Ketones metal hydride reductions

The reduction of an asymmetric cyclohexanone (e.g. a steroidal ketone) can lead to two epimeric alcohols. Usually one of these products predominates. The experimental results for the reduction of steroidal ketones with metal hydrides have been well summarized by Barton and are discussed in some detail in a later section (page 76) unhindered ketones are reduced by hydrides to give mainly equatorial alcohols hindered ketones (more accurately ketones for which axial approach of the reagent is hindered " ) are reduced to give mainly axial alcohols. 

Similar 1,2-addition reactions were also observed in the reaction of 2,3-allenal with organolithiums, Grignard reagents or the reduction of 1,2-allenyl ketones with metal hydrides [190],... 

Reductions of certain aromatic ketones with metal hydrides have been shown to involve radical intermediates formed by an electron-transfer mechanism (25). For example, the reaction of aluminum hydride with dimesityl ketone in THF produced a violet solution that gave an EPR spectrum indicative of the presence of a paramagnetic species. The paramagnetic species is an intermediate in the reduction of the ketone, and is believed to be a radical cation-radical anion pair (25). 

In some circumstances, the production of a 2-halo alcohol by reduction of the carbonyl group of an a-halo ketone with metal hydrides is a useful synthetic reaction ... 

Asymmetric reduction of prochiral ketones. Chiral metal hydrides previously investigated have been effective only for asymmetric reduction of aromatic or a,p-ucclylenic ketones. This new reagent unexpectedly reduces straight-chain aliphatic ketones such as 2-bulanonc and 2-octanone to the corresponding (S)-alcohols in 76%... 

Optically active aliphatic propargylic alcohols are converted to corticoids (90% ee) via biomimetic polyene cyclization, and to 5-octyl-2(5ii)-furanone. The ee s of propargylic alcohols obtained by this method are comparable with those of the enantioselective reduction of alkynyl ketones with metal hydrides, catalytic enantioselective alkylation of alkynyl aldehydes with dialkyIzincs using a chiral catalyst ((S)-Diphenyl(l-methylpyrrolidin-2-yl)methanol) (DPMPM), and the enantioselective alkynylation of aldehydes with alkynylzinc reagents using A(A-dialkylnorephedrines. °... 

The stereochemistry and mechanism of reduction of cyclic ketones by metal hydride reagents provided a unique Of rtunity for comparison of experimental results with theoretical expectation. The models proposed by Cram, Comforth and Karabatsos described above were inadequate to explain the stereochemical outcome, and so a wide range of models was developed to explain the dichotomy between cyclic and acyclic results. The theoretical basis, applications and limitations of these models have been critically reviewed. The effect of steric influences, torsional and electronic factors, and the nature of the cation on the rate of reduction, stereochemical outcome and position of the transition state have also been surveyed. ... 

Rationalization of the stereochemical results obtained from reduction of substituted cyclohexanones with hydrides has resulted in controversy. Reductions of ketones with metal hydrides are exothermic and according to the Hammond postulate, the transition states should be reactant-like. 

The reduction of unsaturated carbonyl compounds by metal hydrides, and the reaction of organometallic nucleophiles with them, is a complicated story.87 It is more common than not, in each case, to get direct attack at the carbonyl group, but reaction in the conjugate position is well known. Conjugate reduction of a/i-unsaturated ketones by metal hydrides increases88 in the sequences Bu2iAlH < LiAlH4 < LiAlH(OMe)3 < LiAlH(OBu )3 and... 

A hydroxybomeol (angelicoidienol, 790) was isolated from Pleurospermum angelicoidesf it was identical with the diol synthesized by Money et al. in 1979 by remote oxidation of bomyl acetate (348) with chromic oxide in acetic anhydride and acetic acid this yielded 40% of the ketone 791, metal hydride reduction of which gave the diol 790. ... 

A discussion of the stereoselectivity in the reduction of ketones by metal hydrides gives an excellent route to axial alcohols ... 

Many miscellaneous exchange reactions are reported in the literature. " Afew are presented here. One such reaction is reduction of pendant carbonyl groups of poly(vinyl methyl ketone) with metal hydrides ... 

