Efficient synthesis of trans- or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles via diazafulvene intermediates: synthetic approach toward human histamine H4)-ligands

(+)-4(5)-[(2R,5R)-5-aminomethyltetrahydrofuran-2-yl]imidazole [(+)-1, imifuramine] and its 2R,5S-stereoisomer (+)-2 were expected as base compounds to develop selective human histamine H4-receptor ligands. The improved synthesis of (+)-1 was done via cyclization of a diazafulvene intermediate generated by Bu3P/N,N,N',N'-tetramethylazodicarboxamide (TMAD) treatment of a diol 17ab bearing an unsubstituted imidazole moiety in good yields. This methodology also afforded an alternative synthetic route to trans- and cis-ethyl 4(5)-(5-hydroxymethyltetrahydrofuran-2-yl)imidazole carboxylates (5 and 6), reported previously. Also, 4(5)-[(2R,5S)-5-aminomethyltetrahydrofuran-2-yl]imidazole (+)-2 was synthesized from ethyl 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole-1-carboxylate (35) via the four steps involving deoxygenation.     

Synthesis and methylation products of 4(5)-(2-furyl)imidazole

Bromination of 2-acetylfuran with copper(II) bromide in a mixture of ethyl acetate and chloroform leads selectively to furacyl bromide, the nucleophilic substitution of bromine in which by OAc and subsequent use of the Weidenhagen reaction enabled the synthesis of 4(5)-(2-furyl)imidazole. On N-methylation of this imidazole in KOH–acetone 2 isomers are formed, the 1-methyl-4- and 1-methyl-5-(2-furyl)imidazoles. It was established that, unlike alkylation of 4(5)-phenylimidazole, the main product of the reaction is 1-methyl-5-(2-furyl)imidazole.     

Acyclic analogues of purine and imidazole nucleosides

Hydroxyl-protected derivatives of 1- and 3-(2-hydroxyethoxymethyl)imidazoles ( 4,5,7-10 ) have been prepared from 5-amino-4-carbamoylimidazoles ( 2 ). The protected derivatives were converted to acyclic analogues of imidazole nucleosides ( 6 ) or subjected to various cyclisation reactions leading to 9-(2-hydroxy-ethoxymethyl)-substituted 2-methyl-, 2-phenyl- and 2-azahypoxanthines ( 18,13 and 20 , respectively) and 1-methylguanine ( 28 ). For assignment of structures to isomeric imidazole and purine derivatives, ¹³C chemical shifts have been used.     

Inhibitory activities and inhibition specificities of caffeic acid derivatives and related compounds toward 5-lipoxygenase

Various caffeic acid derivatives were synthesized, and their effects on 5-lipoxygenase (5-LO), 12-lipoxygenase (12-LO) and prostaglandin (PG) synthase activities were investigated. Among them, caffeic acid octyl amide (5) and 1-(3,4-dihydroxyphenyl)-1-octen-3-one (11) showed very potent inhibitory activities toward 5-LO with IC50 values of 4.2 x 10(-8) and 3.5 x 10(-8) M, respectively. They were very selective inhibitors for 5-LO. Compound 11 showed non-competitive inhibition, and the two adjacent hydroxy groups attached to the benzene ring, as well as the hydrophobic alkyl side chain, were required for its strong binding to 5-LO.     

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.     

Acrylamide derivatives as antiallergic agents. III. Synthesis and structure-activity relationships of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]- and N-[4-(4-diphenylmethylene-1-piperidyl)butyl]-3-heteroarylacry lamides

A new series of 3-heteroarylacrylamides 2 and 4 was prepared and the inhibitory activities against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase (5-LO) were tested. Most of the compounds exhibited an anti-PCA activity superior to or equivalent to ketotifen and had a 5-LO inhibitory activity. The 3-heteroarylacrylamide derivatives including 3-(3-pyridyl)acrylamides represent a new structural class of compound that exhibits not only an in vivo anti-PCA activity but also an in vitro 5-LO inhibitory activity.     

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.     

