P-Trifluoromethyl ligands derived from Josiphos in the Ir-catalysed hydrogenation of 3,4-dihydroisoquinoline hydrochlorides

Abstract

The synthesis of mono P-trifluoromethyl and therefore P-stereogenic Xyliphos-derived ligands 5 and their application in the Ir-catalyzed enantioselective hydrogenation of 1-substituted 3,4-dihydroisoquinolinium species (DHIQ) are reported. The ligands were prepared following previous procedures involving the reaction of a bistrifluoromethylphosphine with lithiated (R)-Ugi amine 1. Chloroiridium(I) cyclooctadiene precatalysts containing these new partially electron-poor ligands 9 were found to be poorly active in the hydrogenation of free 1-phenyl-3,4-dihydroisoquinoline 12a. However, the corresponding hydrochloride 12a·HCl was smoothly reduced at 55–60 °C and 100 bar hydrogen pressure. The (S_P)-configured ligand (S_P)-5 yielded significantly higher enantioselectivity in hydrogenation experiments than its P-stereoisomeric counterpart (R_P)-5. These new ligands were subsequently applied in the hydrogenation of a series of different 1-substituted 3,4-DHIQ chlorides 12a–l·HCl. Good to excellent enantioselectivity was observed for substrates bearing relatively large substituents in position 1, reaching 96% ee for 1-Ph-DHIQ chloride 12a·HCl without the help of any additives. Furthermore, an interesting counter ion effect was found with chloride being the best and hexafluorophosphate being very detrimental to enantioselectivity.