Hydrogenations of Ketones

The reduction of the carbonyl group (and related functionalities) by catalytic methods has been successfully achieved by a number of methods. Rhodium and ruthenium complexes are the most popular catalysts used in the hydrogenation of ketones. While most catalyst systems of this type require the presence of additional chelating functionality on the substrate the recent development of highly active ruthenium(diamine) complexes allows the reduction of simple unfunctionalised ketones. Ruthenium catalysts have also been applied, with much success, to the catalytic asymmetric transfer hydrogenation of ketones in the presence of alcohols or formate. 

This chapter also includes a discussion of the catalytic asymmetric reduction of the C=N bond of imines. This transformation has been achieved with high ee using both metal-based catalysts and also organic Br0nsted acids. 

The reduction of ketones into enantiomericaUy enriched alcohols using hydrogen as the stoichiometric reductant is an appealing transformation. The reaction is atom economical, with no by-products, and has been achieved with very low catalyst loadings. 

Ruthenium and rhodium complexes have maintained the best track record as ketone hydrogenation catalysts. For high enantioselectivities, additional chelating functional groups are often needed. Typical substrates are represented by ketones (3.01) to (3.03), where esters, halides and phosphonates provide an additional donor group on the substrate. BlNAP/ruthenium combinations, such as complex (3.07), have given consistently high enantioselectivities with such 

Catalysis in Asymmetric Synthesis 2e 2009 Vittorio Caprio and Jonathan M.J. WilKams 

Amino Ketones Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Tab. 1.9). The rhodium precatalysts, combined with chiral phosphorous ligands such as BPPFOH [10b], MCCPM [24f-k], Cy,Cy-oxo-ProNOP [79c, e], Cp,Cp-oxoProNOP [79c, e], and IndoNOP [79g], have provided excellent enantioselectivity and reactivity for the asymmetric hydrogenation of a, yS, and y-al-kyl amino ketone hydrochloride salts. 

In principle, the self-supporting strategy (type I MOCP) for chiral catalyst immobilization should be applicable whenever the active catalyst species contains at least two ligands coordinated to the metal (M). However, this would be challenging in 

BCPM R = COO- -C4Ho MCPM R = COOCH3 MCCPM- R = CONHCHi 

SCHEME 45. Ir(I)-catalyzed asymmetric hydrogenation of a,/3-unsaturatcd ketones. 

---

L = P(CH3)3 or CO, oxidatively add arene and alkane carbon—hydrogen bonds (181,182). Catalytic dehydrogenation of alkanes (183) and carbonylation of bensene (184) has also been observed. Iridium compounds have also been shown to catalyse hydrogenation (185) and isomerisation of unsaturated alkanes (186), hydrogen-transfer reactions, and enantioselective hydrogenation of ketones (187) and imines (188). 

Table 2 Results of the transfer hydrogenation of ketones with fluorinated (salen)Ir complexes under biphasic conditions ...

More recently, the same type of hgand was used to form chiral iridium complexes, which were used as catalysts in the hydrogenation of ketones. The inclusion of hydrophihc substituents in the aromatic rings of the diphenylethylenediamine (Fig. 23) allowed the use of the corresponding complexes in water or water/alcohol solutions [72]. This method was optimized in order to recover and reuse the aqueous solution of the catalyst after product extraction with pentane. The combination of chiral 1,2-bis(p-methoxyphenyl)-N,M -dimethylethylenediamine and triethyleneglycol monomethyl ether in methanol/water was shown to be the best method, with up to six runs with total acetophenone conversion and 65-68% ee. Only in the seventh run did the yield and the enantioselectivity decrease slightly. 

Chitosan (Fig. 27) was deposited on sihca by precipitation. The palladium complex was shown to promote the enantioselective hydrogenation of ketones [80] with the results being highly dependent on the structure of the substrate. In the case of aromatic ketones, both yield and enantioselectiv-ity depend on the N/Pd molar ratio. Low palladium contents favored enan-tioselectivity but reduced the yield. Very high conversions were obtained with aliphatic ketones, although with modest enantioselectivities. More recently, the immobilized chitosan-Co complex was described as a catalyst for the enantioselective hydration of 1-octene [81]. Under optimal conditions, namely Co content 0.5 mmolg and 1-octene/Co molar ratio of 50, a 98% yield and 98% ee were obtained and the catalyst was reused five times without loss of activity or enantioselectivity. 

