Electrochemical C\u2013H phosphorylation of arenes in continuous flow suitable for late-stage functionalization

Hao Long,Hai-Chao Xu,Liang-Hua Jie,Chong Huang,Zhao-Yu Li,Jinshuai Song,Yun-Tao Zheng,Shaobin Zhu

doi:10.1038/s41467-021-26960-y

Abstract

The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology. Previous C–H phosphorylation reactions under nonelectrochemical or electrochemical conditions require directing groups, transition metal catalysts, or chemical oxidants and suffer from limited scope. Herein we disclose a catalyst- and external oxidant-free, electrochemical C–H phosphorylation reaction of arenes in continuous flow for the synthesis of aryl phosphorus compounds. The C–P bond is formed through the reaction of arenes with anodically generated P-radical cations, a class of reactive intermediates remained unexplored for synthesis despite intensive studies of P-radicals. The high reactivity of the P-radical cations coupled with the mild conditions of the electrosynthesis ensures not only efficient reactions of arenes of diverse electronic properties but also selective late-stage functionalization of complex natural products and bioactive compounds. The synthetic utility of the electrochemical method is further demonstrated by the continuous production of 55.0 grams of one of the phosphonate products.

Highlights

The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology
Either the arene or the phosphorus coupling partner is oxidized under photochemical[14,15] or transition-metal catalyzed[16,17] conditions to a radical intermediate, which reacts with the other coupling partner to achieve C–P bond formation
The challenge is that the reactivity of P-radical cations toward electron-deficient arenes remains unknown and the trialkyl phosphite radical cations are known to react facilely with trialkyl phosphite precursor to form dimer radical cations[50,51]

Summary

Results

The electrolysis reaction of 1 in the presence of P(OEt)[3] and HPO(OnBu)[2] produced 2 in 51% yield with an only trace amount of 55 (Fig. 4c), suggesting that the PO(OR)[2] moiety of phosphonate product was derived from P(OR)[3] instead of HPO(OR)[2]. Consistent with these results, 18O was not incorporated into 2 when the reaction was carried out with H218O (Fig. 4d). A kinetic isotope effect (KIE) of 1.0 was Variationof arene

P OEt OEt

31 P-NMR spectra compound 2

Methods