Reductions of carbonyl compounds

In several cases the use of tellurium reagents is clearly advantageous compared to the usual previously described methods because of the mildness of the experimental conditions and the great selectivity. 

Additional advantages are the possibility of generating the reducing agents in situ as well in catalytic amounts in the presence of an inexpensive co-reductant, and recovery of the tellurium material (for example, elemental tellurium from the above inorganic reagents and ditellurides from tellurols). 

Most reductions of carbonyl and other functional groups are now done with reagents that transfer a hydride ion from boron or aluminum. The numerous 

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS 

O 11 RCOH RCH2OH Pd, Ni, Ru Very strenuous conditions required 

O 11 RCNH2 RCH2NH2 Cu-Cr Very strenuous conditions required 

The mechanism by which all the group III complex hydrides effect reduction is believed to be quite similar. It involves nucleophilic transfer of hydride to the carbonyl group. Activation of the carbonyl group by coordination with a metal cation is probably involved under most conditions. Since all of the hydrides are 

Hydride donor Iminium ion Acyl halide Aldehyde Ketone Ester Amide Carboxy- late salt 

LiAlH4b Amine Alcohol Alcohol Alcohol Alcohol Amine Alcohol 

LiAlH[(OC(CH3)]3d Aldehyde6 Alcohol Alcohol Alcohof Aldehydef  

Aldehydes and ketones are easily reduced to primary and secondary alcohols, respectively. Reduction can be accomplished in many ways, most commonly by metal 

The most common metal hydrides used to reduce carbonyl compounds are lithium aluminum hydride (LiAlHJ and sodium borohydride (NaBH4). The metal-hydride bond is polarized, with the metal positive and the hydrogen negative. Therefore, the reaction involves irreversible nucleophilic attack of the hydride (H ) at the carbonyl carbon  

The initial product is an aluminum alkoxide, which is subsequently hydrolyzed by water and acid to give the alcohol. The net result is addition of hydrogen across the carbon-oxygen double bond. A specific example is 

PROBLEM 9.20 Show how the following alcohols can be made from lithium aluminum hydride and a carbonyl compound  

Because a carbon-carbon double bond is not readily attacked by nucleophiles, metal hydrides can be used to reduce a carbon-oxygen double bond to the corresponding alcohol without reducing a carbon-carbon double bond present in the same compound. 

Instead of the addition of an organometallic reagent to an aldehyde, very often a reduction of the corresponding ketone is the preferred reaction. The advantages 

In most cases, the stereochemical outcome heavily depends on the type of reducing reagent used [28bj. 

The application of proUne methylester as an auxihary in the stereoselective reduction of a-keto amides is such an example [29]. This process is interesting because of the opportunity to obtain mandeUc acid derivatives in both optically pure forms from one single proUne enantiomer. 

In contrast, the use of diisobutylaluminum hydride in combination with lithium bromide affords (J )-mandelic 64 acid in somewhat moderate ee of 66%. Unfortunately, the authors do not provide a model to explain this significant difference, but the Lewis acidic nature of diisobutylaluminum hydride as opposed to lithium borohydride plays an important role. 

Chiral amino alcohols display a variety of different pharmacological properties and are highly desirable compounds [30]. Phenyl(2 -pyrrohdinyl)methanol is one of these biologically active congeners and has been used as a racemate [31]. 

The rate of reduction of aldehydes is faster than that of ketones, because there is less steric hindrance for delivery of hydride to the carbonyl carbon. In extreme cases, reduction of highly hindered ketones may have a half-life that measures in days, but rarely does reduction fail to occur in contrast to results obtained with other reducing agents such as sodium borohydride (sec. 4.4), which reduces only selected functional groups. A typical synthetic use of this reaction is reduction of the ketone moiety in 10 to give alcohol 11 (quantitative yield) in Overman s synthesis of scopadulcic acid B.22 The conversion of heptanal to 1-heptanol (ether, reflux, 15 min) in 86% yield is an example of the reduction of aldehydes with LiAIH4. 2 

One of the more important characteristics of carbonyl reduction with LiAlH4 is the diastereoselectivity of the reaction when reduction introduces a second stereogenic center. As a general rule, hydride is delivered to 

House pointed out that 16 can disproportionate (as mentioned above) or that another mechanism may be operative in this reduction.24 Inverse addition of the hydride (a slurry of LiAlH4 is added to the carbonyl compound), short reaction times, and low reaction temperatures generally give moderate to good yields of the conjugate reduction product.24 Good yields of allylic alcohols can often be obtained from a,P-unsaturated aldehydes, however, when the reaction is done at low temperatures with strict control of the stoichiometry. 

