Regioselectivity of SNAr reactions in the synthesis of isomeric difluorinated 4- and 6-piperidino-5-azaindoles

For the targeted synthesis of fluorinated analogues of 5-azaindoles used for the prevention and treatment of diabetes and obesity, the regioselectivity of fluorine replacement by piperidine residue in their precursors is explored. The reverse sequence of the S_NAr reaction and cyclization steps enables the selective preparation of isomeric 5-azaindoles containing substituents at positions 4 vs. 6, respectively. A quantum-chemical justification of the predominant positions of nucleophilic attack in polyfluoroarenes is given.