Ketone with metal hydride reagents

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],... 

The reduction of carbonyl compounds with metal hydride reagents can be viewed as nucleophilic addition of hydride to the carbonyl group. Addition of a hydride anion to an aldehyde or ketone produces an alkoxide anion, which on protonation gives the corresponding alcohol. Aldehydes give 1°-alcohols and ketone gives 2°-alcohols. 

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. ... 

In contrast to the considerable amount of successful attention devoted to the asymmetric reduction of prostereogenic ketones to chiral alcohols with metal hydride reagents (see Section D.2.3 and ref 1), corresponding studies and identification of useful stereoselective conversions of stereo-genic imine derivatives to amines have been sparse, and only limited success has been obtained. 

Stereoselective reduction of a-silyl ketones such as 182 with metal hydride reagents such as DIBAH, UAIH4, NaBH4, and L-Selectride has been reported to give the corresponding yS-hydroxyalkylsilanes 183 (Scheme 2.116) [11, 304, 316, 319]. Peterson reaction of the 2-silyl-l,3-diol 183 with KH gives a mixture of the corresponding alkene 184 and its isomer 185. 

Similarly reductions with metal hydrides, metals and other compounds may give predominantly one isomer. The stereochemical outcome depends strongly on the structure of the ketone and on the reagent, and may be alfected by the solvents. 

The most useful reagents for reducing aldehydes and ketones are the metal hydride reagents. Complex hydrides are the source of hydride ions, and the two most commonly used reagents are NaBlTj and LiAlH4. Lithium aluminium hydride is extremely reactive with water and must be used in an anhydrous solvent, e.g. dry ether. 

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. 

The milder metal hydride reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodextrins reduce ketones to optically active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc broniidc-iV./V.A V -tetra-methylethylenediamine (TMEDA) reduces a,a-difluoro-(3-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The threo isomers arc formed on reduction with aluminum isopropoxide... 

This reduction is unft -selective in the reduction of a-oxy and a-amino ketones. This contrasts with syn-selectivity for metal hydride reagents and for hydrosilanes in trifluoroacetic acid. 

Lithium tri-sec-butylborohydride, also known as L-selectride, is a metal hydride reagent that contains three sec-butyl groups bonded to boron. When this reagent is used to reduce cyclic ketones, one stereoisomer often predominates as product. Explain why the reduction of 4-ferf-butylcyclohexanone with L-selectride forms the cis alcohol as the major product. 

Diastereocontrolled reduction of amino ketones represents an attractive route to amino alcohols, many of which are pharmacologically important, and has been exhaustively reviewed. Even in the case of a-amino ketones, examples of high stereoselectivity were rare with conventional metal hydride reagents, and mixtures were common as the amino group became more distant. In contrast, a-triazolyl ketones (64) were reduced with high stereoselectivity by tetraalkylammonium borohydrides to the syn-alcohols (63) in dichloromethane or to the anti isomers (65) when titanium tetrachloride was added (Scheme 10). ... 

The 2,3-dialdehyde of furan reacts with ketones in syntheses of furotro-pones similar to 218a. Deuterium analogs (e.g., 218b) are available from labeled dimethylformamide used to prepare the furan starting material.319 Metal hydride reagents afford (tautomeric ) cycloheptatrienes (219), but... 

Section 8-6 presents two u.seful reduction processes. Carbonyl compounds such as ketones and aldehydes arc useful precursors (starting materials) for the synthesis of alcohols. Either metal-catalyzed Ht addition or reaction with the hydride reagents NaBH and LiAIH converts aldehydes to primary alcohols. The same processes convert ketones to secondary alcohols. The.se hydride reductions are the lirst of many examples that you will. see of nucleophilic additions to the electrophilic carbons of carbonyl groups. This is one of the most important clas.ses of reactions in organic chemistry. 

Reactions of highly electron-rich organometalate salts (organocuprates, orga-noborates, Grignard reagents, etc.) and metal hydrides (trialkyltin hydride, triethylsilane, borohydrides, etc.) with cyano-substituted olefins, enones, ketones, carbocations, pyridinium cations, etc. are conventionally formulated as nucleophilic addition reactions. We illustrate the utility of donor/acceptor association and electron-transfer below. 

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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