Reduction of carboxylic acids with 1 mole of LiAlH4 consumes three of the four hydrides that are available,25 and the reduction product is an alcohol. The acid has the acidic hydrogen of the OH unit, and this reacts first. Subsequent reduction of the carbonyl unit leads to the usual alkoxyaluminate, which is hydrolyzed to the alcohol. Reduction of acid 20 to alcohol 21 in 87% yield is a useful example.26 Reduction of acids to alcohols bearing a heteroatom at the a-position is also possible. 

Acid derivatives are also reduced by L1A1H4. Reduction of the highly reactive acid chlorides 2 and acid anhydrides27 is rapid. Partial reduction of aromatic anhydrides to lactones has been reported by controlling the stoichiometry of L1A1H4 and the anhydride.28 In most cases, however, complete reduction to the diol 

Reduction of aldehydes and ketones usually occurs by the addition of hydrogen across the carbon-oxygen double bond to yield alcohols, but reductive conversion of a carbonyl group to a methylene group requires complete removal of the oxygen, and is called deoxygenation. 

Group III Hydride-Donor Reagents 5.2.1. Reduction of Carbonyl Compounds 

Most reductions of carbonyl compounds are done with reagents that transfer a hydride from boron or aluminum. The numerous reagents of this type that are available provide a considerable degree of selectivity and stereochemical control. Sodium borohydride and lithium aluminum hydride are the most widely used of these reagents. Sodium borohydride is a mild reducing agent which reacts rapidly with aldehydes and ketones but quite slowly with esters. Lithium aluminum hydride 

LiAlH[OC(CH3)3]3 Aldehyde Alcohol Alcohol Alcohol Aldehyde NR 

The reduction reaction occurs by the transfer of hydrogen atoms bound to the surface of the metal catalyst to the carbonyl oxygen and carbon atoms. We recall that the same types of catalysts are used for the hydrogenation of alkenes, a much faster reaction. Alkenes can be reduced at room temperature under 1 atm. pressure of hydrogen gas. Carbonyl compounds require higher temperatures and pressures as high as 100 atm. Therefore, transition metal-catalyzed reduction of carbonyl compounds that also have a carbon—carbon double bond results in reduction of both functional groups. 

At high pressure, both the vinyl and the carbonyl groups are reduced. 

NO2CH2CH2CH2CHO NaBHVEtOH NO2CH2CH2CH2CH2OH Cl3CCH(OH)2 NaBHVH20 CI3CCH2OH 

The reduction of carbonyl compounds in aqueous media has been carried out by a number of reagents under mild conditions. The most frequently used reagent is sodium borohydride, which can also be used using phase-transfer catalysts or inverse phase transfer catalyst in a two phase medium in the presence of surfactants. 

The carbonyl compounds can be quantitatively reduced regio- and stereo-selectively by NaBH at room temperature in aqueous solution containing glycosidic amphiphiles like methyl-P-D-glactoside, dodecanoyl-P-D-maltoside, sucrose etc. By using this procedure, a,P unsaturated ketones give 

2-reduction product (corresponding allylic alcohols) and cyclohexanones give the more stable alcohol. 

The reduction of aldehydes like benzaldehyde and p-tolualdehyde with Raney Ni in 10% aqueous NaOH give the corresponding benzyl alcohols in 17-80% yields along with the corresponding carboxylic acids as byproducts obviously by cannizzaro reaction. It has been found that in aqueous NaHCO under sonication conditions give the corresponding alcohols in good yields. 

---

The disadvantages associated with the Clemmensen reduction of carbonyl compounds (see 3 above), viz., (a) the production of small amounts of carbinols and unsaturated compounds as by-products, (h) the poor results obtained with many compounds of high molecular weight, (c) the non-appUcability to furan and pyrrole compounds (owing to their sensitivity to acids), and (d) the sensitivity to steric hindrance, are absent in the modified Wolff-Kishner reduction. 

