Reduction with Aluminum Alkoxides

Manufacture. Hydroxypivalyl hydroxypivalate may be produced by the esterification of hydroxypivaUc acid with neopentyl glycol or by the intermolecular oxidation—reduction (Tishchenko reaction) of hydroxypivaldehyde using an aluminum alkoxide catalyst (100,101). 

Evans, D.A. Nelson, S.G. Gagne, M.R. Mud, A.R. J. Am. Chem. Soc., 1993,115,9800. It has been that shown in some cases reduction with metal alkoxides, including aluminum isopropoxide, involves free-radical intermediates (SET mechanism) Screttas, C.G. Cazianis, C.T. Tetrahedron, 1978, 34, 933 Nasipuri, D. Gupta, M.D. Baneijee, S. Tetrahedron Lett., 1984, 25, 5551 Ashby, E.C. Argyropoulos, J.N. Tetrahedron Lett.,... 

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. 

Reduction of Carbonyl Compounds with Aluminum Alkoxides... 

The pioneering work of Posner, on the reduction of carbonyl compounds with isopropyl alcohol and alumina [116], has now been adapted to an expeditious solvent-free reduction procedure that utilizes aluminum alkoxides under microwave irradiation conditions (Scheme 6.37) [117]. 

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. 

Carbonyl compounds addition to, 73 659 a-alkylation of, 73 658s reduction with alumina—sodium borohydride, 76 572-573 reduction with aluminum alkoxides, 76 572... 

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

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. 

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. 

Modified MPV-type reductions carried out with chiral magnesium alkoxides and with chiral Grignard reagents have been discussed in detail (1). These reagents differ from the aluminum alkoxides since the Grignard reaction is essentially irreversible. Chiral alkali metal alkoxides have also been used to effect asymmetric reductions (1). 

Moreover, alcohol functionalities have been introduced into the polynor-bornene (PNB) backbone by copolymerization of norbornene with a few percent of 5-acetate norbornene and subsequent acetate reduction. After transformation of the pendant hydroxyl functions into diethyl aluminum alkoxides, sCL has been ring opening polymerized (Scheme 31). Owing to the controlled/ liv-ing character of both polymerization processes the isolated poly(NB- -CL) graft copolymers were characterized by well-defined composition, controlled molecular weight and branching density, and narrow MWD (PDI=1.2-1.4) [92]. 

The Meerwein-Ponndorf-Verley reduction (reduction with aluminum alkoxides). Wilds, A.L., Org. Reactions 2, 178 (1944). 

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 mechanism for reduction by LiAlH4 is very similar. However, because LiAlH4 reacts very rapidly with protic solvents to form molecular hydrogen, reductions with this reagent must be carried out in aprotic solvents, usually ether or THF. The products are liberated by hydrolysis of the aluminum alkoxide at the end of the reaction. 

REDUCTION WITH ALUMINUM ALKOXIDES (The Meerwein-Ponndorf-Verley Reduction)... 

Table I. Reduction of Aldehydes with Aluminum Alkoxides.206...

---