Meerwein- Pondorf-Verley

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 reaction which is carried out in presence of isopropyl alcohol is also called Meerwein-Pondorf-Verley reduction. An example is the reduction of crotonaldehyde to crotyl alcohol. 

Finally, /i-hydrogen transfer is the key step in the Meerwein-Pondorf-Verley (MPV) reduction of ketones by alcohols, catalyzed by aluminium alkoxides and many other catalysts. In that case, competition is not an issue, since polymerization is usually not thermodynamically favourable. The accepted mechanism for this reaction is direct transfer of the hydride from alkoxide to ketone. 

Aluminium Alkoxides and Ketones Meerwein-Pondorf-Verley Reduction... 

Meerwein-Pondorf-Verley reduction, discovered in the 1920s, is the transfer hydrogenation of carbonyl compounds by alcohols, catalyzed by basic metal compounds (e.g., alkoxides) [56-58]. The same reaction viewed as oxidation of alcohols [59] is called Oppenauer oxidation. Suitable catalysts include homogeneous as well as heterogeneous systems, containing a wide variety of metals like Li, Mg, Ca, Al, Ti, 2r and lanthanides. The subject has been reviewed recently [22]. In this review we will concentrate on homogeneous catalysis by aluminium. Most aluminium alkoxides will catalyze MPV reduction. 

The Meerwein-Pondorf-Verley reaction involves transfer of a hydride from the oxygen-substituted carbon atom of an isopropoxide group to a carbonyl group, thus effecting the reduction of the carbonyl compound to an alcohol. 

Figure B.4. Intermediate in the Meerwein-Pondorf-Verley reaction.

The Oppenauer oxidation. When a ketone in the presence of base is used as the oxidizing agent (it is reduced to a secondary alcohol), the reaction is known as the Oppenauer oxidation,95 This is the reverse of the Meerwein-Pondorf-Verley reaction (6-25), and the mechanism is also the reverse. The ketones most commonly used are acetone, butanone, and cyclohexanone. The most common base is aluminum f-butoxide. The chief advantage of the method is its high selectivity. Although the method is most often used for the preparation of ketones, it has also been used for aldehydes. 

Aluminum methoxide Al(OMe)3 is a solid which sublimes at 240 °C in vacuum. Aluminum isopropoxide melts in the range 120-140 °C to a viscous liquid which readily supercools. When first prepared, spectroscopic and X-ray evidence indicates a trimeric structure which slowly transforms to a tetramer in which the central Al is octahedrally coordinated and the three peripheral units are tetrahedral.162,153 Intramolecular exchange of terminal and bridging groups, which is rapid in the trimeric form, becomes very slow in the tetramer. There is MS and other evidence that the tetramer maintains its identity in the vapour phase.164 Al[OCH(CF3)2]3 is more volatile than Al[OCH(Me)2]3 and the vapour consists of monomers.165 Aluminum alkoxides, particularly Al(OPr )3, have useful catalytic applications in the synthetic chemistry of aldehydes, ketones and acetals, e.g. in the Tishchenko reaction of aldehydes, in Meerwein-Pondorf-Verley reduction and in Oppenauer oxidation. The mechanism is believed to involve hydride transfer between RjHCO ligands and coordinated R2C=0— A1 groups on the same Al atom.1... 

A reaction mechanism quite similar to the Claisen-Tishchenko and Meerwein-Pondorf-Verley reactions assumes tetravalent aluminum in an anionic complex and is more likely to correspond to the requirements. 

If, while formulating the theory, the valency angles are considered, and the alkoxy group is marked as a chain, the relationship to the six-ring complexes (4) formulated in the reaction of Meerwein-Pondorf-Verley and Claisen-Tishchenko is at once clear. 

Figure 46. Catalyst preparation for an asymmetric Meerwein-Pondorf-Verley reduction.

An intriguing chiral samarium complex for the Meerwein-Pondorf-Verley (MPV) reduction of ketones has been reported by Evans.100 The soluble catalyst, prepared as indicated in Figure 46, promoted the asymmetric MPV reduction of aryl methyl ketones in up to 97% ee with as little as 5 mol % loading (Figure 47). 

Equation 15.3.1 Meerwein-Pondorf-Verley reduction of 4-tert-butylcyclohexanone 27... 

Fig. 15.6 Meerwein-Pondorf-Verley reduction of 4-tert-bytylcyclohexanone 27 catalyzed by alkali-metal exchanged BEA effect of cation on cw-4-tert-bytylcyclohexanol selectivity...

The Oppenauer oxidation can also afford a convenient alternative to more traditionally used oxidants. Oxidation of quinine (13) using benzophenone and KO/Bu gave the ketone in excellent yield (Figure 3.14) other oxidants were less effective [27]. This reaction can be viewed as an Oppenauer oxidation or a Meerwein-Pondorf-Verley reduction, depending on whether one considers the oxidation or the reduction to be the primary reaction. A magnesium-catalyzed Meerwein-Pondorf-Verley reduction was determined to form significant amounts of impurities in a Grignard reaction [28]. 

Wilk, B. K. Helom, J. L. CoughHn, C. W., Magnesium Meerwein-Pondorf-Verley-Oppenauer Reaction.The Origin of an Impurity in PDA-641 Batches. Org. Process Res. Dev. 1998,2,407. 

Manganese pentacarbonyl (Mn(CO)5), 177 Markovnikov s rule, 277 McLafferty rearrangement, 65 MCPBA, see zn-Chloroperbenzoic acid Meerwein-Pondorf-Verley reaction, 84, 308 Metal cations... 

A pivalamide of an indole, introduced with PvCl (NaH, DMF, 0°C, 1 h, 96% yield) is efficiently cleaved with MeSNa (MeOH, 20°C, 2h, 96% yield).The use EDA (THE, 45°C, 79-93% yield) cleaves the pivalamide by a Meerwein-Pondorf-Verley reduction. 

In modem terminology, the core of Marckwald s definition is the conversion of an achiral substance into a chiral, nonracemic one by the action of a chiral reagent. By this criterion, the chiron approach falls outside the realm of asymmetric synthesis. Marckwald s point of reference of course, was biochemical processes, so it follows that modern enzymatic processes [30-32] are included by this definition. Marckwald also asserted that the nature of the reaction was irrelevant, so a self-immolative reaction or sequence such as an intermolecular chirality transfer in a Meerwein-Pondorf-Verley reaction would also be included ... 

The reaction of a chiral alkene with borane in the proper stoichiometry may afford alkyl boranes R BH2 or dialkyl boranes R BH, where R is a chiral ligand. Attempts to achieve highly selective reductions of ketones using such reagents have met with little success, however. Trialkyl boranes R3B were first reported to reduce aldehydes and ketones (under forcing conditions) in 1966 by Mikhailov [50]. Mechanistic studies (summarized in ref. [46]) showed that there are two limiting mechanisms for the reduction of a carbonyl compound by a trialkylborane, as shown in Scheme 7.4 a pericyclic process reminiscent of the Meerwein-Pondorf-Verley reaction (Scheme 7.4a), and a two step process that involves dehydro-... 

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