Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap “BecaP”

Abstract

Carbon–phosphorus bond formation is significant in synthetic chemistry because phosphorus-containing compounds offer numerous indispensable biochemical roles. While there is a plethora of methods to access organophosphorus compounds, phosphonylations of readily accessible alkyl radicals to form aliphatic phosphonates are rare and not commonly used in synthesis. Herein, we introduce a novel phosphorus radical trap “BecaP” that enables facile and efficient phosphonylation of alkyl radicals under visible light photocatalytic conditions. Importantly, the ambiphilic nature of BecaP allows redox neutral reactions with both nucleophilic (activated by single-electron oxidation) and electrophilic (activated by single-electron reduction) alkyl radical precursors. Thus, a broad scope of feedstock alkyl potassium trifluoroborate salts and redox active carboxylate esters could be employed, with each class of substrate proceeding through a distinct mechanistic pathway. The mild conditions are applicable to the late-stage installation of phosphonate motifs into medicinal agents and natural products, which is showcased by the straightforward conversion of baclofen (muscle relaxant) to phaclofen (GABAB antagonist).

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

“…The facile 1,5-HAT process translocates the radical to the α-amino position, giving the key intermediate alkyl radical B . , Then, PC* + promotes the RPC through SET, delivering iminium intermediate C , along with the regeneration of the neutral, ground-state photocatalyst . The direct radical addition of B to trialkyl phosphite is unlikely due to the low reactivity of these two species. ,,, Iminium C is readily captured by trialkyl phosphite through nucleophilic attack, giving phosphonium D , which is then dealkylated by iodide through an Arbuzov-type process to give the targeted α-aminophosphonate (methyl iodide was observed as a byproduct, see Supporting Information S5.4). Although an energy-transfer pathway could not be excluded at this stage, we believe that it plays a minor role in this transformation (see Supporting Information S5.9 for details).…”

“…However, despite extensive studies in photocatalytic HAT-induced C­(sp 3 )–H functionalization, the development of C–P bond formation remains a formidable challenge at the current stage (Figure A). The hurdles include the sensitivity of commonly used P­(III) and H–P­(V) reagents towards oxidation, , poor compatibility between P-reagents and electrophilic HAT reagents, ,− low reactivity between nucleophilic alkyl radicals and common P-reagents, ,,− and the requirement of excess C–H substrates in most intermolecular HAT processes. , …”

Photoinduced Decarboxylative Radical Phosphinylation

“…In particular, we introduced the copper‐catalyzed decarboxylative phosphonylation of N ‐acyloxyphthalimides (also known as redox‐active esters, RAEs) with trialkyl phosphites and proposed the “copper‐assisted phosphite transfer” mechanism (Scheme 1a) [8] . The second strategy relies on the β‐scission of phosphoranyl radicals (Scheme 1b) [10–12] . Taking advantage of the high stability of diphenylmethyl radicals, the decarboxylative phosphonylation of RAEs with diphenylmethyl o ‐phenylene phosphite was accomplished, as reported by Aggarwal et al [10] .…”

“…The second strategy relies on the β‐scission of phosphoranyl radicals (Scheme 1b) [10–12] . Taking advantage of the high stability of diphenylmethyl radicals, the decarboxylative phosphonylation of RAEs with diphenylmethyl o ‐phenylene phosphite was accomplished, as reported by Aggarwal et al [10] . The radical addition‐β‐scission sequence also led to the implementation of deboronophosphonylation, [10] dehalophosphonylation [11] and deoxyphosphonylation [12] reactions.…”

“…[8] The second strategy relies on the β-scission of phosphoranyl radicals (Scheme 1b). [10][11][12] Taking advantage of the high stability of diphenylmethyl radicals, the decarboxylative phosphonylation of RAEs with diphenylmethyl o-phenylene phosphite was accomplished, as reported by Aggarwal et al [10] The radical addition-βscission sequence also led to the implementation of deboronophosphonylation, [10] dehalophosphonylation [11] and deoxyphosphonylation [12] reactions. Herein we introduce a different strategy, namely the radical addition-oxidation mode, [13] based on which the decarboxylative phosphinylation of RAEs with dimethyl arylphosphonites or diethyl alkylphosphonites is successfully achieved under mild conditions (Scheme 1c).…”