Modular, Three-Component and Concurrent One-Pot Libraries of γ-Keto Sulfones and γ-Keto Phosphine Oxides. Brønsted Acidic Eutectic Mixtures Are the Answer

A modular, three-component, and sustainable one-pot/one-step protocol has been developed for the efficient and regioselective synthesis of libraries of γ-keto sulfones and γ-keto phosphine oxides through concurrent C-C and C-X bond formation (X = S or P). The acidic eutectic mixture ChCl/p-TSA·H2O (1:2) (ChCl = choline chloride; p-TSA = p-toluenesulfonic acid) serves as both promoter and reaction medium. This transformation involves a cascade process comprising three consecutive steps: i) hydration of terminal alkynes to methyl ketones; ii) Claisen-Schmidt condensation with aldehydes, and iii) Sulfa-Michael or Phospha-Michael additions using sodium sulfinates or secondary phosphine oxides, respectively. The methodology provides high yields (up to 99%), excellent atom economy, and operational simplicity, as the products are isolated without the use of any toxic volatile organic solvents (VOCs) or tedious chromatographic purification. Its modular nature accommodates a broad range of substrates, including electron-rich and electron-deficient components, demonstrating robustness and versatility (112 examples). Furthermore, the protocol enables scalable (ten-fold) and recyclable (3 cycles) synthesis of biologically relevant γ-keto derivatives under green conditions (E-factor ≤ 10), offering a general strategy for sustainable and modular C-C and C-X bond-forming reactions.