Reduction of 4-/-butylcyclohexanone

Reductions.2 In contrast to NaCNBHj, the complex I reduces acid chlorides only to aldehydes under neutral conditions in 50-90% yield. However, under acidic conditions, I reduces carbonyl groups to alcohols (70-80%, yield), although diaryl ketones are reduced in low yields. A useful feature of this reagent is that reduction of ketones is more stereoselective than that with NaCNBH,. Thus reduction of 4-/-butylcyclohexanone gives a 94 6 mixture of irons cis isomeric alcohols if 80% yield. 

Under these conditions the stereoselectivity is higher, as the attack of the reagent occurs equatorially, leading to axial amines (72-92%). A comparison with the results of reduction of 4-/-butylcyclohexanone shows a complete inversion of stereoselectivity (16-27% of equatorial attack). Reductions of 2-alkylcyclohexanone enamines also proceed with high stereoselectivity, leading predominantly to the cis amines in the six-membered ring derivatives (6 96%), and almost exclusively in the case of the five-membered enamines (95-98%) (Seheme 84). The A strain in fact would shift the conformational equilibrium towards the axial (or pseudoaxial) orientation of the substituent. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

This mixture is available from Aldrich Chemical Company, Inc. The checkers used a 7 93 mixture of the cis- and traws isomers, prepared by lithium aluminum hydride [Aluminate(l —), tetrahydro-, lithium, (T-4)-] reduction of 4-ferf-butylcyclohexanone and recrystallization of the crude product. The ketone was purchased from Aldrich Chemical Company, Inc. 

Hydride reduction of 4-fert-butylcyclohexanone 3 shows a preference for axial addition [axial additioniequatorial addition = 91-88.5 9-11.5 (LiAIH ) [16,17, 50, 51] or 87-86 13-14 (NaBH )] [50, 52]. Addition of acetyhde anion, Na(Li or K) C=CH, also showed a similar axial preference [14, 15, 53]. 

Cathodic surfaces of finely divided platinum, palladium and nickel have a low hydrogen overvoltage and the dominant electrochemical reaction is the generation of a layer of hydrogen atoms. The electrocatalytic hydrogenation of aldehydes and ketones can be achieved at these surfaces. Cathodes of platinum or palladium black operate in both acid solution [203] and in methanol containing sodium methoxide [204], The carbonyl compound is converted to the alcohol. Reduction of 4-tert-butylcyclohexanone is not stereoselective, however, 1,2-diphenylpropan-l-one is converted to the / reo-alcohol. 

Rehydrated Mg/Al-OH catalysts have been found to be inactive in the MPV reduction of 4-ferf-butylcyclohexanone by isopropanol, whereas the bifunctional character of the Mg(Al)0 mixed oxides made them highly active in this reaction. The aluminium alkoxidc intermediate of the MPV reaction indeed involves a cooperation between basic and acidic sites. On mixed oxides, the abstraction of a proton from isopropanol on O2 sites gives isopropoxide anions, which are then stabilized on Al3+ and form intermediates with the aldehyde. The high activity of mixed oxide comes from the synergetic effect of strong Lewis basicity and mild acidity. 

In the attack by sterically undemanding reducing agents, this stereoelectronic effect is fully effective (for a completely different but perfectly diastereoselective reduction of 4-fert-butylcyclohexanone to the equatorial alcohol, see Figure 14.46). However, in the attack of such a bulky hydride donor as L-Selectride the stereoelectronic effect is overcompensated by the opposing steric effect discussed above. 

A very high stereoselectivity was observed in the reduction of 4-tert-butylcyclohexanone to the m-alcohol (> 95%), which is the industrially relevant product. The observed high selectivity to the thermodynamically unfavorable cis-alcohol was explained by a restricted transition-state for the formation of the trans-alcohol within the pores of the zeolites (Scheme 5). This reaction was found not only to be catalysed by Al-Beta, van der Waal et al. reported the catalytic activity of aluminum-free zeolite titanium beta (Ti-Beta) in the same reaction.74 Again, a very high selectivity to the cis-alcohol was observed indicating similar steric restrictions on the mechanism. Kinetically restricted product distributions were also reported for the 2-,3- and 4-methylcyclohexanone the cis, trans- and ds-isomers being the major products, respectively. In this case the tetrahedrally coordinated Ti-atom was assumed to behave as the Lewis acid metal center. Recent quantum-chemical calculations on zeolite TS-1 and Ti-Beta confirm the higher Lewis acidic nature of the latter one.75... 

