenylate trimers 41–44 carrying the (tert-butyl)dimethylsilyl (tbds) group at the 3′-OH position of various sugar moieties were synthesized via the phosphoramidite method. The use of the (tert-butyloxy)carbonyl (boc) and 2-(4-nitrophenyl)ethylsulfonyl (npes) groups for 2′-OH protection in neighbourhood to the 3′-O-tbds residue was compared during the synthesis of the target trimers. For other functional positions, the use of the 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) blocking groups were favoured.     

Imidazole derivatives

It is shown that 4(5)-(4-alkoxyphenyl)-5(4)-nitroimidazoles are obtained when 4(5)-(4-alkoxyphenyl)imidazoles are refluxed with 3–4 N nitric acid. The use of concentrated nitric acid (d ₄ ²⁰ 1.42, 1.46) leads to di- and trinitro-substituted phenylimidazoles. The mass spectra of the nitro derivatives were studied, and the principles of the fragmentation were ascertained.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1384–1388, October, 1977.     

Substitutional and positional disorder in Sr2.88Cu3.12(PO4)4

The title compound, a hydrothermally synthesized strontium copper(II) phosphate(V) (2.88/3.12/4), is isotypic with Sr₃Cu₃(PO₄)₄, obtained previously by solid‐state reaction, but not with Sr₃Cu₃(PO₄)₄, obtained previously by the hydrothermal method. A surplus of copper was observed by both structural and chemical analysis, and the formula obtained by the structural analysis is in full agreement with results of the EDX (energy‐dispersive X‐ray diffraction) analysis. The structure consists of layers of Cu₃O₁₂ groups which are linked via the PO₄ tetrahedra. The Cu₃O₁₂ groups are formed by one Cu1O₄ and two Cu2O₅ coordination polyhedra sharing corners. The central Cu1 atom of the Cu₃O₁₂ group is located at an inversion centre (special position 2a). The unique structural feature of the title compound is the presence of 12% Cu in the Sr1 site (special position 2b, site symmetry ). Moreover, disordered Sr2 atoms were observed: a main site (Sr2a, 90%) and a less occupied site (Sr2b, 10%) are displaced by 0.48 (3) Å along the b axis. Such substitutional and positional disorder was not observed previously in similar compounds.     

Synthesis of new potentially bioactive bicyclic 2-pyridones

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields.