MPV reduction

The Michael addition/Meerwein-Ponndorf-Verley (MPV) reduction sequence developed by Node and coworkers is another easily implementable strategy for the... 

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. 

Binuclear Al111 complexes for MPV reduction have been developed. In the presence of 5mol.% of the bidentate catalyst (Scheme 69, compound (R)), the reduction proceeds smoothly at room... 

Alcohols have always been the major group of hydrogen donors. Indeed, they are the only hydrogen donors that can be used in Meerwein-Ponndorf-Verley (MPV) reductions. 2-Propanol (16) is most commonly used both in MPV reductions and in transition metal-catalyzed transfer hydrogenations. It is generally available and cheap, and its oxidation product, acetone (14), is nontoxic and can usually be removed readily from the reaction mixture by distillation. This may have the additional advantage that the redox equilibrium is shifted even more into the direction of the alcohol. As a result of sigma inductive electronic ef-... 

Lanthanide(III) isopropoxides show higher activities in MPV reductions than Al(OiPr)3, enabling their use in truly catalytic quantities (see Table 20.7 compare entry 2 with entries 3 to 6). Aluminum-catalyzed MPVO reactions can be enhanced by the use of TFA as additive (Table 20.7, entry 11) [87, 88], by utilizing bidentate ligands (Table 20.7, entry 14) [89] or by using binuclear catalysts (Table 20.7, entries 15 and 16) [8, 9]. With bidentate ligands, the aluminum catalyst does not form large clusters as it does in aluminum(III) isopropoxide. This increase in availability per aluminum ion increases the catalytic activity. Lanthanide-catalyzed reactions have been improved by the in-situ preparation of the catalyst the metal is treated with iodide in 2-propanol as the solvent (Table 20.7, entries 17-20) [90]. Lanthanide triflates have also been reported to possess excellent catalytic properties [91]. 

MPV reductions with aluminum(III) isopropoxide as the catalyst can be hugely enhanced by microwave irradiation [96]. 

In summary, the reduction of ketones and aldehydes can both be performed with MPV and transition-metal complexes as catalysts. Reductions of alkenes, al-kynes, and imines require transition-metal catalysts MPV reductions with these substrates are not possible. 

Aluminum Alkoxides and the Meerwein-Ponndorf-Verley (MPV) Reduction... 

In an NMR study of the MPV reduction of acetophenone with Al(OtV)3, Shiner and Whittaker (118,119) showed that the trimer is more reactive than the tetramer. Furthermore, the rate-determining step is alcoholysis of the mixed alkoxide, and not hydride transfer. They proposed that the ketone coordinates directly with trimer or tetramer by expansion of die coordination number of aluminum, and not with monomeric aluminum alkoxide. 

Kumbhar et al. found that Mg/Al-COs LDHs heated in N2 up to 823 K are highly active and selective catalysts for the Uquid phase MPV reduction of carbonyl compounds using 2-propanol as the hydrogen donor [46] the catalysts can also readily be regenerated. The same LDH precursor after thermal decarbonation and rehydration has been used in the cyanoethylation of alcohols [54], showing high activity and air stabihty (in contrast to other soUd base catalysts). 

The Meerwein-Ponndorf-Verley (MPV) reduction [236] of carbonyl moieties to produce the corresponding alcohols is usually conducted under the influence of stoichiometric or excessive amounts of Al-based catalysts, in particular Al(0 Pr)3 ... 

Scheme 12.26 Proposed mechanism for the MPV reduction catalyzed by MCM-41-supported Nd-alkoxide complexes (1 and 8A-D) (i) and (iv) alcohol exchange reactions (ii) adduct formation and (iii) acetone elimination.

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. 

With j -branched aluminium alkyls like Al(i-Bu)3, reduction is often the main reaction [52]. Ligand modification can be used to increase the amount of reduction still further, and also to control the diastereoselectivity. In this respect, the phenoxide-modified complex 7 appears to be particularly effective [53]. A recurring problem in diastereoselective reductions is that the product can epimerize through MPV reduction (see next section) of the starting material [54]. The kinetics of this complicated system have been analyzed in terms of the iso-inversion principle [55]. 

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. 

