Enantioselective α-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System

Abstract

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides.

Figure 1

State of the art for the enantioselective α-arylation of carbonyl compounds to set tertiary stereocenters.

Figure 2

(A) Benchmark reaction and ligand screening. Yields are reported in the Supporting Information. (B) Single parameter correlation between the measured enantioselectivity and the ligand P=O stretching frequency for an unbiased ligands subset. (C) Multidimensional correlation between the ligand structure and the observed enantioselectivity for a ligand set excluding 3t, 3m, and 3e. Tol = 4-Me-Ph, Xyl = 3,5-Me₂-Ph, DMM = 4-OMe-3,5-Me₂, BTFM = 3,5-(CF₃)₂, DTBM = 4-OMe-3,5-tBu₂.

Figure 3

Reaction scope. Yields and selectivity are expressed according with the formula NMR y(isol. y)%, er. Conditions: diaryliodonium salt 5 (0.1 mmol), silyl enol ether 4 (0.2 mmol), (CuOTf)₂·Tol (4 mol %), 3x (12 mol %), DCM (0.5 mL). (a) 3.0 equiv of silyl enol ether 4 was used. (b) ent-3z was used instead of 3x. (c) Reaction time: 6 h. (d) Reaction time: 24 h. (e) The er was determined on the corresponding alcohol after reduction with LiAlH₄.

Figure 4

Preliminary mechanistic considerations. Bis(phosphine) dioxides 3 promote the reaction as the ligand to the Cu center rather than as a Lewis base.