Arylation of Axially Chiral Phosphorothioate Salts by Dinuclear Pd^I Catalysis

Abstract

S‐aryl phosphorothioates are privileged motifs in pharmaceuticals, agrochemicals, and catalysts; yet, the challenge of devising a straightforward synthetic route to enantioenriched S‐aryl phosphorothioates has remained unsolved to date. We demonstrate herein the first direct C−SP(=O)(OR′)(OR′′) coupling of diverse and chiral phosphorothioate salts with aryl iodides, enabled by an air‐ and moisture‐stable PdI dimer. Our mechanistic and computational data suggest distinct dinuclear PdI catalysis to be operative, which allows for operationally simple couplings with broad scope and full retention of stereochemistry.

Validation of Arylphosphorothiolates as Convergent Substrates for Ar-SF4Cl and Ar-SF5 Synthesis

“…18 Schoenebeck has recently shown that Ar-S-P(O)(OR) 2 can also be easily accessed via palladium catalysis from the parent aryl iodides. 19 Additionally, Gooen and Tang have developed protocols which enable the synthesis of aryl phosphorothiolates through S E Ar from electron-rich arenes or via Cu-catalyzed/mediated cross-coupling from the corresponding diazonium salt or boronic acid. 20 The possibility to access these compounds from a myriad of diverse starting materials further supports the consideration of Ar-S-P(O)(OR) 2 as convergent linchpin reagents.…”

“…As noticed in previous works, Ar-SF 4 Cl compounds are highly reactive and their isolation is extremely challenging. Therefore, the yields were calculated by 19 F NMR spectroscopy by using an internal standard.…”

Catalysis with Palladium(I) Dimers

“… Heteroatom bond formation via dinuclear catalysis using thiolates or selenolates (top) [35] and phosphorothioates (bottom) [36] …”

“…Phosphorothioates ( − SP(=O)(OR) 2 ) were also demonstrated to be suitable coupling partners in Pd I ‐mediated bond formation, which enabled the first C−SP(=O)(OR) 2 coupling of aryl halides (Figure 8). By contrast, traditional Pd 0 /Pd II catalysis failed to deliver the phosphorothioate cross‐coupling product as a consequence of a prohibitively high activation barrier for the reductive elimination from the key Pd II intermediate and a lack of driving force [36] . Stoichiometric experiments with Pd I dimer 2 and 31 P NMR analysis clearly indicated the formation of a new Pd I dimer, demonstrating the competence of phosphorothioates to stabilize the Pd I scaffold and the altered driving force for exchange at Pd I .…”

A Robust Methodology for the Synthesis of Phosphorothioates, Phosphinothioates and Phosphonothioates

“…[11] The preparation of these compounds using PÀ S bond forming chemistry has been the subject of extensive study in recent years. Metal-catalysed coupling reactions employing copper, [12] rhodium, [13] palladium, [14] iron [15] and iridium [16] catalysts have been developed. Unfortunately, these routes are largely restricted to S-aryl products and are often low yielding or incompatible with S-alkyl targets.…”