In principle, one could write two mechanisms for the MPV reduction a stepwise mechanism involving a discrete hydride intermediate, and a direct hydride transfer from alkoxide to ketone. These alternatives are similar to the two mechanisms usually assumed for transition-metal-catalyzed transfer... 

Finally, for MPV reduction we find nearly equal barriers for aluminium and gallium, and a much lower one for magnesium. Again, one should be careful not to attach too much value to these numbers, since for magnesium-catalyzed MPV, in particular, the metal will probably prefer a higher coordination number than 4. 

Meerwein-Ponndorf-Verley-Type Reduction Reduction of ketones by 2-propanol or related alcohols, known as Meerwein-Ponndorf-Verley (MPV) reduction, is promoted by various metal alkoxides, typically aluminum 2-propoxide [2a,d,281]. The C2 hydrogen of 2-propanol is transferred directly to the carbonyl carbon through a six-membered pericyclic transition state [284], Earlier, a stoichiometric quantity of a metal alkoxide was required for this purpose, but recently, lanthanide [285] and aluminum [286] complexes acting as excellent catalysts have been reported. 

A tandem 1,4-addition-Meerwein-Ponndorf-Verley (MPV) reduction allows the reduction of a, /i-unsaturated ketones with excellent ee and in good yield using a camphor-based thiol as reductant.274 The 1,4-addition is reversible and the high ee stems from the subsequent 1,7-hydride shift the overall process is thus one of dynamic kinetic resolution. A crossover experiment demonstrated that the shift is intramolecular. Subsequent reductive desulfurization yielded fiilly saturated compounds in an impressive overall asymmetric reductive technique with apparently wide general applicability. 

Intramolecular hydride transfer under MPV reduction conditions occurs in substrate (25) with complete stereospecificity to generate (26).275 A 2 1 mixture of product to reactant was observed, irrespective of reaction tune or relative excess of Al(0 Pr)3, indicative of an equilibrium, hitennolecular hydride transfer to give (27) does not occur and the absence of the epimer of (25) implies that complete stereodifferentiation also occurs in the reverse process (Oppenhauer oxidation). Stereodifferentiation under... 

Recent mechanistic studies on transition metal-catalysed hydrogen transfer reactions have been reviewed. Experimental and theoretical studies showed that hydrogen transfer reactions proceed through different pathways. For transition metals, hydridic routes are the most common. Within the hydridic family there are two main groups the monohydride and dihydride routes. Experimentally, it was found that whereas rhodium and iridium catalysts favour the monohydride route, the mechanism for ruthenium catalysts proceeds by either pathway, depending on the ligands. A direct hydrogen transfer mechanism has been proposed for Meerwein-Ponndorf-Verley (MPV) reductions.352... 

High yields and enantiopurity have been realized by a highly diastereoselective MPV reduction of protected a-amino aromatic ketones using catalytic amounts of aluminium isopropoxide. The high anti selectivity resulted from the chelation of the (g) nitrogen anion to the aluminium. In contrast, high syn selectivity was obtained with a-alkoxy ketones and other compounds via Felkin-Ahn control.354... 

Grignard Reagents will sometimes yield the result of an MPV reduction if the carbonyl carbon is too hindered for nucleophilic addition. 

Catalytic Oppenauer oxidations (Eq. 28) and Meerwein-Ponndorf-Verley reductions (Eq. 29) were studied in detail [232,234]. The gadolinium derivative, employed in situ without elimination of LiCl, was reported to be ten times more reactive in the MPV reduction of cyclohexanone as the standard reagent Al(OiPr)3 [235]. 

Chiral induction was also observed in lanthanide(III)-alkoxide-mediated MPV reductions. The optically active ligand (Fig. 35C) was used in enantioselec-tive samarium-catalyzed MPV reductions of arylmethyl ketones (Scheme 30) [253], The resulting mixed alkoxide-iodide complex shows higher reactivity than (rBuO)SmI2. It was pointed out that the tridentate, secondary alkoxide ligand is not oxidized under the reaction conditions and that tridendate ligands... 

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). 

A new type of lanthanoid complex, prepared from BINOL and SmCl3, served as an asymmetric catalyst for MPV reduction of aryl methyl ketones in the presence of molecular sieves. Moderate enantioselectivity was obtained.101... 

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