2- Phenylimidazole

Freshly prepared phenacylbromide (20 g, 0.10 mol) is added to formamide (100 ml) with stirring. The temperature is raised to 150-180°C and maintained at that level (2 h). After cooling somewhat the solution is boiled with concentrated hydrochloric acid (200 ml) containing a small quantity of activated charcoal, cooled, filtered (CeUte), and basified with aqueous ammonia, when the product crystallizes. Filtration, washing repeatedly with water, and reciys-tallization from water gives 4-phenylimidazole as colourless plates (3.6 g, 25%), m.p. 129-1 SOT. 

Although a-aminoketones readily form imidazoles when they cyclize in the presence of formamide [48], preparative difficulties (see Sections 2,1.1, 2.2.1 and 4.1) point to alternative use of their precursors, a-oximinoketones, which can be reduced by dithionite or using catalytic methods in formamide at 70-100°C. Subsequent ring closure is achieved merely by raising the temperature to 180°C. 

A solution of diacetyl monoxime (1.01 g, lOmmol), D(/ )-methionine (0.89 g, 10 mmol) and 30% formalin solution (1.5 g) in ethanol (100 ml) is refluxed (3 h), then cooled and filtered. Rotary evaporation of the filtrate, treating the residue with dry acetone, again filtering, then addition of dry ether precipitates the product, which can be recrystallized from chloroform-hexane and added methanol as colourless crystals (2.35g, 96%), m.p.l78-181°C. 

The old Maquenne synthesis of imidazoles [64] is seldom used nowadays. It was originally used to make imidazole-4,5-dicarboxylic acids from tartaric acid dinitrate and either an aliphatic aldehyde or formaldehyde precursor in the presence of ammonium ions at pH 3.5-6.5. The procedure is not an entirely pleasant experience, and has been happily superseded by other approaches, but it may be useful on occasion to make compounds such as vinyl-, hydroxy-and methoxy-substituted 2-arylimidazole-4,5-dicarboxylic acids [65]. Use of dialkyltartrate dinitrates gives the corresponding imidazole-4,5-dicarboxylates in 45-65% yields [31]. 

To a boiling mixture of isoamyl nitrite in THE a solution of (6) (R = 2-hydroxy-3-nonyl, X = CN) (l.Og, 4.4 mmol) in THF (20ml) is added drop-wise over 1 h. After the addition in complete, the reaction mixture is refluxed (3h), cooled and rotary evaporated. Flash chromatography of the residue on silica gel eluted with cyclohexane-chloroform-methanol (55 40 5) gives the nitrile (0.46 g, 50%) as an oil. 

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Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

The oxazolone 43, prepared by reaction of 0-methylcaprolactim (42) with compound 1, undergoes a ring-opening reaction with methanolic HCl and cyclizes in alkaline medium to 1,5-pentamethyl-ene-2-phenylimidazole-4-carboxylic acid (44), which can be decar-boxylated easily. 

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

Diphenylimidazole with palladium acetate forms the cyclometallated complex 80 (X = OAc) (97AOC491). The acetate group is replaced by chloride or bromide when 80 (X = OAc) reacts with sodium chloride or lithium bromide, respectively, to give 80 (X = C1, Br). Bromide with diethyl sulfide forms the mononuclear complex 81. Similar reactions are known for 1 -acetyl-2-phenylimidazole (96JOM(522)97). 1,5-Bis(A -methylimidazol-2-yl)pen-tane with palladium(II) acetate gives the cyclometallated complex 82 (OOJOM (607)194). 

The N-coordinated compound [AuCljL] (L= l-ethyl-2-phenylimidazole) with silver tetrafluoroborate gives the cycloaurated species 102, which on further reaction with triphenylphosphine and sodium tetrafluoroborate or ammonium hexafluorophosphate forms the cationic complexes 103 (X = BF., PF,) (00JCS(D)271). 

