Reduction of Aliphatic Ketones

Reduction of saturated ketones to alcohols is very easy by many means but is distinctly slower than that of comparable aldehydes. It is frequently possible to carry out selective reductions of the two types (p. 97). 

Transformation of ketones to alcohols has been accomplished by many hydrides and complex hydrides by lithium aluminum hydride [55], by magnesium aluminum hydride [89], by lithium tris tert-butoxy)aluminum hydride [575], by dichloroalane prepared from lithium aluminum hydride and aluminum chloride [816], by lithium borohydride [750], by lithium triethylboro-hydride [100], by sodium borohydride [751,817], by sodium trimethoxyborohy-dride [99], by tetrabutylammonium borohydride [771] and cyanoborohydride [757], by chiral diisopinocampheylborane (yields 72-78%, optical purity 13-37%) [575], by dibutyl- and diphenylstannane [114], tributylstanrume [756] and others Procedure 21, p. 209). 

As a consequence of the wide choice of hydride reagents the classical methods such as reduction with sodium in ethanol almost fell into oblivion [579, 520]. Nevertheless some old reductions were resuscitated. Sodium di-thionite was found to be an effective reducing agent [262], and the reduction by alcohols [309] was modified to cut down on the temperature [755] or the time required [527], or to furnish chiral alcohols ( in good yields and excellent optical purity ) by using optically active pentyl alcohol and its aluminum salt [522]. Formation of chiral alcohols by reduction of pro-chiral ketones is 

For the reduction of aliphatic ketones to hydrocarbons several methods are available reduction with triethylsilane and boron trifluoride [772], Clemmensen reduction [160, 758] (p. 28), Wolff-Kizhner reduction [280, 281, 759] (p. 34), reduction of p-toluenesulfonylhydrazones with sodium borohydride [785], sodium cyanoborohydride [57i] or borane [786] (p. 134), desulfurization of dithioketals (jaeicaipioles) [799,823] (pp. 130,131) and electroreduction [824]. 

Somewhat less frequent than the reductions of aliphatic ketones to secondary alcohols and to hydrocarbons are one-electron reductions to pinacols. These are accomplished by metals such as sodium, but better still by magnesium or aluminum. Acetone gave 43-50% yield of pinacol on refluxing with magnesium amalgam in benzene [140], and 45% and 51% yields on refluxing in methylene chloride or tetrahydrofuran, respectively [825.  

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The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

B.2. Reduction of aliphatic ketones using the ruthenium complex of 49... 

Fig. 23. Reduction of aliphatic ketones and some ketoesters with ruthenium complexes of 49 yields and ee values refer to isolated pure products.

High enantioselectivities (up to 94%) are obtained in the sodium borohydride reduction of aliphatic ketones using a tartaric acid-derived boronic ester (TarB-N02) as a chiral catalyst. A mechanism (Scheme 14) involving an acyloxyborohydride intermediate has been postulated.319... 

Usually, a stoichiometric amount of metal hydride, such as a selectride reagent, is required for diastereoselective reduction of aliphatic ketones to secondary alcohols. Now the same purpose can be achieved by the Ru-catalysed diastereoselective... 

A study on the reduction of aliphatic ketones, which contributed to understanding the mechanism and provided some examples of synthetic interest, has been in progress in our laboratory. It has involved the reduction of aliphatic ketones in organic solvents with (C4H9)4NBF4 as the electrolyte and dimethylpyrrolidinium (DMP+) in small concentrations as the catalyst. Most of the substrates listed below do not exhibit reduction waves or peaks in the potential window . The reduction of all the substrates can be catalyzed by DMP+ and in the presence of the catalyst preparative reductions could be carried out at potentials at which the substrates are otherwise electroinactive. Catalysis was also ascertained with CV and polarographic measurements like those described in the introduction for cyclohexanone. Product analysis... 

Asymmetric hydride reduction. The complex (2) prepared in situ from 1, LiAlH4, and ethanol (1 1 1 ratio) reduces alkyl aryl ketones to the corresponding (S)-alcohols in 85-98% ee. Optical yields are only moderate (20-35%) in reductions of aliphatic ketones. The complex is comparable to the related complex obtained using optically active 2,2 -dihydroxy-1,1 -binaphihyl (9, 169-170). 

Seleetive reduction of aliphatic ketones and aldehydes to hydrocarbons Aliphatic... 

