Strain control in nucleophilic cyclizations: reversal of <i>exo</i>‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

Abstract

Independent of the nature of alkyne substitution, hydrazides of 4‐arylethynyl‐5‐carboxylic acid annealed at the pyrazole scaffold undergo a regioselective base‐catalyzed 6‐ endo‐dig cyclization with the formation of pyrazolo[3,4‐c]pyridine‐7‐ones. This behavior contrasts the observation of selective 5‐ exo closures in the analogous benzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of a smaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overall cyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests that strategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophilic cyclizations. Copyright © 2012 John Wiley &amp; Sons, Ltd.