<p>Development of efficient and versatile methods for functional group transformations is one major objective in modern organic synthetic chemistry. α-Ketophosphonates are a class of bifunctional compounds playing a prominent role in organic and medicinal chemistry. However, their broader applicability has been hampered by lacking of direct and convenient synthetic methods from stable and abundant starting materials. Direct transformation of readily available and robust amides into labile α-ketophosphonates is thus highly desirable but remains a formidable challenge, as such a reaction is both kinetically and thermo-dynamically unfavorable, and there exists a chemoselective issue for the known bisphosphonylation. Herein, we report unprecedented versatile synthesis of α-ketophosphonates, α-hydroxyphosphonates and α,α-difluorophosphonates from either secondary or tertiary amides. The reactions are enabled by <i>in situ</i> electrophilic activation with trifluoromethanesulfonic anhydride (Tf₂O). The method features high efficiency, good chemoselectivity, wide substrate scope, excellent functional group tolerance, and easy scalability. The practicality of this methodology is highlighted by the late-stage functionalization of drug molecules and concise formal synthesis of an FBPase inhibitor.</p>