Transfer hydrogenation ketone substrates

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]. 

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 water-soluble ligand (TPPTS) was discussed earlier with regard to aldehyde reduction [17]. Similarly, in ketone transfer hydrogenation, high yields are obtained for a variety of substrates with the ability for efficient catalyst recycling at no expense of activity or selectivity (Fig. 15.10). 

In transfer hydrogenation with 2-propanol, the chloride ion in a Wilkinson-type catalyst (18) is rapidly replaced by an alkoxide (Scheme 20.9). / -Elimination then yields the reactive 16-electron metal monohydride species (20). The ketone substrate (10) substitutes one of the ligands and coordinates to the catalytic center to give complex 21 upon which an insertion into the metal hydride bond takes place. The formed metal alkoxide (22) can undergo a ligand exchange with the hydride donor present in the reaction mixture, liberating the product (15). 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

The Meerwein-Ponndorf-Verley reaction is a classic method for ketone/ aldehyde carbonyl group reduction, which involves at least 1 equivalent of aluminum alkoxide as a promoter. In this reaction, the hydrogen is transferred from isopropanol to the ketone/aldehyde substrate, so the reaction can also be referred to as a transfer hydrogenation reaction. 

The procedure is very easy to reproduce and the asymmetric transfer hydrogenation may be applied to a wide range of aromatic ketones. Table 9.3 gives different substrates that can be reduced with the Ru(II)-(2-azanorbornylmetha-nol) complex in Ao-propanol... 

A large number of reports have concerned transfer hydrogenation using isopropanol as donor, with imines, carbonyls-and occasionally alkenes-as substrate (Scheme 3.17). In some early studies conducted by Nolan and coworkers [36], NHC analogues of Crabtree catalysts, [Ir(cod)(py)(L)]PF,5 (L= Imes, Ipr, Icy) all proved to be active. The series of chelating iridium(III) carbene complexes shown in Scheme 3.5 (upper structure) proved to be accessible via a simple synthesis and catalytically active for hydrogen transfer from alcohols to ketones and imines. Unexpectedly, iridium was more active than the corresponding Rh complexes, but... 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

These ligands and their ruthenium complexes are easy to prepare and are useful in asymmetric transfer hydrogenation of a variety of activated ketones. Table 3.4 shows a selection of substrates that can be reduced with the Ru(II)-RS02-DPEN complexes using HC02H-Et3N 5 2. 

A primary alcohol and amines can be used as an aldehyde precursor, because it can be oxidized by transfer hydrogenation. For example, the reaction of benzyl alcohol with excess olefin afforded the corresponding ketone in good yield in the presence of Rh complex and 2-amino-4-picoline [18]. Similarly, primary amines, which were transformed into imines by dehydrogenation, were also employed as a substrate instead of aldehydes [19]. Although various terminal olefins, alkynes [20], and even dienes [21] have been commonly used as a reaction partner in hydroiminoacylation reactions, internal olefins were ineffective. Recently, methyl sulfide-substituted aldehydes were successfully applied to the intermolecu-lar hydroacylation reaction [22], Also in the intramolecular hydroacylation, extension of substrates such as cyclopropane-substituted 4-enal [23], 4-alkynal [24], and 4,6-dienal [25] has been developed (Table 1). 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

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