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 1,4addition products in high yields and stereoselectivities of up to 98% requiring 1-5 mol% of Cinchona alkaloid squaramide.

Abstract. Dithiomalonates proved to be active nucleophiles in the stereoselective additions to chalcones, dienones, and en‐ynones affording the desired Michael adducts with good to high yields and enantioselectivities. In contrast, the analogous dibenzyl malonate remained inactive. Bifunctional Cinchona squaramides secured the effective chirality transfer and the selectivity towards Michael adducts of various bisthiomalonates following the soft enolization approach. The thioester’s nature impacted the reactivity and stability of the reactants or products. While the reactions performed in solution led to the products, the required time along with byproducts formation such as sulfa‐Michael adducts, limiting the applicability of reactive dithioesters. On the contrary, reactions performed under solvent‐free, ball milling conditions furnished adducts with essentially shorter time, with subtly or no byproduct generation. Therefore, the mechanochemical approach revealed to be an effective tool for supporting the hardly effective reactions under standard solution conditions. Detailed KS‐DFT studies supported the experimental observations shedding more light on the intricate active nucleophile formation, and different chemical reaction pathways, as well as indicating the crucial transitions state governing the observed stereoselectivities