Ketones reduction with complex metal hydrides

The main methods of reducing ketones to alcohols are (a) use of complex metal hydrides (b) use of alkali metals in alcohols or liquid ammonia or amines 221 (c) catalytic hydrogenation 14,217 (d) Meerwein-Ponndorf reduction.169,249 The reduction of organic compounds by complex metal hydrides, first reported in 1947,174 is a widely used technique. This chapter reviews first the main metal hydride reagents, their reactivities towards various functional groups and the conditions under which they are used to reduce ketones. The reduction of ketones by hydrides is then discussed under the headings of mechanism and stereochemistry, reduction of unsaturated ketones, and stereochemistry and selectivity of reduction of steroidal ketones. Finally reductions with the mixed hydride reagent of lithium aluminum hydride and aluminum chloride, with diborane and with iridium complexes, are briefly described. 

Thus, in the fine chemicals industry, reduction of ketones and aldehydes relies mainly on the use of complex metal hydrides that require time-consuming workup of reaction mixtures and produce significant amounts of inorganic and organic wastes. Similarly, the oxidation of alcohols into carbonyls is traditionally performed with stoichiometric inorganic oxidants, notably Cr(VI) reagents or a catalyst in combination with a stoichiometric oxidant [1]. 

In the steroid field, a comparison of product ratios with those resulting from reductions with alkali metals reveals both similarities and differences, which led Dauben and co-workers [i] to postulate in 1956 that the observed stereochemical composition of products is a consequence of the interplay of two opposed factors. So successful was Dauben s treatment that it provided a virtually complete qualitative explanation of the relative proportions of axial and equatorial alcohols from reduction of each of the common steroid ketones. Dau-ben s approach developed from Barton s recognition in 1953 [46] that sterically unhindered ketones are reduced by complex hydrides as well as by metal/alcohol systems to give... 

Numerous methods for the reduction of ketones and aldehydes to the corresponding secondary and primary alcohols, such as the use of several complex metal hydrides, have found wide application in organic synthesis. Lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) are the most popular of these achiral reagents. However, since a natural product synthesis has to fulfill demands in terms of both efficiency and stereoselectivity, these methods can seldom be used with prochiral substrates. 

Optimum conditions for the reduction of saturated ketones by the complex reducing agent formed from sodium hydride, sodium t-amylate, and Ni" acetate (NiCRA) have been delineated.Reoxidation of the secondary alcohol products is dramatically postponed by the addition of alkali- or alkaline-earth-metal salts, and catalytic ketone reductions are achieved with NiCRA-MgBr2 mixtures. Full details of the reducing properties of various complex metal hydrides (12) of copper, formed by reaction of UAIH4 with appropriate lithium methylcuprates [equation (1)], have been published for example enones are reduced pre-... 

The milder metal hydnde reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodexnins reduce ketones to opucally active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc bromide-MMA. A -tetra-methylethylenediamme (TMEDA) reduces a,a-difluoro-[i-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The three isomers are formed on reduction with aluminum isopropoxide... 

The hydroacylation of olefins with aldehydes is one of the most promising transformations using a transition metal-catalyzed C-H bond activation process [1-4]. It is, furthermore, a potentially environmentally-friendly reaction because the resulting ketones are made from the whole atoms of reactants (aldehydes and olefins), i.e. it is atom-economic [5]. A key intermediate in hydroacylation is a acyl metal hydride generated from the oxidative addition of a transition metal into the C-H bond of the aldehyde. This intermediate can undergo the hydrometalation ofthe olefin followed by reductive elimination to give a ketone or the undesired decarbonyla-tion, driven by the stability of a metal carbonyl complex as outlined in Scheme 1. 

The complexes [RuRR (CO)2(PMe2Ph)2] also decompose intramolecularly in CHC13 at 298 K to yield ketones RR CO. A proposed mechanism (Scheme 49) involves reductive elimination by C—C bond formation. For R = R = p-Tol, the unusual product (188) is isolated and it is suggested that this arises from oxidative addition of the ketone in the proposed Ru° intermediate to form (189) and subsequent reaction with CHC13 replaces hydride by chloride.16794 There is a report of the crystal structure of (188) and further examples of the synthesis of ortAo-metallated ketone complexes.1679b... 

In the metal hydride reduction of two different ketones, the sterically less hindered ketone is generally reduced more easily, and modification of hydride reagents by replacement of the hydrides with sterically bulky substituents or electron-withdrawing groups enhances the chemoselectivity. MAD, however, preferentially forms complexes with sterically less hindered or more basic ketone carbonyls, enabling selective reduction of a more hindered, free ketone. Here, MAD behaves as a protector of carbonyl substrates (Sch. 118) [160]. 

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