Phosphonium-Salt Mediated Activation of C-O Bonds: Applications and Mechanistic Studies

Abstract

The C-O single bond is found in numerous functional motifs including carboxylic acids, alcohols, and ethers. These compounds represent ideal precursors towards C-X (X = C, H, or heteroatom) bond formation due to their inherent stability and abundance in nature. As such, synthetic chemists continue to develop new technologies for the transformation of these precursors into biologically useful targets such as amides and amines. However, due to the stability of the C-O single bond, accessing such targets remains a consistent challenge. The activation of the carboxylic acids towards peptide synthesis has been facilitated through various coupling agents, including organoboron and transition metal catalysts. However, coupling agents can generate stochiometric, difficult-to-remove, toxic waste by-products. Organoboron/transition metal catalyzed condensations offer a more atom economical approach but suffer from varying degrees of optical erosion and poor sustainability. Phosphonium-based deoxyaminative technologies provide access to amines from alcohols via a phosphorus oxygen double bond formation driving force, but possesses a narrow nucleophilic nitrogen source scope, and poor atom economy. Transition metal/enzyme catalyzed “hydrogen borrowings” represent atom economical deoxyaminative alternatives. Still, their respective use of costly metals, and multiple enzymatic cascade steps severely limit the sustainability and scope of such protocols. An ambient deoxyamidation of carboxylic acids and deoxyamination of alcohols was developed through the use of N-haloimides activated by triphenylphosphine. Such technologies were found to possess broad functional tolerance and formed C-N bonds via a coupling to free amines, and the direct installment of the imide motif. Mechanistic experiments suggest that such transformations take place via the in situ generation of two separate phosphonium reactive species.