Copper-catalyzed hydrofunctionalization of alkenes

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Copper-catalyzed hydrofunctionalization of alkenes refers to the enantioselective addition of hydrogen and an electrophile to a carbon–carbon pi bond.[1] Activated alkenes linked to an electron-withdrawing group undergo addition of hydrogen at the β-position and the electrophile at the α-position (“α-functionalization”). Copper(I) hydride complexes containing chiral phosphine ligands are typically employed along with an organosilane or other stoichiometric reducing agent. The scope of the reaction includes carbon electrophiles, such that copper(I) hydride catalysts can be used to effect reductive aldol reactions, hydroalkylations, hydroarylations, and other carbon–carbon bond forming reactions. Other heteroatom-based electrophiles may also be used to prepare chiral amines, silanes, etc. Besides alkenes with an electro-withdrawing group, other alkenes with an aryl, silyl, boryl or alkyl substituent are also viable substrates for this type of transformation.

The general mechanism of copper-catalyzed hydrofunctionalization reactions begins with coordination of the chiral ligand to copper(I) or copper(II) in the presence of a hydride source, affording a chiral copper(I) hydride species. The alkene then undergoes hydrocupration, which yields a chiral organocopper species. This intermediate is intercepted by an electrophile to afford the functionalized product and reaction of the resulting copper complex with the hydride source regenerates the copper hydride species. The regioselectivity of hydrocupration is governed by the polarization of the double bond (for electron-deficient alkenes) or steric differences between the alkene carbons (for alkyl-substituted alkenes). Although copper(I) hydrides are capable of reducing a variety of functional groups including carbonyls, imines, and nitroarenes, a careful choice of reaction conditions can result in chemoselective functionalization of alkenes in the presence of these groups.

Chiral bisphosphines such as L1L3 are commonly employed in this reaction (Figure 1).

References

  1. Buchwald, S. L.; Wang, H. Org. React. 2019, 100, 3. (link)