Phospha-Mannich reactions of hypophosphorous acid H3PO2

Abstract

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.