Phospha-Mannich reactions of phosphonous acids RP(OH) 2 and their derivatives

Primary phosphinic acids (PPAs), RPO2H2 (R = alkyl or aryl), are derivatives of H3PO2 and PCl3. Due to acid- or base-catalyzed tautomerization to phosphonous acids RP(OH)2, PPAs react with imine/iminium species, or their donors (phospha-Mannich reactions), to form secondary phosphinic acids with a P–Csp3–N linkage, (α-aminoalkyl)phosphinic acids. These are used, for example, to design phosphinic enzyme inhibitors, flame-retardants, and chelators of di- and tri-valent metal ions useful in metal-based (radio)pharmaceuticals, and as precursors in organic synthesis. The PCl3-path allows for many phosphonous acid dichlorides RPCl2 (primary dichlorophosphines) that are widely used in phospha-Mannich reactions, mainly in the presence of AcOH, bringing diversity and synthetic potential in phospha-Mannich chemistry that is particularly useful in constructing P,N,O- and P,N-heterocycles. RPCl2 are also precursors for several trivalent derivatives of primary phosphonous acids that are available as P-components for phospha-Mannich reactions. Esters of phosphonous acids RP(OR’)2 (also known as phosphonites and dialkoxyphosphines), similar to RPCl2, are significantly stable than HP(OR’)2 and participate in phospha-Mannich reactions mainly via Arbuzov-type intermediates (Mannich-Arbuzov reactions) that, in some cases, can form stable, reactive P,N-heterocycles useful in organic synthesis (e.g., phospha-Münchnones). Phospha-Mannich chemistry of phosphonous acid bisamides RP(NR’2)2 (diaminophosphines) and ester-amides RP(OR’)NR”2 (alkoxyaminophosphines), although reported, has been studied to a lesser extent than that of RPCl2 and RP(OR’)2.