Intermolecular processes alkyl halides

In 2004, Vignola and List [111] demonstrated the ability of proline-derived catalysts to overcome drawbacks associated with the stoichiometric alkylation of preformed aldehyde enolates when they described an elegant amino acid catalyzed intramolecular a-alkylation reaction of haloaldehydes. The reaction furnished substituted cyclopentanes, cyclopropanes, and pyrrolidines in good yields and good enantio-selectivities (Scheme 8.23), when commercially available (5)-a-methyl proline (LV) as catalyst was used. The presence of a stoichiometric amount of additional base (tertiary amine) was required, not only to trap the hydrogen halide produced in the reaction but also because it has also significant effect on the stereoselectivity of the C—C bond-formation process by stabilizing the ant/ -TS of the /ra 5-enamine intermediate. Nevertheless, an intermolecular version of the reaction remains still elusive, mainly because of the deactivation of the amine catalyst by A -alkylation with the alkyl halide [112]. 

The great majority of photoredox reachons rely on reductive electron-transfer process to an alkyl halide (usually a bromide) generating an electron-deficient alkyl radical. The so-formed electrophilic radicals can be trapped by electron-rich olefins by intra- or intermolecular reaction [25]. 

In the example shown in Scheme 6.12, one molecule of organic halide and two molecules of acrolein are coupled under tin hydride-mediated conditions [20]. As the first intermolecular C-C bond-forming process, the homoallyl radical adds to acrolein to form a radical a to a carbonyl group. The subsequent 5-exo cydization produces a nucleophilic alkyl radical, which undergoes addition to the second molecule of acrolein. 

The acylation of alkanes has also been known for a long time, but for synthetic purposes is limited to simple substrates. The initial step is hydride abstraction by an acylium ion, a process well established in the presence of a powerful Lewis acid, most commonly an aluminum halide, or strong protic acid. The carbocation so formed can then undergo elimination, possibly after hydride or alkyl migration, to give an alkene which is then acylated. In the presence of excess alkane, saturated ketones are formed by a further intermolecular hydride transfer, whereas with an excess of acyl halide, the product is the (conjugated) unsaturated ketone. -" The synthetic potential is obviously likely to be limited to simple substrates. 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

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