The Importance of Alkali Cations in the [{RuCl₂(p‐cymene)}₂]–Pseudo‐dipeptide‐Catalyzed Enantioselective Transfer Hydrogenation of Ketones

Abstract

We studied the role of alkali cations in the [{RuCl2(p-cymene)}2]-pseudo-dipeptide-catalyzed enantioselective transfer hydrogenation of ketones with isopropanol. Lithium salts were shown to increase the enantioselectivity of the reaction when iPrONa or iPrOK was used as the base. Similar transfer-hydrogenation systems that employ chiral amino alcohol or monotosylated diamine ligands are not affected by the addition of lithium salts. These observations have led us to propose that an alternative reaction mechanism operates in pseudo-dipeptide-based systems, in which the alkali cation is an important player in the ligand-assisted hydrogen-transfer step. DFT calculations of the proposed transition-state (TS) models involving different cations (Li+, Na+, and K+) confirm a considerable loosening of the TS with larger cations. This loosening may be responsible for the fewer interactions between the substrate and the catalytic complex, leading to lower enantiodifferentiation. This mechanistic hypothesis has found additional experimental support; the low ee obtained with [BnNMe3]OH (a large cation) as base can be dramatically improved by introducing lithium cations into the system. Also, the complexation of Na+, K+, and Li+ cations by the addition of [15]crown-5 and [18]crown-6 ethers and cryptand 2.1.1 (which selectively bind to these cations and, thus, increase their bulkiness), respectively, to the reaction mixture led to a significant drop in the enantioselectivity of the reaction. The lithium effect has proved useful for enhancing the reduction of different aromatic and heteroaromatic ketones.

Ruthenium‐Catalyzed Tandem‐Isomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols

“…The ATH of aryl alkyl ketones in 2‐propanol was positively influenced by the addition of catalytic amounts of lithium chloride, and mechanistic investigations strongly support a hydride transfer via the bimetallic 6‐membered transition state shown in Figure 1 b 31. 32…”

“…[26][27][28][29][30] The ATH of aryl alkyl ketones in 2-propanol was positively influenced by the addition of catalytic amounts of lithium chloride, and mechanistic investigations strongly support a hydride transfer via the bimetallic 6-membered transition state shown in Figure 1 b. [31,32] The combination of the isomerization of allylic alcohols with a consecutive ketone reduction would allow for the formation of saturated alcohols in a straightforward manner as depicted in Scheme 1. The same type of compounds can, in principle, be reached by direct hydrogenation of the allylic alcohol; however, the sensitivity of the substrate being both allylic and ben- zylic would often lead to a nonselective reaction.…”

Highly Diastereo‐ and Enantioselective Palladium‐Catalyzed [3+2] Cycloaddition of Vinyl Aziridines and α,β‐Unsaturated Ketones

“…Thus, the SIOCPhox ligand developed in our group, with which high diastereo-and enantioselectivities were obtained in the palladium-catalyzed asymmetric allylic alkylation of different nucleophiles, was tested. [8] The absence of KBr led to a sharp decrease of diastereoselectivity and a little reduction of enantioselectivity while the yield was still high (entry 6 versus entry 2). However, the d.r.…”

Oxidation and Reduction

“…An alternative reaction mechanism for the pseudo-dipeptide-based systems, in which the alkali metal cation is an important player in the ligand-assisted hydrogen-transfer step, has been proposed. 370 Asymmetric transfer hydrogenation of cyclic imines and iminiums in water was carried out in high yields and enantioselectivities with sodium formate as the hydroee gen source and CTAB as an additive, catalysed by a water-soluble and recyclable ruthenium(II) complex of the ligand (23). 371 A class of simple, modular, and highly efficient α-amino acid amides ligands for Ruand Rh-catalysed asymmetric transfer hydrogenation of aromatic ketones in propan-2ee ol has been developed.…”