Synthesis of Bi- and tridentate imidazole ligands

A number of imidazole derivatives were prepared in the course of studying the limits of carbon-metal bond formation in complexes of imidazole with first-row transition metals. Seven of the compounds were new. The 4- and 5-methyl and 4,5-dimethyl derivatives of l-(2-pyridyl)-imidazole were prepared by reaction of the appropriate imidazole with 2-bromopyridine. Alkylation of imidazole, 4,5-dimethylimidazole, and benzimidazole with 2-chloromethylpyridine gave a series of 1-(2-pyridylmethyl)imidazoles. 1-(2,3-Diaminopropyl)imidazole was prepared in six steps via a Gabriel sequence.     

Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange.

Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted 1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-catalyzed hydrogenolysis.     

Studies on antiplatelet agents. I. Synthesis and platelet inhibitory activity of 5-alkyl-2-aryl-4-pyridylimidazoles.

5-Alkyl-2-aryl-4-pyridylimidazoles were synthesized and tested in rat ex vivo platelet aggregation studies. Among these compounds, 2-(2-fluorophenyl)-5-methyl-4-(3-pyridyl)imidazole (25) was most potent, and showed 98% inhibition at a dose of 10 mg/kg (p.o.). 25 had inhibitory activity on cyclooxygenase, thromboxane A2 (TXA2) synthetase, and phosphodiesterase, and also showed inhibited KCl-induced contraction of rat aorta. All compounds have little acute toxicity and appear to be free of adverse effects on the stomach.     

Nucleosides: Synthesis of Some New Naphthimidazole Ribonucleosides as Potential Antibacterial Agents

Reaction of 2-trifluoromethyl- or 2-cyanonaphth[2,3-d] imidazole (1 or 2) with 1-O-acetyl-2,3,5-tri-O- benzoyl-β-D-ribofuranose (3), using the triflate or fusion method afforded 2-trifluoromethyl-1-(2,3,5-tri- O-benzoyl-α-D- or -β-D-ribofuranosyl)naphth[2,3-d]imidazole (4 or 6) and 2-cyano-1-(2,3,5-tri-O-benzoyl-α-D- or β-D-ribofuranosyl)naphth[2,3,-d] imidazole (5 or 7), respectively. The products 4 and 5 or 6 and 7 were separated by chromatography on silica gel. Treatment of the blocked nucleosides 4-7 with methanolic NH₃ at 0 °C furnished the deblocked nucleosides 8-11 respectively. Treatment of 10 with 5% NH₃ (aq) at 60 °C gave 11. Structural elucidation is based on elemental analysis, UV, FAB-MS and ¹H NMR spectra. Compounds 4-11 were subjected to antibacteial testing. Compounds 5, 7 and 10 have significant activity against Staphylococous aureus (gram positive) and Esherichia coli (gram negative) bacteria, whereas the other tested compounds showed no significant activity.     

Silver(I) complexes of 9-anthracenecarboxylic acid and imidazoles: synthesis, structure and antimicrobial activity

[Ag(2)(9-aca)(2)] (1) (9-acaH = 9-anthracenecarboxylic acid) reacts with a series of imidazoles to give [Ag(imidH)(2.3)(CH(3)CN)(0.7)](9-aca) (3), [Ag(6)(imidH)(4)(9-aca)(6)(MeOH)(2)] (4), {[Ag(1-Me-imid)(2)](2)[Ag(4)(9-aca)(6)]} (5), {[Ag(1-Bu-imid)(2)](2)[Ag(4)(9-aca)(6)]} (6) and [Ag(apim)](9-aca)·H(2)O (7) (imidH = imidazole; 1-Me-imid = 1-methylimidazole; 1-Bu-imid = 1-butylimidazole; apim = 1-(3-aminopropyl)imidazole). The mononuclear complex 3, hexanuclear 4-6, and polymeric 7, were all characterised using X-ray crystallography. While many of the complexes possess excellent in vitro antifungal and antibacterial activities they are, unanimously, more effective against fungal cells. The insect, Galleria mellonella, can survive high doses of the Ag(i) complexes administered in vivo, and a number of the complexes offer significant protection to larvae infected with a lethal dose of pathogenic Candida albicans cells.     

