Ketones, reaction with aluminum alkoxides

The Meerwein-Ponndorf-Verley (MPV) reaction is an important route in the reduction of ketones with aluminum alkoxides (111). The mechanism has been... 

As is apparent (Table 26.33), the reduction of methylcyclohexanones (entries 1, 2, 4, 6, and 7) requires longer reaction times to achieve satisfactory conversions. This results in the equilibration of epimeric alcohols, leading to higher formation of more stable alcohols (entries 6 and 7). The isomerization is because of the intermolecular hydride transfer, which is similar to Meerwein-Pondorf-Verley reduction of ketones with aluminum alkoxides (Scheme 26.8). 

There are also reactions in which hydride is transferred from carbon. The carbon-hydrogen bond has little intrinsic tendency to act as a hydride donor, so especially favorable circumstances are required to promote this reactivity. Frequently these reactions proceed through a cyclic TS in which a new C—H bond is formed simultaneously with the C-H cleavage. Hydride transfer is facilitated by high electron density at the carbon atom. Aluminum alkoxides catalyze transfer of hydride from an alcohol to a ketone. This is generally an equilibrium process and the reaction can be driven to completion if the ketone is removed from the system, by, e.g., distillation, in a process known as the Meerwein-Pondorff-Verley reduction,189 The reverse reaction in which the ketone is used in excess is called the Oppenauer oxidation. 

Dauben et al. (15) applied the Aratani catalyst to intramolecular cyclopropanation reactions. Diazoketoesters were poor substrates for this catalyst, conferring little asymmetric induction to the product, Eq. 10. Better results were found using diazo ketones (34). The product cyclopropane was formed in selectivities as high as 77% ee (35a, n = 1). A reversal in the absolute sense of induction was noted upon cyclopropanation of the homologous substrate 34b (n = 2) using this catalyst, Eq. 11. Dauben notes that the reaction does not proceed at low temperature, as expected for a Cu(II) precatalyst, but that thermal activation of the catalyst results in lower selectivities (44% ee, 80°C, PhH, 35a, n = 1). Complex ent-11 may be activated at ambient temperature by reduction with 0.25 equiv (to catalyst) DIBAL-H, affording the optimized selectivities in this reaction. The active species in these reactions is presumably the aluminum alkoxide (33). Dauben cautions that this catalyst slowly decomposes under these conditions. 

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. 

The reaction between an aluminum alkoxide and a ketone can be reversed. This is the basis of the Oppenauer oxidation of a secondary alcohol to the ketone.44 8 The aluminum derivative of the alcohol is prepared by mOans of aluminum t-butoxide and is oxidized with a large excess of acetone or cyclohexanone. 

The earliest report of a reaction mediated by a chiral three coordinate aluminum species describes an asymmetric Meerwein-Poimdorf-Verley reduction of ketones with chiral aluminum alkoxides which resulted in low induction in the alcohol products [1]. Subsequent developments in the area were sparse until over a decade later when chiral aluminum Lewis acids began to be explored in polymerization reactions, with the first report describing the polymerization of benzofuran with catalysts prepared from and ethylaluminum dichloride and a variety of chiral compounds including /5-phenylalanine [2]. Curiously, these reports did not precipitate further studies at the time because the next development in the field did not occur until nearly two decades later when Hashimoto, Komeshima and Koga reported that a catalyst derived from ethylaluminum dichloride and menthol catalyzed the asymmetric Diels-Alder reaction shown in Sch. 1 [3,4]. This is especially curious because the discovery that a Diels-Alder reaction could be accelerated by aluminum chloride was known at the time the polymerization work appeared [5], Perhaps it was because of this long delay, that the report of this asymmetric catalytic Diels-Alder reaction was to become the inspiration for the dramatic increase in activity in this field that we have witnessed in the twenty years since its appearance. It is the intent of this review to present the development of the field of asymmetric catalytic synthesis with chiral aluminum Lewis acids that includes those reports that have appeared in the literature up to the end of 1998. This review will not cover polymerization reactions or supported reactions. The latter will appear in a separate chapter in this handbook. 

The most extensive application of the Oppenauer oxidation has been in the oxidation of steroid molecules. The most common aluminum catalysts are aluminum /-butoxide, i-propoxide, and phenoxide. While only catalytic amounts of the aluminum alkoxide are theoretically required, in practice at least 0.25 mole of alkoxide per mole of alcohol is used. Acetone and methyl ethyl ketone have proved valuable hydride acceptors due to their accessibility and ease of separation from the product, whereas other ketones such as cyclohexanone and p-benzoquinone are useful alternatives, due to their increased oxidation potentials.4 Although the reaction can be performed neat, an inert solvent to dilute the reaction mixture can reduce the extent of condensation, and, as such, benzene, toluene, and dioxane are commonly utilized. Oxidation of the substrate takes place at temperatures ranging from room temperature to reflux, with reaction times varying from fifteen minutes to twenty-four hours and yields ranging from 37% to 95%. 

F.H. Oppenauer Oxidation. In oxidation reactions involving both Cr(VI) and DMSO reagents, the alcohol is converted to a complex in which the a-hydrogen of an alcohol can be removed as an acid. A classical and alternative method for the oxidation of alcohols focuses on the reversible reaction between ketones and metal alkoxides, which is especially effective when the metal is aluminuml34 xhe reversibility of the aluminum alkoxide reaction was first demonstrated by Verley 35 Ponndorf 36 for the reaction of a ketone with an aluminum alkoxide, which led to formation of a new aluminum alkoxide and a new ketone. In... 

When used in combination with TBHP, DIBAL can promote the oxidation of alcohols into the corresponding ketones via an Oppenauer type reaction with the TBHP being reduced by the aluminum alkoxide (eq 39). In the case of allylic alcohols, this combination affords the epoxidation products (eq 40). ... 

Aluminum alkoxides catalyze transfer of hydride from alcohols to ketones. This reaction can be driven to completion if one of the ketones is removed from the reaction system— by distillation, for example. This reaction, usually carried out with... 

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. 

Type-II intramolecular ene reactions of aldehydes and ketones proceed readily with Me2AICl as the Lewis acid. " Unsaturated aldehydes and ketones can be generated in situ by Mc2 AlCl-catalyzed reaction of Acrolein and Methyl Vinyl Ketone with alkylidenecycloalkanes at low temperatures (eq 12). The mono-cyclic aldehyde reacts further under these conditions. The mono-cyclic ketone can be isolated at low temperature but undergoes a second ene reaction at rt to give the bicyclic alcohol. p-Keto esters form tertiary alcohols in intramolecular ene reactions. The products are stable because they are converted to the aluminum alkoxide (eq 13). Intramolecular Me2AlCl-catalyzed ene reactions have been used for the preparation of the bicyclic mevinolin ring system (eq 14). ... 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

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