Beta'-Lithiation of Alpha, Beta-Unsaturated Amides
Kempf, Dale John
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https://hdl.handle.net/2142/70197
Description
Title
Beta'-Lithiation of Alpha, Beta-Unsaturated Amides
Author(s)
Kempf, Dale John
Issue Date
1982
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 novel (beta)'-lithiation of (alpha)-alkyl-(alpha),(beta)-unsaturated secondary and tertiary amides is reported. N-Methyl-1-cyclohexenecarboxamide and N-methyl-1-cyclopentenecarboxamide are metalated at nitrogen and at the (beta)'-carbon with either sec-butyllithium/TMEDA at -78(DEGREES)C or n-butyllithium at 0(DEGREES)C. Further reaction with a variety of electrophiles leads in good yield to the (beta)'-substituted products. Similarly, lithiation of N,N-diisopropyl-1-cyclohexenecarboxamide by sec-butyllithium/TMEDA at -78(DEGREES)C followed by treatment with electrophiles affords the (beta)'-substituted tertiary amides. N-Methyl-3-ethyl-2-methyl-2-pentenamide and (E)-N-methyl-2-methyl-2-butenamide also undergo exclusive (beta)'-metalation. However, deprotonation occurs at the (gamma)-position in N-methyl-2-ethyl-3-methyl-2-butenamide, in which the cis-(gamma)-carbon is less highly substituted than the (beta)'-carbon. The acyclic amides afford unsymmetrical allylic anions, which react with electrophiles to give mixtures of isomeric products. The dianion from N-methyl-4-t-butyl-1-cyclohexenecarboxamide is deuterated non-selectively but reacts with benzophenone to give only the diastereomer which results from addition cis to the t-butyl group. The reactions of the lithiated amides with aldehydes show only a slight erythro selectivity.
Elaborations of the products from the (beta)'-lithiated amides are described. The hydroxyamides prepared from secondary amides and ketones or aldehydes can be thermally cyclized to (alpha)-alkylidene-(gamma)-butyrolactones, including the naturally occurring bicyclic lactone neocnidilide. Metalation and intramolecular cyclization to a spiro system is demonstrated with N,N-diisopropyl-6-(4-chlorobutyl)-1-cyclohexenecarboxamide. The anions from N,N-diisopropyl-6-trimethylsilyl-1-cyclohexenecarboxamide and N,N-diisopropyl-6-phenylthio-1-cyclohexenecarboxamide undergo regioselective reaction with most electrophiles to give the vinyl silanes and sulfides. Treatment of N,N-diisopropyl-6-bromo-1-cyclohexenecarboxamide with silver tetrafluoroborate allows the substitution of several nucleophiles at the (beta)'-position.
Synthetically, this novel lithiation allows facile functionalization of a previously unavailable site in (alpha),(beta)-unsaturated acid derivatives. Mechanistically, the kinetically controlled metalation at the (beta)'-position is interpreted in terms of a mechanism involving initial complexation of the amide to the alkyllithium base.
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