Imidazoles reaction with 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 (80AHC(27)241). 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. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

The medium has no specific oxidative action towards the alkyl radicals, and in the presence of protonated base the major reaction is a substitution. Thus, imidazoles and 1-substituted imidazoles are alkylated exclusively at C-2, albeit in rather low yields. The use of isopropyl and r-butyl radicals gives improved yields (80-90%) but benzyl and allyl radicals tend to dimerize in preference. Benzimidazoles are also alkylated at C-2, and with isopropyl and t-butyl radicals yields of 50-80% can be achieved (80AHC(27)24l, 74AHC(16)123). 

Trifluoromethylation of pyrrole (and indole and imidazole) occurs on irradiation of a mixture of the compound with difluorodiiodomethane, again via a SET mechanism involving fragmentation of the radical anion (Scheme 31). The presence of the CF3 group in the final products, 45 and 46, is a result either of secondary decomposition of the initially formed—but not isolated—difluoroiodomethyl derivatives, or of formation of the CF3 anion or radical in situ [94], Perfluoroalkyla-tion of pyrroles can also be achieved by an SrnI mechanism—by reaction with perfluoroalkyl iodides in the presence of magnesium or zinc [95]. Indole, on the other hand, gives a mixture of the seven possible alkylated derivatives when irradiated in the presence of ethyl chloroacetate [96],... 

Imidazoles normally undergo free-radical reactions at the 2-position. For example, homolytic free-radical alkylation of histidines and histamines yields 2,3-disubstituted histidines and histamines. In these reactions, the free radical was generated via silver-catalyzed oxidative decarboxylation of acids with peroxydisulfate 433 (Scheme 103) <2001BML1133>. 

Radical cyclizations of nucleophilic N-alkyl radicals 96 onto the benzimidazole 2-position, mediated by tributyltin hydride and activated by quater-nizing the pyridine-like N-3 of imidazole with camphorsulfonic acid, have recently been reported (Scheme 20) [67]. These new five-, six- and seven-membered homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred upon the use of large excesses of the azo-initiator, l,T-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. The intermediate 97 aromatizes in high yields to the cy-clized benzimidazoles 98. 

A detailed reexamination of the thermal rearrangement of 1-methyl-imidazole originally reported by Wallach has been extended to encompass a wide range of 1-substituted imidazoles. The reaction appears to be of potential synthetic utility since it leads easily to 2-alkyl- and 2-arylimidazoles. It is an irreversible reaction, uncatalyzed, intramolecular, and does not involve radicals [l,5]-sigmatropic shifts, as shown in Scheme 40, are probably implicated. The major product is the 2-substituted imidazole (134), but small amounts of the 4- (or 5-) isomer (135) are also formed. A 1-allyl substituent migrates with equal facility to both 2- and 4(or 5)-positions, suggesting that a Cope-type rearrangement may also be involved for this substituent. ... 

AAHeterocyclic carbene-borane complexes have been shown to be useful as hydrogen sources through radical mechanisms, as Chu et al [85] determined after their initial work with the reduction of xanthates mentioned earlier. Also, substituted imidazol-2-ylidene and triazol-3-ylidenes have been employed in the reduction of dodecyl iodide to dodecane without the addition of any radical initiator. Furthermore, even in the presence of usually borane-reactive species, such as ketones or alkenes, the reduction of the alkyl halide is the only reaction observed. Later, however, Ueng et al foimd that alkyl halides with nearby... 

---