Heterocyclic aromatic systems, lithiation

The directed metalation reaction—lithiation with n-butyl-lithium of a position ortho to a substituent on an aromatic ring—is described. Aromatic systems in which the reaction has been studied are benzene, thiophene, naphthalene, and ferrocene. A systematic listing of the bond types that can be formed at the site of metalation is provided. Also of interest is the assessment of the relative directing abilities of directing substituents and comments and observations on the mechanism of the reaction. Utility of the reaction is indicated by the results from asymmetric-directed lithiation and the synthesis of heterocycles. 

Lithiation with subsequent alkylation results in alkylation of the exocycUc phosphorus atom, and formation of an aromatic system in the central heterocycle analogous to a cyclopentadienide. Spectroscopically, the effect is a severing of the exocyclic phosphorus atom from the conjugated ring system, accompanied by a significant upheld shift of the phosphorus resonance by over AS= -300 ppm, dependent on the alkyl substituent. 

The a-metalation of azoles (aromatic nitrogen-containing five-mem-bered rings) is a much more facile process than that for the analogous saturated systems, and a small number of heterocycles containing free NH groups can undergo some direct lithiation, despite the ionization of the... 

A variety of heterocyclic systems containing unsaturated nitrogen can partake in directed aromatic or heteroaromatic lithiations. Pyrazole (II,D), tetrazole (II,G,2), imidazoline (V,B,2), and pyridine (IV,A,4) derivatives were discussed in the sections indicated. In addition, lithio derivatives of 2-oxazoline 178 (76LA183), 4,4-dimethyl-2-oxazoline 179 (790R1 85T837),... 

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>. 

Directed lithiations of aromatic and heteroaromatic systems, as well as those involving non-aromatic heterocycles, are processes that have continued to evolve this year. Various 3,5-dialkoxy-4-substituted phenols (18) have been prepared by a selective lithi-ation reaction. The use of a bulky silyl substituent inhibits metallation of (17) at C-2, and the application of this chemistry to a concise synthesis of sophoraflavanone A has been presented... 

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