Transfer Hydrogenation - Organocatalytic Transfer Hydrogenation

Organocatalytic Transfer Hydrogenation

Organocatalytic transfer hydrogenation has been described by the group of List in 2004 in a system with a Hantzsch ester as proton donor and an amine catalyst:

In this particular reaction the substrate is an α,β-unsaturated carbonyl compound. The proton donor is oxidized to the pyridine form and resembles the biochemically relevant coenzyme NADH. In the catalytic cycle for this reaction the amine and the aldehyde first form an iminium ion, then proton transfer is followed by hydrolysis of the iminium bond regenerating the catalyst. By adopting a chiral imidazolidinone MacMillan organocatalyst an enantioselectivity of 81% ee was obtained:

The group of MacMillan independently published a very similar asymmetric reaction in 2005:

In an interesting case of stereoconvergence, both the E-isomer and the Z-isomer in this reaction yield the (S)-enantiomer.

Extending the scope of this reaction towards ketones or rather enones requires fine tuning of the catalyst (add a benzyl group and replace the t-butyl group by a furan) and of the Hantzsch ester (add more bulky t-butyl groups):

With a different organocatalyst altogether, hydrogenation can also be accomplished for imines. In one particular reaction the catalysts is a BINOL based phosphoric acid, the substrate a quinoline and the product a chiral tetradehydroquinoline in a 1,4-addition, isomerization and 1,2-addition cascade reaction:

The first step in this reaction is protonation of the quinoline nitrogen atom by the phosphoric acid forming a transient chiral iminium ion. It is noted that with most traditional metal based catalysts, hydrogenation of aromatic or heteroaromatic substrates tend to fail.