Stereoselective synthesis of cis-1,3-disubstituted cyclobutyl kinase inhibitors

Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]     

Application of photoelectron spectroscopy to biologically active molecules and their constituent parts IV. Methylnitroimidazoles

Photoelectron (PE) spectra of imidazole ( 1), 1 -methylimidazole ( 2 ), 2-methylimidazole ( 3 ), 4(5)-nitroimidazole ( 4 ), 2-methyl-4(5)nitroimidazole ( 5 ), 1,2-dimethyl-5-nitroimidazole ( 6 ), 1-ethyl-2-methyl-5-nitroimidazole ( 7 ), 1-bromoethyl-2-methyl-5-nitroimidazole ( 8 ) and 1-hydroxyethyl-2-methyl-5-nitroimidazole ( 9 ) have been recorded using Hel excitation. The electronic structure of the potent antitrichomonal agent 9 is discussed in comparison with compounds 1–8 allowing for the study of the influence of substituents on the imidazole ring.     

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 and biological evaluation of 5-substituted-4-nitroimidazole ribonucleosides

The imidazole nucleosides, 4(5)-bromo-5(4)-nitro-1-β-D-ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)-bromo-5(4)-nitroimidazole, with tetra-O-acetyl-β-D-ribo-furanose followed by removal of the acetyl protecting groups. The 5-bromo-4-nitro-1-β-D-ribofuranosylimidazole nucleoside was acetonated to produce 5-bromo-4-nitro-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′-anhydro-4-nitro-5-oxo-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5-bromo-4-nitroimidazole nucleoside provided 5-mercapto-4-nitro-1-β-D-ribofuranosylimidazole 5-sodium salt which was alkylated with E-1,5-diiodopent-1-ene to yield 5-(E-1-iodo-1-penten-5-yl)thio-4-nitro-1-β-D-ribofuranosylimidazole. The corresponding iodine-125-labeled compound was prepared similarly using radiolabeled diiodopentene. The 5-bromo-4-nitroimidazole, 5-mercapto-4-nitroimidazole, and 5-iodopentenylthio-4-nitroimidazole nucleosides were cytotoxic to Molt-3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5-iodopentenylthio-4-nitroimidazole nucleoside showed 2-fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.     

Nitroimidazoles. V . Synthesis of 1-methyl-2-(2-methyl-4-thiazolyl)nitroimidazoles

Reaction of readily available 2-methyl-4-formylthiazole ( 1 ) with glyoxal and ammonia gave 2-(2-methyl-4-thiazolyl)imidazole ( 2 ). Nitration of 2 with a mixture of nitric acid-sulfuric acid at 100° yielded 2-(2-methyl-4-thiazolyl)-4,5-dinitroimidazole ( 3 ) as the sole reaction product, while nitration at 65° afforded 2-(2-methyl-4-thiazolyl)-4-(or 5)-nitroimidazole ( 4 ). N-Methylation of compound 4 in the presence of base gave 1-methyl-2-(2-methyl-4-thiazolyl)4-nitroimidazole ( 6 ), whereas N-methylation with diazomethane afforded 1-methyl-2-(2-methyl-4-thiazolyl)-5-nitroimidazole ( 5 ). N-Methylation of compound 3 yielded 1-methyl-2-(2-methyl-4-thiazolyl)-3,5-dinitroimidazole ( 7 ) in high yield.     

Long distance-SRN1 in nitroimidazole series favored by temperature

New reductive alkylating agents in 4- and 5-nitroimidazole series produce exclusively O-alkylation with nitronate anions under classical S_RN1 conditions at room temperature. Electron-transfer C-alkylation is observed under microwave irradiation or under conventional heating. Furthermore, X-ray spectroscopy shows that the dihedral angles between the phenyl and imidazole rings for the two series are different, which could greatly influence reactivity in 4- and 5-nitroimidazole series.     

Simple Synthesis of Highly Functionalized Ketenimines

The 1:1 reactive intermediate generated by the addition of alkyl isocyanides to dibenzoylacetylene or dialkyl acetylenedicarboxylates was trapped by fairly strong NH acids such as isatin, phthalimide, 4-nitroimidazole, or 2-benzoylimidazole to yield highly functionalized ketenimines.     

Palladium(0)-catalyzed allylation of 4(5)-substituted imidazoles, 5(6)-substituted benzimidazoles,benzotriazole and 5(6)-methylbenzotriazole

Pd(0)-Catalyzed allylations of 4(5)-nitroimidazole, 1 , 2-methyl-4(5)-nitroimidazole, 2 , 4(5)-bromo-imidazole, 7 , 4(5)-methoxyimidazole, 10 , 5(6)-nitrobenzimidazole, 16a , 5(6)-methylbenzimidazole, 16b , benzotriazole, 19 , and 5(6)-methylbenzotriazole, 22 , were studied under several reaction conditions. Nitroimidazoles 1 and 2 were regioselectively allylated under thermodynamic control, leading to 1-allyl-4-nitro derivatives.     

