Ketones or Aldehydes to Alcohols

To a solution of LAH (1.0 M in THF, 1.01 mL, and 1.01 mmol) was added a solution of the ketone (596 mg, 1.01 mmol) in THF (6 mL) at -78 °C under nitrogen. After 1 h, saturated aqueous sodium potassium tartrate (6 mL) was added carefully, and the mixture was stirred rapidly at ambient temperature for 1 h. The resulting mixture was diluted with water (6 mL) and extracted with ether (3 x 25 mL). The combined organic extracts were dried (MgS04) and purified by flash chromatography (20% EtOAc in hexane, then 50% EtOAc in hexane) to give 330.5 mg (55%) of the equatorial alcohol and 266.1 mg (45%) of the axial alcohol as colorless oils. 

Note compare diastereoselectivity of the above reaction with example 4.5.8. 

Sodium borohydride is a widely used mild and selective reducing agent. It selectively reduces an aldehyde or ketone in the presence of esters, lactones, carboxylic acids, and amides in methanol or THF at room temperature. Reviews (a) Seyden-Penne, J. 

Reductions by the Alumino- and Borohydrides in Organic Synthesis Wiley-VCH New York, 1997,2nd edition, (b) Brown, H. C. Krishnamurthy, S. Tetrahedron 1979, 35, 567-607. 

A mixture of the amido ketone (1.70 g, 3.86 mmol) and sodium borohydride (293 mg, 7.72 mmol) in anhydrous methanol (60 mL) was stirred at -10 °C for 25 min. Saturated NaHC03 (40 mL) and CH2C12 (80 mL) were added, and the mixture was stirred at 0 °C for 5 min. The organic layer was removed, and the aqueous layer was extracted with CH2C12 (3 x 40 mL). The combined organic layers were dried (Na2S04) and concentrated to give 1.68 g (95%) of the secondary alcohol as a white solid. 

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NaBH4, MeOH A reducing agent. Can be used to reduce ketones or aldehydes to alcohols. Will not reduce esters or caiboxyhc acids. 

Nucleophilic addition reaction (Section 19.4) A reaction in which a nucleophile adds to the electrophilic carbonyl group of a ketone or aldehyde to give an alcohol. 

Let s do some problems where we use LAH or NaBH4 to reduce ketones or aldehydes into alcohols. 

Both H and R can attack a ketone or aldehyde to give an alcohol. The main difference is the effect on the carbon skeleton. With H, the carbon skeleton does not change at all. But with R, the carbon skeleton gets larger. We are forming a C—C bond. We will soon see that this is very important for synthesis problems. For now, let s focus on how we can make R in the first place. After all, a negative charge on a carbon atom is not very stable (and therefore not trivial to make). 

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-... 

The production of alcohols by the reduction of aldehydes and ketones is probably one of the most useful and fundamental steps in the synthetic chemist s arsenal. Although there are many well developed methods for the reduction of ketones and aldehydes to alcohols, there is still much interest in developing new or improved methodologies which are milder and can be brought about under special conditions, especially in the presence of other reducible functional groups. Of particular interest to the modern synthetic organic chemist are the aldehyde and ketone reductions which are accomplished in an enantioselective fashion. Advances in this field up to 1992 have been the subject of a review by Singh198. The present section covers very recent work in this area. 

The Grignard Reaction is the addition of an organomagnesium. halide (Grignard reagent) to a ketone or aldehyde, to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol. 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

Hydrolysis to yield a ketone or aldehyde plus alcohol (Sec. 19.10)... 

If an achiral ferrocene derivative is converted to a chiral one by chiral reagents or catalysts, this may be called an asymmetric synthesis. All asymmetric syntheses of ferrocene derivatives known so far are reductions of ferrocenyl ketones or aldehydes to chiral secondary alcohols. Early attempts to reduce benzoylferrocene by the Clemmensen procedure in (5)-l-methoxy-2-methylbutane as chiral solvent led to complex mixtures of products with low enantiomeric excess [65]. With (25, 3R)-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol as chiral modifier for the LiAlH4 reducing agent, the desired alcohol was formed with 53% ee (Fig. 4-9 a) [66]. An even better chiral ligand for LiAlH4 is natural quinine, which allows enantioselective reduction of several ferrocenyl ketones with up to 80% ee [67]. Inclusion complexes of ferrocenyl ketones with cyclodextrins can be reduced by NaBH4 with up to 84% enantioselectivity (Fig. 4-9 b) [68 — 70]. 

Many reagents are used to reduce ketones and aldehydes to alcohol but sodium borohydride, NaBH4, is usually chosen because of its safety i ease of handling. Sodium borohydride is a white, crystalline solid that be weighed in the open atmosphere and used in either water or alcohol solj tion. High yields of products are usually obtained. 

We have shown that THF-MeOH solutions of Sml2 are excellent reducing agents of ketones or aldehydes to the corresponding alcohols [15]. A mechanistic study... 

Fig. 8.14 The coenzyme NAD accepting a hydride ion, shown in blue, from lactate. NAD -dependent dehydrogenases catalyze the transfer of a hydride ion (H ) from a carbon to NAD in oxidation reactions such as the oxidation of alcohols to ketones or aldehydes to acids. The positively charged pyridine ring nitrogen of NAD increases the electrophilicity of the carbon opposite it in the ring. This carbon then accepts the negatively charged hydride ion. The proton from the alcohol group is released into water. NADP functions by the same mechanism, but it is usually involved in pathways of reductive synthesis.

Both sodium borohydride and lithium aluminum hydride reduce ketones or aldehydes to alkoxides, and hydrolysis gives the alcohol. Lithium aluminum hydride is a more powerful reducing agent than sodium borohydride. 

In the presence of a transition metal catalyst, hydrogen gas converts an alkene to an alkane and an alkyne to an alkene. Hydrogenation of an alkyne with palladium in the presence of quinoline gives the Z-alkene in what is known as Lindlar reduction. In the presence of a transition metal catalyst, hydrogen gas converts a ketone or aldehyde to an alcohol. 

Both sodium borohydride and lithium aluminum hydride reduce ketones or aldehydes to alkoxides, and hydrolysis gives the alcohol. Lithium aluminum hydride is a more powerful reducing agent than sodium borohydride 2, 4, 6, 30, 31, 35, 36, 37, 39, 40, 44, 45, 46, 50, 59, 60. 

The reaction requires a reducing agent, which is itself oxidized as a result of the reaction. In this section, we will explore three reducing agents that can be used to convert a ketone or aldehyde to an alcohol ... 

The reactive center in NADH (highlighted in orange) functions as a hydride delivery agent (very much like NaBH4 or LAH) and can reduce ketones or aldehydes to form alcohols. NADH acts as a reducing agent, and in the process, it is oxidized. The oxidized form is called NAD. ... 

Grignard reagents are carbon nucleophiles that are capable of attacking a wide range of electrophiles, including the carbonyl group of ketones or aldehydes, to produce an alcohol. 

FIGURE 16.19 Addition of water to an alkene to give an alcohol is analogous to addition to a ketone or aldehyde to give a hydrate. 

Deprotonation of (1) with lithium diisopropylamide takes a different course (eq 4). The initially formed allenyl anion isomerizes to the acetylide, which is trapped with ketones or aldehydes to produce propargyl alcohols (S). The isomerization is postulated to take place through proton transfer steps mediated by diisopropylamine. This is consistent with the observation that no such isomerization takes place with alkyUithium reagents. The propargyl alcohols (3) are converted to methoxydihydrofurans (4) with catalytic potassium hydride in DMSO. ... 

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