Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones

Abstract

Combination of [Cu(MeCN)4]TFA•TFAH (TFA = O2CCF3) with Feringa's phosphoramidite ligand (L A ) provides an exceptionally active (0.75 mol%) catalyst for asymmetric conjugate additions of ZnR2 (R = Et, Me at -40 to -80 o C) to enones. Kinetic and other studies of the addition of ZnEt2 to cyclohex-2-en-1-one indicate a transition state stoichiometry composition: (ZnEt2)3(enone)4Cu2(L A )3 that is generated by transmetalation from Et2Zn(enone)2. Catalyst genesis is significantly slower than turnover (which has limited previous attempts to attain useful kinetic data); in the initial stages varying populations of catalytically inactive, off-cycle, species are present. These issues are overcome by a double-dosing kinetic analysis protocol. A rest state of [L A Cu(Et)(µ-TFA)(µ-{(enone)(ZnEt)2(enolate)})CuL A2 ] + (through the equivalence of enolate = enone + ZnEt2) is Manuscript for Organometallics, Woodward and co-workers Page 2 of 19supported by DFT studies (ωB97X-D/SRSC). Rate determining ZnEt2(enone)2 transmetalation drives the exceptionally high catalytic activity of this system.