It was suggested in the 1950s that the reduction of aliphatic ketones by dissolving metals proceeded by two sequential one-electron additions to provide a dianion (equation 1). This mechanism was based on the observation that benzophenone affords a dianion on reaction with excess Na in liquid NH3, and it was inferred that aliphatic ketones would behave similarly. A number of workers presented mechanistic rationalizations for the stereochemical course of the dissolving metal reductions of cyclic aliphatic ketones based on this dianion concept. However, in a 1972 review, it was noted that the reduction potentials of alkali metals were not sufficient to effect the addition of two electrons to an aliphatic carbonyl group, and an alternative mechanism was suggested which with some modification is now generally accepted. ... 

Selective reduction of aliphatic ketones and aldehydes to hydrocarbons,6 Aliphatic ketones and aldehydes can be reduced selectively in high yields to hydrocarbons with sodium cyanoborohydride and p-toluenesulfonylhydrazine in DMF-sulfolane containing p-toluenesulfonic acid at 100-105°. The prior preparation of tosylhydrazones is not necessary because carbonyl groups are reduced slowly by sodium cyanoborohydride. Maximum yields are obtained with a fourfold molar excess of NaBH3CN. Yields are in the range 62-98%. Ester groups, if present, are not affected. Aromatic ketones are not reduced. 

A complex Zn(BH4)2-1.5 DMF has been described [HJl]. This shows a greater selectivity than Zn(BH4)2 in diethylether and does not react with the a-enones. In MeCN, this complex allows the reduction of aldehydes in the presence of ketones, the reduction of some sterically unhindered ketones in the presence of other less accessible ketones, or even the reduction of aliphatic ketones in the presence of aromatic ones (Section 3.2.1). 

The alcohol dehydrogenase from Thermoanaerobium brockii is very suitable for the reduction of aliphatic ketones[18, 19L Even very simple aliphatic ketones can be reduced enantioselectively. An interesting substrate size-induced reversal of enantio-selectivity was observed. The smaller substrates (methyl ethyl, methyl isopropyl or methyl cyclopropyl ketones) were reduced to the (R)-alcohols, whereas higher ketones produced the (S -enantiomers. 

This example and the next one (Sect. 15.1.4.5) using G. candidum show that the biocatalytic reduction system is very beneficial for the reduction of aliphatic ketones over a non-enzymatic system where no report on highly enantioselective (> 99% ee) reduction of unfunctionalized dialkyl ketones can be found, to the best of our knowledge. 

Table 15-13. Asymmetric reduction of aliphatic ketones with the alcohol dehydrogenase from Thermoanaerobium brockii11.

This reagent reduces 1-phenylethanone to (Sf-l-phcnylcthanol with 77% ee. A useful feature of this reagent is that it is effective for the asymmetric reduction of aliphatic ketones, such as 2-octanone. and is thus one of the few reagents which will effectively reduce this class of ketones. 

Clemmensen500 has described the preparation of H-undecane from 2-un-decanone as an example of the reduction of aliphatic ketones to straight-chain hydrocarbons ... 

Several new chiral modifications of lithium aluminium hydride have been reported, including those formed by reaction with chiral secondary benzylamines (14), with diols such as (15) derived from D-mannitol, or with terpenic glycols such as (16). These complexes reduce phenyl alkyl ketones to optically active phenyl carbinols, and enantiomeric excesses of up to 50% have been observed in the case of reagents derived from (14). However, in the diol complexes, believed to have structures of the type shown in (17), lower chiral selectivity is observed, e.g. up to ca. 12% in the case of (15), or up to an optical yield of 30% with an ethanol-modified complex of (16). Better results have been reported with the chiral diamine complex (18), derived originally from L-proline, which reduces acetophenone in 92% optical yield. Asymmetric induction with reagents in this class (i.e. derivatives of lithium aluminium hydride) is usually low in the reduction of aliphatic ketones, but a complex of UAIH4 and the amino-alcohol (19) has been shown to reduce... 

Table 10.1 Reduction of aliphatic ketones by the dried cell of G. candidum, NAD+ and secondary alcohol ...

See also Itsuno, S, Ito, K, HIrao, A, Nakahama, S, Asymmetric Reduction of Aliphatic Ketones with the Reagent Prepared from (S)-(-)-2-Amino-3-methyl-1,1-dlphenylbutan-1-ol and Borane" J. Org. Chem. 1984,49,555-557. Fora review see Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986-2012,... 

Masamune s Chiral 2,5-Dimethylborolanes Enantioselective reduction of aliphatic ketones like 2-butanone, 4-methyl-2-pentanone, and several others where both the appendages of the carbonyl group are stericaUy similar is very chaUenging. Masamune s dimeric ligand (RJi)- (Scheme 2.138) or (5,5)-2,5-dimelhylborolane (not shown) is very efficient in reducing those types of ketones [66]. 

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