Compounds of palladium halides with substituted imidazoles

Summary Compounds of the type PdL₂X₂ (L=1-methylimidazole, 1-vinylimidazole, 1-n-butylimidazole, 1,2-dimethylimidazole, 1-vinyl-2-methylimidazole, 1,2-dimethyl-5-nitroimidazole, 2-isopropyl-4(5)-nitroimidazole and 2-methyl-4(5)-nitro-imidazole; X=Cl or Br) are obtained by treating PdX₂ (1 mole) with solutions of the ligands L (2 moles). An excess of L gives PdL₄X₂ complexes (L=1-methylimidazole, 1-vinylimidazole, 1,2-dimethylimidazole and 1-vinyl-2-methylimidazole). The compounds were characterized by chemical analyses, molar conductivity measurements and i.r. spectra.     

1-[18F]Fluoroethyleneglycol-2-nitroimidazoles, a new class of potential hypoxia PET markers

Summary 1-[2-(2-Fluoroethoxy)ethyl]-2-1H-nitroimidazole (3a), 1-{2-[2-(2-fluoroethoxy)ethoxy]ethyl}-2-1H-nitroimidazole (3b) and 1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-2-1H-nitroimidazole (3c) were synthesized in a two step sequence.Coupling the ditosylate of di-, tri- or tetraethylene glycol with 2-nitroimidazole followed by fluoride substitution afforded the reference compounds in high yield and¹⁸F labeling gave the corresponding markers in 70-82% radiochemical yield.     

Efficient synthesis of DNA containing the guanine oxidation-nitration product 5-guanidino-4-nitroimidazole: generation by a postsynthetic substitution reaction

[reaction: see text] A convertible nucleoside was synthesized and used to prepare the 2'-deoxynucleoside of 5-guanidino-4-nitroimidazole, a putative in vivo product of the reaction of peroxynitrite with guanine. The convertible nucleoside was incorporated into an oligodeoxynucleotide by the phosphoramidite method and converted postsynthetically to yield an oligodeoxynucleotide containing 5-guanidino-4-nitroimidazole at a specific site. The oligodeoxynucleotide was inserted into a viral genome. Melting temperature analysis revealed that duplexes containing 5-guanidino-4-nitroimidazole were greatly destabilized relative to unmodified duplexes.     

Reactions of 5-diazo-4-nitroimidazole with hydrochloric acid

Reaction of 5-diazo-4-nitroimidazole with concentrated hydrochloric acid leads to 4-chloro-5-diazoimidazole. The same product is formed together with a small quantity of 5-chloro-4-nitroimidazole with 1 N hydrochloric acid, but with 0.1 N hydrochloric acid only chloronitroimidazole was isolated. The results obtained are explained with the aid of quantum chemical calculations.Urals State Technical University-Urals Polytechnical Institute (UPI), Ekaterinburg 620002, Russia; Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 199–202, February, 1999.     

Reaction between alkyl isocyanides and dibenzoylacetylene in the presence of strong NH-acids: synthesis of highly functionalized aminofurans

Protonation of the highly reactive 1:1 intermediates produced in the reaction between alkyl isocyanides and dibenzoylacetylene by saccharin, phthalimide, or 4-methyl-5-nitroimidazole, leads to vinylnitrilium cations, which undergo carbon-centered Michael type addition with the conjugate base of the NH-acid to produce highly functionalized aminofuran derivatives.     

Nitroimidazoles. VI. Syntheses of 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole

Starting from readily available 1-methyl-5-nitroimidazole-2-carboxylic acid hydrazide (1), 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole (4) and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole (10) were prepared. The reaction of 1 with formic acid gave 1-(1-methyl-5-nitroimidazole-2-carboxyl)-2-(formyl)hydrazine ( 8 ) in high yield. Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 4 in 50% yield. Reaction of compound 8 with phosphorus pentoxide afforded compound 10 in 60% yield.     

Construction of a Pillared-layer Framework Based on Charge Balance:CO_2 Adsorption and Luminescence

Via the strategy of charge balance,one new pillared layered metal-organic framework [Zn2(TNB)(2-nim)](H_3TNB = 4,4?,4??-nitrilotribenzoicacid,2-nim = 2-nitroimidazole)(1) was successfully synthesized based on mixed ligands,where binuclear [Zn_2(CO_2)_3]~+ cluster-based cationic layers [Zn_2(TNB)]~+ are connected by deprotonated 2-nitroimidazole.Meanwhile,CO_2 adsorption bahaviors and luminescent property of compound 1 were investigated.     

