Heteroaromatic imidazo pyridine

Wang, Ji, and coworkers developed a CuI/BF3-Et20/02 system for the synthesis of heteroaromatic imidazo[l,2- ]pyridines from ketones with 2-aminopyridines (Scheme 8.61). The C(sp )-H bonds of ketones are activated under these oxidation conditions. A total of four hydrogen atoms are removed, and two new C-N bonds are formed in one step to construct the imidazo[l,2- ] pyridines [103]. Hajra et al. developed a Cu(0Ac)2-H20-catalyzed direct oxidative cyclization via C-H amination between 2-aminopyridines and methyl aryl/heteroaryl ketones... 

In condensed heteroaromatic systems with a bridge-head pyrrolic nitrogen atom, tr-electron density is always shifted from the electron-rich six-membered ring (formally contains 7 Tr-electrons) towards the five-membered ring (formally has 6 Tr-electrons). As a result electrophiles are directed to carbon atoms of the latter. Thus, imidazo[ 1,2-a]pyridines (140) unsubstituted at C-3 almost always react with electrophiles at that position. 

Imidazo[4,5-c]pyridine (408 R = R = H) and a number of its 2-substituted and 1,2-disubstituted derivatives have been prepared in moderate to good yields by the reaction of the 3,4-diaminopyridines (407) with aliphatic, aromatic and heteroaromatic aldehydes in aqueous alcohol solution in the presence of excess copper(II) acetate in a sealed tube at 130-150 °C (38CB2347, 42CB1936). The Schiff bases (409) are formed primarily in this synthesis, and in many cases it is preferable to isolate the base (409) and effect the subsequent oxidation in a separate operation in alcohol solution. Ring closure of 5-substituted, 6-substituted and 2,6-disubstituted 3,4-diaminopyridines (410) to 7-substituted, 6-substituted... 

Needless to say that this unexpected result is much more interesting than if the classic Ugi-4CR adduct 91 were obtained. Indeed, the importance of imidazo[l,2-a]pyridine and the related bicychc heterocycles has stimulated intensive studies on the scope and appHcation of this novel three-component reaction. There seems to be no major hmitation regarding the selection of aldehydes and isonitriles. For 2-aminoazenes, both heteroaromatic amidines and heteroaromatic guanidines participated in this novel 3CR. However, ahphatic amidines were found to be inactive. Many variants have since been reported from different research groups, both from academia and industry, because of the medicinal relevance of this family of heterocycles [47]. 

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