Abstract
A mild, convenient coupling of aliphatic aldehydes and unactivated alkyl bromides has been developed. The catalytic system features the use of a common Ni(ii) precatalyst and a readily available bioxazoline ligand and affords silyl-protected secondary alcohols. The reaction is operationally simple, utilizing Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The use of 1,5-hexadiene as an additive is an important reaction parameter that provides significant benefits in yield optimizations. Initial mechanistic experiments support a mechanism featuring an alpha-silyloxy Ni species that undergoes formal oxidative addition to the alkyl bromide via a reductive cross-coupling pathway.
Highlights
The coupling of carbonyl compounds and carbon-nucleophiles is of broad interest to the chemical community to build molecular complexity
Among the most common systems are Rh,[10] Ni11,14–16 and Cr17–24-catalyzed couplings of aldehydes and organohalides. Each of these systems are proposed to proceed via Grignard-type mechanisms, generating organometallic nucleophiles that undergo formal additions to carbonyl electrophiles.[11,14,20,25]
An initial screen of ligands commonly employed in reductive cross-couplings revealed BiOX as a uniquely promising candidate for selective coupling (Table 1, see Electronic supplementary information (ESI)† for more optimization details)
Summary
The coupling of carbonyl compounds and carbon-nucleophiles is of broad interest to the chemical community to build molecular complexity. An especially appealing strategy for introducing Grignardtype couplings for medicinal chemistry efforts is through transition-metal catalysis These processes are attractive due to the generation of metalated intermediates of lower nucleophilicity, a higher control of selectivity by tuning the catalytic systems, and ability to be applied on process scales.[6,7,8] Net reductive couplings using organohalide feedstocks have been developed using stoichiometric reductants to enable catalyst turnover, obviating the need for pre-generation of the organometallic nucleophile.[9,10,11,12,13,14,15,16] Among the most common systems are Rh,[10] Ni11,14–16 and Cr17–24-catalyzed couplings of aldehydes and organohalides. Duroquinone instead of 1,5-hexadiene 6 bpy instead of BiOX terpy instead of BiOX
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