Thermolysis of 4-benzyl-3,7-diphenyl-4/7-l,2,4-triazepine gives a mixture of the rearranged pyrazole 2, 2.4-diphenylpyrimidine and l-benzyl-4-phenylimidazole.341... 

Synthesis and crystal structure of the novel five-membered cycloaurated complex of l-efhyl-2-phenylimidazole. 

More than 2,000 potential replacements for the bromophenyl or pyridyl groups were then screened using the NMR-screening technique. Several fragments were identified which caused chemical shift changes in the desired binding site of the protein, amongst them indole (7) and 2-phenylimidazole... 

In the direct alkylation of 4-phenylimidazole the desired l-ethyl-5-phenylimidazole is obtained only as a minor product [1]... 

For this reason the regioselective methylation of various 4-substituted 1-acetyl-imidazoles was studied.1[2] While reaction with l-acetyl-4-phenylimidazole furnished the isomers l-methyl-5-phenylimidazole and l-methyl-4-phenylimidazole in a ratio of 93 7, reaction with l-acetyl-4-methylimidazole produced an isomer ratio of 86 14. 

This approach (Scheme 3) has been applied (53JCS1636) to the synthesis of 4(5)-aminoimidazole derivatives with potential antihistamine or anthelmintic properties. For example, 4(5)-amino-2-thymyloxymethylimidazole (47) was obtained from benzyl-thymyloxy acetothioimidate hydrochloride (42) (75%). Similarly, 4(5)-amino-2-phenylimidazole (48) and 4(5)-amino-2-(thiophen-3-yl)imidazole (49) were prepared (72CA19645) from benzyl-phenyl acetothioimidate hydrochloride (43) and benzyl-(thiophen-3-yl) acetothioimidate hydrochloride (44), respectively. 

Scheme 7 shows that the method of sequential arylation with a high selectivity, using 2-phenylimidazole motif, proves to be applicable for pharmaceuticals and fluorescent and chemiluminescent probes.85 The direct 4-arylation of free 2-phenylimidazole is achieved with iodoarenes as the aryl donors in the presence of palladium catalyst (Pd/PPh3) and MgO as the base. A complete switch from G4 to C2 arylation is accomplished using a ruthenium catalyst [CpRu(PPh3)2Cl] and Gs2G03. 

Positive inotropic properties have been observed also with compounds bearing an imidazol-2-ylphenyl group (17) and with compounds in which the pyridazinone core is attached to C-4 of a 2-phenylimidazole system (18) [27]. 

AOM, azoxymethane MNNG, JV-methyl-JV -nitro-JV-mtrosoguamdine DMH, 1,2-dimethyl-hydrazine MNU, W-methyl-W-nitrosourea PhIP, 2-amino-l-methyl-6-phenylimidazole[4,5-b] pyridine sc, subcutaneous ip, intra-peritoneal ir, intra-rectal po, by mouth. 

Recently the synthesis of NHC complexes by a base catalyzed tautomeric rearrangement has been introduced. Af-Phenylimidazole coordinates via the unsubstituted nitrogen atom to Mn to give complex 82 (Fig. 26a) [198]. Subsequent attempts to deprotonate the C2 carbon atom in complex 82 led to the intermediate... 

Starting from l-amino-2-methylthio-4-phenylimidazole, a double aza-Wittig reaction (Scheme 111) furnishes the imidazo[l,2,4]triazine (309) (89S843). 

Poulos, T. L. and Howard, A. J. (1987) Crystal structure of metyrapone- and phenylimidazole-inhibited complexes of cytochrome. Biochemistry 26, 8165. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

Two rearrangements may well be regarded as further examples of interconversion between meso-ionic isomers. The 1,3-diazolium chloride (310) and warm dilute aqueous potassium hydroxide yield 4-anilino-l-methyl-2-phenylimidazole (311), presumably via the indicated meso-ionic intermediates. The transformation 312 - 313 by treatment of the thiazolium chloride with warm aniline may be similarly interpreted. ... 

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