Enantioselective hydrogen transfer

The catalysts for transfer hydrogenations are usually late transition metal complexes with tertiary phosphine ligands or bidentate nitrogen ligands, and the donors are usually organic compounds whose oxidation potential is sufficiently low to tolerate hydrogen transfer under mild conditions. Suitable donors are secondary alcohols such isopropanol. This alcohol is the most convenient since it is stable, non-toxic, environmentally friendly, easy to handle (bp 82°C), inexpensive and dissolves many organic compounds. 

The most striking feature of this mechanism is that, in contrast to the currently accepted catalytic mechanisms, it does not require the formation of 

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Keywords Iridium, Enantioselective, Hydrogenation, Transfer hydrogenation, Allylation, Vinylation... 

Scheme 5 Enantioselective hydrogen -transfer reduction of acetophenone.

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

Inspired by the visionary paper of Whitesides, we adapted and extended the concept of artificial metalloenzymes (or hybrid catalysts) based on the biotin-avidin technology to enantioselective hydrogenation, transfer hydrogenation, and aUyhc alkylation reactions, which are summarized herein. 

Aqueous ammonia was found to increase the yield of the alcohol but not of the amine in the highly enantioselective hydrogen-transfer reductive amination of acetophenone, as recently described by Kadyrov et al. [18]. AU these reactions were performed in methanol/NHj with [((Kj-tol-binapjRuClJ as catalyst with a best asymmetric induction of 98% ee. 

Scheme 7.18 Model reaction for enantioselective hydrogen transfer.

Table 7.12 Results of enantioselective hydrogen transfer to acetophenone (Scheme 7.18).

Sibi and co-workers explored the power of the radical chemistry through a terminal proton abstraction to achieve the enantioselective proton transfer (Scheme 31.31). Indeed, the formation of a bidentate complex by coordination of a chiral Mg complex to a Michael acceptor bearing an achiral template can promote the 1,4-radical addition followed by an enantioselective hydrogen transfer. This strategy is believed to form a bidentade complex aimed to control the enolate geometry, which is a key point of the enantiodetermining step of the reaction. 

The first metal-free organocatalytic enantioselective hydrogen transfer involving unprotected ort/zo-hydroxybenzophenone N-H ketimines (317) using the chiral phosphoric acid catalyst (300) and a the Hantzsch ester... 

L = P(CH3)3 or CO, oxidatively add arene and alkane carbon—hydrogen bonds (181,182). Catalytic dehydrogenation of alkanes (183) and carbonylation of bensene (184) has also been observed. Iridium compounds have also been shown to catalyse hydrogenation (185) and isomerisation of unsaturated alkanes (186), hydrogen-transfer reactions, and enantioselective hydrogenation of ketones (187) and imines (188). 

The hydrogen transfer reaction (HTR), a chemical redox process in which a substrate is reduced by an hydrogen donor, is generally catalysed by an organometallic complex [72]. Isopropanol is often used for this purpose since it can also act as the reaction solvent. Moreover the oxidation product, acetone, is easily removed from the reaction media (Scheme 14). The use of chiral ligands in the catalyst complex affords enantioselective ketone reductions [73, 74]. 

The modifier in these cases seems to generate enantioselective sites at the metal surface and helps the molecule to adsorb in a preferred fashion so that the formation of only one stereo- product is possible. There are several milestones that have contributed to this state-of-the-art technology. Discovery of Wilkinson s catalyst led to the feasibility of asymmetric hydrogen transfer with the aid of an optically active Wilkinson-type catalyst for L-DOPA (Monsanto s anti-Parkinson disease drug) synthesis (Eqn. (21)). 

In the same study, these authors have prepared another series of amino-sulf(ox)ide ligands based on the (Nor)ephedrine and 2-aminodiphenylethanol skeletons, bearing two chiral centres in the carbon backbone.Their application to the iridium-catalysed hydrogen-transfer reduction of acetophenone generally gave better yields, but the enantioselectivity never exceeded 65% ee (Scheme 9.4). 

In another context, chiral thioimidazolidine ligands have been successfully applied to the ruthenium-catalysed asymmetric hydrogen transfer of several aryl ketones by Kim et al., furnishing the corresponding chiral alcohols with high yields and enantioselectivities of up to 77% ee (Scheme 9.12). ... 

Finally, the use of S/P ligands derived from (i )-binaphthol has been considered by Gladiali et al. in the asymmetric rhodium-catalysed hydrogen-transfer reduction of acetophenone performed in the presence of i-PrOH as the hydrogen donor.It was noted that racemisation occurred when the reaction time increased and consequently the corresponding alcohol was obtained in only low enantioselectivities (< 5% ee) as shown in Scheme 9.21. Similar results were more recently reported by these authors by using iridium combined with the same ligands. ... 

On the other hand a direct hydrogen transfer through a Meerwein-Ponndorf mechanism, involving coordination of both the donor alcohol and the ketone to the copper site may also be considered. In this case, by using alcohols other than 2-propanol, we could expect some difference in stereochemistry. This would also imply the possibility of carrying out the enantioselective reduction of a prochiral ketone with a chiral alcohol as donor. 

Since the initial work of Onto et al. (1) a considerable amount of work has been performed to improve our understanding of the enantioselective hydrogenation of activated ketones over cinchona-modified Pt/Al203 (2, 3). Moderate to low dispersed Pt on alumina catalysts have been described as the catalysts of choice and pre-reducing them in hydrogen at 300-400°C typically improves their performance (3, 4). Recent studies have questioned the need for moderate to low dispersed Pt, since colloidal catalysts with Pt crystal sizes of <2 nm have also been found to be effective (3). A key role is ascribed to the effects of the catalyst support structure and the presence of reducible residues on the catalytic surface. Support structures that avoid mass transfer limitations and the removal of reducible residues obviously improve the catalyst performance. This work shows that creating a catalyst on an open porous support without a large concentration of reducible residues on the Pt surface not only leads to enhanced activity and ee, but also reduces the need for the pretreatment step. One factor... 

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