Scheme 1. Synthesis of PFEx substrates.

(A) Synthesis of phosphoramidic difluorides, cyclic phosphoramidofluoridates, and cyclic thiophosphoramidofluoridates.

(B) Synthesis of phosphoramidofluoridates and thiophosphoramidofluoridates. General reaction conditions: POCl₃ or PSCl₃ (1.0 equiv) and Et₃N (1.0 equiv) were added to relevant phenol (1.0 equiv) in CH₂Cl₂ (0.25 M) at −78 °C then stirred overnight at room temperature. The required amine (1.0 equiv) was added, followed by Et₃N (1.0 equiv) dropwise at −78 °C. The reaction was stirred at room temperature until complete (³¹P NMR). The reaction was filtered and concentrated. KF (8.0 equiv) and ⁿBu₄NCl (0.10 equiv) were added to the crude in acetone (0.25 M). After completion (³¹P NMR), the reaction was filtered, concentrated, and purified by silica column chromatography. Isolated yields are reported. Reactions were performed on 5.0 mmol following general procedures detailed in the supporting information unless stated otherwise. See supporting information for a complete list of products.

(C) Stability studies of representative P–X compounds.

^[a]Product had limited stability.

^[b]11a was completely consumed after 1 h; P–Cl exchange product was identified.