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Strain control in nucleophilic cyclizations: reversal of exo ‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold
Author(s) -
Vasilevsky Sergei F.,
Gold Brian,
Mikhailovskaya Tatyana F.,
Alabugin Igor V.
Publication year - 2012
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.2990
Subject(s) - chemistry , regioselectivity , pyrazole , alkyne , nucleophile , pyridine , scaffold , carboxylic acid , stereochemistry , combinatorial chemistry , medicinal chemistry , catalysis , organic chemistry , medicine , biomedical engineering
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 & Sons, Ltd.