Ketones hydrogen transfer reactions

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). 

The hydrogen transfer reaction (HTR), a chemical redox process in which a substrate is reduced by an hydrogen donor, is generally catalysed by an organometallic complex [72]. Isopropanol is often used for this purpose since it can also act as the reaction solvent. Moreover the oxidation product, acetone, is easily removed from the reaction media (Scheme 14). The use of chiral ligands in the catalyst complex affords enantioselective ketone reductions [73, 74]. 

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]. 

The scope of hydrogen transfer reactions is not limited to ketones. Imines, carbon-carbon double and triple bonds have also been reduced in this way, although homogeneous and heterogeneous catalyzed reductions using molecular hydrogen are generally preferred for the latter compounds. 

Aromatics occur as ligands in ruthenium complexes that are used for hydrogen transfer reaction, i.e. two hydrogen atoms are transferred from a donor molecule, e.g. an alcohol, to a ketone, producing another alcohol. Especially the enantiospecific variant has become important, see Chapter 4.4. The substitution pattern of the aromatic compound influences the enantioselectivity of the reaction. 

In Figure 13.19 we have shown a route to L-699,392 published by Merck involving three steps based on homogeneous catalysts, viz. two Heck reactions and one asymmetric hydrogen transfer reaction, making first an alcohol and subsequently a sulphide [21], Stoichiometric reductions for the ketone function have been reported as well [22] and the Heck reaction on the left-hand side can be replaced by a classic condensation reaction. L-699,392 is used in the treatment of asthma and related diseases. 

One of the systems was found to be very efficient catalyzing enantioface-selective hydrogen transfer reactions to aromatic and in particular to aliphatic ketones with up to 95% ee. Regarding the latter reaction these are unprecedented ee values. The reaction mechanism of these transformations is best described as a metal-ligand bifunctional catalysis passing through a pericyclic-like transition state. 

The mechanism for the iridium-catalyzed hydrogen transfer reaction between alcohols and ketones has been investigated, and there are three main reaction pathways that have been proposed (Scheme 4). Pathway (a) involves a direct hydrogen transfer where hydride transfer takes place between the alkoxide and ketone, which is simultaneously coordinated to the iridium center. Computational studies have given support to this mechanism for some iridium catalysts [18]. 

Hydrogen transfer reactions from an alcohol to a ketone (typically acetone) to produce a carbonyl compound (the so-caUed Oppenauer-type oxidation ) can be performed under mild and low-toxicity conditions, and with high selectivity when compared to conventional methods for oxidation using chromium and manganese reagents. While the traditional Oppenauer oxidation using aluminum alkoxide is accompanied by various side reactions, several transition-metal-catalyzed Oppenauer-type oxidations have been reported recently [27-29]. However, most of these are limited to the oxidation of secondary alcohols to ketones. 

I 5 Catalytic Activity of Cp Iridium Complexes in Hydrogen Transfer Reactions Table 5.3 Transfer hydrogenation of ketones and imines catalyzed by ll. "... 

Unlike the reactions described in the previous two sections, competition between insertion and j5-hydrogen transfer is usually not an issue here. Ketone polymerization is nearly thermoneutral and disfavoured by entropy. However, aldehyde insertion is thermodynamically more favourable, and the Tishchenko reaction mentioned in the previous section can plausibly be written as a sequence of insertions and j -hydrogen transfer reactions (Scheme 4). 

The recovered catalyst was washed with dichloromethane four times and reused in the hydrogen transfer reaction by reloading HCOOH-Et3N azeotrope (1.0 ruL) and the ketone (1.0 mmol). 

The procedure for getting the polymer-bound ligands is very easy to reproduce. Three jS-functionalized aromatic ketones were successfully reduced to the corresponding alcohols by heterogeneous asymmetric hydrogen transfer reaction with formic acid-triethylamine azeotrope as the hydrogen donor. One of the product alcohols (19c) is an intermediate for the synthesis of optically active fluoxetine. 

All hydrogen transfer reactions were carried out under N2 at 90°C. According to GLC analysis the time required for the reduction of 1 to the corresponding ketones ranged between 20 min and 1.5 hours, whereas the reduction of 2 to the corresponding alcohols required 2-4 hours. 

Among the hydrogen transfer reactions, the Meerwein-Ponndorf-Verley reduction and its counterpart, the Oppenauer oxidation, are undoubtedly the most popular. These are well-established selective and mild redox reactions and they have been studied extensively [4, 5]. Nevertheless, traditional Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reactions have some drawbacks, as they usually suffer from poor reactivity of the traditional Al(OiPr)3/iPrOH system, for which continuous removal of the produced acetone is necessary in order to shift the equilibrium between reduction of the ketone and oxidation of the donor alcohol. 

Another interesting implication of hydrogen transfer reactions is the isomerization of allylic alcohols to the corresponding saturated ketones, due to its potential for use in organic synthesis. Actually, it forms an elegant shortcut to carbonyl... 

Ruthenium compounds are widely used as catalysts for hydrogen-transfer reactions. These systems can be readily adapted to the aerobic oxidation of alcohols by employing dioxygen, in combination with a hydrogen acceptor as a cocatalyst, in a multistep process. For example, Backvall and coworkers [85] used low-valent ruthenium complexes in combination with a benzoquinone and a cobalt Schiff s base complex. The proposed mechanism is shown in Fig. 14. A low-valent ruthenium complex reacts with the alcohol to afford the aldehyde or ketone product and a ruthenium dihydride. The latter undergoes hydrogen transfer to the benzoquinone to give hydroquinone with concomitant... 

Ramamurthy and coworkers reported the photochemical electron-transfer-initiated intermolecular hydrogen transfer reaction [80,81] of phenyl cyclohexyl ketone 25 in chiral amine-immobilized zeolk cavities. 

The asymmetric reduction of aryl ketone can be achieved with ruthenium catalysts (Scheme 24), prepared separately or in situ by formation of [RuCl2(arene)]2 and ligand, in z-PrOH [81]. The high enantioselectivities and rate are very dependent upon the functionality of the substrate, T -arene and A -substitution of the diamino or amino alcohol ligands on ruthenium [81]. The hydrogen transfer reaction in z-PrOH is reversible, necessitating low concentrations, while extensive... 

N-propargylamide 173 (Scheme 3.53) [104]. The helical polymer-Ru complex 174 was used as a catalyst for the hydrogen-transfer reaction of ketones to give the alcohols with moderate enantioselectivities. 

Several of the most common hydrogen donors, such as formic acid and formates, ascorbic acid, EDTA or 2-propanol are well or at least sufficiently soluble in water. In addition, H20 itself can serve as a source of hydrogen. Frequently, hydrogenation of unsaturated substrates is achieved by using C0/H20 mixtures such reactions are discussed in 3.8. As written in eq. (3.11) the hydrogen transfer reaction is often reversible, an obvious example being the reduction of ketones using 2-propanol as donor. 

The Meerwein-Ponndorf-Verley reduction of aldehydes and ketones and its reverse, the Oppenauer oxidation of alcohols, are hydrogen-transfer reactions that can be performed under mild conditions and without the risk of reducing or oxidizing other functional groups [1]. The hydrogen donors are easily oxidizable secondary alcohols (e. g. i-PrOH) and the oxidants are simple ketones (e. g. cyclohexanone). Industrial applications of the MPVO reactions are found in the fragrance and pharmaceutical industries, for example. 

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