Bulky ketone reductions

Fig. 10.29. Reduction (Left) and enolate formation (right) in reactions of sterically demanding Grignard reagents with bulky ketones.

The principal interest of these reagents resides in their bulkiness. The reductions of slightly hindered cyclic ketones and imines occurs on the equatorial face (Sections 3.2.2, 3.3.1), and aliphatic carbonyl compounds are reduced with a high stereoselectivity (Section 3.2.2). The Li and K Selectrides selectively reduce the carbon-carbon double bond of a-enones and a,p-ethylenic esters unless the p position is disubstituted (Section 3.2.9) in the latter case, the carbonyl of the a-enones is reduced. 

Steric bulkiness of substituents in ketones (25), for example, makes it possible to differentiate two pairs of lone-pair electrons (a or b in 25) on carbonyl oxygen for coordinating with the Lewis acidic center of boron in oxazaborolidine (28). The complex (29) formed from 28 with catecholborane binds ketone (32) stereospecifically by using the lone-pair electrons at the less hindered side so as to direct the smaller substituent Rs toward the bulky N-tert-butyl group. The intramolecular hydride transfers to the favorably coordinated carbonyl group as shown in 30, Scheme 1.82, results in asymmetric reduction of ketones. Reduction of trifluoromethyl and methyl ketones (25) (R = CF3 or CH3) by this system afforded the corresponding alcohols (26 or 27) with an opposite stereochemistry (Scheme 1.82). 

Bulky ketones such as diaryl ketones can be also reduced by biocatalysts. For example, a rice plant growth regulator, (S )-N-isonicotinoyl-2-amino-5-chlorobenzhy-drol, was prepared by microbial reduction of 2-amino-5-chlorobenzophenone with Rhodosporidium toruloides followed by isonicotinoylation as shown in Fig. 15-42(a)1243). A phosphodiesterase 4 inhibitor was also prepared by microbial reduction of a diaryl ketone 9 with Rhodotorula pilimanae, which was found by the screening of 310 microbial strains [Fig. 15-42(b)][244. ... 

Other limitations of the reaction are related to the regioselectivity of the aryl radical addition to double bond, which is mainly determined by steric and radical delocalization effects. Thus, methyl vinyl ketone gives the best results, and lower yields are observed when bulky substituents are present in the e-position of the alkene. However, the method represents complete positional selectivity because only the g-adduct radicals give reductive arylation products whereas the a-adduct radicals add to diazonium salts, because of the different nucleophilic character of the alkyl radical adduct. ... 

Zhu, D. and Hua, L. (2006) Enantioselective enzymatic reductions of sterically bulky aryl alkyl ketones catalyzed by a NADPH-dependent carbonyl reductase. The Journal of Organic Chemistry, 71 (25), 9484—9486. 

Selective reduction of ketones.1 This reagent can be used to effect selective reduction of the more hindered of two ketones by DIBAH or dibromoalane. Thus treatment of a 1 1 mixture of two ketones with 1-2 equiv. of 1 results in preferential complexation of the less hindered ketone with 1 reduction of this mixture of free and complexed ketones results in preferential reduction of the free, originally more hindered, ketone. An electronic effect of substituents on a phenyl group can also play a role in the complexation. This method is not effective for discrimination between aldehydes and ketones, because MAD-complexes are easily reduced by hydrides. MAD can also serve as a protecting group for the more reactive carbonyl group of a diketone. The selectivity can be enhanced by use of a more bulky aluminum reagent such as methylaluminum bis(2-f-butyl-6-( 1,1-diethylpropyl)-4-methylphenoxide). 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

In many cases also the reduction agent itself influences the result of the reduction, especially if it is bulky and the environment of the function to be reduced is crowded. A more detailed discussion of stereochemistry of reduction with hydrides is found in the section on ketones (p. 114). 

In ketones having a chiral cluster next to the carbonyl carbon reduction with lithium aluminum hydride gave one of the two possible diastereomers, erythro or threo, in larger proportions. The outcome of the reduction is determined by the approach of the reducing agent from the least hindered side (steric control of asymmetric induction) [828]. With lithium aluminum hydride as much as 80% of one diasteromer was obtained. This ratio is higher with more bulky reducing hydrides [837]. 

The effect of steric hindrance can be nicely demonstrated in the reduction of two bicyclic ketones, norcamphor and camphor. The relatively accessible norcamphor yielded on reduction with complex hydrides predominantly (the less stable) endo norborneol while sterically crowded camphor was reduced by the same reagents predominantly to the less stable exo compound, isobor-neol [837], From the numerous examples shown it can be deduced that the stereoselectivity increases with increasing bulkiness (with some exceptions), and that it is affected by the nucleophilicity of the reagent and by the solvent. 

Biochemical reduction of a,/3-unsaturated ketones using microorganisms (best Beauveria sulfurescens) takes place only if there is at least one hydrogen in the /3-position and the substituents on a-carbons are not too bulky. The main product is the saturated ketone, while only a small amount of the saturated alcohol is formed, especially in slightly acidic medium (pH 5-5.5). The carbonyl is attacked from the equatorial side. Results of biochemical reduction of 5-methylcyclohex-2-en-l-one are illustrative of the biochemical reduction by incubation with Beauveria sulfurescens after 24 hours 74% of the enone was reduced to 3-methylcyclohexanone and 26% to 3-methylcy-clohexanol containing 55% of cis and 45% of trans isomer. After 48 hours the respective numbers were 70% and 30%, and 78% and 22%, respectively [878]. 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

Palladium-catalyzed a-arylation of ketones is performed with arylene dihalides and bifunctional aromatic ketones 148 to result in the bond formation at the r/) -a-carbon of the ketone, leading to polyketone 149. The reaction is carried out in the presence of Pd(0) and various phosphines. Several bidentate phosphines and bulky alkylphosphines such as dppf, BINAP, PCys, and P Bu3 are shown to be effective, while PPh3 results in no reaction. Arylene dibromide and diiodide are applicable as the co-monomers. The polymerization reaction is carried out in THE in the presence of NaO Bu at 75 °C under N2, and polymers 149 are isolated in 60-80% yields (M = 7000-15 000). Polyketone 149 is further transformed to conjugated polymer PPV by reduction of the ketone moiety with LiAlH4 followed by dehydration with an acid (Equation (69)). 

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