Many biological processes involve oxidation of alcohols to carbonyl compounds or the reverse process reduction of carbonyl compounds to alcohols Ethanol for example is metabolized m the liver to acetaldehyde Such processes are catalyzed by enzymes the enzyme that catalyzes the oxidation of ethanol is called alcohol dehydrogenase... 

Product of reduction of carbonyl compound by specified reducing agent... 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Two classes of charged radicals derived from ketones have been well studied. Ketyls are radical anions formed by one-electron reduction of carbonyl compounds. The formation of the benzophenone radical anion by reduction with sodium metal is an example. This radical anion is deep blue in color and is veiy reactive toward both oxygen and protons. Many detailed studies on the structure and spectral properties of this and related radical anions have been carried out. A common chemical reaction of the ketyl radicals is coupling to form a diamagnetic dianion. This occurs reversibly for simple aromatic ketyls. The dimerization is promoted by protonation of one or both of the ketyls because the electrostatic repulsion is then removed. The coupling process leads to reductive dimerization of carbonyl compounds, a reaction that will be discussed in detail in Section 5.5.3 of Part B. 

Clemmensen reaction is the reduction of carbonyl compounds with amalgamated zinc and concentrated hydrochloric acid... 

Reduction of carbonyl compounds with chiral oxazaborolidine catalysts 98AG(E)1987. 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

Perhaps the most valuable reaction of alcohols is their oxidation to yield car-bony compounds—the opposite of the reduction of carbonyl compounds to yield alcohols. Primary alcohols yield aldehydes or carboxylic acids, secondary alcohols yield ketones, but tertiary alcohols don t normally react with most oxidizing agents. 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

The future direction of reduction of carbonyl compounds is as follows ... 

Development of new reduction systems that reduce sterically hindered compounds The reported examples of reduction of carbonyl compounds are usually for the substrates that can be easily reduced such as methyl ketones. Since the demand for reduction of various types of compounds is increasing, investigation of new biocatalytic reductions is required. Photosynthetic organisms are not investigated yet, and they may have new type of enzymes, which can reduce sterically hindered compounds. 

Corey, E.J. Helal, C.J. (1998) Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angewandte Chemie International Edition, 37, 1986-2012. 

Reduction of carbonyl compounds can be carried out in an aqueous medium by various reducing reagents. Among these reagents, sodium borohydride is the most frequently used. The reduction of carbonyl compounds by sodium borohydride can also use phase-transfer catalysts (Eq. 8.4),10 inverse phase-transfer catalysts,11 or polyvinylpyridines12... 

Ernst, M., Kaup, B., Mueller, M. et al. (2005) Enantioselective reduction of carbonyl compounds by whole-cell biotransformation, combining a formate dehydrogenase and a (R)-specihc alcohol dehydrogenase. Applied Microbiology and Biotechnology, 66 (6), 629-634. 

Rhin(bpy)3]3+ and its derivatives are able to reduce selectively NAD+ to 1,4-NADH in aqueous buffer.48-50 It is likely that a rhodium-hydride intermediate, e.g., [Rhni(bpy)2(H20)(H)]2+, acts as a hydride transfer agent in this catalytic process. This system has been coupled internally to the enzymatic reduction of carbonyl compounds using an alcohol dehydrogenase (HLADH) as an NADH-dependent enzyme (Scheme 4). The [Rhin(bpy)3]3+ derivative containing 2,2 -bipyridine-5-sulfonic acid as ligand gave the best results in terms of turnover number (46 turnovers for the metal catalyst, 101 for the cofactor), but was handicapped by slow reaction kinetics, with a maximum of five turnovers per day.50... 

Reduction of Carbonyl Compounds with Aluminum Alkoxides... 

The pioneering work of Posner, on the reduction of carbonyl compounds with isopropyl alcohol and alumina [116], has now been adapted to an expeditious solvent-free reduction procedure that utilizes aluminum alkoxides under microwave irradiation conditions (Scheme 6.37) [117]. 

Reduction of Carbonyl Compounds to Alcohols - Sodium Borohydride-... 

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

Tab. 13.3 Borodeuteride reduction of carbonyl compounds under microwave conditions (750W, 1 min).

---