Phospha-Mannich reactions of hypophosphorous acid H ₃ PO ₂

Hypophosphorous (phosphinic) acid H2P(O)OH, due to the acid-promoted equilibrium with the trivalent tautomer – phosphonous acid HP(OH)2, participates in phospha-Mannich reactions with imine/iminium species, or their donors, to give a variety of mono- and bis-(α-aminoalkyl)phosphinic compounds (PO2,N-acetals). These reactions are more complex than those involving phosphines or secondary phosphine oxides, reviewed previously, and are commonly accompanied by several side-reactions, resulted from instability of H3PO2 and the presence of hypophosphite anion, a reductant. Unlike basic phosphines and neutral phosphine oxides, H3PO2 and its phospha-Mannich products can mimic carboxylic acids in biological processes and chemistry, and synthesis of phosphinic analogs of natural α-amino acids, used to design phosphinic pseudopeptides, is one of the major applications of H3PO2 and its synthons, such as phosphonites (RO)2PH (R = SiMe3, alkyl) and alkyl dialkoxymethylphosphinates (R’O)2CHP(O)(OR’)H. H3PO2 is a unique P-nucleophile that can produce relatively stable acetals with a P–H function, widely used for further derivatization. Phospha-Mannich reactions of H3PO2 also provide a variety of (α-aminoalkyl)phosphinic compounds, applied as flame-retardant or chelators of di- and tri-valent metal ions useful in metal-based (radio)pharmaceuticals for imaging and therapy.