Catalytic Asymmetric Transfer Hydrogenation

ohn Blacker recently described Avecia’s catalytic transfer hydrogenation technology CATHy TM) for the asymmetric reduction of ketones and imines to secondary alcohols and amines respectively.  A generic catalyst structure is shown below:

M is normally rhodium, but can be iridium or ruthenium.  The cyclopentadienyl unit is usually pentamethylcyclopentadienyl and the chlorine is derived from the metal precursor, e.g. bis(pentamethylcyclo-pentadienyl)dirhodium tetrachloride. The ligand R1CH(X)CH(N)R2 is typically a chiral aminoalcohol or monotosylated diamine of the type shown below.:

where the aryl group can be any of the groups shown in the following box.  So a family of catalysts has been developed which can be prepared by reacting the appropriate metal derivative with either an aminoalcohol ligand and sodium isopropoxide or with a mono-N-sulphonyldiamine ligand without added base.  Two transfer hydrogenation reagents can be used – isopropanol or triethylamine / formic acid (TEAF, molar ratio 2:5).  Isopropanol is the reagent for catalysts with aminoalcohol ligands while the triethylamine / formic acid system works best with catalysts containing mono-N-sulphonyldiamine ligands.  The advantage of the triethylamine / formic acid (TEAF) is that the reaction is irreversible as the by-product, carbon dioxide evaporates out of the reaction mixture.  The isopropanol reaction on the other hand generates acetone, which if it is not distilled out of the reaction mixture can act as a hydrogen acceptor in the reverse reaction.

Both systems tolerate a wide variety of functional groups in the substrates, such as halides, thio, alkenes, amides, acids, esters and nitriles.  Most ketones are reduced in good yield and >85% ee although aliphatic ketones work best when there are other functional groups present which can take part in secondary binding to the catalyst.  A variety of ketimines can be reduced with this system – cyclic imines give secondary amines, while benzylimines and phosphinylimines both give primary amines.  Phosphinylimines are preferred as they are more stable, being less susceptible to tautomerisation, and they are more easily reduced.  Phosphinylimines are readily prepared by reaction of the appropriate ketone with diphenylphosphinyl amine, which is commercially available (price ~£25/kg) or can be synthesized by reacting diphenylphosphinic chloride with ammonia as shown in the next scheme.

In this case the amine is produced in 99%ee.  Some other model primary amine systems are given below

and some secondary and tertiary amines are shown in the next box.

When the TEAF reduction system is scaled up the reaction does not proceed to completion unless the gaseous by-products are disengaged.  The desired reaction – the conversion of formic acid in to carbon dioxide whilst reducing the imine to the amine is accompanied by a side reaction in which the formic acid is converted in to water and carbon monoxide (CO).  On larger scales the CO complexes with the catalyst and deactivates.  Good agitation and a nitrogen sparge are required to ensure effective gas disengagement.

This work was presented at Scientific Update’s Oxidation and Reduction Conference held in London on October 28th and 29th, 2002.