Remote Lithiations of Carboxamides: The Manifestation of a Post-Complexation Proximity Effect (Homoenolate)
Hunter, James Edward
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https://hdl.handle.net/2142/70327
Description
Title
Remote Lithiations of Carboxamides: The Manifestation of a Post-Complexation Proximity Effect (Homoenolate)
Author(s)
Hunter, James Edward
Issue Date
1986
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
Abstract
The remote metalations of tertiary amides, (beta) and (gamma) substituted with vinyl, phenyl and thiophenol groups, are reported. N,N-Diisopropyl-2-methylpent-4-enecarboxamide (59), N,N-diisopropyl-2-methyl-3-phenylpropanecarboxamide (139), N,N-diisopropyl-2-methyl-3-phenylthiopropanecarboxamide (174), N,N-diisopropyl-2-methyl-3-phenylthiobutanecarboxamide (176), N,N-diisopropyl-3-phenylthio-2-(phenylthiomethyl)propanecarboxamide (215) and N,N-diisopropyl-2-methyl-3-phenylthio-2-(phenylthiomethyl)butanecarboxamide (217), undergo deprotonation at the (beta) position upon reaction with sec-BuLi/TMEDA. The intermediate benzyl and thiomethylene anions react with a variety of electrophiles to yield (beta) substituted products. In the case of 217, metalation and electrophilic substitution occurs at a (beta) secondary carbon atom. The allylic alkyllithium generated undergoes electrophilic at the (beta) or (delta) position. Lithiation and substitution at the (gamma) position occurs upon treatment of N,N-diisopropyl-2-methyl-4-phenylthiobutanecarboxamide (193), with sec-BuLi/TMEDA, followed by an electrophile. The synthetic consequences of the metalations are discussed and demonstrated.
The stereochemistry of electrophilic addition to the anion may be controlled in some cases. With the allyllithium from 59, preferential or exclusive (delta) substitution is observed. When magnesium is employed as the counterion only (delta) substitution is observed. In all (delta) addition products the olefin has a Z geometry. The benzyl anion of 139 reacts with electrophiles at -78 (DEGREES)C to give predominantly the R*,R* diastereoisomer. Greater selectivity towards the R*,R* isomer is achieved at higher reaction temperatures.
The mechanism of the remote metalation has been investigated. In the metalation of 59, 139, and 193 the (beta) anion is generated without initial or concurrent (alpha) proton abstraction. It was also shown that in DMSO, the (alpha) proton of N,N-diisopropylcyclohex-3-enecarboxamide (33), is thermodynamically more acidic than the (beta) proton. The amide functionality is postulated to promote (beta) and (gamma) metalation through its ability to coordinate sec-BuLi in a pre-equilibrium complex in which the butyl group is positioned to direct deprotonation at a proximate site.
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