R. Noyori and T. Ohkuma, Asymmetric Catalysis by Architectural and Functional Molecular Engineering Practical Chemo- and Stereoselective Hydrogenation of Ketones , Angew. Chem. Int. Ed. Engl, 2001, 40, 40. 

For transition-metal-catalyzed hydrogenation of ketones and aldehydes, H2 or the combination of PrOH with a base has been widely used as the hydrogen source (Scheme 8). In case of using H2, the reaction is called hydrogenation, whereas the reaction using the combination of PrOH with a base is especially called transfer hydrogenation. ... 

These transition-metal catalysts contain electronically coupled hydridic and acidic hydrogen atoms that are transferred to a polar unsaturated species under mild conditions. The first such catalyst was Shvo s diruthenium hydride complex reported in the mid 1980s [41 14], Noyori and Ikatiya developed chiral ruthenium catalysts showing excellent enantioselectivity in the hydrogenation of ketones [45,46]. 

In 2007, Casey showed that 11, which corresponds to the Shvo s complex catalyzes hydrogenations of ketones and aldehydes [47]. Reaction of benzaldehyde in the presence of catalytic amount of 11 under H2 (3 atm) afforded the corresponding benzylalcohol in 90% yield within 1 h (Scheme 10). 

Table 4 Iron complex-catalyzed hydrogenation of ketones...

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

Transfer hydrogenation of aldehydes with isopropanol without addition of external base has been achieved using the electronically and coordinatively unsaturated Os complex 43 as catalyst. High turnover frequencies have been observed with aldehyde substrates, however the catalyst was very poor for the hydrogenation of ketones. The stoichiometric conversion of 43 to the spectroscopically identifiable in solution ketone complex 45, via the non-isolable complex 44 (Scheme 2.4), provides evidence for two steps of the operating mechanism (alkoxide exchange, p-hydride elimination to form ketone hydride complex) of the transfer hydrogenation reaction [43]. 

Hydrido(alkoxo) complexes of late transition metals are postulated as intermediates in the transition metal-catalyzed hydrogenation of ketones (Eq. 6.17), the hydrogenation of CO to MeOH, hydrogen transfer reactions and alcohol homologation. However, the successful isolation of such complexes from the catalytic systems was very rare [32-37]. 

On the other hand, one of the first chiral sulfur-containing ligands employed in the asymmetric transfer hydrogenation of ketones was introduced by Noyori el al Thus, the use of A-tosyl-l,2-diphenylethylenediamine (TsDPEN) in combination with ruthenium for the reduction of various aromatic ketones in the presence of i-PrOH as the hydrogen donor, allowed the corresponding alcohols to be obtained in both excellent yields and enantioselectivities, as... 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

The solvent is very important for the hydrogenation of ketones. One of the most important factors in the liquid-phase hydrogenation of ketones is whether the medium is acidic, neutral, or basic, and a great deal of work has gone into attempting to understand chemoselectivity and stereoselectivity based on combinations of the metal catalyst and the reaction medium. 

Whereas general activities and selectivities for hydrogenations of ketones are similar to those of aldehydes, one big difference exists between the two. The hydrogenation of prochiral ketone carbonyls produces chiral carbons. Over symmetrical catalysts, racemic alcohols are formed however, over unsymmet-rical surfaces, enantioselectivity may occur. Enantioselective hydrogenations of ketones is an increasingly active research held and is covered in Chapter 3. Here we discuss that aspect of stereoselectivity associated with ring systems. 

Noyori, R. and Okhuma, T. (2001) Asymmetric catalysis by architectural and functional molecular engineering practical chemo- and stereoselective hydrogenation of ketones. Angewandte Chemie-International Edition, 40 (1), 40-73. 

---