Photocatalytic Hydrogen Atom Transfer-Induced Arbuzov-Type α-C(sp³)–H Phosphonylation of Aliphatic Amines

Abstract

Despite remarkable progress in photocatalytic hydrogen atom transfer (HAT)-induced C(sp 3 )−H functionalization, achieving C(sp 3 )−H to C(sp 3 )−P transformation by the HAT process remains highly challenging due to P-reagents' compatibility issues. α-Aminophosphonic acids have shown great potential in medicinal chemistry, yet their synthesis is hindered by limited substrate scopes, poor functional group tolerance, and reliance on prefunctionalized substrates, restricting their broad applications. Herein, we report photocatalytic HAT-induced α-C(sp 3 )−H phosphonylation of aliphatic amines, providing rapid access to structurally diverse α-aminophosphonates from abundant amines. Leveraging intramolecular HAT, radical polar crossover, and an Arbuzov-type phosphonylation cascade, the challenges associated with HAT-induced C(sp 3 )−H to C(sp 3 )−P transformation were overcome. This protocol features base-free, redox-neutral, and mild conditions and broad scopes, employing amines as limiting reagents, and allows for late-stage phosphonylation of complex drug molecules possessing amine moieties.

Development of a General Organophosphorus Radical Trap: Deoxyphosphonylation of Alcohols

“…As a result of this mechanistic limitation, no general method for the construction of C­( sp 3 )–P­(V) species via phosphoranyl radical fragmentation has been described in the literature . Alternative free radical methods have emerged, including addition of phosphorus-centered radicals to π systems, , carbocation formation by radical polar crossover (RPC) followed by S N 1 trapping, , and transition-metal-catalyzed cross-coupling methods. , Although these transformations represent significant inroads toward the formation of C­( sp 3 )–P­(V) species, we hypothesized that the development of a general P­(III) alkyl radical trap and subsequent merger with photoredox conditions would enable access to a novel organophosphorus chemical space.…”

Construction of C–P Bonds from Free Cyclobutanone Oximes and Chlorophosphines via Radical–Radical Coupling

“…Traditional strategies of phosphonylation have largely relied on nucleophilic substitutions of alkyl or acyl halides (e.g., Arbuzov reaction) and electrophilic phosphoryl species, and transition metal-catalyzed cross-coupling . With the resurgence of radical chemistry, a new impulse has recently been given to the radical phosphonylation, showcasing a great potential for the synthesis of organophosphorus compounds. − In particular, radical Arbuzov reactions have been elegantly disclosed by König, Aggarwal, , Li, − Wu, et al The radical variants significantly extend the scope of Arbuzov reaction to include aryl halides, alkanes, alkyl BF 3 K salts, and carboxylic esters instead of alkyl or acyl halides via distinct mechanism pathways. , …”

Regioselective α-Phosphonylation of Unprotected Alicyclic Amines

“…However, due to the difficulty in accessing enolizable cyclic imines, the synthesis of α-aminophosphonates and α-amino phosphine oxides in which the α-P-substituent is placed on the ring of a cyclic amine is difficult to achieve via the traditional Kabachnik-Fields reaction. A highly attractive alternative to the synthesis of these cyclic α-aminophosphonates is based on the α-C–H bond functionalization of cyclic amines. , Such reactions have been achieved via cross-dehydrogenative coupling (CDC), photoredox catalysis, and electrochemical methods (Scheme b). Traditionally, these methods have largely been limited to acyclic N , N -dialkylanilines and N -aryl tetrahydroisoquinolines, although recent advances have extended the scope to the synthesis of N -benzoyl protected α-aminophosphonates and α-amino phosphine oxides .…”