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Title:Lithiation of Alkyl 2,6-Substituted Benzoates Adjacent to Oxygen: Alpha-Lithioalkyl Alcohol Synthons
Author(s):Carter, Linda Gay
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Chemistry, Organic
Abstract:The removal of an sp('3) proton alpha to the bivalent oxygen of an ether or alcohol to generate a formal stable (alpha)-oxocarbanion is unknown. However, formation of an (alpha)-lithio alcohol derivative from an ester might be feasible because the formally bivalent oxygen has a partial positive charge which could provide dipole-stabilization of the formal adjacent carbanion. In order to achieve the formation of an (alpha)-oxocarbanion from an ester by direct proton removal, it would be necessary to select structures in which proton removal and nucleophilic addition to the ester carbonyl are not competitive with metalation.
This thesis reports the syntheses and successful (alpha)-oxometalations of the esters of methyl and primary alcohols of 2,4,6-triisopropylbenzoates and 2,6-bis(dimethylamino)-3,5-diisopropylbenzoates. These benzoates lack an acidic (alpha)-proton and bear bulky substituents at both ortho positions of the benzene ring. These results show that the benzylic hydrogens in the structures are not competitively acidic with the proton adjacent to oxygen and that 2,6-disubstitution of a relatively large group is sufficient to prevent competitive nucleophilic addition to the carbonyl.
The starting esters can be prepared in good yields via reasonable synthetic routes. Both types of esters can be successfully lithiated adjacent to oxygen and the resultant organolithium subjected to successful subsequent reaction with a wide variety of electrophiles to afford the corresponding substituted esters in reasonable yields.
The ethyl, n-propyl, n-octyl, n-hexadecyl, n-benzyl and 2'-(N,N-dimethylamino)ethyl 2,4,6-triisopropylbenzoates afforded stable (alpha)-oxocarbanions upon treatment with sec-butyllithium-tetramethylethylenediamine at -78(DEGREES)C. Allyl and 2'-methoxyethyl 2,4,6-triisopropylbenzoate underwent successful (alpha)-oxometalation but did not afford stable (alpha)-oxocarbanions. Successful metalations under these conditions were also performed on methyl, ethyl and n-pentyl 2,6-bis(dimethylamino)-3,5-diisopropylbenzoate. Electrophiles successfully employed in this synthetic sequence include deuteriomethanol, methyl iodide, 1-iodobutane, 1-iodopentane, allyl bromide, chlorotrimethylsilane, chlorotri(n-butyl)tin, N,N-dimethylmethyleneammonium iodide, acetaldehyde, cyclohexanone, acetone, and 2-cyclohexen-1-one. The isopropyl esters of 2,4,6-triisopropylbenzoate and 2,6-bis(dimethylamino)-3,5-diisopropylbenzoate could not be metalated under a wide variety of conditions.
The modes of cleavage of the substituted esters to afford the substituted alcohols for these two ester types are complimentary. The 2,4,6-triisopropylbenzoates are cleaved under basic reductive conditions using lithium aluminum hydride. The secondary alcohols are obtained from the 2,6-bis(dimethylamino)-3,5-diisopropylbenzoates under mild acid hydrolytic conditions. Thus, both acid and base sensitive esters can be successfully cleaved by one of these methods.
The sequence of esterification, metalation, electrophilic substitution, and cleavage provides an (alpha)-lithio alcohol synthon. The 2,6-bis(dimethylamino)-3,5-diisopropylbenzoates are preferred because of better secondary alcohol yield from the parent alcohols and the ease of starting material regeneration. The 2,4,6-triisopropylbenzoates are attractive if the ease of starting material preparation is important.
In summary, the present work reports the syntheses and successful (alpha)-oxometalation of n-alkyl 2,6-substituted benzoates. This new synthetic scheme for (alpha)-oxometalation offers a formal case of a dipole-stabilized carbanion and provides a new approach to (alpha)-oxocarbanion formation and the (alpha)-lithio alcohol synthons. This synthetic approach is the only procedure to allow formation of the (alpha)-lithio alcohol synthon from the parent alcohol.
Issue Date:1980
Type:Text
Language:English
Description:140 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1980.
URI:http://hdl.handle.net/2142/67236
Other Identifier(s):(UMI)AAI8108460
Date Available in IDEALS:2014-12-13
Date Deposited:1980


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