Studies on organophosphorus compounds: XV. A new method for the synthesis of α-amino-substituted benzylphosphonic acids

A new synthetic method for the preparation of α-amino-substituted benzylphosphonic acids with moderate to good yields was developed by the following sequence of reactions. Diethyl phosphoramide was reacted with substituted benzaldehyde and triphenyl phosphite in the presence of catalytic amount of BF₃·Et₂O. Diphenyl α-(N-phosphorylamino)-substituted benzylphosphonates (1) thus obtained was then treated with hydrogen bromide in acetic acid to remove selectively the amino-protecting group with the formation of diphenyl α-amino-substituted benzylphosphonates (2), a key intermediate in phosphorus peptide synthesis, which was then successively hydrolyzed with hydrobromic acid to give corresponding hydrobromide of α-amino-substituted benzylphosphonates with excellent yields. The free aminophosphonic acid (3) was obatined from the latter by treatment with propylene oxide. ³¹P NMR studies demonstrated that a linear relationship exists in plotting δ versus δ constants of nuclear substituent in 1 series. The p-substituted compounds give, as a rule, higher value in ³¹P NMR spectra than those from meta- and ortho-substituents.