Double catalytic enantioselective Michael addition reactions of tertiary nucleophile precursors—tertiary/quaternary and quaternary/quaternary carbon–carbon bond formations

Recent Developments in Enantioselective Nickel(II)‐Catalyzed Conjugate Additions

“…employed a chiral dibenzofuran‐bisoxazoline ligand, such as ( R,R )‐DBFOX‐Ph, to in situ generate a nickel(II) aqua complex, which catalyzed the Michael addition of malononitrile to α,β‐unsaturated N ‐acyloxazolidinones with enantioselectivities of 55–93% ee 62. Later in 2006, these authors demonstrated that enantioselective Michael additions of related tertiary nucleophilic precursors, such as substituted malononitriles, could be activated by a chiral nickel complex in situ generated from ( R,R )‐DBFOX‐Ph ligand and Ni(ClO 4 ) 2 ⋅6 H 2 O 63. The most efficient electrophilic substrates were found to be α,β‐unsaturated amides of 3,5‐dimethylpyrazoles which afforded the corresponding Michael adducts in moderate to good yields and moderate to excellent enantioselectivities of up to 99% ee , as shown in Scheme .…”

“…Among recent examples involving nickel catalysts, Kanemasa et al. have reported the enantioselective domino Michael/cyclization reaction of dimedone to afford 1‐(2‐crotonoyl)‐3,5‐dimethylpyrazoles 39 catalyzed by an in situ generated bis(oxazoline) chiral nickel(II) catalyst of ( R,R )‐DBFOX‐Ph 63,78. The reaction could begin with the Michael addition of the nickel enolate of dimedone to 1‐(2‐crotonoyl)‐3,5‐dimethylpyrazole 39 to give nickel intermediate 40 which further underwent cyclization to provide intermediate 41 .…”

Highly enantioselective Michael addition of α‐nitroacetate to α,β‐unsaturated pyrazolamide catalyzed by a bifunctional squaramide

“…Recently, Ooi group has developed a highly enantioselective Michael addition of azlactone to N ‐acylbenzotriazoles mediated by an elegant charge‐assisted supramolecular catalyst . Despite these impressive efforts, significant challenges remain, especially with respect to α,β‐unsaturated pyrazolamides . A stoichiometric amount of promoter was required for the conjugate amine addition, and only α,β‐unsaturated pyrazolamides possessing intensively electron‐withdrawing trifluoromethyl motifs provided satisfactory reactivity and enantioselectivity in the conjugate thiol addition .…”

“…A stoichiometric amount of promoter was required for the conjugate amine addition, and only α,β‐unsaturated pyrazolamides possessing intensively electron‐withdrawing trifluoromethyl motifs provided satisfactory reactivity and enantioselectivity in the conjugate thiol addition . Therefore, whereas the corresponding Michael addition catalyzed by transition metal complexes constitutes a solved problem, the efficient and general organocatalytic process involving α,β‐unsaturated pyrazolamides urgently awaits further attention.…”

Catalytic activation through metal enolization of nucleophile precursors and synthetic applications to enantioselective Michael additions

“…The Lewis acid should work to activate the nucleophile precursors as shown with D to catalyze the enolization leading to E . This method of using a cationic chiral Lewis acid in alcohol media should be highly successful 7…”