Synthesis of new thietanylpyrimidine and thietanylimidazole derivatives

New thietanyl-substituted derivatives of pyrimidine-2,4(1H,3H)-dione and imidazole were synthesized. The alkylation of 6-methylpyrimidine-2,4(1H,3H)-diones with 2-chloromethylthiirane in water involved the N¹ atom of the pyrimidine ring and afforded 6-methyl-1-(thietan-3-yl)-pyrimidine-2,4(1H,3H)-diones. Under analogous conditions 6-aminopyrimidine-2,4(1H,3H)-dione gave rise to 6-(thietan-3-ylamino)pyrimidine-2,4(1H,3H)-dione. Unsymmetrically substituted 2-methyl-4(5)-nitro- and 5(4)-bromo-2-methyl-4(5)-nitro-1H-imidazoles reacted with 2-chloromethylthiirane to produce mixtures of isomeric 2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles and 5(4)-bromo-2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles.     

Efficient synthesis of 4,4'-bi-1H-imidazol-2-ones from 5-amino-alpha-imino-1H-imidazole-4-acetonitriles and isocyanates

Reactions of 5-amino-alpha-imino-1H-imidazole-4-acetonitriles 1 with alkyl and aryl isocyanates led to efficient syntheses of 5'-amino-5-imino-4,4'-bi-1H-imidazol-2-ones 3 formed by intramolecular cyclization of the corresponding 5-amino-alpha-(N-alkyl/arylcarbamoyl)imino-1H-imidazole-4-acetonitriles 2. The cyclization occurs only slowly in solution but is considerably accelerated by the addition of a catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The reaction of the N-arylamidine 6b, the synthetic precursor of the imidazole 1b, with benzyl isocyanate also led to the formation of 4,4'-bi-1H-imidazol-2-one 3b in quantitative yield. The imidazole intermediate 2b has been isolated and found to be identical with the compound obtained by reaction of the imidazole 1b and benzyl isocyanate. The N-arylamidine 6c (R = 4-NCC(6)H(4)) reacted with benzyl isocyanate in a similar way, but the electrophilicity of the amidine carbon atom resulted in rapid hydrolysis of the intermediate 7c leading ultimately to the isolation of the urea 9. The N-alkylamidines 6a and 6d behaved differently in their reaction with benzyl isocyanate, and the major product isolated in these reactions is again the urea 9.     

Researches on imidazoles

A number of 1-alkyl (1, 2-dialkyl)-4-nitro-5-alkyl (aryl, dialkyl) aminoimidazoles are synthesized by reacting 1-alkyl (1, 2-dialkyl)-4-nitro-5-chloroimidazoles with aliphatic, aromatic, and heterocyclic amines. Hydrogenation of 1-ethyl-2-methyl-4-nitro-5-(N-morpholino) imidazole in acetic anhydride gives 1-ethyl-2-methyl -4-diacetylamino-5-(n-morpholino) imidazole, characterized as its picrate.Paper presented at the All-Union Conference on the Chemistry of Five-Membered Heterocyclic Rings, Rostovon-Don, 1962.     

Imidazolyl derivatives of the thiochroman ring

The synthesis of 2-(1H-imidazol-1-yl)-4H-1-benzothiopyran- 4 -ones 3 from 3-bromo-4H-1-benzothiopyran-4-ones 1 and imidazole is described. The reaction of 1 with secondary amines gives the corresponding 3 -amino-thiochromones 11. Compounds 3 can be oxidized to the sulfones 4 from which the thiochromanols 5 and thiochromene 7 can be easily obtained. 3-Bromo-2,3-dihydro-6-methyl-4H-1-benzothiopyran-4-one 12 and imidazole led by dehydrohalogenation to thiochromone, while the ketal 13 rearranged to benzo[b]thiophene 16.     

Efficient and beta-Stereoselective Synthesis of 4(5)-(beta-D-Ribofuranosyl)- and 4(5)-(2-Deoxyribofuranosyl)imidazoles(1)

