Amino Acid Derived Chiral Aminobenzimidazole Manganese Catalysts for Asymmetric Transfer Hydrogenation of Ketones

Abstract

A series of Mn(I) catalysts with chiral bidentate benzimidazoles derived from easily available amino acids has been developed. These types of phosphine-free chiral Mn catalysts demonstrate high activity and enantioselectivity in asymmetric transfer hydrogenation (ATH) for a broad range of ketone substrates. A bulkier substrate, such as 2,6-dichloro-3fluoroacetophenone, can be converted into the drug intermediate alcohol with up to 90% yield and 92% ee (e.g., crizotinib). On the basis of experimental and DFT studies, a possible mechanism for this Mn-catalyzed ATH is also proposed. DFT calculations further render a plausible model for enantiocontrol in ketone hydrogenation, in which the π−π stacking interaction between the catalyst and the substrate plays an important role.

Manganese-catalyzed hydrogenation, dehydrogenation, and hydroelementation reactions

“…Recently, Sun synthesized a series of chiral catalysts Mn67 and Mn68 having benzimidazole-amine ligand system synthesized from chiral amino acid precursors (Table 9, entry 8). 171 A range of ketones were asymmetrically hydrogenated with good to excellent yields and moderate ee. Ketones with bulky The TONs were calculated employing the formula TON = percent yield of product/mol percent of the catalyst.…”

Iridium-Catalyzed Asymmetric Transfer Hydrogenation of Quinolines in Biphasic Systems or Water

“…A solution of L2 NH -Boc (303 mg, 1 mmol) and benzyl bromide (257 mg, 1.5 mmol) in dimethylformamide (DMF) (3 mL) was treated at room temperature with K 2 CO 3 (691 mg, 5 mmol). After 24 h, the reaction mixture was extracted with CH 2 Cl 2 (10 mL × 3) and washed with brine (5 mL).…”

“…The aminobenzimidazole ligands L1, L3, L4, L6, and L7 were prepared according to the reported method from the corresponding Bocprotected amino acids. 23 The substrates 1g, 25a 1k, 25a 1l, 25b 1m, 9b 1n, 25c and 1o 25d were prepared according to the reported procedures. Other substrates were purchased from commercial sources.…”

“…Based on the aforementioned work, to realize Ir-catalyzed ATH of quinolines in water, a suitable chiral nitrogen ligand beyond typical DPEN is necessary. More recently, we disclosed a series of new manganese catalysts with chiral aminobenzimidazole ligands derived from amino acids to exhibit high enantioselectivity in the phosphine-free ATH of ketones . Encouraged by these results, we envision that these aminobenzimidazole ligands can be used in Ir-catalyzed ATH in water (Scheme b).…”

“…More recently, we disclosed a series of new manganese catalysts with chiral aminobenzimidazole ligands derived from amino acids to exhibit high enantioselectivity in the phosphine-free ATH of ketones. 23 Encouraged by these results, we envision that these aminobenzimidazole ligands can be used in Ir-catalyzed ATH in water (Scheme 2b). Herein, we report the ATH of various quinoline derivatives with chiral aminobenzimidazole Ir catalysts in undegassed biphasic systems or neat water, employing formic acid as the hydrogen source.…”