Alkyl Stille cross-coupling

The Stille cross-coupling reaction between various heteroarylstannanes and ring-brominated benzylphosphonates (107) has been used to prepare heterobiaryl phosphonates 108. A key step in the synthesis of individual optical isomers of 2-hydroxymethyl-4-[3-(diethoxyphosphinyl)propyl]-5-alkylpiperazines 109 as CPP analogues is the alkylation of protected 5-alkyl-2-hydroxymethylpiperazines with (3-bromopropyl)phosphonate (Scheme 5). Compound 110, a new member... 

A simple way to avoid toxic and intractable triorganotin waste is to use monoorganotin reagents that are much less toxic and less lipophilic. Unactivated secondary alkyl halides can be coupled with aryl-trichlorotin in a nickel-catalyzed Stille cross-coupling reaction" (e.g. Scheme 5.8.15). 

Two reports have described palladium-catalyzed Stille cross-couplings of unactivated alkyl electrophiles. Specifically, these investigations by Fu demonstrate that primary alkyl bromides and iodides can be coupled with vinylstannanes [27,28] and arylstannanes [28] (Eq. 10). 

Cross-coupling Reactions. Many cross-coupling reactions are critically influenced by the ligand used to form a reactive complex with the metal catalyst. Often, the use of di-iert-butyl(methyl)phosphine as a ligand leads to positive results. As an example, the Stille cross-coupling between a vinyl stannane and a primary alkyl bromide with -hydrogens, and therefore potentially subjected to undesired /3-hydride elimination, gives the best results with di-ferf-butyl(methyl)phosphine (eqs 1 and 2) ... 

Powell DA, MaM T, Fu GC. Stille cross-couplings of unactivated secondary alkyl halides using monoorganotin reagents. J. Am. Chem. Soc. 2005 127(2) 510-511. 

PdCl2-, PdCl2(tppms)2- or Pd/tppds-catalysed Stille-Couplings of water soluble aryl and vinyl halides with alkyl-, aryl- or vinyltrichlorostannates (Figure 21) proceed in aqueous alkaline media to give cross-coupled products at 90-100°C with good to excellent yields.515 516... 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

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