Solid-phase linkers halide linker

C-Alkylations have been performed with both support-bound carbon nucleophiles and support-bound carbon electrophiles. Benzyl, allyl, and aryl halides or triflates have generally been used as the carbon electrophiles. Suitable carbon nucleophiles are boranes, organozinc and organomagnesium compounds. C-Alkylations have also been accomplished by the addition of radicals to alkenes. Polystyrene can also be alkylated under harsh conditions, e.g. by Friedel-Crafts alkylation [11-16] in the presence of strong acids. This type of reaction is incompatible with most linkers and is generally only suitable for the preparation of functionalized supports. Few examples have been reported of the preparation of alkanes by C-C bond formation on solid phase, and general methodologies for such preparations are still scarce. 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

Since the renaissance of solid-phase organic chemistry in 1992, carbon-carbon bond formation reactions on solid support have probably been the best studied reactions. Many different facets of the Suzuki, Heck and Stille reactions have been evaluated. The influence of linkers, catalyst, solvents, microwave, polymer-bound aryl halides or polymer-bound arylboronic acids (or stannanes) have been studied in detail. 

Routledge et al. [7] investigated the formation of dihydrobenzofuran 1 from an aryl halide precursor (Scheme 1). With polystyrene, more than 1 equivalent of AIBN was required, while the reaction was complete within 20 h using 6 mol% of AIBN on TentaGel resin (which has a polyethylene spacer between the polystyrene and the site of compound attachment). Addition of t-butanol helped prevent an alternative y -elimination pathway. An attempt to force the latter was made with thiyl linker 2, but only trace amounts of the )9-elimination product 3 were formed. Also investigated were the cyclizations of iodides 4, in which the cyclization of an alkyl radical to an acetylene is approximately 10 times slower than the aryl radical cyclization to a double bond. A direct comparison of the same reaction on solution phase was attempted, but yields could not be determined for the latter because of contamination by tin residues. This illustrates one advantage of solid-phase radical reactions mediated by tributyltin hydride, namely the ease of product purification. 

Thiadiazoles. Sulfonyl hydrazide resin 74 could also serve as a sulfone linker in SPS. Porco and coworkers have demonstrated the use of resin 74 for the preparation of sulfonylhydrazone resin 112, which was subsequently applied to the synthesis of 1,2,3-thiadiazoles 113 (Scheme 12.27a).Resin 74 has also been efficiently employed in the resin capture of ketones in a hybrid solution/solid-phase synthesis of 1,2,3-thiadiazoles (Scheme 12.27b). The resin-bound sulfonylhydrazones with aryl halide substituents 112a could be subjected to Stille reaction for the generation of more diverse thiadiazole structures 113a. 

Ngul997b Ngu, K. and Patel, D.V., Preparation of Acid-Labile Resins with Halide Linkers and Their Utility in Solid Phase Organic Synthesis, Tetrahedron Lett., 38 (1997) 973-976. 

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