Pd-catalyzed Fukuyama cross-coupling of secondary organozinc reagents for the direct synthesis of unsymmetrical ketones

Abstract

The coupling of acyl electrophiles with organometallic reagents represents a convergent route toward complex and versatile ketone products. Despite the mild conditions and high functional group tolerance, the cross-coupling of carboxylic acid derivatives, such as thioesters, and secondary organometallic reagents is an underdeveloped transformation. Herein, we disclose a convenient and efficient protocol for the Pd-catalyzed Fukuyama cross-coupling of secondary organozinc reagents with thioester electrophiles. Under these mild conditions, a range of thioesters possessing sensitive functional groups can be coupled with either activated or unactivated secondary organozinc halides in good yields. This method was expanded to include an acid chloride substrate, generating an aryl alkyl ketone in high yield. In addition, a modest dynamic kinetic resolution of the organozinc reagent can be achieved using chiral phosphoramidite ligands to furnish enantioenriched ketone products.