A synthetic route to 4(5)-(beta-D-ribofuranosyl)imidazole (1), starting from 2,3,5-tri-O-benzyl-D-ribose (5), was developed via a Mitsunobu cyclization. Reaction of 5 with the lithium salt of bis-protected imidazole afforded the corresponding 5-ribosylimidazole 7RS. Hydrolysis of 7RS gave a 1:1 mixture of diol isomers 8R and 8S having an unsubstituted imidazole. Mitsunobu cyclization of the mixture 8RS using N,N,N',N'-tetramethylazodicarboxamide and Bu(3)P exclusively afforded benzylated beta-ribofuranosyl imidazole 9beta in 92% yield, accompanied by alpha-anomer 9alpha, in a ratio of 26.3:1. The configuration of 9beta was established by X-ray crystallography of ethoxycarbonyl derivative 10beta. Reductive debenzylation of 9beta over Pd/C was carried out, and the synthesis of 1 was attained from starting 5 in four steps and 87% overall yield. This synthetic methodology was extended to the synthesis of 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole (2). Mitsunobu cyclization of a 1:1 mixture of the corresponding diol isomers 14RS produced 15beta and 15alpha in a ratio of 5.4:1. The synthesis of 2 was attained in a 59% overall yield from the starting 3,5-di-O-benzyl-2-deoxy-D-ribose (12). beta-Stereoselective glycosylation in the key step is discussed and explained by intramolecular hydrogen bonding between an NH in the imidazole and the oxygen functional group in the sugar moiety.     

Synthesis of Halogenated 1,5-Diarylimidazoles and Their Inhibitory Effects on LPS-Induced PGE2 Production in RAW 264.7 Cells

A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE₂ production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles, regardless of the species of halogen, exhibited very strong inhibitory activities of PGE₂ production. Among them, 4-chloro-5-(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole (3, IC₅₀ 3.3 nM ± 2.93), and 4-chloro-5-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)imidazole (13, IC₅₀ 5.3 nM ± 0.23) showed the best results.     

Syntheses and characterization of six coordination polymers of zinc(II) and cobalt(II) with 1,3,5-benzenetricarboxylate anion and bis(imidazole) ligands

Six new coordination polymers, namely [Zn1.5(BTC)(L1)(H2O)2].1.5H2O (1), [Zn3(BTC)2(L2)3] (2), [Zn3(BTC)2(L3)1.5(H2O)].H2O (3), [Co6(BTC)4(L1)6(H2O)3].9H2O (4), [Co1.5(BTC)(L2)1.5].0.25H2O (5), and [Co4(BTC)2(L3)2(OH)2(H2O)].4.5H2O (6), where L1 = 1,2-bis(imidazol-1-ylmethyl)benzene, L2 = 1,3-bis(imidazol-1-ylmethyl)benzene, L3 = 1,1'-(1,4-butanediyl)bis(imidazole), and BTC = 1,3,5-benzenetricarboxylate anion, were synthesized under hydrothermal conditions. In 1-6, each of L1-L3 serves as a bidentate bridging ligand. In 1, BTC anions act as tridentate ligands, and compound 1 shows a 2D polymeric structure which consists of 2-fold interpenetrating (6, 3) networks. In compound 2, BTC anions coordinate to zinc cations as tridentate ligands to form a net with (64.82)2(86)(62.8)2 topology. In compound 3, BTC anions act as tetradentate ligands and coordinate to zinc cations to form a net with (4.62.83)2(8.102)(4.6.83.10)2 topology. In compound 5, each BTC anion coordinates to three Co cations, and the framework of 5 can be simplified as (64.82)2(62.82.102)(63)2 topology. For 4 and 6, the 2D cobalt-BTC layers are linked by bis(imidazole) ligands to form 3D frameworks. In 6, the Co centers are connected by micro3-OH and carboxylate O atoms to form two kinds of cobalt-oxygen clusters. Thermogravimetric analyses (TGA) for these compounds are discussed. The luminescent properties for 1-3 and magnetic properties for 4-6 are also discussed in detail.     

Magnetism and Luminescence of a MOF with Linear Mn3 Nodes Derived from an Emissive Terthiophene-Based Imidazole Linker

A new terthiophene-based imidazole luminophore 5,5’-(1H-thieno[3,4-d]imidazole-4,6-diyl)bis(thiophene-2-carboxylic acid) (TIBTCH₂, 5) was synthesized in one step from previously reported 4,6-di(thiophen-2-yl)-1H-thieno[3,4-d]imidazole (DTTI, 4), and their photophysical properties were studied and compared accordingly. Under solvothermal conditions, reacting 5 with Mn(OAc)₂ yielded a new three-dimensional metal-organic framework (MOF, 6) which was structurally defined by single-crystal X-ray diffraction. In 6, all Mn(II) ions octahedrally bind to carboxylate-O atoms to form a linear Mn₃ secondary building unit (SBU) that contains three distinct coordination modes. Importantly, 6 exhibits dual functional properties of ligand-based emission and metal-based magnetic behaviors.