Applications of Thermal Activation, Ball-milling and Aqueous Medium in Stereoselective Michael Addition of Nitromethane to Enynones Catalyzed by Chiral Squaramides

Stereoselective addition of nitromethane to conjugated en-ynones was performed through the application of chiral squaramides. Three non-classical approaches to promote the addition reaction were tested, including activation of the nucleophile by inorganic base in a biphasic aqueous system, thermal activation, and ball-milling. Hydrogen-bonding catalysis was effective in all these methods, providing 1,4-addition products in high yields and stereoselectivities of up to 98% requiring 1-5mol% of Cinchona alkaloid squaramide.