Enantioselective lateral lithiation-substitution reactions using benzamide directing groups
Thayumanavan, Sankaran
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https://hdl.handle.net/2142/22934
Description
Title
Enantioselective lateral lithiation-substitution reactions using benzamide directing groups
Author(s)
Thayumanavan, Sankaran
Issue Date
1996
Doctoral Committee Chair(s)
Beak, Peter
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
Reactions involving organolithium reagents under the influence of the chiral ligand to affect the enantioselective replacement of a carbon-proton bond with a carbon-carbon bond or a carbon-heteroatom bond are described.
Highly enantioenriched substitution products are obtained when N,N-diisopropyl-o-ethylbenzamide is treated with sec-butyllithium/($-$)-sparteine followed by the reaction with electrophiles. When the electrophilic substitution is carried out with alkyl chlorides as electrophiles, the products are obtained with 68-92% ee in moderate to high yields. When alkyl tosylate is used as the electrophile, opposite enantiomer of the products are obtained with 78-97% ee in low to high yields.
The enantioselectivity of the reaction can be achieved in one of the three steps in the reaction: the deprotonation step, the complexation step, or the substitution step. Tin-lithium exchange experiments of enantioenriched stannyl substrate in the presence and absence of ($-$)-sparteine suggests that the enantioselectivity is achieved in the substitution step. Deprotonation of racemic N,N-diisopropyl-o-(l$\sp\prime$-deutereo)ethylbenzamide using sec-butyllithium/($-$)-sparteine suggests that the initial deprotonation reaction proceeds enantioselectively to afford enantioenriched organolithium intermediate which racemizes under the reaction conditions and the enantioselectivity of the product is determined in the substitution step.
Investigation of the enantioselectivity of the products with electrophiles with a variety of leaving groups suggested that electrophiles with fast and/or non-coordinating eletrophiles react with (R)-N,N-(diisopropyl-o-(1$\sp\prime$-lithio)ethylbenzamide with inversion of configuration to afford enantioenriched products. Slow and coordinating electrophiles react with (R)-N,N-diisopropyl-o-(1$\sp\prime$-lithio)ethylbenzamide with retention of configuration to afford products with the opposite enantiomer enriched.
Effect of reaction conditions such as solvent, temperature, directing groups, substrate structure, and structure of the chiral ligands are also studied.
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