Direct conversion of diethyl hydrogen phosphate into diethyl phosphoramides

Opening up the Toolbox: Synthesis and Mechanisms of Phosphoramidates

“…The selective alkylation of (EtO) 2 P(O)NH 2 via silylation was achieved by Zwierzak in 1982 using [n-Bu 4 N]Br catalyst (Scheme 2 route E) [88]. In 1984, Zwierzak and Osowska-Pacewicka reported the synthesis of various P-Ns via inorganic salt elimination [89] and the direct conversion of phosphoric acid [90]. In 1985, Riesel et al reacted primary amines or NH 3 with (RO) 3 P (R = alkyl) and CCl 4 as an effective route to P-Ns [91].…”

“…Either column chromatography (on silica) or recrystallization were used to purify the P-Ns to obtain isolated yields in the range of 30-80%. In another salt elimination route, this time using inorganic bases and [n-Bu4N]Br as a catalyst, Zwierzak and Osowska-Pacewicka synthesized P-Ns from (EtO)2P(O)H (diethyl H-P) and various amines (Scheme 5a) [89]. Aromatic amines such as aniline and 4-chloroaniline, aliphatic amines such as cyclohexylamine, n-butylamine, and ethanamine, and alkanolamines such as 2-aminoethan-1-ol, 3-aminopropan-1-ol, and bis(2-(-ethoxy)ethyl)amine were explored to demonstrate the broad scope of this synthetic transformation.…”

“…Apart from the stoichiometric Et3N salt waste generated, the synthetic process is prone to the formation of significant quantities of pyrophosphate or phosphanetetraamine bromide salt side products, resulting in a low yield. The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al [89]; however, based on the roles of KHCO3, K2CO3, and [n-Bu4N]Br as outlined in the paper and a recently proposed mechanism for an Atherton-Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121]. In the reacting system, the HCO3 − migrates to the The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al [89]; however, based on the roles of KHCO 3 , K 2 CO 3 , and [n-Bu 4 N]Br as outlined in the paper and a recently proposed mechanism for an Atherton-Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121].…”

“…The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al [89]; however, based on the roles of KHCO3, K2CO3, and [n-Bu4N]Br as outlined in the paper and a recently proposed mechanism for an Atherton-Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121]. In the reacting system, the HCO3 − migrates to the The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al [89]; however, based on the roles of KHCO 3 , K 2 CO 3 , and [n-Bu 4 N]Br as outlined in the paper and a recently proposed mechanism for an Atherton-Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121]. In the reacting system, the The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al [89]; however, based on the roles of KHCO3, K2CO3, and [n-Bu4N]Br as outlined in the paper and a recently proposed mechanism for an Atherton-Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121].…”

“…The crude P-Ns were recrystallized to afford pure products in 35–93% yield. Due to the difficulty encountered in phosphorylating aromatic amines, as mentioned by Zwierzak [ 87 , 89 ], Lukanov et al proposed a similar synthetic route using N -phenylformamide or 2-chloro- N -phenylacetamide as the N-source, which offered less steric hindrance and better N-H acidity ( Scheme 5 c) [ 96 ]. Derivatives of N -phenylformamide or 2-chloro- N -phenylacetamide (R’R’’NC(O)R’’’) were used containing a wide range of aryl-substituents (e.g., R’’ = Ph, 4-MeOPh, 4-ClPh, 2-MeOPh, 2,3-Cl 2 Ph, 2-MePh, and 2,6-(C 2 H 5 ) 2 Ph and 2,6-(CH 3 ) 2 Ph).…”