Alkyl bromides Stille coupling

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). 

Table 6 Stille couplings of alkyl bromides and iodides with vinyl- and arylstannanes...

In the initial study, which focused on palladium-catalyzed cross-couplings of primary alkyl bromides with vinylstannanes, use of P(t-Bu)2Me provided the best yields (solvent=THF) [27]. PCy3 was slightly less effective, whereas a variety of other ligands, including JV-heterocyclic carbenes, were essentially ineffective. The choice of activator (Me4NF) and the presence of molecular sieves were important for the success of these reactions. Some examples of Pd/P(t-Bu)2Me-catalyzed Stille couplings of alkyl bromides with vinylstannanes are provided in entries 1-3 of Table 6. 

The first report of the oxidative addition of zinc metal to organic halides dates back to the work of Frankland [1-4] around 1850. He discovered that dialkylz-inc compounds could be prepared from zinc metal and methyl iodide or ethyl iodide. However, the reaction did not proceed with alkyl bromides or chlorides. Also, no aryl halides were found to undergo the oxidative addition reaction. Several approaches have been reported since that time to increase the reactivity of the zinc metal. The majority of these modifications have employed zinc-copper couples [5-8] or zinc-silver couples. However, all of these procedures still only worked with alkyl iodides. Noller used a mixture of alkyl iodides and bromides but found that the mixture must contain a large percent of alkyl iodide [9]. 

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) ... 

Table 1 Effect of the Ligand on the Stille Coupling of an Alkyl Bromide...

After having proposed a general solution to the Stille coupling of unactivated aryl chlorides, the Fu laboratories reported in 2003 a general method for the coupling of unactivated primary alkyl bromides with vinylstannanes (33 + 34 35). It is a real tour de force since these substrates harbor p-hydrogens... 

A series of potent, linear C2-symmetric HIV-1 protease inhibitors with K, values in the nanomolar range was prepared from a diaryl bromide precursor emanating from a carbohydrate scaffold, by application of Heck, Suzuki, Stille, and cyanation reactions. Included in this series was the first reported microwave-promoted Suzuki coupling with an alkyl borane [41]. A very high-yielding Suzuki coupling is presented... 

The attachment of a C5-side chain by SN2-alkylation at the intended benzylic position with the protected ketoester 139 as the nucleophile proceeded reliably and in good yield to form the alkylated ketoester 140 [86]. The second chain could also be coupled very efficiently by reacting the vinylic bromide 140 in a palladium-catalyzed Stille reaction [106] (review [107]) with the allyl tin compound 141 to afford the dialkylated naphthoquinone 142 (Scheme 36). Halonaphthoquinones have previously been coupled in a palladium/copper-catalyzed reaction by Echavarren et al. [108]. 

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