Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

Abstract

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.

Ligand Effects in the Formation of Tertiary Carbanions from Substituted Tertiary Aromatic Amides

“…[1,2] Metalation directing groups, which typically combine inductive electron withdrawal with the presence of an electron-rich metal-coordinating atom, may promote deprotonation of adjacent aryl C À H bonds (ortholithiation, to form an arylmetal derivative), [2,3,4] at nearby positions adjacent to the ring (lateral lithiation, forming a benzylic organometallic species) [2,5] or at more remote sites ("directed remote metalation"). [2,6] Where possible, lateral lithiation is generally favored due to benzylic stabilization of the resulting anion.…”

A Facile Synthesis of Substituted 1,4-Benzothiazepin-5(4H)-ones and Pyrido[3,2-f][1,4]thiazepin-5(4H)-ones − Crystal and Molecular Structure of 2-Ethylthio-4-methyl-5(4H)-oxopyrido[3,2-f][1,4]thiazepine-3-carbonitrile

“…In contrast to the expected formation of a compound analogous to 3 a halogen metal exchange in ortho position occured [39] [40] [41] followed by attack of carbon disulfide and cyclization to 4-methoxy-3-methylthio-6-nitro-2-benzothiopyran-1-thione (isothiocumarin-thione) (6). Scheme 2 The structure assigned to product 6 is supported by spectral and analytical data as follows: The mass spectrum contains peaks at m/z 255 (M Ϫ CS) and 135 (MeOC 6 H 4 CO, 85%) and the 1 H-NMR spectral properties are characteristic for a nitrophenyl, methoxy (but not for a methylamino) and methylthio group.…”

The Directed Lithiation of Benzenoid Aromatic Systems

“…[2] The elaboration of aromatic substituents by means of directed lateral lithiation, that is metallation of, for example, alkyl groups located ortho to a directing group, [3] has facilitated the preparation of many polycyclic products, including corydalic acid methyl ester and fredericamycin.…”

“…[39] Solvated analogues exhibit even more diverse behaviour; 2,6-(C 10 H 7 ) 2 C 6 H 3 Li·2THF (18), [40] 2,6-Ph 2 C 6 H 3 Li·2OEt 2 (19), [41] 2,6-[4-(tBu)C 6 H 4 ] 2 C 6 H 3 Li·2OEt 2 (20), [42] 2,6-(4-MeOC 6 H 4 ) 2 C 6 H 3 Li·2OEt 2 (21) (wherein the methoxy groups are passive with respect to the metal), [43] 2,6-[2,4,6-(iPr) 3 C 6 H 2 ]C 6 H 3 Li·L (L ϭ OEt 2 22, [44] η 6 -C 6 H 6 23 [39] ) and 2,4,6-Ph 3 C 6 H 2 Li·2OEt 2 (24) [45] are monomers in the solid state while 2,4,6-(iPr) 3 C 6 H 2 Li·OEt 2 (25) [46] and 2,4,6-Me 3 C 6 H 2 Li·2THF (26) [47] form differently solvated dimers. The complex 2,4,6-Ph 3 structure straddle the formal charge centres, one is mono-THF solvated and the other is bis(η 2 -Ph) supported. [40] In a like vein, the dimer of 2,6-Ph 2 C 6 H 3 Li· 1 / 2 THF, 28, reveals Lewis base stabilisation of one metal centre and the η 2 -interaction of two phenyl rings with the other.…”