Aldehydes Meerwein-Ponndorf-Verley reduction

We recently reported a modified Meerwein-Ponndorf-Verley reduction in which low-boiling alcohols such as EtOH and w-PrOH, but preferably i-PrOH, were used at temperatures near 225 °C in the absence of aluminum alkoxides [42]. The carbonyl moiety of an olefinic aldehyde such as cinnamaldehyde was reduced selectively to the alcohol without the carbon-carbon double bond being affected (Scheme 2.7). Since base was not present, aldol and Claisen-Schmidt condensations were avoided. 

The reduction of ketones to secondary alcohols and of aldehydes to primary alcohols using aluminum alkoxides is called the Meerwein-Ponndorf-Verley reduction.The reverse reaction also is of synthetic value, and is called the... 

In this way, an aldehyde or ketone could be reduced to the corresponding alcohol after hydrolysis of the resulting aluminium alkoxide. This reaction is known as the Meerwein-Ponndorf-Verley reduction. 

The aluminium-catalyzed hydride shift from the a-carbon of an alcohol component to the carbonyl carbon of a second component, which proceeds over a six-membered transition state, is named Meerwein-Ponndorf-Verley-Reduction (MPV) or Oppenauer Oxidation (OPP) depending on the isolated product. If aldehydes or ketones are the desired products, the reaction is viewed as the Oppenauer Oxidation. 

Meerwein-Ponndorf-Verley reductions. Zirconocene or hafnocene can catalyze reduction of carbonyl compounds with isopropanol. This method is useful for preferential reduction of keto aldehydes to hydroxy ketones and of a,(i-enones or -enals to allylic alcohols.1... 

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33], This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2CI2 at 21 °C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, rert-alco-hols, nitriles and nitro compounds, as depicted in Sch. 10. 

Kinetic studies of the Midland reduction confirmed that the reduction of aldehydes is a bimolecular process and the changes in ketone structure have a marked influence on the rate of the reaction (e.g., the presence of an EWG in the para position of aryl ketones increases the rate compared to an EDG in the same position). However, when the carbonyl compound is sterically hindered, the rate becomes independent of the ketone concentration and the structure of the substrate. The mechanism with sterically unhindered substrates involves a cyclic boatlike transition structure (similar to what occurs in the Meerwein-Ponndorf-Verley reduction). The favored transition structure has the larger substituent (Rl) in the equatorial position, and this model correctly predicts the absolute stereochemistry of the product. 

Meerwein-Ponndorf-Verley reduction The reduction of aldehydes and ketones by metal alkoxides to the corresponding alcohols 280... 

Okano, T., Matsuoka, M., Konishi, H., Kiji, J. Meerwein-Ponndorf-Verley reduction of ketones and aldehydes catalyzed by lanthanide tri-2-propoxides. Chem. Lett. 1987, 181-184. 

Aryl-2-alkynols In a process mechanistically analogous to the Meerwein-Ponndorf-Verley reduction, transfer of arylethynyl group to certain aldehydes (such as chloral and pentafluorobenzaldehyde) can be achieved via the trialkoxyaluminum species derived from 4-aryl-2-methyl-3-butyn-2-ols and the aluminum reagent [or 12,2 -bipheny lenedioxy-(/-butoxy)aluminum]. 

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. 

The Meerwein-Ponndorf-Verley reduction is so named because of the simultaneous and independent contributions from the labs of Meerwein, Ponndorf and Verley. The first report to appear in the literature was from Meerwein and Schmidt in 1925 who showed that an aldehyde could be reduced to a primary alcohol by Al(OEt)3 in an ethanolic medium.4 Independently, Verley demonstrated that butyraldehyde could be reduced by geraniol and Al(OEt)3.5 The following year, Ponndorf extended this reaction to include the reduction of ketones by using an easily oxidized secondary alcohol, such as i-PrOH, as the hydride source and Al(Oi-Pr)3 as the metal catalyst.6... 

Meerwein-Ponndorf-Verley reduction of ketones to secondary alcohols proceeds analogously to that of aldehydes, although usually more slowly. The method cannot, however, be used for ketones such as j8-keto esters or / -diketones that have a strong tendency to enolize, since they form aluminum enolates which are not reduced such compounds are preferably reduced by sodium borohydride, by potassium borohydride, or catalytically. 

