Imidazoles radical substitution

Alkyl radicals. Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus, imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position. Scheme 72 shows the substitution of a protected histidine <2001BML1133>. Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. A-Alkyl-1,2,-4-triazoles can be radical substituted at C(5) <2001TL7353>. 

Above 170 °C the amidrazone ylide (36) decomposes with loss of triethylamine and concurrent cyclization to give an 85% yield of 2-phenylbenzimidazole (Scheme 19) (B-75M140800). Poorer yields ( 40%) are obtained when N-benzyl-o-nitroaniline is pyrolyzed in the presence of iron oxalate. No doubt this last reaction is similar in many respects to the reactions shown in Scheme 2. Both 2-phenyl-imidazoles and -benzimidazoles (as well as other 2-substituted analogues) can be obtained as a result of thermal rearrangement of the 1-substituted isomers (Section 4.07.1.2.2), by radical substitution methods (Section 4.07.1.7) or via the 2-lithio derivatives (Sections 4.07.1.6, 4.07.3.7). 

Radical substitution reactions include alkylations and arylations in the main. Nucleophilic radicals produced by the silver-catalyzed oxidative decarboxylation of carboxylic acids (by peroxydisulfate ion) attack proton-ated azoles at the most electron-deficient sites.Thus, imidazole and 1-alkylimidazoles are methylated exclusively at C-2 in rather low yields. The use of isopropyl and t-butyl radicals gives improved yields, but benzyl and acyl radicals tend to dimerize rather than substitute the... 

Common sources of phenyl radicals are A-nitrosoacetanilide, diazoaminobenzene, or benzoyl peroxide which induce 2-phenylation of imidazoles and benzimidazoles. The 2-position is frequently the most susceptible to nucleophilic attack (CHEC-I). Most photochemically induced arylations also probably involve radical substitution, for example, photolysis of l,3-dialkyl-4,5-dichloro-2-imidazolone (95) in benzene (Scheme 47) <81AG(E)6I2>. Under photolytic conditions pentafluoro-... 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

There are few examples of radical substitution of benzofnran or benzothiophene perfluoroalkylation of benzofuran is one snch, as illnstrated. This process can also be applied to 2-snbstitution of thiophene, pyrrole, imidazole and indole. 

The preferred site for radical substitution of imidazoles in acid solution is C-2. In contrast, intramolecular alkylation of a 4-formylimidazole in neutral solution took place at C-5. Intramolecular displacement of tosyl as a C-2 substitutent, has also... 

The redox potentials of zinc-substituted phthalocyanines are shown to be linearly dependent on the total Hammett substituent constant.837 In 1987, Stillman and co-workers used the absorption and magnetic circular dichroism spectra of the zinc phthalocyanine and its 7r-cation-radical species to assign the observed bands on the basis of theoretical calculations. The neutral and oxidized zinc phthalocyanine complexes with cyanide, imidazole, and pyridine were used with the key factor in these studies the stability of the 7r-cation-radical species.838 The structure of zinc chloro(phthalocyaninato) has been determined and conductivity investigated.839... 

Owing to the existence of two centers for nucleophilic attack (at C2 and C5) in radical cations (220) obtained from the oxidation of 4-H -imidazole-1,3-dioxides (219), the formation of two products of methoxy group addition was observed, namely NNR (221) and NR of 3-imidazoline-3-oxide (222). The ratio of the products depends on the electronic nature of substitutes R1 and R2. Both, the donor character of R1 and acceptor character of R2 facilitate the formation of nitroxyl radicals (222) with the yield of (221) increasing with the inverted effect of the substituents. As was mentioned in Section 2.4, the results of preparative electrochemical oxidative methoxylation of 4H -imidazole-1,3-dioxides are similar to the results of chemical oxidation. 

Oxidation of mono-iV -oxides 4H -imidazole (223) and (224) with Pb02 in methanol leads to the formation of stable a,a-dimethoxy-substituted nitroxyl radicals (271) and methoxy substituted imino nitroxyl radicals (INR) (272)-(274) (Scheme 2.101) (514). 

Oxidative Animation of Nitrones to a-Amino-Substituted Nitroxyl Radicals Similar to the oxidative methoxylation reaction, oxidative animation of 4H -imidazole TV-oxides, in amine saturated alcohol solutions, give stable nitroxyl (282), nitronyl nitroxyl (283), imino nitroxyl (284) and (285) radicals with the amino group at the a-carbon atom of the nitroxyl group (Scheme 2.107) (520, 521). The observed influence of substituents on the ratio of animation products at C2 and C5 atom is close to the ratio observed in the previously mentioned oxidative methoxylation reaction. It allows us to draw conclusions about the preference of the radical cation reaction route. 

Reduction of p-oxo-bis[tetraphenylporphin iron(iii)] with sodium amalgam gives several products sequentially. The first reduction product is the radical-anion [(tpp)Fe ] , which has a spin state of - at 77 K and at 300 K. This is the first reported study of an Fe -porphyrin.Mossbauer data on a range of tetra-aryl-substituted iron-porphines and their p-oxo-bridged derivatives have been reported. A crystallographic study on bis(imidazole) otPy -tetraphenylporphinatoiron(iii) chloride-methanol solvate shows the [FeN ] core to be quasitetragonal. An n.m.r. study has been made of the related... 

The most common reactions involving nucleophiles and porphyrin systems take place on the metalloporphyrin 77-cation radical (i.e. the one-electron oxidized species) rather than on the metalloporphyrin itself. One-electron oxidation can be accomplished electrochemi-cally (Section 3.07.2.4.6) or by using oxidants such as iodine, bromine, ammoniumyl salts, etc. Once formed, the 77-cation radicals (61) react with a variety of nucleophiles such as nitrite, pyridine, imidazole, cyanide, triphenylphosphine, thiocyanate, acetate, trifluoroace-tate and azide, to give the correspondingly substituted porphyrins (62) after simple acid catalyzed demetallation (79JA5953). The species produced by two-electron oxidations of metalloporphyrins (77-dications) are also potent electrophiles and react with nucleophiles to yield similar products. 

Other radical methods for heterocycle synthesis involve SrnI reactions. The synthesis of indoles [95BCSF306], imidazoles [95JOC8015], imidazopyrimdines [95T9643], and substituted 1,3-dioxanes [95JCS(P1)609] have been reported. 

Eq. 5.17 shows ipso substitution of imidazoles (30) at the 2-position by an sp3 carbon-centered radical. Here, the tosyl group plays an important role in both activation of the ipso 2-position and as an effective leaving group, Ts [40-46]. The phosphoryl group also shows the same leaving ability as the tosyl group. Preparation of [1.2-b]-fused bicyclic pyrazoles (33) from l-(phenylselenoalkyl)pyrazoles (32) also works well, as shown in eq. 5.18. 

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