Borane selective ketone reduction

Selective reduction of ot,a-dihalo ketones." Reduction of a,a-dihalo ketones can he effected without hydrogenolysis of the halo groups with either DIBAH or borane dimethyl sulfide. Reactions with the former reagent are generally faster but work-up can be complicated by gelatinous aluminum salts. In general, the yields are roughly comparable. 

The structurally more rigid (S)-prolinol-based amino alcohol was introduced early in the study of borane reductions [18]. Sterically more hindered ox-azaborolidines 4 (Fig. 1) based on (S)-(-)-diphenylhydroxymethylpyrrolidine have been prepared by Corey [23,25]. These catalysts have been widely used for the borane reduction of various kinds of ketones. After these successful results had appeared for asymmetric ketone reduction, several oxazaborohdines (Fig. 1) were prepared. Many of them were successfully used in the reduction of aromatic ketones. Selected results of enantioselective borane reduction using various oxazaborohdines are shown in Scheme 4. The table to this scheme shows only the data obtained from the reduction of acetophenone as a representative aromatic ketone. In most cases, high enantioselectivity is obtained in the nearly quantitative yield. 

In the early work on the synthesis of prostaglandins, zinc borohydride was used for the reduction of the 15-ketone function and a 1 1 mixture of epimeric 15(S)- and 15(/ )-alcohols was generally obtained. Subsequent studies led to reaction conditions for highly selective reduction to the desired 15(S)-alcohol. Some of the results are summarized in the following table. The most practical method is E which utilizes borane as the stoichiometric reductant and a chiral, enzyme-like catalyst which is shown. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

This observation has led to the preparation of more effective bicyclic oxaza-borolidines such as 1, prepared from (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine and BH3 (la) or methylboronic acid (lb). Both reagents catalyze borane reduction of alkyl aryl ketones to furnish (R)-alcohols in > 95% ee, by face-selective hydride transfer within a complex such as B. Catalyst lb is somewhat more effective than... 

Reduction of aldehydes and ketones. Earlier work on amine borane reagents was conducted mainly with tertiary amines and led to the conclusion that these borane complexes reduced carbonyl compounds very slowly, at least under neutral conditions, and that the yield of alcohols is low. Actually complexes of borane with primary amines, NHj or (CH3)3CNH2, reduce carbonyl compounds rapidly and with utilization of the three hydride equivalents. BH3 NH3 is less subject to steric effects than traditional complex hydrides. A particular advantage is that NH3 BH3 and (CH3)3CNH2 BH3 reduce aldehyde groups much more rapidly than keto groups, but cyclohexanone can be reduced selectively in the presence of aliphatic and aromatic acyclic ketones. 

Borane (as BH3 in tetrahydrofuran or dimethyl sulfide) is an even milder reducing agent than BH4G for the carbonyl group of aldehydes and ketones. This difference in reactivity can be used to advantage when selective reduction is necessary. For example, borohydride reduces a ketone carbonyl more rapidly than a carbon-carbon double bond, whereas borane reduces the carbon-carbon double bond more rapidly than carbonyl ... 

Various polymer-supported hydrides have been applied successfully to reductions of both carbonyl and olefin groups. Rajasree and Devaky13 describe a cross-linked polystyrene-supported ethylenediamine borane reagent for the selective reduction of aldehydes in the presence of ketones (entry 9). This borane reagent is easily prepared and can be recycled after completion of the reaction. This is a practical alternative to standard borane reagents such as diborane, borane-amine, or borane-sulfide complexes. 

It is more interesting that reduction of complex ketones could be dramatically improved by optimization of the reaction temperature. In the case of the phenoxyphenylvinyl methyl ketone (6), a 5-lipoxygenase inhibitor synthesis intermediate, we were able to improve the enantiomeric excess from the 80-85% range up to 96% by selection of the optimal temperature for the reduction. In this case, the temperature range for an acceptable enantiomeric excess is very narrow. Generally, Me-CBS is the best catalyst with borane complexes as reducing agent. 

A new selective and very mild method for the reduction of ketone tosylhydrazones to hydrocarbons offers promise for steroid chemistry reduction with catechol-borane and buffered hydrolysis gives the hydrocarbon in good yield.193 2,4-Dinitrobenzenesulphonylhydrazine is superior to toluene-p-sulphonylhydrazine for... 

The catalyst-product complex is a highly active but less selective catalyst for the reduction of the starting ketone.16 Accumulation of this undesired intermediate can be avoided by running the reaction at higher temperatures (40°C) as well as using a slow inverse addition of the ketone to the catalyst-borane mixture. 

Hydration with boranes proved difficult due to extensive reductive cleavage of the epoxide (Scheme 45). The best results (54%) were achieved with borane in THF. The subsequent oxidation with basic hydrogen peroxide led to the primary alcohol as well as to saponification of the acetate. Selective protection of the primary alcohol 397 as trichloroethyl carbonate was followed by oxidation with RuCl3/NaI04, thereby producing not only the y-lactone but also the cyclic ketone. 

Deoxygenation of sulfoxides. Tris(phenylseleno)borane is an effective reagent for the reduction of sulfoxides under mild conditions. Although this reagent converts ketones to selenoketals, selective deoxygenation of keto sulfoxides is possible. Deoxygenation of vinyl sulfoxides also proceeds smoothly. 

Hydrosilylation of carbon-oxygen bonds is a mild method for selective reduction of carbonyl functions. Parks and Piers have found that aromatic aldehydes, ketones, and esters are hydrosilylated at room temperature in the presence of 1-4 mol % B(CgF5)3 and 1 equiv. PhsSiFl [154]. On the basis of kinetic experiments the authors suggested that the reduction takes place by an unusual nucleophilic/electrophilic mechanism— the substrate itself serves to nucleophilically activate the Si-H bond, and hydride transfer is facilitated by the borane Lewis aeid (Eq. 99). 

A similar approach was employed in our laboratory for the development of molecularly imprinted catalysts for the enantio-selective reduction of prochiral ketones with borane (CBS reaction) [122]. A stable, polymerisable transition state analogue of this reaction leading to the formation of one particular enantiomer product was prepared (Fig. 4.9). After polymerisation, the template molecule can... 

However, also in this case enantio-selectivities never exceeded the values obtained with the oxazaborolidine in solution, probably because of diffusional limitations within the polymer support, which enhanced the contribution of the non-selective, direct borane reduction of the ketone. In spite of the rather low imprinting effects obtained in these initial attempts, we feel that this approach still represents a most interesting application of molecularly imprinted polymers in catalysis and deserves further attention in the near future. 

Saturated ketones are not readily reduced by Alpine-Borane. However, the intramolecular version of this reduction using (Ipc)2BH proceeds with good yield and facial selectivity. ... 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

With respect to reactivity, the amine-boranes lie somewhere between BHj-THF and NaBH4. They reduce aldehydes and ketones without affecting ester, ether, SPh, and NOj groups (Section 3.2,1), The reduction of ketones can be accelerated by the addition of Lewis acids or when carried out in acetic acid [PSl], On alumina or silica supporrts, amine-boranes can selectively reduce aldehydes without affecting keto groups (Section 3.2.1) [BSl], Chiral amino acids can be reduced to amino alcohols without epimerization [PSl],... 

---