Noriyuki Utsumi

Asymmetric Hydrogenation of Alkynyl Ketones with the η6-Arene/TsDPEN–Ruthenium(II) Catalyst

Enantioselective hydrogenation of alkynyl ketones catalyzed by Ru(OTf)(TsDPEN)(η(6)-p-cymene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) affords the propargylic alcohols in up to 97% ee. The alkynyl moieties are left intact in most cases. The reaction can be conducted with a substrate-to-catalyst molar ratio as high as 5000 under 10 atm of H2. The mode of enantioselection is elucidated with the transition state models directed by the CH/π attractive interaction between the substrate and the catalytic species.

Chiral eta(6)-Arene/N-Tosylethylenediamine-Ruthenium(II) Complexes: Solution Behavior and Catalytic Activity for Asymmetric Hydrogenation

Aromatic ketones are enantioseletively hydrogenated in alcohols containing [RuX{(S,S)-Tsdpen}(eta(6)-p-cymene)] (Tsdpen=TsNCH(C(6)H(5))CH(C(6)H(5))NH(2); X=TfO, Cl) as precatalysts. The corresponding Ru hydride (X=H) acts as a reducing species. The solution structures and complete spectral assignment of these complexes have been determined using 2D NMR ((1)H-(1)H DQF-COSY, (1)H-(13)C HMQC, (1)H-(15)N HSQC, and (1)H-(19)F HOESY). Depending on the nature of the solvents and conditions, the precatalysts exist as a covalently bound complex, tight ion pair of [Ru(+)(Tsdpen)(cymene)] and X(-), solvent-separated ion pair, or discrete free ions. Solvent effects on the NH(2) chemical shifts of the Ru complexes and the hydrodynamic radius and volume of the Ru(+) and TfO(-) ions elucidate the process of precatalyst activation for hydrogenation. Most notably, the Ru triflate possessing a high ionizability, substantiated by cyclic voltammetry, exists in alcoholic solvents largely as a solvent-separated ion pair and/or free ions. Accordingly, its diffusion-derived data in CD(3)OD reflect the independent motion of [Ru(+)(Tsdpen)(cymene)] and TfO(-). In CDCl(3), the complex largely retains the covalent structure showing similar diffusion data for the cation and anion. The Ru triflate and chloride show similar but distinct solution behavior in various solvents. Conductivity measurements and catalytic behavior demonstrate that both complexes ionize in CH(3)OH to generate a common [Ru(+)(Tsdpen)(cymene)] and X(-), although the extent is significantly greater for X=TfO(-). The activation of [RuX(Tsdpen)(cymene)] during catalytic hydrogenation in alcoholic solvent occurs by simple ionization to generate [Ru(+)(Tsdpen)(cymene)]. The catalytic activity is thus significantly influenced by the reaction conditions.

Asymmetric Hydrogenation of Aromatic Heterocyclic Ketones Catalyzed by the MsDPEN–Cp*Ir(III) Complex

Asymmetric hydrogenation of aromatic heterocyclic ketones catalyzed by Cp*Ir(OTf)(Msdpen) (MsDPEN = N-(methanesulfonyl)-1,2-diphenylethylenediamine) affords the heterocyclic alcohols in 93% to >99% ee. The reaction is conducted in a methanolic solution with a substrate-to-catalyst molar ratio of 200-5000 under 15 atm of H 2 . The heterocyclic rings of substrates are left intact.

Asymmetric Hydrogenation of Polysubstituted Aromatic Ketones Catalyzed by the DIPSkewphos/PICA Derivative–Ruthenium(II) Complexes

The DIPSkewphos/PICA derivative‐Ru(II) complexes catalyzed asymmetric hydrogenation of significantly sterically hindered 2’,3’,4’,5’,6’‐pentamethylacetophenone, which was not reduced with NaBH4 at 25 °C, with a substrate‐to‐catalyst molar ratio (S/C) of 2000 under 50 atm of H2 in a base‐containing 2‐propanol to afford the alcohol in 99 % ee quantitatively. A series of polysubstituted aromatic ketones was smoothly reacted with an S/C of 300–10,000 under 10–50 atm of H2, yielding the alcoholic products in up to 99 % ee. The catalyst system achieved an industrial‐scale (50 kg) hydrogenation of 2’,6’‐dichloro‐3’‐fluoroacetophenone, affording the alcohol in 96 % isolated yield and in 98 % ee. The obtained alcoholic product is known as a key intermediate for the synthesis of the medicine crizotinib.