Facile Substituent Exchange at H‐Phosphonate Diesters Limiting an Effective Synthesis of D‐Phosphonate Diesters

Abstract

Research on using H-phosphonate diesters to introduce phosphorus functionality into molecules and polymers, some of which have medicinal applications, has recently attracted a lot of attention. Deuterium labelling to yield the corresponding D-phosphonate diesters, although desirable in order to help with the mechanistic elucidation of reactions containing H-phosphonate diesters, has been demonstrated to be a challenge. Deuterium exchange at Hphosphonate diesters using D 2 O, MeOD and ND 2 Bn has shown competitive behavior with hydrolysis, alcoholysis and aminolysis reactions, respectively. This facile substituent exchange for the addition of D 2 O and MeOD can be attributed to the similar energy required to eliminate ROH or H 2 O (ROD or HOD, R = iPr, Et, Me) from a pentavalent P(V) intermediate which is generated from axial delivery of an OD or OR group from D 2 O and MeOD, respectively. The trend in reaction rate for the exchange processes follows the order of R = Me > Et > iPr in (RO) 2 P(O)H and also depends on the nucleophilicity of the incoming group. Attempted synthesis of D-phosphonate diesters directly from PCl 3 and alcohols or via lithiation reactions further demonstrated just how sensitive the H/D-scrambling process is. These results have implications for the general reactivity of H-phosphonate diesters towards water, alcohol, and amines and their potential to selectively undergo substitution at either P-OR or P-H. Moreover, insight into the mechanism(s) of selective deuterium exchange, for example to give D-phosphonate diesters via the direct exchange of D for H, was illuminated through this research. at 101 MHz and are given in parts per million relative to CDCl 3 (δ = 77.0 ppm). Chemical shifts for 31 P NMR spectra are recorded at 161.97 MHz and given relative to external 85% phosphoric acid (δ = 0 ppm). Data are represented as follows: chemical shift, multiplicity (app = apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in Hertz (Hz), and integration.

The Synthesis and Mechanistic Considerations of a Series of Ammonium Monosubstituted H‐Phosphonate Salts

“…Instead, on the basis of previous work, [14] we propose that diphenyl H ‐phosphonate, 1 d , reacts with trace phenol (present in 2 d ), which results in the formation of 5‐membered intermediate, Int‐1 . Following pseudorotation, Int‐1 undergoes phenol‐assisted dehydration to form P(OPh) 3 and water (Scheme 9).…”

“…a doublet of quartets for 2 a (δ P =11.5 ppm, 1 J PH =619 Hz, 3 J PH =12 Hz) was observed by 31 P NMR spectroscopy (Table 2, Figure S25). An intermediate aminolysis product, [14] 5 a ((MeO)(BnNH)P(O)H, δ P =14.2 ppm, 1 J PH =696 Hz, 3 J PH =12 Hz Scheme 5) was also observed at early reaction times as a doublet of sextets in the 31 P NMR spectra (Table 3) and then disappeared after 7 hours. ESI‐MS analysis and 1 H NMR spectroscopy were performed on the sample after the timed experiment, revealing that the cation in 1 a was a mixture of [BnMeNH 2 ] + , [BnMe 3 N] + and [BnNH 3 ] + (Figures S26 and S27) with the [(MeO)PH(O)O] − anion visible in the negative infusion spectrum (Figure S28).…”

“…Tautomerization is the first step when H ‐phosphonates are attacked by a nucleophile such as an alcohol, [11] water, [12] or an amine [13] and lead to the formal exchange of the OR substituent with the nucleophile (e.g. OR’, OH, or NHR’, respectively) [14] …”