Triethylamine‐Mediated Transformation of Phosphonates into Phosphonamidates

Abstract

Organophosphorus compounds such as phosphonamidates are gaining attention across different fields of chemistry, with interesting applications as pharmaceuticals, or pesticides. However, practical application of phosphonamidates is complicated by their difficult syntheses which often involve expensive or unstraightforward reagents and harsh conditions. To remedy these issues, we present a flexible, room temperature synthesis for novel P‐alkylphosphonamidates without the need for intermediary purification. Commonly available phosphonates are first chlorinated by use of oxalyl chloride and phosphonylaminium salts are used to mediate the harsh reactivity of phosphonochloridates, giving rise to the desired products. We demonstrate the compatibility of our protocol with primary and secondary amines, as well as with different phosphonate esters. The proposed pathway also enables the synthesis of primary phosphonamidates using ammonium acetate as a cheap and safe alternative for ammonia. In future research, this protocol will also enable the synthesis of bioactive targets that are incompatible with current protocols.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides

“…Similar to our previous work, we also wanted to extend our methodology to commercially available phosphoryl chlorides [14]. However, to our surprise, symmetric N-phosphorylated glycine or proline methyl esters have not yet been described in the literature.…”

“…The only group of nucleophiles missing from this library are phenols, which have not been studied so far. Trying to summarize the work in this paper as well as the work from our previous paper [14], parallels can be drawn to the work of Mayr on the nucleophilicity parameters of organic compounds. In the same solvent, the difference in nucleophilicity between triethylamine (nucleophilicity parameter: 17.30 in CH2Cl2) and pyridine (nucleophilicity parameter: 12.9 in CH2Cl2) is almost five units.…”

“…Recently, we described the use of phosphonylaminium salts as phosphonylating agents with good results in combination with amines and anilines [14]. An interesting expansion of this work would be in the direction of phenols and toward the formation of mixed n-alkylphosphonate diesters.…”

“…The scheme shows an overview of the published methodologies for the synthesis of amino acid-based phosphonamidates. These moieties can be synthesized via (A) the classical approach [2][3][4][5][6][7], (B) a direct coupling method [8][9][10][11][12], (C) triflic anhydride activation [13] or our methodology [14].…”

“…In a recent paper [14], we have demonstrated the use of phosphonylaminium salts for the synthesis of phosphonamidates without the need for harsh or expensive reagents while still ensuring that the protocol remains widely applicable. In this paper, we expand the application scope of these salts to reactions with phenols and amino acids, leading to a series of mixed n-alkylphosphonate diesters or n-alkylphosphonamidates, respectively (Scheme 1d, only shown for phosphonamidates).…”