Imidazopyridine formation

Condensation of a 2-aminopyridine with an a-haloketone provides an alternative method for budding the imidazopyiridine. For example, reaction of 2-aminopicoline (9-1) with para-methylphenacyl bromide (9-2) leads directly to the imidazopyridine (9-4). The overall transformation can be rationalized by assuming an initial alkylation on ring nitrogen (9-3) imine formation followed by bond reorganization then forms... 

The proposed mechanism for formation of 151 is shown in (Scheme 27). Proton abstraction by the hydride base from the activated 2-position of the W-fluoropyridinum triflate yields a highly reactive carbene which undergoes attack by the acetonitrile solvent. The resulting nitrilium ylide eliminates fluoride and subsequently adds the isonitrile with cyclization. Finally, reduction by the hydride reagent and aromatization provide the imidazopyridine 151. The undesired amide 152 is a product of hydrolysis of the intermediate nitrilium compound. 

In this context, a polyfluorinated imidazopyridine system 21 has been prepared by a multistep synthetic route (see Figure 11.7) beginning from 3-chlorotetrafluoropyridine 22, via the formation and subsequent condensation of 3,4-diamino-2,5,6-trifluoropyridine with diethoxymethyl acetate [45], Subsequent reaction of the ring-fused system with ammonia demonstrated the potential of such systems as polyfunctional scaffolds, if much shorter... 

However, formation of IP is known to occur also under rather mild conditions. For example, imidazopyridine 22 was obtained as a result of boiling a mixture of 2,3 -diamino-4,4 -dipyridylamine 21 with excess AcoO in the presence of acetic acid (96ZOR586). 

The formation of imidazopyridines is known to be a two-step process. It was shown earlier [46] that the first step in the reaction - the alkylation of 2-aminopyridine with bromomethyl (adamantan-l-yl) ketone was successfully carried out with a high yield of l-[3-adamantan-l-yl)-2-oxoethyl]-2-amino-pyridinium bromide 29a by boiling the reagents for 1 h in ethanol or ethyl acetate. They have established that the introduction of an electron-acceptor substituent into the pyridine ring, considera-bly hinders the reaction. When 2-aminopyridine, 2-amino-4-methylpyridine, or 2-amino-3-methylpyridine were heated with bromomethyl(adamantan-l-yl) ketone in ethyl acetate for 1 h, the yields of compounds 29a, 52a, 56a varied within the limits of 80-95% and, whereas with 2-amino-6-bromo and 2-amino-5-chloropyridine the corresponding alkylation products - compounds 49a, 57a were obtained in yields of only 50%. In the case of 2-amino-5-bromo-3-trifluoromethylpyridine, the formation of only a negligible amount of compound 58a was observed after 1 h and the yield reached 42% only after 5 h... 

Imidazopyridines are important nitrogen-containing heterocycles that show a wide range of bioactivities. Hajra and coworkers have developed an iron-catalyzed oxidative diamination of nitroalkene with 2-aminopyridine to access 2-nitro-3-arylimidazo[l,2- ]pyridines under mild and aerobic reaction conditions (Scheme 9.6) [8]. In particular, the method allows the formation of two new C-N bonds through sequential Michael addition and vinyl C(sp )-H/N-H functionalizations and represents the first example of employing molecular oxygen as the terminal oxidant for the selective C-H amination. 

The surprising formation of 2-methylimidazole 228 in a good yield from pyrolysis of the azadiene 227 (Scheme 46 2013T722) bears an obvious similarity to the formation of the imidazopyridine from 110 mentioned in Section 4.1 (Scheme 23). The pyridylbenzotriazole 229 is a good precursor for synthesis of the benzimidazopyridine 230 and the corresponding... 

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