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https://hdl.handle.net/2142/67272
Description
Title
The Ortho Lithiation of Tertiary Benzamides
Author(s)
Brown, Roger Allen
Issue Date
1981
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
The use of the diethyl and diisopropyl amide functions as acid oxidation level directing groups was explored. Addition of N,N-diethylbenzamide to s-BuLi-TMEDA at -78(DEGREES) in THF solution results in rapid formation of the o-lithio species. The anion was treated with D(,2)O, alkyl iodides, carbonyl compounds, ClSiMe(,3) and B(OMe)(,3) followed by H(,2)O(,2) to give the ortho substituted products in yields of 52-84%. Similarly, N-N-diisopropylbenzamide was treated with s- or n-BuLi-TMEDA followed by D(,2)O, MeOD, allyl bromide or CO(,2) to give ortho substituted products in yields of 21-87%. A mechanistic study indicated lithiation of the ortho position is direct rather than the result of rearrangement of an initially formed (alpha)-aza anion.
Lithiation of substituted diethylbenzamides bearing CO(,2)H or one of the known directing groups OMe, Cl, SO(,2)NEt(,2), SO(,2)NHMe, 4,4-dimethyl-2-oxazoline or CH(,2)NMe(,2) occurs only ortho to the amide function. Competition of the tertiary amide with a secondary amide, however, appears to give a mixture of aryllithiums in which the anion bearing lithium ortho to the secondary amide predominates. The tertiary amide is thus indicated to be a more powerful directing group in intramolecular competition than all other known directing groups with the exception of the secondary amide, which is roughly comparable in directing power under the conditions of the competition.
The site of lithiation in tertiary p-toluamides can be controlled through proper selection of reaction conditions. Benzylic hydrogens on the para methyl groups are not competitively acidic with aryl hydrogens ortho to the amide in the presence of s-BuLi-TMEDA, but are specifically removed with LDA. In contrast, lithiation of o-toluamides occurs regiospecifically on the methyl group, even with s-BuLi-TMEDA. Only in the case of N-N-diethyl-m-toluamide is nonregiospecific ring lithiation observed; a mixture of the 2-lithio and 6-lithio species is formed.
For synthetic applications, tertiary amides appear to be the directing groups of choice for lithiation ortho to an acid oxidation level functionality. The required reaction conditions are extremely mild and do not disturb sensitive functionalities in the molecule. Furthermore, for tertiary benzamides bearing a wide variety of substituents, methods are available to control the site of metalation and obtain regioisomerically pure products in most cases.
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