Enantioselective Catalytic Aldol Reactions in the Presence of Knoevenagel Nucleophiles: A Chemoselective Switch Optimized in Deep Eutectic Solvents Using Mechanochemistry

Abstract

In the presence of different nucleophilic Knoevenagel competitors, cyclic and acyclic ketones have been shown to undergo highly chemoselective aldol reactions with aldehydes. In doing so, the substrate breadth for this emerging methodology has been significantly broadened. The method is also no longer beholden to proline-based catalyst templates, e.g., commercially available O-t-Bu-L-threonine is advantageous for acyclic ketones. The key insight was to exploit water-based mediums under conventional (in-water) and non-conventional (deep eutectic solvents) conditions. With few exceptions, high aldol-to-Knoevenagel chemoselectivity (>10:1) and good product profiles (yield, dr, and ee) were observed, but only in DESs (deep eutectic solvents) in conjunction with ball milling did short reaction times occur.

Keywords: Knoevenagel reaction; aldol reaction; deep eutectic solvents; green chemistry; in-water conditions; organic synthesis; organocatalysis.

Scheme 1

Chemoselective switch: aldol/Knoevenagel competition reactions with aldol selectivity.

Figure 1

Previously studied substrates enabling chemoselective aldol versus Knoevenagel reactions.

Figure 2

Investigated amino acid catalysts.

Scheme 2

Benchmark aldol/Knoevenagel competition reaction.