The discovery and development of new chiral ligands for transition-metal complexes is critical for expanding the scope of catalytic asymmetric synthesis. [1] The P,N ligands are a highly successful class, [2] in which quinap [3] holds a special place because it displays unique reactivity and selectivity [4] (e.g. in hydroboration, [4a] alkyne addition, [4c] diboration [4d] and azomethine cycloaddition). [4e] Herein, we present new, readily available atropisomeric P,N ligands (pinap) [5] that are structurally similar to quinap and have parallel reactivity. They have the additional advantage, however, that, unlike quinap, they are conveniently prepared and resolved as well as easily amenable to structural and electronic modifications. We describe their synthesis, as well as applications in reactions involving Rh, Ag, and Cu catalysts, which demonstrate their utility. In the Cu-catalyzed coupling of acetylenes and imines they are superior to quinap and afford products with the highest enantioselectivity reported to date.
Quinap was developed by Brown and co-workers in 1993. [6] The six-step sequence for its synthesis includes a Pdcatalyzed coupling of 2-methoxy-1-naphthylboronic acid and 1-chloroisoquinoline to generate the biaryl scaffold. After introduction of the phosphinyl group, the resolution of the enantiomeric atropisomers is carried out as the final step by treatment of (AE )-quinap with a preformed chiral Pd complex prepared from (R)-or (S)-N,N-dimethyl-1-naphthalen-1ylethylamine. [7] Quinap is commercially available, but it is rather expensive. [8] The design and synthesis of related biaryl P,N ligands has been the focus of numerous research groups. [2a, c] However, resolution of the ligands has proven difficult and has inevitably involved fractional crystallization of diastereomeric Pd complexes. This has limited the extent of structural and electronic modification that can be examined with this scaffold.
Key to our ligand design is the use of a covalently bound chiral group, which facilitates resolution at any of the various steps of the ligand synthesis. As shown in Scheme 1, the core of the ligand is easily accessed by coupling 1,4-dichlorophthalazine with 2-naphthol to give 1 in 77 % yield. [9] Importantly, the use of the dichlorophthalazine allows both convenient construction of the biaryl unit and subsequent introduction of a chiral amine or an alcohol.
Treatment of 1 with (R)-phenylethanol afforded the diastereomeric aryl ethers (82 % yield, d.r. = 1:1), which were subsequently converted into triflates 2 (91 % yield). Ni-catalyzed coupling of 2 with HPPh 2 furnished ligands 3 a and 3 b in 70 % combined yield. The two atropisomeric diastereomers were separated at this stage either by chromatography on silica gel or, alternatively, by crystallization. [10] The absolute configuration of 3 a was shown to be R,M by Xray structure analysis. [11] The synthesis of a related structure incorporating (R)-(+)a-phenethylamine was carried out similarly (Scheme 1). Ligands 5 a and 5 b were isolated in 69 % yield over three [*] T.