ZnCl₂-Mediated Double Addition of Dialkylphosphite to Nitriles for the Synthesis of 1-Aminobisphosphonates

Abstract

In this study, the double addition of dialkylphosphite to nitriles in a ZnCl2/Et3N system is described. The reaction was conveniently and directly used for the synthesis of biologically important 1-aminobisphosphonates (ABPs) from nitriles. The one-pot synthesis of 1-aminobisphosphonates from aldehydes via the in situ generation of nitriles is also described.

Synthesis of Aminomethylene-gem-bisphosphonates Containing an Aziridine Motif: Studies of the Reaction Scope and Insight into the Mechanism

“…Syntheses of 1-aminobisphosphonates (or aminomethylene-gem-bisphosphonates) are described through numerous methods, 14, namely the condensation of ethyl orthoformates and phosphites, 15,16 the Beckmann rearrangement of oximes, 17,18 or the bisphosphorylation of amides, 19,20 imines, 21 isonitriles, [22][23][24] or nitriles. 25 To our knowledge, such derivatives when containing an aziridine motif are not reported in the literature. Thus, we propose an original synthetic route involving lithiated diethylphosphite for the valorization of these three-membered rings in phosphorus chemistry (Scheme 1).…”

One-Pot and Catalyst-Free Transformation of N-Protected 1-Amino-1-Ethoxyalkylphosphonates into Bisphosphonic Analogs of Protein and Non-Protein α-Amino Acids

“…Great potential for application as a contrast agent in MRI imaging is demonstrated by the complex of the BPAMD ligand with gadolinium, containing a fragment of ABP as a “bone-seeking” moiety ( Figure 1 b) [ 19 ]. The chelating properties of some ABPs are also used to remove radioactive metallic toxins from water or blood [ 20 ], as well as for the functionalization of the surface of supermagnetic iron oxide nanoparticles (SPION) used in MRI [ 18 ].…”

ZnCl2-mediated stereo- and chemoselective synthesis of vinylphosphonates

“…22 However, to the best of our knowledge, there are only a few reports on the reaction with methylphosphonates as nucleophilic species in the presence of TiCl 4 / N-methylmorpholine and (i-PrO) 3 TiCl/NaH. 23,24 We recently reported a double hydrophosphonylation of nitriles in the presence of ZnCl 2 /Et 3 N. 25 In continuation of our efforts in developing new synthetic methods for organophosphorous compounds, [26][27][28][29][30][31][32][33] we decided to study the vinylphosphonate-forming reaction using a Lewis acid/base combination. Herein we report an efficient and practical method via the Knoevenagel condensation reaction of carbonyl compounds with cyanomethylphosphonates to yield (E)vinylphosphonates.…”

“…22 However, to the best of our knowledge, there are only a few reports on the reaction with methylphosphonates as nucleophilic species in the presence of TiCl 4 / N -methylmorpholine and ( i -PrO) 3 TiCl/NaH. 23,24 We recently reported a double hydrophosphonylation of nitriles in the presence of ZnCl 2 /Et 3 N. 25…”