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Heteroatom‐facilitated lithiation reactions have assumed an increasingly important role in the elaboration of carbocyclic aromatic and heteroaromatic systems in the 40 years subsequent to the seminal review on metalation with organolithium reagents by Gilman and Morton. Of particular note has been the development of methodology for the lateral lithiation of alkyl‐substituted aromatic systems promoted by an extensive array of heteroatomic substituents. These lithiations involve deprotonation at a benzylic (side chain) position that is lateral to, or flanked by, a heteroatom‐containing substituent (G); this substituent facilitates lithiation relative to the parent system in which G is not present. The derived lithiated species have great synthetic utility for functionalization of benzylic sites, for chain extensions, and for the synthesis of fused carbocyclic and heterocyclic systems via annelation processes. This chapter summarizes the significant amount of work reported on heteroatom‐facilitated lateral lithiations and the synthetic applications thereof. The survey covers the substituents that promote these reactions, and the methods of formation, stability, reactivity, and synthetic utility of the lithiated species. Coverage is limited to examples in which the R 1 group in the representative equation is hydrogen (toluene derivatives), alkyl, or aryl. Examples that would be better classified as alpha ‐lithiations are not covered, for example, where R 1 is an anion‐stabilizing group such as cyano, carboxy, and so on. Rare examples of lithiations of alkyl groups that are meta or para to the facilitating group G are included in the chapter, although these are not, strictly speaking, lateral lithiations. Also included are a limited number of older lateral metalations that were originally effected with sodium or potassium bases but would now be more conveniently carried out with lithium dialkylamide bases. The aromatic nucleus may be carbocyclic or heterocyclic, but lateral lithiations of heterocycles lacking the heteroatomic substituent are not covered. For example, lithiation of nicotinamides (Eq. 2) are included; however, lithiations of picolines, and other heterocyclic systems, are considered beyond the scope of this chapter. The relationship of lateral lithiation reactions to heteroatom‐facilitated ortho lithiations is obvious and the two fields have developed, for the most part, in concert. With several notable exceptions, the same heteroatomic substituents (G) promote both types of lithiations. A number of reviews cover various aspects of ortho lithiation reactions, including the comprehensive chapter in Organic Reactions by Gschwend and Rodriguez that surveyed the literature to 1979. In the present chapter, the relationship of lateral lithiation and ortho lithiation reactions is discussed within the contexts of mechanism, reactivity, and synthetic utility. In addition, the sequential use of these two lithiation processes for the synthesis of complex aromatic and heteroaromatic systems is covered.
Heteroatom‐facilitated lithiation reactions have assumed an increasingly important role in the elaboration of carbocyclic aromatic and heteroaromatic systems in the 40 years subsequent to the seminal review on metalation with organolithium reagents by Gilman and Morton. Of particular note has been the development of methodology for the lateral lithiation of alkyl‐substituted aromatic systems promoted by an extensive array of heteroatomic substituents. These lithiations involve deprotonation at a benzylic (side chain) position that is lateral to, or flanked by, a heteroatom‐containing substituent (G); this substituent facilitates lithiation relative to the parent system in which G is not present. The derived lithiated species have great synthetic utility for functionalization of benzylic sites, for chain extensions, and for the synthesis of fused carbocyclic and heterocyclic systems via annelation processes. This chapter summarizes the significant amount of work reported on heteroatom‐facilitated lateral lithiations and the synthetic applications thereof. The survey covers the substituents that promote these reactions, and the methods of formation, stability, reactivity, and synthetic utility of the lithiated species. Coverage is limited to examples in which the R 1 group in the representative equation is hydrogen (toluene derivatives), alkyl, or aryl. Examples that would be better classified as alpha ‐lithiations are not covered, for example, where R 1 is an anion‐stabilizing group such as cyano, carboxy, and so on. Rare examples of lithiations of alkyl groups that are meta or para to the facilitating group G are included in the chapter, although these are not, strictly speaking, lateral lithiations. Also included are a limited number of older lateral metalations that were originally effected with sodium or potassium bases but would now be more conveniently carried out with lithium dialkylamide bases. The aromatic nucleus may be carbocyclic or heterocyclic, but lateral lithiations of heterocycles lacking the heteroatomic substituent are not covered. For example, lithiation of nicotinamides (Eq. 2) are included; however, lithiations of picolines, and other heterocyclic systems, are considered beyond the scope of this chapter. The relationship of lateral lithiation reactions to heteroatom‐facilitated ortho lithiations is obvious and the two fields have developed, for the most part, in concert. With several notable exceptions, the same heteroatomic substituents (G) promote both types of lithiations. A number of reviews cover various aspects of ortho lithiation reactions, including the comprehensive chapter in Organic Reactions by Gschwend and Rodriguez that surveyed the literature to 1979. In the present chapter, the relationship of lateral lithiation and ortho lithiation reactions is discussed within the contexts of mechanism, reactivity, and synthetic utility. In addition, the sequential use of these two lithiation processes for the synthesis of complex aromatic and heteroaromatic systems is covered.
188ChemInform Abstract The anion of the nitrile (I) undergoes oxidative coupling on treatment with dibenzoyl peroxide to give the ethane (II). A similar coupling is observed for 2-and 4-methylpyridine; however, in these cases the coupling reaction is accompanied by addition to the carbonyl group of dibenzoyl peroxide. The ethenyl side chain of (I) can be converted into the alcohol (III) and the ketone (IV), both of which in their protected forms are useful intermediates in alkaloid synthesis.
Several synthetic peptides, modelled from a Ca"-binding loop of the EF-hand family of proteins, were prepared containing cysteine residues. The peptide, GDKNADGFICFEEL, was labelled covalently at the cysteine residue (loop position 9) with iodoacetamidosalicylic acid. This novel conjugate is a metal-binding loop containing a salicylic acid side chain that could not only chelate Tb3' in conjunction with the other chelating groups in the sequence, but could also sensitize Tb3+ luminescence. The loop had a high Tb'+ aftinity, with stoichiometric binding observed under experimental conditions. The luminescence from the Tb"-peptide complex was more than lo-fold greater than the luminescence reported from a related peptide which contained Trp as the Tb'+ donor at loop position 7. This peptide has significant potential for use in lanthanide-based time-resolved luminescence immunoassays.
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