Solid-supported lithiation

Despite the general interest in the transposition of solution-phase organic reactions to the solid phase [122], only few examples of DoM chemistry applied on a solid support have been described (Scheme 26.5). A phthalide library was prepared by directed ort/w-lithiation of resin-bound benza-mides 22 [123, 124]. The lithiation substitution is followed by cychzation—resin release induced by simply warming of the reaction mixture in toluene or dioxane, yielding the desired phthahde compounds 23 in high purity. 

Scheme 6.41. Solid-supported directed o/tho-lithiation followed by a cyclizative cleavage toward the synthesis of phthalides. R = H, MeO, t-Bu, / -PrO, CF3, Ph, Et2N R and R = 4-CI-C6H4, Ph, H, 4-OMe-CeH4, 4-NO2-C6H4N, 4- N(Et)2-CeH4, 4-Ph-C6H4,4-OH-CeH4.

The third t)tpe of linkage (solid support-O-Si-C-) is called a traceless linker after cleavage, the substrate is released in an unmodified form, which means that the silicon atom is replaced with a hydrogen atom. An example is shown in eq 16. The substrate 25 was lithiated and then silylated with i-Pr2SiCl2 to give a chlorodi-isopropylsilyl intermediate in 71% yield this was next attached to 4-hydroxylmethyl polystyrene (26) to give 27. The ultimate... 

Farrall and Frechet recognized the possibility of forming polymer-bound boronic acids in 1976.66 Supported pnra-benzeneboronic acid groups were generated by direct lithiation of polystyrene, giving a para-lithio intermediate that could be used to generate a host of other resins also (Scheme 27). Conversion to the boronic acid was one of the more successful transformations. The purpose of this transformation was to allow the attachment of sugars to the solid phase via the boronate. 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

Bachmann and Seebach [159] have reported the preparation and characterization of cyclic lactones (MeCHCH2C(0)0)n, where n = 4 and 8. The reaction product between butyl lithium in benzene and the solid polystyrene support PS-C6H4CH2NH2 leads to a lithiated species that can be represented as PS-Cfd bCI 12N11 Li(BuI i)x, where x 4 is active in the ring-opening of the cyclic esters L-lactide, rac-lactide, and 2,5-morpholinediones, leading to their respective cyclic oligoesters and cyclodepsipeptides (Fig. 49) [160]. The... 

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