Preparation of benzylphosphonates via a palladium(0)-catalyzed cross-coupling of H-phosphonate diesters with benzyl halides. Synthetic and mechanistic studies

Abstract

We have developed a new, efficient method for the synthesis of benzylphosphonate and benzylphosphonothioate diesters via a palladium(0)-catalyzed cross-coupling reaction between benzyl halides and H-phosphonate or H-phosphonothioate diesters, using Pd 2 (dba) 3 (CHCl 3 ) as a palladium source and Xantphos as a supporting ligand. Some mechanistic aspects of these reactions were investigated using 31 P NMR spectroscopy.

Copper‐Catalyzed Synthesis of Alkylphosphonates from H‐Phosphonates and N‐Tosylhydrazones

“…The Michaelis–Becker reaction sometimes requires a strong base and long reaction times, and these drawbacks can limit the range of substrates and the yield of products. The demand for functionalized organic phosphonates has stimulated extensive studies on phosphorylation8 and PC( sp 3 ) bond‐forming reactions involving arylmethyl halides/alcohols/carboxylic acids catalyzed by Pd,9a,b Lewis acids,9c,d Cu9e and N 2 H 4 9f…”

Synthesis of Aryl and Arylmethyl Phosphonates by Cross‐Coupling of Aryl or Arylmethyl Halides (X = I, Br and Cl) with Diisopropyl H‐Phosphonate

“…Another type of approach is the transition‐metal‐catalysed cross‐coupling of alkyl halides with dialkyl H‐phosphonates 3n–3q. In the development of these two types of phosphonations of arylmethyl halides, significant progress has been achieved by Rousseau,3e Salvatore,3c Zografos3h and Stawinski3p and their co‐workers.…”

Recent Advances in H-Phosphonate Chemistry. Part 2. Synthesis of C-Phosphonate Derivatives

“…They were performed in the presence of p-benzoquinone ( p-BQ), the most efficient reoxidant for the conversion of Pd(0) into the catalytically active Pd(II) species. Mechanistically, this reaction differs from Pd(0)-catalyzed arylations in the formation of aryl-palladium complexes via transmetallation instead of oxidative addition [104,105].…”

“…Various glyceryl, cholesteryl, and dinucleoside benzylphosphonates, with a diverse substitution pattern in the benzyl moiety, could be obtained. Some mechanistic aspects of this reaction were also investigated [105]. An example of the application of this method to the synthesis of dinucleoside benzylphosphonates is shown in Scheme 15.…”

“…This is particularly true for cross-coupling reactions with phosphorus nucleophiles, for which a new, efficient method for the synthesis of benzylphosphonate diesters was recently developed [104,105]. This protocol makes use of Pd(OAc) 2 [104] or Pd 2 (dba) 3 (CHCl 3 ) [105] as a palladium source and Xantphos (Fig. 3) as a supporting ligand.…”