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

Abstract

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 NaBH 4 at 25 8C, with a substrate-to-catalyst molar ratio (S/ C) of 2000 under 50 atm of H 2 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 H 2 , 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.

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

“…Some substrates bearing strongly electron withdrawing groups (−CF 3 , −CN) underwent the ATH reaction with good enantioselectivities and yields ( 2j , 91% yield and 86% ee). It is noteworthy that the polysubstituted (2,6-disubstituted acetophenone) ketones were well tolerated to give the chiral alcohols in good enantioselectivities ( 2m – o ) at 80 °C for 24 h. Among them, in particular, 1-(2,6-dichloro-3-fluorophenyl)­ethanol is a key intermediate for the building of crizotinib, for the treatment of advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. , In 2017, Clarke and co-workers investigated the AH of the corresponding ketone by using a PNN manganese catalyst; inspiringly, excellent conversion and 72% ee were afforded . Further elaboration with an electron-rich phosphine moiety led to an 82% ee .…”

Kinetic and Product Study of the S‐oxidation vs HAT Chemoselectivity in Reactions Promoted by Nonheme Iron(IV)‐oxo Complex/NHPI Mediator System

“…Substrates 1 – 12, 13 are commercially available. Aryl sulfide 14 was synthetized following a literature procedure [59] . All the products are commercially available except for 1‐(4‐(methylsulfinyl)phenyl)ethan‐1‐ol and (4‐(methylsulfinyl)phenyl)methanol.…”

“…1‐(4‐(methylsulfinyl)phenyl)ethan‐1‐ol was synthetized by S‐oxidation of 4‐methylthioacetophenone with NaIO 4 followed by reduction of the carbonyl group with NaBH 4. [59–61] (4‐(methylsulfinyl)phenyl)methanol was prepared by S‐oxidation of 4‐methylthiobenzyl alcohol ( 13 ) with NaIO 4 according to the literature [62] …”

“…1-(4-(methylsulfinyl)phenyl)ethan-1-ol was synthetized by S-oxidation of 4methylthioacetophenone with NaIO 4 followed by reduction of the carbonyl group with NaBH 4. [59][60][61] (4-(methylsulfinyl)phenyl)methanol was prepared by S-oxidation of 4-methylthiobenzyl alcohol (13) with NaIO 4 according to the literature. [62] Kinetic studies of the oxidation of compounds 9, 10, 12-14 by [(N4Py)Fe IV (O)] 2 + : Spectrophotometric measurements were performed on a single beam UV-Vis spectrophotometer using a quartz cuvette (10 mm path length) at 25 °C.…”

Ruthenium-catalyzed asymmetric hydrogenation of aromatic and heteroaromatic ketones using cinchona alkaloid-derived NNP ligands

“…Ruthenium [47][48][49][50][51] was chosen owing to its superior performances in terms of low price, selectivity and activity. Takeshi Ohkuma, 52 Hanmin Huang 53,54 and Johannes G. de Vries 55 all successfully used ruthenium catalysts for asymmetric hydrogenation of ketones. Admittedly, there is a continuing interest in the development of cheaper, simpler and more efficient catalysts for the asymmetric hydrogenation of ketones under mild conditions to access corresponding secondary alcohols.…”