Carbonyl reduction using borohydrides

Scheme 6.38 Reduction of carbonyl compounds using alumina-supported sodium borohydride.

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

Reduction of carbonyl groups using tetra-n-butylammonium borohydride... 

A study of the influence of the nature of the solid support showed that silica, celite, cellulose or magnesium sulphate in combination with borohydride can also be used successfully in the microwave-assisted reduction of carbonyl compounds. The choice of the solid support has been reported to influence the chemoselectivity of the reduction of chalcone. Under optimised conditions the reduction of the alkene can be suppressed using borohydride on silica, whereas the use of cellulose as solid support seems to favour C=C reduction (Scheme 4.11 )27. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

Varma, R.S. and Dahiya, R., Sodium borohydride on wet clay solvent-free reductive amination of carbonyl compounds using microwaves, Tetrahedron, 1998, 54, 6293-6298. 

Enamidines (2). Lithiation of 1 followed by treatment with aldehydes or ketones results in Peterson olefination to give a mixture of isomeric enamidines (2) in good yield. These enamidines can be used to convert the carbonyl compounds used in (heir preparation to homologated amines, aldehydes, and ketones. Conversion to a mclhylaminc involves reduction with sodium borohydride (pH 6) to an aminal, which is then hydrolyzed by dilute acid. The sequence can be carried out from 1 without isolation of any intermediates (equation I). 

A solvent-free reductive amination of carbonyl compounds using sodium borohydride supported on moist montmorillonite K10 clay also was facilitated by microwave irradiation (Scheme 8) [54]. Clay served the dual purpose of a Lewis acid and provided water from its interlayers to enhance the reducing ability of NaBH4. 

Unprotected aldoses and ketoses can be reduced to afford alditols while aldonolactones can be reduced to give either aldoses or alditols. The reagent of choice for reduction to alditols is sodium borohydride since it is both cheap and convenient to use. The reduction is carried out under mild conditions at room temperature in an aqueous solution. Sodium borohydride is stable in water at pH 14 while it reacts with the solvent at neutral or slightly acidic pH, but at a slower rate than the rate of carbonyl reduction. In some cases, the product will form esters with the generated boric acid. These borate complexes can be decomposed by treatment with hydrochloric acid or a strongly acidic ion-exchange resin and the boric acid can be removed in the work-up as the low boiling trimethyl borate by repeated co-evaporation with methanol at acidic pH [155]. 

This reaction, known as the Bouveauft-BJanc reduction, used to be used to reduce carbonyl compounds to alcohols, but now aluminium hydrides and borohydrides are usually more convenient. You met an example of ttie Bouveault-Blanc reduction in Chapter 33 (conformational analysis-reduction of cyclohexanones). oy raii ... 

By Reduction of Carbonyl Compounds. Use of high (10 kbar) pressures has been shown to effect trialkylstannane reductions of ketones in the absence of radical initiators or Lewis acids.10 Zinc borohydride has been demonstrated to be a mild reducing agent for the conversion of benzenethiol esters into alcohols in good yield. Use of mixed solvents containing methanol has been found to confer some chemoselectivity upon reductions with lithium borohydride and permits enhanced rates of reduction of esters, lactones, and... 

Reducing agents can be used, but most convert the ozonide to an alcohol rather than to a carbonyl. Reduction of the ozonide with lithium aluminum hydride or sodium borohydride generates the alcohol products, as expected, by further reducing the intermediate carbonyl products. It is noted that 1 mol of L1A1H4 is required per mole of ozonide and the temperature is usually maintained below The most... 

The Cram chelation model (sec. 4.7.B) is an example where the chelation effects of the heteroatom influence the rotamer population and, thereby, the selectivity of the reduction. Zinc borohydride [Zn(BH4)2], effectively chelates the carbonyl oxygen and alcohol oxygen atoms in the reduction of 42 and leads to intermediate 43. Transfer of hydride to the carbonyl gave primarily the anti diastereomer, 45 (4 96, 44/45). When the chelating hydroxyl group was blocked as a tert-butyldiphenylsilyl ether (in 46 - sec. 7.3.A.i), reduction with Red-Al (sec. 4.3) led to a reversal in selectivity (96 4, 47/48).The ability to chelate a heteroatom varies with the reagent used. Lithium aluminum hydride shows less selectivity, due in part to poorer coordination with the heteroatom and reduction of 42 gave a 27 73 mixture of 44 and 45,... 

Professor Fraga reported the study of diastereoselective reduction In cyclic 1,3-keto ester substrates in 2004 [1], using CaCU as additive to form complexation with 1,3-keto esters substrates to control the reduction. Sodium borohydride was added to the mixture and the selective reduction of ketone carbonyl group happened with 90 % diastereoselectivity. The transition state proposed is shown in Fig. 3.5. 

Third, hydrogenation of control and Fe-TAML/H202 treated effluents indicated that aliphatic double bonds like those found in stilbenes were removed in the treated sample (J7). Finally, reduction using sodium borohydride, which reduces carbonyl groups in structures such as a-carbonyls and quinones (37), revealed that both types of structures were removed in the treated samples. 

Simple hydrides such as sodium or potassium hydride are too insoluble in organic solvents to be useful in reductions. The compounds sodium borohydride, Na[BHj, and lithium aluminum hydride, Li[AlHj, are the usual sources of hydride for carbonyl reduction reactions. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Borohydrides reduce a-substituted ketones to the corresponding a-substituted alcohols, and such products can be further reduced to olefins (see section VIII). Other reagents serve, through participation of the carbonyl group, to remove the substituent while leaving the ketone intact. The zinc or chromous ion reduction of a-halo ketones is an example of this second type, which is not normally useful for double bond introduction. However, when the derivative being reduced is an a,jS-epoxy ketone, the primary product is a -hydroxy ketone which readily dehydrates to the a,jS-unsaturated ketone. Since... 

The well-known reduction of carbonyl groups to alcohols has been refined in recent studies to render the reaction more regioselective and more stereoselective Per-fluorodiketones are reduced by lithium aluminum hydride to the corresponding diols, but the use of potassium or sodium borohydride allows isolation of the ketoalcohol Similarly, a perfluoroketo acid fluonde yields diol with lithium aluminum hydnde, but the related hydroxy acid is obtainable with potassium borohydnde [i f] (equations 46 and 47)... 

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