CATHy catalysts

Two technical applications of C = N-X substrates have been reported. Noyori s Ru-PP-NN catalyst system was successfully applied in a feasibility study by Dow Chirotech for the hydrogenation of a sulfonyl amidine [77], while Avecia showed the commercial viability of its CATHy catalyst based on a pentamethyl cyclopentadienyl Rh complex for the reduction of phosphinyl imines [78] (Fig. 34.11). 

The standard ruthenium arene and CATHy catalysts are insoluble in water, but are nevertheless stable in the presence of water. Reactions in the I PA system can be carried out in mixtures of isopropanol and water the net effect is a lower rate due to dilution of the hydrogen donor. The use of formate salts in water, with CATHy or other transfer hydrogenation catalysts dissolved in a second immiscible phase was shown to work well with a number of substrates and in some cases to improved reaction rates [34]. The use of water as reaction solvent will be discussed in more detail in Section 35.5. 

For the ruthenium arene and CATHy catalysts, the mechanism has been studied in some detail. An outline mechanism for the reaction is illustrated in Figure 35.4. 

Alcohols will serve as hydrogen donors for the reduction of ketones and imi-nium salts, but not imines. Isopropanol is frequently used, and during the process is oxidized into acetone. The reaction is reversible and the products are in equilibrium with the starting materials. To enhance formation of the product, isopropanol is used in large excess and conveniently becomes the solvent. Initially, the reaction is controlled kinetically and the selectivity is high. As the concentration of the product and acetone increase, the rate of the reverse reaction also increases, and the ratio of enantiomers comes under thermodynamic control, with the result that the optical purity of the product falls. The rhodium and iridium CATHy catalysts are more active than the ruthenium arenes not only in the forward transfer hydrogenation but also in the reverse dehydrogenation. As a consequence, the optical purity of the product can fall faster with the... 

Enantioselective Michael reactions have been achieved using both the Rh-based CATHy catalysts [89 a] and the Ru-based Noyori catalysts [89 b]. 

Typically, heterogeneous transfer hydrogenations are carried out at higher temperatures. The Noyori-Ikariya ruthenium arene catalysts are stable up to temperatures around 80 °C, whilst the rhodium and iridium CATHy catalysts are... 

Catalytic asymmetric transfer hydrogenation is an efficient method for producing optically active alcohols and amines. Analysis of launched and development pharmaceuticals show that these types of chiral centers occur most frequently, so this technology is proving particularly valuable. The chapter will describe the background, development, and application of asymmetric transfer hydrogenation, with particular emphasis on Avecia s proprietary CATHy catalysts. 

The CATHy catalysts, like their ruthenium analogues are also active in the reduction of ketones and imines using the formate system [5], Wills has published on the reduction of ketones [9], and Baker on the reduction of imines [6], The development of this process for large-scale use has proven more complex and this will be described elsewhere in this chapter. 

Fig. 1 Formation of a CATHy catalyst and proposed catalytic cycle.

Since the CATHy catalysts involve precious metals, their activity is a key to providing an economic process. In our experience, for the average pharmaceutical intermediate, a substrate to catalyst ratio of <5000/1 is sufficient that the catalyst contribution is negligible, and these are regularly achieved. Consequently there... 

Rather surprisingly alcohols are poor at reducing imines, yet TEAF works well. During our studies we rationalized that the TEAF system was sufficiently acidic (pH approximately 4) to protonate the imine (pK l approximately 6) and that it was an iminium that was reduced to an ammonium salt [14]. When an iminium was used in the I PA system, it was reduced albeit with a low rate and moderate enan-tioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Hydrogen will not reduce ketones or imines using the CATHy catalysts, but hydrides such as sodium borohydride have been shown to work. 

The CATHy catalysts are best used below 40 °C, above this temperature we have observed signs of decomposition. In the I PA system, preventing the back-re-action depends on how efficiently acetone is distilled. Normally this would be best done at around 80 °C, the boiling point of isopropanol, but an optimal performance of the catalyst requires ambient temperature or less, and reduced pressure. Whilst acetone can be fractionally distilled, it is simpler to distil the mixture with isopropanol and to maintain constant volume by continuously charging with fresh solvent. In the TEAF system the reaction is normally operated at ambient temperature. Operating at lower temperatures can improve the enantiomeric excess slightly but gives lower rates, for example with 4-fluoroacetophenone the results described in Tab. 3 were achieved. 

Avecia undertakes screening and development programs and are ideally positioned to manufacture at the small- and large-scale if this is required [17]. CATHy catalyst kits are available for research purposes from Strem Chemicals Inc. 

Figure 15.16 summarizes a series of optically active alcohols and amines reported (in a review by Blacker at Avecia ) to be produced by the CATHy catalysts. These include the types of products described for the different classes of hydrogenations described in the previous sections. These products include those from the reduction of alkyl aryl ketones, a-ketoesters, aliphatic ketones, a,(3-unsaturated ketones, cyclic ketones, and a-hydroxy ketones. In addition, transfer hydrogenation allows for the asymmetric formation of amines by the reduction of N-diphenylphosphinylimines. These transfer hydrogenations... 

CATHy catalyst CATHy catalyst CATHy catalyst CATHy catalyst TsDPEN complex/HCOOH, N(C2H5)3 90-99% ee 93% ee 95% ee... 

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