Tuning selectivity of anionic cyclizations

Competition between 5-exo and 6-endo-dig closures of hydrazides of o-acetylenyl benzoic acids and based-catalyzed fragmentation/recyclization of the initial 5-exo-dig products

Sergey F. Vasilevsky, Tat'yana F. Mikhailovskaya, Victor I. Mamatyuk, Georgy E. Salnikov, Georgy A. Bogdanchikov, Mariappan Manoharan, Igor V. Alabugin

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

(Chemical Equation Presented) Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles. The competition between 5-exo and 6-endo cyclizations of the "internal" nitrogen nucleophile is controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic isomerization. DFT computations provide insight into the nature of factors controlling relative rates of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and relative stability for the anionic precursor for this process, provide, for the first time, the benchmark data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects controlling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We show that the stability gain due transformation of a weak π-bond into a stronger σ-bond (the usual driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much more sensitive to external conditions and substituents than similar cyclizations of neutral species. However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic isomerization of the initially formed carbanions into the more stable N-anions. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes.

Original languageEnglish
Pages (from-to)8106-8117
Number of pages12
JournalJournal of Organic Chemistry
Volume74
Issue number21
DOIs
Publication statusPublished - 6 Nov 2009
Externally publishedYes

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Benzoates
Cyclization
Tuning
Nitrogen
Alkynes
Isomerization
Anions
Stereoselectivity
Nucleophiles
Discrete Fourier transforms
Kinetics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Tuning selectivity of anionic cyclizations : Competition between 5-exo and 6-endo-dig closures of hydrazides of o-acetylenyl benzoic acids and based-catalyzed fragmentation/recyclization of the initial 5-exo-dig products. / Vasilevsky, Sergey F.; Mikhailovskaya, Tat'yana F.; Mamatyuk, Victor I.; Salnikov, Georgy E.; Bogdanchikov, Georgy A.; Manoharan, Mariappan; Alabugin, Igor V.

In: Journal of Organic Chemistry, Vol. 74, No. 21, 06.11.2009, p. 8106-8117.

Research output: Contribution to journalArticle

Vasilevsky, Sergey F. ; Mikhailovskaya, Tat'yana F. ; Mamatyuk, Victor I. ; Salnikov, Georgy E. ; Bogdanchikov, Georgy A. ; Manoharan, Mariappan ; Alabugin, Igor V. / Tuning selectivity of anionic cyclizations : Competition between 5-exo and 6-endo-dig closures of hydrazides of o-acetylenyl benzoic acids and based-catalyzed fragmentation/recyclization of the initial 5-exo-dig products. In: Journal of Organic Chemistry. 2009 ; Vol. 74, No. 21. pp. 8106-8117.
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abstract = "(Chemical Equation Presented) Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles. The competition between 5-exo and 6-endo cyclizations of the {"}internal{"} nitrogen nucleophile is controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic isomerization. DFT computations provide insight into the nature of factors controlling relative rates of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and relative stability for the anionic precursor for this process, provide, for the first time, the benchmark data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects controlling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We show that the stability gain due transformation of a weak π-bond into a stronger σ-bond (the usual driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much more sensitive to external conditions and substituents than similar cyclizations of neutral species. However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic isomerization of the initially formed carbanions into the more stable N-anions. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes.",
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AU - Mikhailovskaya, Tat'yana F.

AU - Mamatyuk, Victor I.

AU - Salnikov, Georgy E.

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