Amino aldehydes are also reduced by LiAlH4. For instance, Hayes and Drake345 describe the reduction of 2,2-dimethyl-3-(methylamino)propional-dehyde by an excess of LiAlH4, obtaining the corresponding alcohol in 72% yield, whereas in this case Meerwein-Ponndorf-Verley reduction gave only a 27% yield ... 

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." ... 

Step 6 is the final step in the cellulose-to-lactic acid cascade, involving the isomerization of the 2-keto-hemi-acetal (here pyruvic aldehyde hydrate) into a 2-hydroxy-carboxyhc acid. This reaction is known to proceed in basic media following a Cannizzaro reaction with 1,2-hydride shift [111], Under mild conditions, Lewis acids are able to catalyze this vital step, which can also be seen as an Meerwein-Ponndorf-Verley reduction reaction mechanism. The 1,2-hydride shift has been demonstrated with deuterium labeled solvents [110, 112], Attack of the solvent molecule (water or alcohol) on pymvic aldehyde (step 5) and the hydride shift (step 6) might occur in a concerted mechanism, but the presence of the hemiacetal in ethanol has been demonstrated for pyruvic aldehyde with chromatography by Li et al. [113] andfor4-methoxyethylglyoxal with in situ CNMRby Dusselier et al. (see Sect. 7) [114]. 

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 reduction is a reversible reaction and the reverse pathway was reported in detail a couple of years later by Oppenauer who selectively oxidised hydroxyl functions into ketones or aldehydes with the help of acetone or cyclohexanone as proton quencher (oxidant) and aluminium tert-butoxide as catalyst (other common oxidants are acetaldehyde, anisaldehyde, benzaldehyde, benzophenone and cinnamalde-hyde). This mild oxidation method was in many cases used in the synthesis of steroids and terpenoids. 

A clean hydrogen-transfer reduction of aldehydes and ketones to the corresponding alcohols has been reported. In a typical experiment, propan-2-ol is employed as reductant and solvent in an autoclave at 220-230°C and 4-5MPa. Although formally similar to Meerwein-Ponndorf-Verley reduction, the reaction requires no catalyst, which tends to cut down on side-products. 

Zr compounds are also useful as Lewis acids for oxidation and reduction reactions. Cp2ZrH2 or Cp2Zr(0 Pr)2 catalyze the Meerwein-Ponndorf-Verley-type reduction and Oppenauer-type oxidation simultaneously in the presence of an allylic alcohol and benzaldehyde (Scheme 40).170 Zr(C)1 Bu)4 in the presence of excess l-(4-dimethylaminophenyl) ethanol is also an effective catalyst for the Meerwein-Ponndorf-Verley-type reduction.1 1 Similarly, Zr(0R)4 catalyze Oppenauer-type oxidation from benzylic alcohols to aldehydes or ketones in the presence of hydroperoxide.172,173... 

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. 

It was noticed as early as 1925 that alkoxides of calcium, magnesium and particularly aluminum could catalyze the reduction of aldehydes by ethanol as shown in equation (65).242,243 Removal of very volatile acetaldehyde is easily achieved to drive the reaction to the right. In 1926, Ponndorf devised a method in which both aldehydes and ketones could be reduced to alcohols by adding excess alcohol and aluminum isopropoxide.244 Such reductions are today referred to as Meerwein-Ponndorf-Verley reactions. Although alkoxides of a number of metals, e.g. sodium, boron, tin, titanium and zirconium, have been used for these reactions, those of aluminum are by far the best. 

The synthetic method (a) is the regioselective reduction of an a,/ -unsaturated aldehyde or ketone (Section 5.18.2, p. 798), which is most conveniently effected by the Meerwein-Ponndorf-Verley procedure (Section 5.4.1, p. 520). The further disconnection shown of the a, -carbonyl compound is a retro-aldol condensation (Section 5.18.2, p. 799) however it should be emphasised that other routes to the unsaturated carbonyl compound, such as the Horner-Emmons reaction (Section 5.18.2, p. 799), may also be feasible. 

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

Cha, J. S., Park, J. H. Reaction of aldehydes and ketones with boron triisopropoxide. The Meerwein-Ponndorf-Verley type reduction of boron aikoxides. 1. Bull. Korean Chem. Soc. 2002, 23, 1051-1052. 

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