Reduction with metal hydride reagents

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 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. 

The state of the art of reductions with metal hydrides a decade ago was the subject of comprehensive reviews. A detailed survey of reductions of carbonyl compounds with alkali and alkaline earth metal hydrides, borane and derivatives, alane and derivatives, metal borohydrides, metal aluminohydrides, silanes, stannanes and transition metal hydrides was compiled. The properties, preparation and applications of each reagent were discussed together with methods for their determination, handling techniques... 

Benzotriazoles, like their monocyclic counterparts, are often synthesized by reductive cyclizations and it is only when they are activated as salts that reductions with metal hydrides occur. Potassium borohydride, for example, reacts with aqueous solutions of the salt (261) to give 2-methylaminoaniline (262). Some A-demethylation leading to the triazole (263) also takes place, and this may be caused by the prevailing alkaline reaction conditions. LAH in diethyl ether is a more effective reagent for the reductive ring opening of benzotriazoles, and this reagent also cleaves 1,3-dimethylbenzotriazolium methylsulfate (264) to l,2-di(methylamino)benzene(265)." ... 

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. 

FIGURE 16.65 Alcohols can be oxidized to carbonyl compounds. This reaction is the reverse of what you have just learned— the reduction of carbonyl compounds to alcohols through reactions with metal hydride reagents. 

Treatment of epoxides with Cp2TiCl and 1,3-cyclohexadiene caused reductive opening of the epoxide by a radical mechanism (Scheme 1), sometimes with a different regioselectivity to that obtained with metal hydride reagents. When the reaction was conducted on epoxide (40) in the absence of cyclohexadiene as a H donor, deoi genation occurred to give the unsaturated product (41). Some attempts to open an epoxide by... 

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. 

Reduction with Metals and Metal Hydrides. Practically any ester can be reduced by Na—C2H OH, Li or Na—NH, LiAlH, LiBH, or NaBH to give alcohols in excellent yield (35,36). Carbon-carbon double bonds are usually preserved using these reducing 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. 

Using different reagents or under various conditions, 2,3-epoxy alcohols can undergo ring-opening reactions with metallic hydrides, giving 1,3-diols or 1,2-diols. As shown in Scheme 4-16, reduction of 3-substituted 2,3-epoxy alcohols with Red-Al leads to the exclusive formation of 1,3-diols, and this can be applied in the preparation of 1,3-diol compounds.31... 

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],... 

C. Reduction of Imines with Chiral Metal Hydride Reagents. 112... 

Some carbyne complexes, in particular cationic ones with good Ji-accepting ligands, can react with nucleophiles to give carbene complexes [187,521]. Several reductions of carbyne complexes to carbene complexes by treatment with metal hydrides have been reported. Similarly, organolithium or other carbanionic reagents can react with electrophilic carbyne complexes to yield carbene complexes. Illustrative examples of both reactions are sketched in Figure 3.23. 

For a review, see Challis Challis, in Zabicky The Chemistry of Amides, Wiley New York, 1970, pp. 795-801. For a review of the reduction of amides, lactams, and imides with metallic hydrides, see Gaylord. Ref. 536. pp. 544-636. For a lisl of reagents, with references, see Ref. 21. pp. 432-433. 

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. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

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... 

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