Solvent-Free/Scalable Mechanochemical-Assisted Addition of Phosphine Oxides to Aldehydes: Sustainable Protocol for One-Pot Tandem P-C Bond Formation

Abstract

The development of greener and more efficient synthetic methodologies is a central goal in modern organic and main-group chemistry, particularly in the context of reducing solvent use, energy consumption and environmental impact. Mechanochemistry is introduced here as an efficient, cost-effective, solvent- and catalyst-free, and scalable synthetic tool for the chemoselective formation of P–C bonds with a markedly reduced environmental footprint. Using an atom-economical ball-milled protocol, the addition of a broad range of phosphine oxides [R2P(=O)H] to aromatic, heteroaromatic, and aliphatic aldehydes cleanly affords the corresponding α-hydroxyphosphine oxides in excellent yields and with high functional-group tolerance, all performed at room temperature and under air/moisture without the need for an inert atmosphere. In addition, we have developed an unprecedented mechanochemical one-pot tandem protocol that enable the chemoselective synthesis of α-hydroxyphosphine oxides directly from primary alcohols, further expanding the efficiency and synthetic versatility of this solvent-free approach. These results highlight the potential of mechanochemistry to streamline main-group synthetic transformations and pave the way for future solvent-free strategies in sustainable phosphorus chemistry.