The mechanism and an improved asymmetric allylboration of ketones catalyzed by chiral biphenols

Abstract

A mechanistic study of the enantioselective asymmetric allylboration of ketones with allyldiisopropoxyborane catalyzed by chiral biphenols resulted in the development of improved reaction process. In a ligand exchange process involving the chiral biphenol and the boronate to liberate isopropanol as the key step, addition of isopropanol to the reaction was found to increase the overall rate and enantioselectivity. In the design of an improved reaction, a boronate possessing a tethered alcohol would more readily liberate catalyst at the end of a reaction. The use of allyldioxaborinane with 2 mol% (S)-3,3′-Br2-BINOL and 2 equivalents t-BuOH relative to ketone at room temperature results in high yields and enantioselectivities. Insight gathered from the mechanistic investigation resulted in the development of a reaction process that uses less catalyst (from 15 mol% to 2 mol%) at warmer temperatures (from -35 °C to room temperature).

Figure 1. Effect of isopropanol on rate and enantioselectivity^[a]

[a] Reactions were run with 0.075 mmol 1, 1.5 mmol boronate 2, and 0.75 mmol acetophenone in PhCH₃ (0.25 M) for 15 h under Ar at RT, followed by flash chromatography on silica gel. Enantiomeric ratios were determined by chiral HPLC methods.

Figure 2. Effect of t-butanol on rate and enantioselectivity^[a]

[a] Reactions were run with 0.15 mmol 1, 1.5 mmol boronate 9, and 0.75 mmol acetophenone in PhCH₃ (0.3 M) for 15 h under Ar, followed by flash chromatography on silica gel. Enantiomeric ratios were determined by chiral HPLC methods.

Scheme 1. Proposed Catalytic Cycle for Asymmetric Allylboration Reaction Catalyzed by Chiral Biphenols

Scheme 2. Asymmetric crotylboration of acetophenone