Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

Abstract

The asymmetric hydrogenation of 2,2,2‐trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well‐defined chloride‐bridged dinuclear rhodium(III) complex bearing Josiphos‐type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2‐trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2‐phenyl‐3‐(haloacetyl)‐indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.

Chemo‐ and Stereoselective Synthesis of Fluorinated Amino Alcohols through One‐pot Reactions using Alcohol Dehydrogenases and Amine Transaminases

“…Previous metal‐catalyzed enantioselective reduction studies of diketone 1 a allowed the chemoselective formation of the corresponding hydroxy ketone ( S )‐ 2 a through asymmetric hydrogenation of the trifluoroacetophenone moiety using chloride‐bridged dinuclear rhodium(III) complexes bearing Josiphos‐type diphosphine ligands, [17] while its antipode ( R )‐ 2 a was synthesized by using diethylzinc as the β‐hydrogen donor and a phosphinamide chiral ligand [18] …”

“…Previous metal-catalyzed enantioselective reduction studies of diketone 1 a allowed the chemoselective formation of the corresponding hydroxy ketone (S)-2 a through asymmetric hydrogenation of the trifluoroacetophenone moiety using chloride-bridged dinuclear rhodium(III) complexes bearing Josiphos-type diphosphine ligands, [17] while its antipode (R)-2 a was synthesized by using diethylzinc as the β-hydrogen donor and a phosphinamide chiral ligand. [18] Inspired by the exquisite reactivity display by ADHs towards the bioreduction of prochiral methyl/ trifluoromethyl diketones, [19] the synthesis of para-, meta-and ortho-substituted aryl diketones 1 a-c possessing the acetyl and trifluoroacetyl groups was undertaken, starting from the corresponding 2'-, 3'-or 4'-bromoacetophenones (see the Supplementary Information).…”

Having Fun (and Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands.

“…Among the many contributions of Antonio ’s group to the chemistry of ferrocenyl based ligands we would like to select work which applied his interest in fluorine chemistry to Josiphos. In a series of articles, they described the synthesis, characterization and catalytic application of trifluoromethyl derivatives of Josiphos with an additional stereogenic center [13,14] . The corresponding Rh and Ir complexes achieve remarkable results for the enantioselective hydrogenation of various C=X functions, especially of perfluoroalkyl aryl ketones ( Figure 5).…”

“…In a series of articles, they described the synthesis, characterization and catalytic application of trifluoromethyl derivatives of Josiphos with an additional stereogenic center. [13,14] The corresponding Rh and Ir complexes achieve remarkable results for the enantioselective hydrogenation of various C=X functions, especially of perfluoroalkyl aryl ketones ( Figure 5).…”

Copper-Catalyzed Regio- and Enantioselective Hydroallylation of 1-Trifluoromethylalkenes: Effect of Crown Ether

“…However, in comparison to Ar-CF 3 and alkenyl-CF 3 , the synthesis of C sp 3 -CF 3 molecules, in particular, their enantioenriched forms, still remains underdeveloped. While several chiral α-CF 3 alcohols/amines and related α-CF 3 carbonyls are relatively easily prepared by the stereoselective trifluoromethylation of carbonyls/imines or reduction and addition reactions of trifluoromethylated carbonyl/imines, the construction of the point chirality at a position α to CF 3 without any proximal heteroatoms is a formidable challenge. Limited successful examples include the Ni-catalyzed enantioconvergent cross-coupling reaction of racemic CF 3 -substituted secondary alkyl halides with organometallic reagents (Scheme a), the Pd-catalyzed enantioselective three-component coupling reaction of gem -difluoroalkenes, aryl halides, and AgF (Scheme b), and the Pd-catalyzed asymmetric allylic substitution of allylic fluorides with trifluoromethylsilanes (Scheme c) .…”