Regioselectivity aromatic compound lithiation

Certain derivatives of benzene and naphthalene can be lithiated with sec-butyllithium (sec-BuLi). This reaction is regioselective. It takes place exclusively in the ortho-position (Directed ortho Metalation, DoM) to a so-called Directed-Metalation Group (DMG), whose presence, accordingly, is a prerequisite for such a metalation. Figure 5.37 gives examples of DMGs that are bound through a C, an O, or an N atom to the aromatic compound. 

By means of an orfho-lithiation of suitably functionalized aromatics it is possible to obtain aryllithium compounds from halogen-free aromatics in a way and with a regioselectivity (Section 5.3.1) for which there is no analogy in the preparation of aryl Grignard reagents. 

The aldol reaction in carbonyl compounds has its equivalents in 7i-electron deficient heterocycles. In the carbanion approach, lithiated acetophenone added rapidly and regioselectively to 1-substituted 2-pyrimidinones to form the 3,4-dihydro isomer (279) (Scheme 45) <85ACS(B)195>. The adducts are readily oxidized to their aromatic equivalents (280) by DDQ. With the lithium enolate of mesityl oxide, however, equal amounts of the two dihydro isomers were formed <88JOM(338)34l>. In highly 7i-electron deficient heterocyclic systems, aldol reactions will also take place under the influence of acid catalysis such as in the addition of acetone to the pyrimidinone (281) the product is fully conjugated (282) after DDQ dehydrogenation <79ACS(B)150>. 

Numerous examples exist in which TMEDA not only facilitates the lithiation of aromatic and heteroaromatic substrates but also controls the regioselectivity of lithiation. While tertiary ben-zamides are susceptible to nucleophilic attack by n-butyllithium to give aryl butyl ketones, the use of s-ButyllithiumnMEDA in THF at —78 °C provides the synthetically useful ortho metalated tertiary benzamide which may be treated with a large variety of electrophiles (eq 4). Even with compounds having a second more acidic site the above conditions allow ortho lithiation to take place under kinetic control. Thus a p-toluamide is ortho lithiated with s-butyllithium/TMEDA in THF at —78 °C, but when Lithium Diisopropylamide is used as the base in THF at 0 °C the thermodynamically favored benzyllithium species is obtained (eq 5). The very marked influence of TMEDA on the lithiation of naphthyl methyl ether in hydrocarbon solvents is dramatically illustrated in the example in eq 6. ... 

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