Copper‐Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics

Abstract

A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodology using TMSCF2PO(OEt)2, iodonium salts and a copper salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in good to excellent yields. This method represents the first general synthetic route to this important class of fluorinated scaffolds, which are well-recognized as in vivo stable phosphate surrogates.

An Electrophilic Reagent for the Direct Introduction of the SCF2PO(OEt)2 Group to Molecules

“…Thus,t he design of ab ench-stable reagent to directly introduce an SCF 2 PO(OEt) 2 residue will enlarge the current toolbox of fluorinated groups and open new routes for functionalizing complex molecules.H erein, we disclosed as imple and straightforward synthesis of the first electrophilic SCF 2 PO(OEt) 2 source and its broad application in various transformations.I nspired by the recent studies from Gooßen and co-workers, [5a,b,12] and taking advantage of our own expertise for the preparation of N-(cyanosulfanyl)aniline derivatives, [13] we hypothesized that the synthesis of the electrophilic SCF 2 PO(OEt) 2 reagent might be realized in two steps from the corresponding and readily available aniline and TMSCF 2 PO(OEt) 2 .Indeed, the N-(cyanosulfanyl)aniline derivative 1,prepared in 66 %yield (on 10 mmol scale) from 2,4,6-trimethylaniline and NaSCN, [13,14] was engaged in an ucleophilic cyanide-CF 2 PO(OEt) 2 substitution with in situ generated CuCF 2 PO(OEt) 2 . [15] With this approach, the electrophilic SCF 2 PO(OEt) 2 source 2 was prepared in 71 %y ield on 0.25 mmol scale (Scheme 2). Its synthesis was conveniently scalable and the bench-stable reagent [16] 2 was obtained in 60 %yield on 4.4 mmol scale.…”

Copper‐Mediated Aromatic 1,1‐Difluoroethylation with (1,1‐Difluoroethyl)trimethylsilane (TMSCF2CH3)

“…The low efficiency of the cross‐coupling reaction between aryl iodides and “CuCF 2 CH 3 ” is probably due to the fact that the oxidative addition process usually requires high temperature and/or long reaction time. Thus, we envisioned that diaryliodonium salts, a more reactive version of aryl iodides in metal‐catalyzed or ‐mediated reactions, could react with “CuCF 2 CH 3 ” for the synthesis of (1,1‐difluoroethyl)arenes. After optimization of the reaction conditions, the reaction of diaryliodonium salts with “CuCF 2 CH 3 ” neutralized by Et 3 N⋅3HF (0.5 equiv) could provide the desired products in good yields at room temperature for 1 hour (Scheme ).…”

New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics

“…One of the major advantages to use iodonium salts is beyond doubt the broad range of available compounds, since aryl, heteroaryl, vinyl and alkynyl derivatives are readily accessible (Scheme 14). [34] The aromatic substrate bearing an electron-donating group reacted smoothly giving the corresponding product 20 b in pretty good yield. In contrast to the methodology using aryldiazonium salts, the halogenated scaffolds (20 c, d) could be readily synthesized in good yields.…”