Radical Arbuzov Reaction

The Arbuzov reaction (also known as the Michaelis- Arbuzov reaction) is one of the most fundamental transformations in organic chemistry and has been extensively used for the synthesis of organophosphorus compounds for over a century. However, the reaction generally requires an elevated temperature and is applicable mainly to primary alkyl halides with poor functional group tolerance. We report herein a radical alternative to the conventional nucleophilic substitution reaction. Thus, new radical phosphonylation reagents, 9-fluorenyl o-phenylene phosphite and benzhydryl o-phenylene phosphite, have been developed for this purpose. The photoredox-catalyzed reaction of a wide range of alkyl bromides or iodides with 9-fluorenyl (or benzhydryl) o-phenylene phosphite followed by workup with methanol (or ethanol) provides the corresponding dimethyl (or diethyl) alkylphosphonates in satisfactory yields at room temperature under mild conditions. The method is applicable to primary, secondary, and even tertiary alkyl iodides and bromides and exhibits an excellent functional group tolerance, thereby enabling the late-stage modification of complex molecules and rapid synthesis of phosphonate-containing natural products and drug molecules. A mechanism involving the formation and subsequent beta-scission of phosphoranyl radicals is proposed.