Aluminum hydrides, Meerwein-Ponndorf-Verley reduction

The Meerwein-Ponndorf-Verley procedure has largely been replaced by reduction procedures that use lithium aluminum hydride, sodium borohydride or derivatives thereof. The Meerwein-Ponndorf-Verley reduction however has the advantage to be a mild and selective method, that does not affect carbon-carbon double or triple bonds present in the substrate molecule. 

The lithium aluminum hydride-aluminum chloride reduction of ketones is closely related mechanistically to the Meerwein-Ponndorf-Verley reduction in that the initially formed alkoxide complex is allowed to equilibrate between isomers in the... 

Reduction ofpyrimidine-2(lH)-ones.1 The pyrimidinone 2 is reduced by metal hydrides such as lithium tri-f-butoxy aluminum hydride to a mixture of the 3,6- and 3,4-dihydro derivatives in the ratio 9 1. In contrast, Meerwein-Ponndorf-Verley reduction with 1 in isopropanol results only in the 3,4-dihydro derivative (3a) but the reaction is slow and stops after two days to provide only a 25% yield. However, introduction of a halo substituent at C5 results in enhanced yields of the 3,4-dihydro derivatives, with the highest yields obtained with the 5-chloro derivative. 

Zeolites are not typically used in Lewis acid type catalysis due to the absence of Lewis acid centers in zeolites. This is due to the coordination of the Al-site to four lattice-oxygens in a perfect zeolite framework. It has, however, been shown for zeolite Beta that the aluminum atom can reversibly move between a framework Brpnsted acid site and a framework-grafted Lewis-acid site.70 Accordingly, Creyghton et al. showed that zeolite Beta is active in the Meerwein-Ponndorf-Verley reduction (MPV) of ketones (scheme 4).71 In this reaction a hydrogen hydride transfer reaction between an alcohol and a ketone takes place. 

In fact, a variation of this reaction has been utilized in the well-known Meerwein-Ponndorf-Verley reduction of carbonyl compounds (reverse of Oppenauer oxidation of alcohols) by aluminum isopropoxide The reaction involves a six-centered transition state, wherein the P-hydride is delivered into an incoming carbonyl group [Eq. (6.86)]. The stereochemistry of this reaction has been studied in detail. ... 

A different stereochemical outcome is observed in the reduction of the tetracyclic indanone derivative using lithium aluminum hydride in diethyl ether to afford the rranx-alcohol (83 %)212 or the cw-alcohol in the Meerwein-Ponndorf-Verley reduction employing aluminum isopropox-ide and isopropanol (99% 212 83 %213). The stereochemistry of the products were confirmed by mass spectroscopy giving a high M+-water peak (.vyn-climination) in the case of the c/.v-al-cohol213. 

A similar observation has been made in the reduction of fenchone a-fenchol [d.r. (exojendo) 5 9518S] is formed in the Meerwein-Ponndorf-Verley reduction, and /f-fenchol (exo) is formed in the lithium aluminum hydride reduction187. 

This reaction was first reported concurrently by Meerwein and Schmidt and Verley in 1925, and by Ponndorf in 1926, respectively. It is an aluminum alkoxide-catalyzed reduction of carbonyl compounds (ketones and aldehydes) to corresponding alcohols using another alcohol (e.g isopropanol) as the reducing agent or hydride source. Therefore, it is generally known as the Meerwein-Ponndorf-Verley reduction (MPV) or Meerwein-Ponndorf-Verley reaction. Occasionally, it is also referred to as the Meerwein-Ponndorf reduction, Meerwein-Ponndorf reaction, or Meerwein-Schmidt-Ponndorf-Verley reaction. About 12 years later, Oppenauer reported the reversion of this reaction in which alcohols were reversely oxidized into carbonyl compounds. Since then, the interchanges between carbonyl compounds and alcohols in the presence of aluminum alkoxide are generally called the Meerwein-Ponndorf-Oppenauer-Verley reduction or Meerwein-Ponndorf-Verley-Oppenauer reaction." ... 

In a different vein and as already pointed out in Chapter 8 (Scheme 8.6), the Meerwein-Ponndorf-Verley reduction is the reverse of the Oppenauer oxidation of aldehydes and ketones, and it is only a change of solvent that dictates whether the reaction that occurs is an oxidation or a reduction.The same catalyst is used. Scheme 9.19 is the reverse of Scheme 8.6. Thus, it is now suggested that the carbonyl oxygen of cyclohexen-3-one displaces an isopropoxy group (2-propoxy [ OCH(CH3)2]) from the catalyst, aluminum isopropoxide [Al(0-iPr)3].Then, after intramolecular hydride transfer, propanone (acetone, CH3COCH3) is lost by displacement from aluminum by the solvent, 2-propanol (isopropanol [CH3CH(OH)CH3]), and finally, the cyclo-... 

