Ketones, reduction with aluminum alkoxides

The following tables are intended to include all the reductions with aluminum alkoxides which were reported prior to February, 1943, although some examples doubtless have been overlooked. Table I lists the reduction of aldehydes, which have been subdivided into (a) aliphatic aldehydes and (b) alicyclic and aromatic aldehydes. Table II lists the reduction of ketones, which have been classified as (a)-satu-rated and unsaturated aliphatic ketones, (b) aromatic ketones, (c) alicyclic ketones, (d) unsaturated alicyclic and aromatic ketones, (e) a- — halogen substituted ketones, (f) diketones, (g) protected diketones, (h) alcoholic and phenolic ketones (and ethers or esters of these), and (i) keto esters. 

Jackman, L. M. Macbeth, A. K. and Mills, J. A., Reductions with aluminum alkoxides. Part 1. The relative proportion of epimers in alcohols derived from cyclic ketones. J. Chem. Soc., 2641-2646,1949. 

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

Early studies of the asymmetric reduction of prochiral ketones by chiral aluminum alkoxides have been reviewed by Morrison and Mosher (1). Doering and Young (123) reported the reduction of methyl cyclohexyl ketone with chiral 3-methyl-2-butanol in the presence of a catalytic amount of aluminum alkoxide to give the (S)-( + )-carbinol in a 22% optical yield. Jackman and co-workers (124) similarly reduced methyl n-hexyl ketone with chiral 3,3-dimethyl-2-butanol to the (S)-( - )-carbinol in a 6% optical yield. Other attempts resulted in similar low optical yields or gave only racemic products. Since the reductions were carried out under equilibrium conditions, racemization could have accounted for the low optical yields. 

Reduction of aldehydes or ketones to the corresponding alcohols with aluminum alkoxides. 

Reduction of aldehydes or ketones to the corresponding alcohols with aluminum alkoxides (the reverse of the Oppenauer oxidation, q.v.) ... 

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. 

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. 

Catalytic reduction of codeine gives dihydrocodeine and Oppenauer oxidation (a ketone such as acetone and an aluminum alkoxide, the ketone being reduced to an alcohol) gives hydrocodone. Hydrocodone can also be prepared directly from codeine with a metal catalyst, which isomerizes the allylic alcohol to a ketone. Codeine is prepared by methylation of morphine, which is isolated from the opium poppy. Hydrocodone is more potent than codeine. Acetaminophen is a mild analgesic and is discussed in Section 8. 

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. 

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. 

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... 

Scheme 20.28) [84, 118]. The first step in this procedure is reduction of the ketone, followed by the acetylation of the formed alkoxide. It may be noted that aluminum(III) isopropoxide and zirconium(IV) isopropoxide do not catalyze the acetylation. With these catalysts, the alcohol is obtained. 

The pinacol-like rearrangement of halohydrins typically require elevated temperatures or extended reaction times. One notable exception is the low temperature rearrangement of vinyl alcohols 12. derived from the corresponding a-halo ketones by addition of a metalloalkyne and direct reduction of the resulting adduct with lithium aluminum hydride, providing an efficient and stereocontrolled access to a-alkenyl alcohols 1364-6 The intermediacy of vinyl alcohols 12, as a necessary precedent to rearrangement has been inferred from the observation that metal alkoxides 11 (M = Li, Mg) do not rearrange under the reaction conditions and are stable even at elevated temperatures. 

Unlike sodium borohydride, lithium aluminum hydride reacts violently with water, alcohols, and other protic solvents to liberate hydrogen gas and form metal hydroxides and alkoxides. Therefore, reductions of aldehydes and ketones using this reagent must be carried out in aprotic solvents, most commonly diethyl ether or tetrahydrofuran. The stoichiometry for lithium aluminum hydride reductions is the same as that for sodium borohydride reductions one mole of lithium aluminum hydride per four moles of aldehyde or ketone. Because of the formation of gelatinous aluminum salfs, aqueous acid or base workup is usually used to dissolve them. 

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