Alcohols from ester reduction

Studies of reductions with metal hydndes have concentrated on improvements in selectivity or conditions Replacement of the usual lithium aluminum hydnde-ether combination with potassium borohydride-methanol results m high yields of alcohol from ester [76] and less hazard [77] (equation 62) Reduction of a... 

Both older methods for the reduction of esters to alcohols, catalytic hydrogenation and reduction with sodium, have given way to reductions with hydrides and complex hydrides which have revolutionized the laboratory preparation of alcohols from esters. 

Alcohols from esters. The major problem is reaction selectivity. Paraffin by-product in alcohol results if the catalyst activity is too high. Yet the reduction of esters to alcohols is a difficult reaction. Copper chromite catalyst, 3000-5000 psig hydrogen, and a temperature of 270-300°C are required for the reduction. An alternate catalyst is CuO/ZnO, which is used for methyl ester reduction only. Hydrogen solubility in alcohol is limiting. 

In the amide reduction scheme on p. 618, the step framed in green gives an iminium ion. Stopping the reaction here would therefore provide a way of making aldehydes from amides. Because these tetrahedral intermediates are rather more stable than those from ester reduction, this can often be achieved simply by carrying out the amide reduction, and quenching, at 0°C (-70 °C is usually needed to stop esters overreducing to alcohols). 

NaAlH4 [CB5] or LAH-N-methylpyrrolidine [FSl] is also an efficient reducing agent, as is excess AlHj EtjN [CB7], All these reductions are run in THF at 0°C or at r.t. Ate complexes formed from DIBAH and -BuLi in THF-hexane at r.t. also give alcohols from esters [KAl]. Red-Al in petroleum ether allows the selective reduction of long-chain bromoesters to bromoalcohols [W8],... 

DNA sequence of 12 million nucleotides and 6000 genes has been determined.165 It can be used to reduce /3-ke-toesters in petrol plus a small amount of water to the S alcohol ester in 100% conversion with more than 98%ee.166 When only water is used as the medium, the enantioselec-tivity is reduced greatly.167 In contrast with baker s yeast and Geotrichum candidum,168 which produce the S alcohols from the reduction of ketones, Yarrowia lipolytica gives the R isomer, but in only moderate yields.169 Pichia farinosa also produces the R isomer.170 (For more on the preparation of single optical isomers, see Chap. 10.) Other reductions can also be carried out with baker s yeast as shown in 9.15 for the quinoline oxide.171... 

Alexander Mikhaylovich Saytzev (Saytzeff) (Kazan 20 June 1841 (O.S.)-2 September 1910) studied with Kolbe in Marburg and Leipzig, and was professor in the University of Kazan. He discovered the synthesis of primary and secondary alcohols from esters, ketones, and aldehydes by the action of zinc and alkyl iodides (see Reformatsky, p. 858). He also discovered aliphatic sulphoxides. His brother Mikhayl Mikhaylovich (b. Kazan, 30 August 1845), at first his assistant and later manager of a chemical works in Kazan, discovered the reduction of acid chlorides to aldehydes by hydrogen gas in presence of palladium. ... 

Alcohols may also be prepared by esterification of carboxylic acids followed by reduction. See section 38 (Alcohols from Esters)... 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

By reduction with zinc-dust and acetic acid it yields the acetic ester of perillic alcohol, from which the alcohol itself is separated by saponification. 

Butylcyclohexanol has been prepared from />-/-butylphenol by reduction under a variety of conditions.3 4 Winstein and Holness5 prepared the pure trans alcohol from the commercial alcohol by repeated crystallization of the acid phthalate followed by saponification of the pure trans ester. Eliel and Ro 6 obtained 4-f-butylcyclohexanol containing 91% of the trans isomer by lithium aluminum hydride reduction of the ketone. Iliickel and Kurz 7 reduced />-/-butylphenol with platinum oxide in acetic acid and then separated the isomers by column chromatography. 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

The procedure is outlined in Scheme 8.33, starting from the generic allylic alcohol 125. SAE on 125 would provide epoxide 126, which could easily be transformed into the unsaturated epoxy ester 127 by oxidation/Horner-Emmonds olefmation (two-carbon extension). This operation makes the oxirane carbon adjacent to the double bond more susceptible to nucleophilic attack by a hydride, so reductive opening (DIBAL) of 127 provides, with concomitant ester reduction, diol 128. Pro-... 

The reaction tolerates ketone, chloride, internal C=C bonds, esters, nitriles, and ether functional groups. Given that the DIBAL-H reduction of acid derivatives often suffers from over-reduction to alcohols, these catalytic procedures are of synthetic value for laboratory-scale syntheses. However, it is likely that the requirement for excess (tBuCO)20 will prevent this reaction from ever being used in commercial production. 

In contrast to phenolic hydroxyl, benzylic hydroxyl is replaced by hydrogen very easily. In catalytic hydrogenation of aromatic aldehydes, ketones, acids and esters it is sometimes difficult to prevent the easy hydrogenolysis of the benzylic alcohols which result from the reduction of the above functions. A catalyst suitable for preventing hydrogenolysis of benzylic hydroxyl is platinized charcoal [28], Other catalysts, especially palladium on charcoal [619], palladium hydride [619], nickel [43], Raney nickel [619] and copper chromite [620], promote hydrogenolysis. In the case of chiral alcohols such as 2-phenyl-2-butanol hydrogenolysis took place with inversion over platinum and palladium, and with retention over Raney nickel (optical purities 59-66%) [619]. 

Reduction of esters by trichlorosilane in tetrahydrofuran in the presence of tert-butyl peroxide and under ultraviolet irradiation gave predominantly ethers from esters of primary alcohols, while esters of tertiary alcohols were cleaved to acids and hydrocarbons. Esters of secondary alcohols gave mixtures of ethers and acids/hydrocarbons in varying ratios. 1-Adamantyl trimethylacetate, for example, afforded 50-100% yields of mixtures containing 2-42% of 1-adamantyl neopentyl ether and 58-98% of adamantane and trimethylacetic acid [1033]. 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

The next stage would involve conversion of 18 to a tetra acylated pentaol with a uniquely exposed axial alcohol at C5. Early difficulties were encountered in attempts to cleave the lactone to its corresponding hydroxy ester. Difficulties were also experienced in manipulating the highly polar compounds arising from attempted reductive opening of 18. 

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