While the use of zeolites as catalysts for C=0 reduction with alcohols as a reductant goes back to the eighties, stereoselective versions of this reaction have been developed more recently. In this so-called MPV (Meerwein-Ponndorf-Verley) reaction, the reactant carbonyl compound and the reducing alcohol coordinate simultaneously on a Lewis acid centre. In the reduction of 4-t-butylcyclohexanone, the trans product would normally be thermodynamically favored. However, the cis alcohol isomer is economically much more interesting. Van Bekkum and coworkers discovered that in the constrained pores of an Al- or Ti-Beta zeolite, more than 95 % of the product has the cis configuration (59) ... 

Equation 15.3.1 Meerwein-Pondorf-Verley reduction of 4-tert-butylcyclohexanone 27... 

Table 15.4 MPV reduction of 4-tert-butylcyclohexanone with isopropanol to 4-tert- butylcyclohexanol over various heterogeneous catalysts ...

The MPV reduction of 4-tert-butylcyclohexanone provides an excellent example of stereoselectivity by zeolite BEA, and also an example of unequivocal distinction between external-surface and internal micropore activity. 

Lithium tri-sec-butylborohydride, also known as L-selectride, is a metal hydride reagent that contains three sec-butyl groups bonded to boron. When this reagent is used to reduce cyclic ketones, one stereoisomer often predominates as product. Explain why the reduction of 4-ferf-butylcyclohexanone with L-selectride forms the cis alcohol as the major product. 

A recent example, the stereoselective reduction of 4-tert-butylcyclohexanone to cis-4-tert-butylcyclohexanol with secondary alcohols over zeolite BEA (95% selectivity at 33% conversion)[148] shows however, that not so much the basic character of the molecular... 

Table 6-1. Reduction of 4-t-butylcyclohexanone (equatorial/axial alcohols).

For the reduction of 4-t-butylcyclohexanone (Dow Chem. Co.) to the axial cis-alcohol (99% pure), Eliel and Doyle used iridium trichloride (Fisher) and noted that this catalyst could be reused many times with little loss in stereoselectivity. 

The method is useful in the preparation of other axial alcohols. Henbest has reported the reductions of 3- butylcyclohexanone, 3,3,5-trimethylcyclohexanone, and cholestanone to the axial alcohols by this procedure, although for the preparation of 3-a-cholestanol the procedure of Edward is preferred by the checkers. Recently 2,4,4-trimethylcyclohexanone has been reduced to the pure axial alcohol by this method in 90% yield. 

Zeolite BEA is a stereoselective and regenerable heterogeneous catalyst for the Meerwein Ponndorf Verley (MPV) reduction of 4-ZerZ-butylcyclohexanone to cA-4-/er/-butylcyclohexanol (Scheme 5.41), as demonstrated by Bekkum et The cM -isomer is very important in the fragrance industry and is very difficult to obtain by other methods. 

Recently Creyghton et al. [6,7] reported the use of zeolite beta in the MPVO reduction of 4-t-butylcyclohexanone. ITie high selectivity towards the thermodynamically less favoured ds-alcohol is explained by a restricted transition-state around a Lewis-acidic aluminium in the zeolite pores. When using an aluminium-free zeolite, titanium beta, in the epoxidation of olefins, we have shown that Ti-beta has acidic properties when alcoholic solvents were employed [8], This was ascribed to the Lewis-acidic character of titanium in the zeolite framework. As we reported very recently [9], Ti-beta is found to be an excellent catalyst in MPVO reactions with a tolerance for water. Here, results are presented on the high selectivity, stability and low by-product formation of the catalyst, Ti-beta, in both the liquid-phase and gas-phase MPVO reactions. 

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