Strain control in nucleophilic cyclizations: Reversal of exo-selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

Sergei F. Vasilevsky, Brian Gold, Tatyana F. Mikhailovskaya, Igor V. Alabugin

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)998-1005
Number of pages8
JournalJournal of Physical Organic Chemistry
Volume25
Issue number11
DOIs
Publication statusPublished - 1 Nov 2012
Externally publishedYes

Keywords

  • 5-exo
  • 6-endo
  • Alkyne cyclizations
  • Baldwin rules
  • Strain

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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