Aldehydes chemoselective reductions

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

Reduction to Alcohols. The organosilane-mediated reduction of ketones to secondary alcohols has been shown to occur under a wide variety of conditions. Only those reactions that are of high yield and of a more practical nature are mentioned here. As with aldehydes, ketones do not normally react spontaneously with organosilicon hydrides to form alcohols. The exceptional behavior of some organocobalt cluster complex carbonyl compounds was noted previously. Introduction of acids or other electrophilic species that are capable of coordination with the carbonyl oxygen enables reduction to occur by transfer of silyl hydride to the polarized carbonyl carbon (Eq. 2). This permits facile, chemoselective reduction of many ketones to alcohols. 

Ketones take considerably longer to reduce than aldehydes (10-24 h), although yields are not compromised. Differences in reactivity toward aldehydes and ketones can be used to advantage, with highly chemoselective reduction occurring at the aldehyde in the presence even of a methyl ketone (Eq. 5.22) [44]. 

The second synthetic approach to oidiolactone C (61) is summarized in Scheme 20. This route also commences with the ozonolysis of trans-communic acid 180. Now, when this compound was exposed to ozone in excess, keto aldehyde 187 was obtained in 76% yield. The key step in this approach was the y-lactone closure via chemoselective reduction of the lactone moiety on compound 189 through a SN2 mechanism. Compound 189 could be prepared by saponification of the corresponding methyl ester with sodium propanethiolate. Once the primary alcohol is oxidized, the completion of the synthesis of key lactone 103 only requires the allylic oxidation of the C-17 methyl with concomitant closure of the 8-lactone. This conversion was achieved with Se02 in refluxing acetic acid to give 103 in 51% yield. 

Chemoselective reduction of methyl ester 7 to aldehyde 2 is possible with DIB AH. The metallatcd hemiacetal that results from addition of DIBAII to the carbonyl group of ail ester usually decomposes rapidly in polar solvents like THF to an intermediate aldehyde This then competes with the ester and, as a result of its higher clcctrophilicity. js reduced by DIBAH to an alcohol. However, ester 7 bears a methoxymethyl residue in its a-position, which stabilizes the metallated hemiacetal by chelate formation. Chelate complex 22 is protolytically cleaved by way of the hemiacetal only in the course of aqueous workup, so in this case the DIBAH reaction produces only aldehyde 2, not the alcohol (see also Chapter 3), DIBAH, THF, -78 C 100. ... 

Chemoselective reduction of aldehydes.1 Aldehydes can be reduced in the presence of ketones by 1 with 98-100% chemoselectivity. This chemoselectivity is the highest reported for this reduction. 

Chemoselective reduction of the conjugated double bond of a, /f-unsaturated aldehydes such as citral (556) to give citronellal (577) is possible by Pd-catalysed hydrostannation in the presence of AcOH [213],... 

Fig. 6.42. Preparation of Weinreb amides through SN reactions at the carboxyl carbon. Chemoselective reduction of Weinreb amides to aldehydes.

Fig. 6.43. Chemoselective reduction of carboxylic acid chloride to furnish an aldehyde the keto group of the substrate is compatible with these reaction conditions, too.

Chemoselective reductions. The reactivity of NaBH4 can be decreased by use of a lower temperature or by a mixed solvent such as methanol or ethanolic methylene chloride. This simple strategy can be used to effect selective reduction of ketones in the presence of enones,1 and of aldehydes in the presence of ketones. ... 

Fig. 6.34. Chemoselective reduction of free carboxylic acids to aldehydes. Intermediate B yields, upon hydrolysis, initially an aldehyde hydrate, which dehydrates to the aldehyde spontaneously (mechanism Section 7.2.1).

Fig. 8.2. Chemoselective carbonyl group reductions I. On the left side a chemoselective reduction of the aldehyde takes place, whereas on the right side a chemoselective reduction of the ketone is shown.

Zinc-modified cyanoborohydride, prepared from anhydrous zinc chloride and sodium cyanoborohy-dride in the ratio 1 2 in ether, selectively reduced aldehydes and ketones but not acids, anhydrides, esters and tertiary amides. In methanol the reactivity paralleled the unmodified reagent. Zinc and cadmium borohydrides form solid complexes with DMF, which may prove to be convenient sources of the reducing agents.Aromatic and a,p-unsaturated ketones were reduced much more slowly than saturated ketones, so chemoselective reduction should be possible. 

Hydrostannation of carbonyl compounds with tributyltin hydride is promoted by radical initiation and Lewis or protic acid catalysis.The activation of the carbonyl group by the acidic species allows the weakly nucleophilic tin hydride to react via a polar mechanism. Silica gel was a suitable catalyst allowing chemoselective reduction of carbonyl groups under conditions that left many functional groups unchanged. Tributyltin triflate generated in situ from the tin hydride and triflic acid was a particularly efficient catalyst for the reduction of aldehydes and ketones with tributyltin hydride in benzene or 1,2-di-chloromethane at room temperature. Esters and ketals were not affected under these conditions and certain aldehydes were reduced selectively in preference to ketones. 

Alane (AIH3) and its derivatives have also been utilized in the reduction of carboxylic acids to primary alcohols. It rapidly reduces aldehydes, ketones, acid chlorides, lactones, esters, carboxylic acids and salts, tertiary amides, nitriles and epoxides. In contrast, nitro compounds and alkenes are slow to react. AIH3 is particularly useful for the chemoselective reduction of carboxylic acids containing halogen or nitro substituents, to produce the corresponding primary alcohols. DIBAL-H reduces aliphatic or aromatic carboxylic acids to produce either aldehydes (-75 °C) or primary alcohols (25 C) Aminoalu-minum hydrides are less reactive reagents and are superior for aldehyde synthesis. ... 

Lithium tri-t-butoxyaluminum hydride readily reduces aldehydes and ketones to the corresponding alcohols and reduces acid chlorides to aldehydes. Epoxides, esters, carboxylic acids, tert-amides, and nitriles are not, or only slowly, reduced. Thus, the reagent may be used for chemoselective reductions. ... 

The facile reduction of the -COOH group by BHj THF or BH3 SMej has been employed for chemoselective reductions of the carboxyl group in the presence of ester or lactone functionalities using a stoichiometric quantity of the borane. The carbonyl group in triacylboranes resembles the reactivity of an aldehyde or a ketone more than of an ester (ester resonance) due to electron delocalization from the acyl oxygen into the p orbital of boron. 

Scheme 7.19 Chemoselective reduction of a 3-hydroxy ketone in the presence of an aldehyde.

Polymethylhydrosiloxane (PMHS), a safe and inexpensive polymer co-product of the silicon industry, is an efficient alternative reducing agent for C=0 and C=N bonds when associated with catalysts (1). Mimoun et al. recently reported a new system based on zinc hydride catalysts which enables the chemoselective reduction of unfunctionalized and a,/ -unsaturated- aldehydes, ketones and esters (2). Because gummy silicon residues, which are usually associated with silane reductions, do not form, this PMHS system is attractive for synthetic / industrial purposes. Nevertheless, in contrast to tin-catalyzed reductions of ketones with PMHS... 

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