A new method for the synthesis of α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues

• Main Authors: Anna Kuźnik, Roman Mazurkiewicz, Mirosława Grymel, Katarzyna Zielińska, Jakub Adamek, Ewa Chmielewska, Marta Bochno, Sonia Kubica
• Format: Article
• Language: English
• Published: Beilstein-Institut 2015-08-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: alkylidenebisphosphonate; α-amino acid phosphorus analogues; electrochemical α-methoxylation; 1-phosphinoylalkylphosphonate; 1-phosphinylalkylphosphonate
• Online Access: https://doi.org/10.3762/bjoc.11.153

A convenient approach has been developed to α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues by α-phosphonylation, α-phosphinylation or α-phosphinoylation of 1-(N-acylamino)alkylphosphonates, that, in turn, are easily accessible from N-acyl-α-amino acids. Effective electrophilic activation of the α-position of 1-(N-acetylamino)alkylphosphonates was achieved by electrochemical α-methoxylation of these compounds in methanol, mediated with NaCl, followed by displacement of the methoxy group with triphenylphosphonium tetrafluoroborate to give hitherto unknown 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates. The latter compounds react smoothly with trialkyl phosphites, dialkyl phosphonites or alkyl phosphinites in the presence of Hünig’s base and methyltriphenylphosphonium iodide in a Michaelis–Arbuzov-like reaction to give the expected alkylidenebisphosphonates, 1-phosphinylalkylphosphonates or 1-phosphinoylalkylphosphonates, respectively, in good yields.