Regioselective O/C phosphorylation of α-chloroketones: a general method for the synthesis of enol phosphates and β-ketophosphonates via Perkow/Arbuzov reaction.

Yuepeng Cao,Enxue Shi,Zhenhua Gao,Yongbiao Guo,Ling Yuan,Chengxin Pei,Xiaojing Bi,Junchen Li

doi:10.1039/d0ra05140c

Abstract

A regioselective O/C phosphorylation of α-chloroketones with trialkyl phosphites was performed for the first time, which employed solvent-free Perkow reaction and NaI-assisted Arbuzov reaction under mild conditions respectively. Versatile enol phosphates were prepared in good to excellent yields as well as β-ketophosphinates.

Highlights

The reaction generally gives a mixture of enol phosphates and b-ketophosphonates generating from the competitive O/C phosphorylation (Scheme 1a), which proceeds mainly through the following two possible reaction pathways of a-haloketones (Fig. 1): (i) path a, the nucleophilic P atom of trialkyl phosphite attacks the carbonyl C atom of a-haloketone forming a triatomic heterocyclic I which followed by the ring cleavage transforms into a phosphonium salt II and by the O-demethylation gives the enol phosphates product 3 (Perkow reaction mechanism); (ii) path b, the nucleophilic P atom attacks the halocarbon of a-haloketone to generate a phosphonium salt III, followed by the O-demethylation to give the b-ketophosphonate product 4 (Arbuzov reaction mechanism)
The reaction without solvent used at 40 C proceeded to give enol phosphate 3a and b-ketophosphonate 4a in 50% yield respectively (Table 1, entry 1)
A solvent screen revealed that lower-polar solvents could facilitate the regioselectivity of Perkow reaction, whereas higherpolar solvent could favour the occuration of Arbuzov reaction

Summary

Introduction

As one of the most utilized classic reactions, Perkow reaction offers an efficient way to obtain pharmacologically and biologically important enol phosphates through simple condensation of trialkyl phosphites and a-haloketones. the reaction generally gives a mixture of enol phosphates and b-ketophosphonates generating from the competitive O/C phosphorylation (Scheme 1a), which proceeds mainly through the following two possible reaction pathways of a-haloketones (Fig. 1): (i) path a, the nucleophilic P atom of trialkyl phosphite attacks the carbonyl C atom of a-haloketone forming a triatomic heterocyclic I which followed by the ring cleavage transforms into a phosphonium salt II and by the O-demethylation gives the enol phosphates product 3 (Perkow reaction mechanism); (ii) path b, the nucleophilic P atom attacks the halocarbon of a-haloketone to generate a phosphonium salt III, followed by the O-demethylation to give the b-ketophosphonate product 4 (Arbuzov reaction mechanism). To the date, highly regioselective O/C phosphorylation of a-haloketones with trialkyl phosphites remains unavailable. As one of the most utilized classic reactions, Perkow reaction offers an efficient way to obtain pharmacologically and biologically important enol phosphates through simple condensation of trialkyl phosphites and a-haloketones.. The reaction generally gives a mixture of enol phosphates and b-ketophosphonates generating from the competitive O/C phosphorylation (Scheme 1a), which proceeds mainly through the following two possible reaction pathways of a-haloketones (Fig. 1): (i) path a, the nucleophilic P atom of trialkyl phosphite attacks the carbonyl C atom of a-haloketone forming a triatomic heterocyclic I which followed by the ring cleavage transforms into a phosphonium salt II and by the O-demethylation gives the enol phosphates product 3 (Perkow reaction mechanism); (ii) path b, the nucleophilic P atom attacks the halocarbon of a-haloketone to generate a phosphonium salt III, followed by the O-demethylation to give the b-ketophosphonate product 4 (Arbuzov reaction mechanism).. We wish to report a simple but efficient method for regiospeci c synthesis of enol phosphates and b-ketophosphonates respectively with good to excellent yields under quite mild conditions only by using the most -available and economic achloroketones as the starting metarial (Scheme 1b)

Results and discussion

Conclusions

15. Reactions of silyl phosphites with a-halo