Hydrogenation of unfunctionalized ketones

In some cases, the use of base can be incompatible with substrates or can add an imde-sirable variable to running a process. This base can be avoided by starting with the complexes [Ru(bisphosphine)(diamine)(H)(BH )].  

The hydrogenation of diaryl ketones or aryl heteroaryl ketones can even be conducted enantioselectively, if the ketones contain different steric or electronic properties. One impressive example of such a hydrogenation is shown in Equation 15.74. In this process, the aryl thazolyl ketone is reduced with the optimized Noyori catalyst with exceptionally high enantioselectivity. This product is then carried forward for the synthesis of an FDE-IV inhibitor. 

The ability to catalyze the asymmetric hydrogenation of aliphatic ketones provides an opportunity to extend the scope of these reactions to the dynamic kinetic resolution of ketones that contain a stereocenter in the enolizable a-position. The catalysts containing bisphosphine and diamine ligands are activated by base, and the base used to activate the metal catalyst can also catalyze the racemization of the ketone. An example of such a process is shown in Equation 15.76.  

Catalyst Ar R S/C ratio Reaction conditions Yield (%) Percent ee of product (confign.) References 

The asymmetric hydrogenation of unfunctionalized ketones is a much more challenging task than that of functionalized ketones [3 j, 115]. Many chiral catalysts which are effective for functionalized ketones do not provide useful levels of enantioselectivity for unfunctio-nalized ketones, due to a lack of secondary coordination to the metal center. Zhang demonstrated the enantioselective hydrogenation of simple aromatic and aliphatic ketones using the electron-donating diphosphane PennPhos, which has a bulky, rigid and well-defined chiral backbone, in the presence of 2,6-lutidine and potassium bromide [36]. 

Aromatic Ketones The DIOP-Rh [116] and DBPP-Rh [117] complexes, in conjunction with a tertiary amine, have been employed in the asymmetric hydrogenation of acetophenone, albeit with moderate enantioselectivity (80 and 82% respectively Tab. 1.10). The asymmetric hydrogenation of aromatic ketones was significantly improved by using the Me-PennPhos-Rh complex, with which enantioselectivities of up to 96% ee were achieved [36]. Interestingly, the additives 2,6-lutidine and potassium bromide were again found to be crucial for optimum selectivity, although their specific role has not been determined. 

Aliphatic Ketones The asymmetric hydrogenation of simple aliphatic ketones remains a challenging problem. This may be attributed to the difficulty with which the chiral catalyst differentiates between the two-alkyl substituents of the ketone. Promising results have been obtained in asymmetric hydrogenation of aliphatic ketones using the PennPhos-Rh complex in combinahon with 2,6-lutidine and potassium bromide (Tab. 1.11) [36]. For example, the asymmetric hydrogenation of tert-butyl methyl ketone affords the requisite secondary alcohol in 94% ee. Similarly, isopropyl, Butyl, and cyclohexyl methyl ketones have been reduced to the corresponding secondary alcohols with 85% ee, 75% ee, and 92% ee respectively. 

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I.4.2.I. Aromatic Ketones Although phosphine-Ru(II) dichlorides are poor catalysts for hydrogenation of unfunctionalized ketones [162b,255], a remarkably high reactivity emerges when the Ru compounds are further complexed with a 1,2-diamine ligand. Thus trans-... 

For hydrogenation of unfunctionalized ketones the only efficient solid catalyst is Ni [13]. Catalyst pretreatment conditions are similar to those used for catalysts in the hydrogenation of /6-ketoesters. A major difference is the application of pivalic acid in greater than stoichiometric amounts during the hydrogenation reaction. This additive, with sufficient Na" ions, enhanced the ee from 2 to 80-85% in the reduction of a variety of 2-alkanones. 

Figure 15.13. Noyori s catalyst for the hydrogenation of unfunctionalized ketones.

Table 1. 1-ArylethanoIs by Hydrogenation of Unfunctionalized Aryl Methyl Ketones in the Presence of an in situ Rhodium Catalyst...

As noted previously, one of the most dramatic advances in asymmetric hydrogenation over the past tu o decades has been the development of ruthenium catalysts for the hydrogenation of ketones. Tltese hydrogenations can be divided into the hydrogenation of "functionalized" ketones and "unfunctionalized" ketones. "Functionalized" ketones... 

Hydrogenation of unfunctionalized C=C Hydrogenation of a- or 8-functionalized C=0 Hydrogenation of aryl ketones Hydrogenation of unfunctionalized C=0 Hydrogenation of N-aryl or cyclic imines Hydrogenation of N-alkyl imines Hydrogenation of N-acyl-hydrazones Epoxidation of allylic alcohols Epoxidation of C=C... 

Chirik and co-workers described the electron-rich Fe-CNC dinitrogen pincer complexes 41 which were effective for the catalytic hydrogenation of unfunctionalized alkenes (Figure 13.3). ° Furthermore, the first example of zincocene-NHC adducts 42 was evaluated in the catalytic hydrogenation of imines and ketones (Figure 13.3). ... 

In contrast to unfunctionalized ketones, Wilkinson-type catalysts are quite effective in the hydrogenation of 2-oxo esters. With in situ catalysts consisting of [Rh(cod)Cl]2 2 and a proline derived chelate phosphane BPPM 3l4, quantitative hydrogenation of 2-oxo esters to (7 )-2-hydroxy esters was achieved. Dry benzene or dry tetrahydrofuran as solvent were superior to alcohols usually used in hydrogenation reactions with Wilkinson-type catalysts. While methyl 2-oxopropanoate was reduced to methyl (R)-2-hydroxypropanoate in only 66% eel5, propyl and 2-methylpropyl 2-oxopropanoate gave the (R)-alcohols with 76% and 71 % ee, respectively (Table 2)15,10. 

The hydrogenation of a-amino ketones results in the formation of a-aminoalkanols which are biologically important compounds, e.g., adrenergic drugs. In contrast to unfunctionalized ketones, a-amino ketones can be catalytically reduced with high enantioselectivity (Table 6), indicating that chelation within the catalyst is a necessary prerequisite. 

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