Later, Zhu et al. [70] have also investigated the catalytic activity of thiolate-capped Au25(SR) jg in the stereoselective hydrogenation ofbicyclic ketone 7-(phenylmethyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-one. In industry, these kinds of cyclic alcohol are synthesized by the reduction ofbicyclic ketones by metal hydrides such as NaBH4. This process will yield equal amounts of two isomers. A 100% stereoselectivity to... 

For most laboratory scale reductions of aldehydes and ketones catalytic hydro genation has been replaced by methods based on metal hydride reducing agents The two most common reagents are sodium borohydride and lithium aluminum hydride... 

The reduction of a ketone by a metal hydride involves the formation of two bonds the linking of the carbonyl carbon to a hydride and the formation of a metal oxygen bond (4). 

By a suitable choice of conditions (metal hydrides or metal/ammonia) ketones at the 1-, 2-, 4-, 6-, 7-, 11-, 12- and 20-positions in 5a-H steroids can be reduced to give each of the possible epimeric alcohols in reasonable yield. Hov/ever, the 3- and 17-ketones are normally reduced to give predominantly their -(equatorial) alcohols. Use of an iridium complex as catalyst leads to a high yield of 3a-alcohol, but the 17a-ol still remains elusive by direct reduction. 

Reduction of Ketones and Enones. Although the method has been supplanted for synthetic purposes by hydride donors, the reduction of ketones to alcohols in ammonia or alcohols provides mechanistic insight into dissolving-metal reductions. The outcome of the reaction of ketones with metal reductants is determined by the fate of the initial ketyl radical formed by a single-electron transfer. The radical intermediate, depending on its structure and the reaction medium, may be protonated, disproportionate, or dimerize.209 In hydroxylic solvents such as liquid ammonia or in the presence of an alcohol, the protonation process dominates over dimerization. Net reduction can also occur by a disproportionation process. As is discussed in Section 5.6.3, dimerization can become the dominant process under conditions in which protonation does not occur rapidly. 

Eliel, E. L., and M. N. Rerick Reduction with Metal Hydrides, VIII. Reduction of Ketones and Epimerization of Alcohols with Lithium-Aluminium Hydride — Aluminium Chloride. J. Amer. chem. Soc. 82, 1367 (1960). 

Tributyltin hydride reduction of carbonyl compounds. The reduction of carbonyl compounds with metal hydrides can also proceed via an electron-transfer activation in analogy to the metal hydride insertion into TCNE.188 Such a notion is further supported by the following observations (a) the reaction rates are enhanced by light as well as heat 189 (b) the rate of the reduction depends strongly on the reduction potentials of ketones. For example, trifluoroacetophenone ( re<1 = —1.38 V versus SCE) is quantitatively reduced by Bu3SnH in propionitrile within 5 min, whereas the reduction of cyclohexanone (Erea — 2.4 V versus SCE) to cyclohexanol (under identical... 

Bonne, J. R., Reduction of Cyclic and Bicyclic Ketones by Complex Metal Hydrides, 11, 53. Bonner, W. A., Origins of Chiral Homogeneity in Nature, 18, 1. 

The effect of cryptands on the reduction of ketones and aldehydes by metal hydrides has also been studied by Loupy et al. (1976). Their results showed that, whereas cryptating the lithium cation in LiAlH4 completely inhibited the reduction of isobutyraldehyde, it merely reduced the rate of reduction of aromatic aldehydes and ketones. The authors rationalized the difference between the results obtained with aliphatic and aromatic compounds in terms of frontier orbital theory, which gave the following reactivity sequence Li+-co-ordinated aliphatic C=0 x Li+-co-ordinated aromatic C=0 > non-co-ordinated aromatic C=0 > non-co-ordinated aliphatic C=0. By increasing the reaction time, Loupy and Seyden-Penne (1978) showed that cyclohexenone [197] was reduced by LiAlH4 and LiBH4, even in the presence of [2.1.1]-cryptand, albeit much more slowly. In diethyl ether in the absence of... 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

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