Development of Ruthenium Catalysts for the Enantioselective Synthesis of P-Stereogenic Phosphines via Nucleophilic Phosphido Intermediates

Abstract

This work details the development of ruthenium(II) catalysts for the enantioselective alkylation of chiral racemic secondary phosphines. The reactions proceed through the intermediacy of nucleophilic phosphido species, which have low barriers to pyramidal inversion; this allows for a dynamic kinetic asymmetric alkylation. The initially discovered [((R)-iPr-PHOX)(2)Ru(H)][BPh(4)] (6) catalyst was found to be effective in the reaction with benzylic chlorides; moreover, the alkylation displayed an unusual temperature dependence. However, the limited scope of alkylation of 6 motivated further studies which led to the development of two complementary chiral mixed ligand Ru(II) catalysts of type [L(1)L(2)Ru(H)](+). These catalysts were derived from a combination of one chiral and one achiral ligand, where a synergistic interaction of the two ligands creates an effective asymmetric environment around the ruthenium center. The (R)-MeO-BiPHEP/dmpe (dmpe = 1,2-bis(dimethylphosphino)ethane) catalyst (10) was found to be effective for the asymmetric alkylation of benzylic chlorides, while the (R)-DIFLUORPHOS/dmpe catalyst (11) was optimal for the nucleophilic substitution of less activated alkyl bromides; the scope of the respective catalysts was also explored.

Preparation of phosphines through C–P bond formation

“…The procedure is mainly restricted to benzylic halides but also allowed for the asymmetric alkylation with ethyl bromide. All the phosphines were isolated as their air-stable phosphine–borane complexes 12c , 37 [59–60]. …”

Tert‐butyl‐dibromophosphane tBuPBr2—a new chemical synthesis and first spectroscopic characterization

“…The chiral ligands used in these reactions have continuously been developed for specific applications. Therefore, various P‐stereogenic chiral ligands are known, containing tri‐ or pentavalent phosphorus atoms . So far, many different and successful approaches regarding enantioselective syntheses and racemate resolution have been published …”

(R)- and (S)-2,2′-Bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl

“…A Ru-catalyzed synthesis of P-stereogenic phosphines via nucleophilic phosphide intermediates has been reported, where the optimal conditions for benzylic substitution were observed in the presence of MeOBIPHEP. 109 The use of a chiral ruthenium complex derived from MeOBIPHEP and 1,2bis(dimethylphosphino)ethane (dmpe) allowed the formation of chiral phosphine borane derivatives in good to excellent yields with moderate to good ee (eq 84). Asymmetric Mannich-type Reactions.…”