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On the NH effect in ruthenium-catalysed hydrogenation of ketones: rational design of phosphine-amino-alcohol ligands for asymmetric hydrogenation of ketones.

The asymmetric hydrogenation of simple ketones, such as acetophenones, has become an important synthetic method as a result of the development of [RuCl2(diphosphine)ACHTUNGTRENNUNG(diamine)] catalysts by Noyori and co-workers. A large range of catalysts of this general type have now been prepared. Their reactivity is quite in contrast to simple MACHTUNGTRENNUNG(diphos)Xn salts that are barely active as catalysts for ketones that cannot chelate to the metal centre. The enhanced reactivity for reduction of simple ketones is proposed to be due to the “bifunctional mechanism” in which the ketone hydrogen bonds to the primary amine terminus of the ligand, activating it to attack by Ru–hydride and controlling stereoselectivity. There are reports that suggest these catalysts are not effective for certain ketones, such as bulky ketones (low reactivity), sterically similar aryl–aryl ketones (low selectivity), some ketones with strongly co-ordinating substituents (low reactivity), and alkyl–alkyl ketones (low selectivity) as well as a range of individual substrates that do not undergo asymmetric reduction readily. The discovery of structurally distinct, new classes of ketone hydrogenation catalyst that deviate from the [RuCl2(diphosphine)(di-primary-amine)] blueprint therefore might present one of the best opportunities to solve these problems; the importance of chiral secondary alcohols requires that methodology exists for every possible type of substrate in order to see this technology widely exploited in industry and more generally in synthesis. We have shown that Ru catalysts derived from P^N^NH2 ligands can hydrogenate some poorly reactive ketones with good enantioselectivity. The initial design of the catalyst envisaged hydrogenation of polar bonds facilitated by the primary amine terminus of the ligand in a co-ordination environment that is more accessible for bulky substrates relative to the Noyori catalysts. Rather than synthesising a very large library of new P^N^NH2 catalysts, we felt that an investigation of catalyst– structure activity relationships might throw up some leads for new catalysts, along with shedding light on some mechanistic issues, since it had not been possible to isolate the reaction intermediates in our previous studies. In this communication, we report some surprising findings from our kinetic experiments and the introduction of phosphino-amino-alcohol ligands for Ru-catalysed hydrogenation. The new achiral ligands, 1–3 can be prepared in one step from commercial starting materials and then converted into complexes of type [RuCl2ACHTUNGTRENNUNG(P^NR1N(R2)2ACHTUNGTRENNUNG(dmso)] by microwave-assisted complexation with [RuCl2ACHTUNGTRENNUNG(dmso)4] in THF at 120 8C (Scheme 1). Complexes 4–7 can be obtained pure by chromatography or recrystallisation and are easily handled in air. We carried out kinetic studies on the hydrogenation of a,a-dimethylpropiophenone, a substrate that was initially re-