Diastereoselective Michael addition of ( S)-mandelic acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles

Abstract

A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2 S,5 S)- cis-1,3-dioxolan-4-one derived from optically active ( S)-mandelic acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure α-aryl-α-pyrazolylatrolactic acids. Finally, oxidative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)–Me 2opba complex as catalyst gives α-aryl-α-pyrazolylacetophenones. In this approach four points of diversity are introduced, one of them is the configuration of the ( S)-mandelic acid, which acts as an umpoled chiral equivalent of the benzoyl anion.