The Meerwein-Ponndorf-Verley (MPV) reduction is generally mediated by aluminum triiso-propoxide, Al(01Pr)3. In MPV reduction, reversible hydride transfer occurs via a six-membered transition state (Scheme 67). By removing acetone from the reaction system, the reversible reaction proceeds smoothly. The advantages of the reduction are the mildness of the reaction conditions, chemoselectivity, safety, operational simplicity, and its applicability to large-scale synthesis. It is reported that the addition of trifluoroacetic acid, significantly accelerates the reduction (Scheme 68) 304,305 in which case a catalytic amount of Al(0 Pr)3 is enough to complete the reaction. 

In the fourth and final chapter, Howard Haubenstock discusses asymmetric reduction of organic molecules. Within this general topic of wide and continuing interest, Haubenstock s chapter deals with chiral derivatives of lithium aluminum hydride, their preparation from suitable amino or hydroxy compounds, and their use in reducing carbonyl groups. Related reactions of the Meerwein-Ponndorf-Verley type or involving tri-alkylaluminum reagents are also presented. 

The classical Meerwein-Ponndorf-Verley (MPV) process, named after the independent originators, can be illustrated by the reduction of crotonaldehyde (43) by aluminum isopropoxide (44) in isopropyl alcohol (equation 24). Aluminum isopropoxide transfers hydride reversibly to a carbonyl acceptor. Acetone is formed as a volatile side product, which can be removed during reaction. The reaction of equation (24) is forced even further to the right by the use of excess isopropyl alcohol. MPV reactions have been reviewed.In the Oppenauer variant of this reaction an alcohol is oxidized to a ketone, and acetone is used as hydride acceptor in the presence of a strong base like r-butoxide. This reaction was originally developed for the selective oxidation of sterols. The synthetic aspects of this procedure have also been reviewed. ... 

The Meerwein-Ponndorf-Verley reaction involves reduction of a ketone by treat-ment with an excess of aluminum triisopropoxide. The mechanism of the process is closely related to the Cannizzaro reaction in that a hydride ion acts as a leaving group. Propose a mechanism. 

The deviation from Cram s rule has been attributed to the cyclic nature of the transition state of the Meerwein-Ponndorf-Verley reaction129. The situation may be further complicated by hydride transfer from external aluminum isopropoxide units not involved in the cyclic six-mem-bered transition state49,5S-13°. These competitive mechanistic pathways (external vs internal hydride transfer) depend on the experimental conditions (concentrations of reactants etc.). These have also been observed in the reduction of cyclic 1,2-diones where an internal hydride transfer to the intermediate a-hydroxy ketones may be sterically hindered. In these cases the stereochemical outcome of Meerwein-Ponndorf-Verley reactions cannot be definitely predicted. 

Methylenebicyclo[3.3.1]nonan-3-one (3) preferentially yields the exo-alcohol, e.vo-7-meth-ylenebicyclo[3.3.1]nonan-3-ol (4) (64%) under thermodynamically controlled (110 C, 12 h) Meerwein-Ponndorf-Verley conditions189 lithium aluminum hydride reduction affords the epimeric alcohol. 

The Meerwein-Ponndorf-Verley (MPV) reaction1"3 is the reduction of a carbonyl (1) to an alcohol (2) using an aluminum alkoxide catalyst, generally Al(Oi-Pr)3, and an alcoholic solvent such as i-PrOH. The alcoholic solvent serves as the hydride source for the reduction and in the course of the reaction is oxidized to the corresponding carbonyl. 

One of the chemoselective and mild reactions for the reduction of aldehydes and ketones to primary and secondary alcohols, respectively, is the Meerwein-Ponndorf-Verley (MPV) reduction. The lifeblood reagent in this reaction is aluminum isopropoxide in isopropyl alcohol. In MPV reaction mechanism, after coordination of carbonyl oxygen to the aluminum center, the critical step is the hydride transfer from the a-position of the isopropoxide ligand to the carbonyl carbon atom through a six-mem-bered ring transition state, 37. Then in the next step, an aluminum adduct is formed by the coordination of reduced carbonyl and oxidized alcohol (supplied from the reaction solvent) to aluminum atom. The last step is the exchange of produced alcohol with solvent and detachment of oxidized alcohol which is drastically slow. This requires nearly stoichiometric quantities of aluminum alkoxide as catalyst to prevent reverse Oppenauer oxidation reaction and also to increase the time of reaction to reach complete conversion. Therefore, accelerating this reaction with the use of similar catalysts is always the subject of interest for some researchers. 

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