P‐Phenyl‐2,2,6,6‐tetramethylphosphorinan‐4‐ol: An Air‐Stable P,O‐Type Ligand for Palladium‐Mediated Cross‐Coupling Reactions

Abstract

A two-step entry to a chemically robust, hindered P,O-type phosphorinane-based ligand and its application toward Pd-

Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor

“…Given the sensitivity of the sulfonamidation reaction to residual copper in t -Bu-BrettPhos and the variability of copper levels in commercial batches of t -Bu-BrettPhos, the use of biaryl phosphines that do not require copper for synthesis was explored. A biaryl phosphacycle containing the same biaryl backbone as in t -Bu-BrettPhos was prepared according to the method shown in Scheme . − Lithium-halogen exchange of biaryl iodide 46 followed by the reaction of the resulting Li-biaryl species with diethyl chlorophosphate generated biaryl phosphonate 47 , which was reduced to the biaryl primary phosphine 48 in the presence of LiAlH 4 and TMSCl . Conjugate addition of the primary phosphine to phorone formed the phosphacycle 49 .…”

Pd-Catalyzed Cross-Coupling Reactions Promoted by Biaryl Phosphorinane Ligands

“…Despite significant advances made in the past two decades, new biaryl phosphanes continue to be developed in both academic and industrial groups in order to expand the repertoire of coupling partners and to enable synthesis of progressively more complex molecules. − The availability of structurally diverse phosphanes is essential because extensive ligand screening is often required for the synthesis of highly functionalized molecules and for large-scale applications. ,− While a large number of phosphanes prepared from combinations of biaryl backbones and various alkyl and aryl substituents on phosphorus are known, biaryl phosphacycles as ligands for Pd-catalyzed cross-coupling reactions have not been explored in detail. − We envisioned that the phosphorinanes derived from the privileged biaryl backbones (Scheme ) would form ligands with steric and electronic properties distinct from those of the known biaryl phosphanes and will help further advance the utility of Pd-catalyzed transformations. − Both academic and industrial chemists are continuously faced with cross-coupling reactions of ever-increasing complexity. The discovery and development of a newer family of phosphine ligands, capable of catalyzing challenging reactions, will be of great value while optimizing these reactions.…”

“…We developed a synthetic strategy based on double conjugate addition of primary biaryl phosphines to commercially available 2,6-dimethylhepta-2,5-dien-4-one (phorone), followed by ketalization of the ketone (Scheme ). Following this strategy several biaryl phosphorinanes − , with substituents adjacent to phosphorus resembling the di- t -butyl group were accessed, as exemplified by VincePhos (eq ). ,, VincePhos was successfully used as a ligand for the sulfonamidation reaction to prepare dasabuvir on a multikilogram scale …”

Access to 2′-Substituted Binaphthyl Monoalcohols via Complementary Nickel-Catalyzed Kumada Coupling Reactions under Mild Conditions: Key Role of a P,O Ligand

“…43 McNulty previously proposed that 7 stabilizes reactive Pd 0 species through this type of conformational flip. 32,33 Retardation of the transmetalation step due to bidentate binding and/or the stronger donicity of 7 may outweigh the improved reductive elimination rates in some cases, potentially explaining why poorer results were obtained with 7 versus dppe when electron-poor Grignard reagents were employed. 44 The complementary Kumada coupling protocols presented herein expand the number of accessible 2′-substituted binaphthyl alcohols while also improving upon existing routes to these chiral synthons.…”

“…These disappointing results prompted us to examine phosphinan-4-ol 7 as a ligand in the test reaction. Ligand 7 and variants were recently shown by McNulty and co-workers to be effective for the synthesis of electron-rich and sterically hindered biaryls by palladium-catalyzed Suzuki–Miyaura coupling. , The use of phosphinan-4-ol ligands in Ni-catalyzed coupling processes has not been previously reported, but reports of room-temperature Kumada couplings with nickel − or palladium ,− complexes of other potentially bifunctional P,O-type ligands encouraged us to try 7 . We were gratified to find that a catalyst system comprising 5 mol % NiCl 2 in combination with 10 mol % 7 provided binaphthyl alcohol 3a in 79% yield after 60 min at 25 °C (entry 3).…”