Nucleophilic substitution reactions of 1-methyl-4,5-dinitroimidazole with aqueous ammonia or sodium azide

Chemistry of Heterocyclic Compounds - In this work, 5-amino-1-methyl-4-nitroimidazole was synthesized by amination reaction of 1-methyl-4,5-dinitroimidazole with aqueous ammonia in 95% yield....     

Reactions of 1,2-Dimethyl-5-nitroimidazole,novel methods of conversion of the 2-Methyl group to a nitrile

1, 2-Dimethyl-5-nitroimidazole( 1 )and N,N-dimethylformamide dicyclohexylacetal gave the 2-(β-dimethylaminovinyl) analog 2 and with iodine and pyridine gave the 2-(1-pyridinium)methyl compound 3 . Benzoyl chloride-triethylamine and 1 led to benzoylation of the 2-methyl group to give ketone 9 as the enol benzoate. Nitrous acid or nitrosylsulfuric acid with 9 or its enol ester afforded the oximinoketone 10 which was cleaved with thionyl chloride to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ) in high overall yield. 1-Ethyl-2-methylbenzimidazole ( 22 ) was converted to 2-cyano-1-ethylbenzimidazole ( 25 ) similarly. Reaction of 1 with ethyl oxalyl chloride and triethylamine afforded ethyl 1-methyl-5-nitro-2-imidazolepyruvate ( 19 ) as the enol oxalate. Nitrous acid and 19 gave the oximino pyruvate 20 which effervesced on mild heating to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ). The preparation of 1-methyl-5-nitro-2-imidazoleacetonitrile ( 39 ) is reported.     

Synthesis of 1-beta-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (beta-IAZA): a novel marker of tissue hypoxia

The present work describes the synthesis of the beta-isomer of 1-alpha-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (IAZA). Radioiodinated IAZA ((123)I-IAZA) has been extensively studied as a radiopharmaceutical for the diagnosis of regional and/or focal tissue hypoxia in a variety of clinical pathologies. The beta-anomer of IAZA, 1-beta-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (beta-IAZA, 1), was synthesized via an unconventional route starting from 1-beta-D-(ribofuranosyl)-2-nitroimidazole (AZR), with a change of configuration at the C-2'-position to afford 1-beta-D-(arabinofuranosyl)-2-nitroimidazole (beta-AZA, 7). Nucleophilic iodination of the 5'-O-toluenesulfonyl-2',3'-di-O-acetyl precursor of beta-AZA, 9, followed by deprotection, afforded 1 in satisfactory yield. beta-IAZA (1) was also synthesized from 7 using molecular iodine and triphenylphosphine.     

Modeling competitive reaction mechanisms of peroxynitrite oxidation of guanine

5-Guanidino-4-nitroimidazole is a stable product from the peroxynitrite induced one-electron oxidation of guanine. Reaction mechanisms to form the 5-guanidino-4-nitroimidazole as well as 8-nitroguanine, through the combination of the guanine radical cation and nitrogen dioxide radical and through the combination of the deprotonated neutral guanine radical and nitrogen dioxide radical, have been investigated by the use of the B3LYP method of density functional theory. Our calculations suggest that the guanine radical cation mechanism is preferred over the neutral guanine radical mechanism and that a water molecule is involved in the reaction as a catalyst or as a reactant.     

2-(4′-Fluorophenyl)imidazole. Nitration studies

Reactions of 2-(4′-fluorophenyl)imidazole ( 1 ) and related compounds under various nitrating conditions are discussed. With 90% nitric acid in 20% oleum at ?10°, 1 affords 2-(4′fluorophenyl)-4(5)-nitroimidazole ( 2 ) in 80% yield. Reaction of 2 with the same reagents at 25° affords 2-(4′-fluoro-3′-nitrophenyl)-4(5)-nitroimidazole ( 4 ) in 90% yield, whereas with 90% nitric acid in acetic acid at 95°, 2 affords 4,5-dinitro-2-(4′-fluorophenyl)imidazole ( 5 ) in 80% yield. Reaction of 1 with 70% nitric acid in concentrated sulfuric acid at 25° affords 2-(4′-fluorophenyl)-5-hyroximinoimidazolin-4-one ( 6 ), which rearranges and hydrolyzes to 5-(4′-fluorophenyl)-1,2,4-oxadiazole-3-carboxylic acid. A discussion of these reactions is presented.