4-/-Butylcyclohexanone, reduction with

Scheme 13.1 4-tert-butylcyclohexanone reduction under hydrogen transfer conditions with heterogeneous copper catalysts. 

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) ... 

Nonconjugated ketones can be reduced in the dissolving metal medium to the corresponding saturated alcohol in the presence of excess alcohol prior to workup. In the case of cyclic ketones, the thermodynamically more stable alcohol predominates. For example, 4-t-butylcyclohexanone on reduction with Na in liquid NH3-Et20 and excess t-BuOH furnishes the trans-oicohol in greater than 98% isomeric purity, while reduction of the same ketone with LAH in ether provides the corresponding tran -alcohol in 89% isomeric purity. 

With other less-rigid cyclohexanones, the stereochemical course of the reduction is less easy to predict. In general, a mixture of products is obtained in which, with comparatively unhindered ketones, the more stable equatorial alcohol predominates with hindered ketones, the axial alcohol is often the main product. Thus, reduction of 4-tert-butylcyclohexanone 84 with lithium aluminium hydride gives predominantly the equatorial trans-4-/ crt-butylcyclohexanol, whereas the hindered 3,3,5-trimethylcyclohexanone 85 gives a mixture containing mainly the axial alcohol 86 (7.69,7.70). The latter is almost the only product when a more hindered and hence more selective reducing agent such as L-selectride [LiBH( Bu)3] or lithium hydrido-tri-tert-butoxyaluminate [LiAlH(0 Bu)3] is employed. 

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. 

Examples of palladium-catalyzed reduction are 4-chloro-2,6-di-r-butyl-phenol to 2,6-di-t-butylcyclohexanone (750 psig, 25 C) with loss of halogen 24), 1,8-dihydroxynaphthalene to 8-hydroxy-1-tetralone 30), and 2,4-dimethylphenol to 2,4-dimethylcyclohexanone (27). 

Red phosphorus in bromination of 7 butj rolactone 46, 22 Reduction, of 3/3 acetoxy 5 pregnene 20-one with lithium aluminum tn t butoxyhydnde, 46, 57 of 4-f butylcyclohexanone with lithium aluminum hydride aluminum chloride, 47,16... 

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. 

Reduction of cyclic and bicyclic ketones. This hydride reduces 4-r-butyl- and 3-methylcyclohexanone with some bias favoring formation of the more stable isomer. In contrast, 2-methylcyclohexanone is reduced preferentially to the less stable cis-isomer (72%). Essentially, only the ra-isomer is formed on reduction of 2-f-butylcyclohexanone (98% stereoselectivity). Norcamphor is reduced to the endo-alcohol in > 99% stereoselectivity, whereas the more hindered camphor is reduced to the exo-alcohol with 98% stereoselectivity. 

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 contrast, sterically undemanding hydride donors such as NaBH4 or LiAlH4 reduce 4-fert-butylcyclohexanone preferentially through an axial attack. This produces mainly the cyclohexanol with the equatorial OH group (Figure 8.8, middle and bottom reactions). This difference results from the fact that there is also a stereoelec-tronic effect which influences the diastereoselectivity of the reduction of cyclohexanones. 

TABLE 6.3 Reductive Alkylation of Ammonia with 4-f-Butylcyclohexanone over Platinum Metals ... 

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-f-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 (66-96%), and almost exclusively in the case of the five-membered enamines (95-98%) (Scheme 84). The A1,3 strain112 in fact would shift the conformational equilibrium towards the axial (or pseudo xial) orientation of the substituent. 

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

PhCHO gives PhCH(OH)Pr and PhCH20H by addition and reduction, respectively. The presence of BU4NX salts enhances the addition reaction (79). The stereochemistry of both addition and reduction of m situ n-propylzinc reagent with 4- ert-butylcyclohexanone has been studied 238). 

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