R-Butylcyclohexanone

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. 

The mixture is decanted into an Erlenmeyer flask, the residual green salts are washed with two 15-ml portions of acetone, and the washings are added to the main acetone solution. Cautiously, sodium bicarbonate (approx. 13 g) is added to the solution with swirling until the pH of the reaction mixture is neutral. The suspension is filtered, and the residue is washed with 10-15 ml of acetone. The filtrate is transferred to a round-bottom flask and concentrated on a rotary evaporator under an aspirator while the flask temperature is maintained at about 50°. The flask is cooled and the residue transferred to a separatory funnel, (If solidification occurs, the residue may be dissolved in ether to effect the transfer.) To the funnel is added 100 ml of saturated sodium chloride solution, and the mixture is extracted with two 50-ml portions of ether. The ether extracts are combined, washed with several 5-ml portions of water, dried over anhydrous magnesium sulfate, and filtered into a round-bottom flask. The ether may be distilled away at atmospheric pressure (steam bath) or evaporated on a rotary evaporator. On cooling, the residue should crystallize. If it does not, it may be treated with 5 ml of 30-60° petroleum ether, and crystallization may be induced by cooling and scratching. The crystalline product is collected by filtration and recrystallized from aqueous methanol. 4-r-Butylcyclohexanone has mp 48-49° (yield 60-90 %). 

Hydrogenation of the constrained 4-r-butylcyclohexanone gives 99% ether (97% cis) in ethanol over palladium (68). High yields of methyl ethers are formed by reduction of 5a- and 5 -cholestan-3-ones in methanol over palladium. 

An interesting analog of the Favorskii rearrangement treats a ketone such as 4-/ r/-butylcyclohexanone, without an oc-halogen with T1(N03)3 to give 3-tert-butylcyclopentane-1 -carboxylic acid. ... 

The stereoselectivity is enhanced if there is an alkyl substituent at C(l). The factors operating in this case are similar to those described for 4-r-butylcyclohexanone. The tnms-decalone framework is conformationally rigid. Axial attack from the lower face leads directly to the chair conformation of the product. The 1-alkyl group enhances this stereoselectivity because a steric interaction with the solvated enolate oxygen distorts the enolate to favor the axial attack.57 The placement of an axial methyl group at C(10) in a 2(l)-decalone enolate introduces a 1,3-diaxial interaction with the approaching electrophile. The preferred alkylation product results from approach on the opposite side of the enolate. 

The data below give the ratio of equatoriahaxial alcohol by NaBH4 reduction of each cyclohexanone derivative under conditions in which 4-r-butylcyclohexanone gives an approximately 85 15 ratio. Analyze the effect of the substituents in each case. 

Methylation of aldehydes and ketones. The reagent forms I I adducts with aldehydes and ketones at low temperatures aldehydes undergo addition so much more rapidly that selective reactions are possible in the presence of ketones. Both reactions arc diastcrcoselective. Thus addition to 4-r-butylcyclohexanone results in a mixture of axial and equatorial alcohols in the ratio of 82 18. 

Asynunetric Deprotonation/Protonation of Ketones. Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones. The resulting optically active enols orenol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing Cj symmetry, such as (1). For example, reaction of 4-r-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective the resulting enol silyl ether possesses an 88% ee (eq 4). ... 

Trimethyl-2-norbomanone a-Tebalone Benzaldehyde 4-Iodobenzaldehyde 2-Bromobenzaldenyde 4-Cyanobenzaldehyde Acetaldehyde Cyclohexanecaibaldehyde 4-Nitrobenzaldehyde 4-r-Butylcyclohexanone Benzddehyde Benzaldehyde Benzaldehyde... 

Table 6 Equatorial versus Axial Addition of MeTi and MeZr Reagents to 4-r-Butylcyclohexanone...

As far as the stereoselectivity of the addition is concerned, allyltitanium reagents, unlike their alkyl analogs (Section 1.5.3.1.3), give preferentially axial addition to 4-r-butylcyclohexanone. The selectivity... 

Table 1 Addition of AUyl Organometallics (CHz—CHCHjM) to 4-r-Butylcyclohexanone (32 equation 25)...

Lithium salts are also effective for promoting the cffganolithium or magnesium addition reactions. UCIO4 was found to enhance the rate of MeLi or MezMg addition to 4-r-butylcyclohexanone. Another example is shown in the reaction of 2-acetylpyridine with alkyllithiums, where added LiBr raises the yields of the adducts. This phenomenon is explained by the coordination of LiX to the carbonyl oxygen prior to the C—C bond formation. 

The reactions of substituted arsonium ylides with ciubonyl compounds can be carried out with high stereoselectivity in favor of rranr-disubstituted epoxides (equation 14). Equatorial attack is observed for addition to 4-r-butylcyclohexanone. Good stereoselectivity (S9 l) was observed for the addition of triphenylarsonium methylide to some (A A(-dibenzyl)amino aldehydes at -78 °C in THF. Interestingly, the initial hydroxy tetraalkylarsonium adducts were isolated under these conditions, and had to be cyclized under the action of sodium hydride in a separate step. 

Methylaluminum bis 2,6-di-Ubutyl 4 methylphenoxide) (MAD, 1) methylal-uminum bis(2,4,b-tri Ubutylphenoxide) (MAT, 2). The complexes formed from 4-r-butylcyclohexanone and 1 or 2 (3 equiv.) react with methyllithium or CHjMgBr... 

Cyclohexanecarbaldehyde 4-Nitrobenzaldehyde 4-r-Butylcyclohexanone PhTi(OPr )3 HiTi(OPr )3 PhTi(OPr )3 THF Et20 Et20 1.0 0.5 15.0 -10 -15 r.t. Cyclohexylf nylmethanol (4-Nittophenyl)phenylniethanol 1 -Hienyf-4+-butylcyclohexanol 84 (95) 94 95 a ... 

Figure 47 A model for LiC104-mediated addition of MeLi to 4-r-butylcyclohexanone...

Methylation of aldehydes and ketones.2 Unlike Grignard and alkyllithium reagents, this reagent does not react with esters, S-thiolates, nitriles, and epoxides, but does react with aldehydes even at — 70 to — 20° and ketones at — 25 to — 80° at reasonable rates. Reaction of 1 with 4-r-butylcyclohexanone results in die corresponding adducts in the ratio cis/trans = 85 15. 

Oxidation of primary and secondary alcohols to carbonyl compounds. Corey and Kim2 report that the complex of N-chlorosuccinimide and dimethyl sulfide is somewhat superior to the complex of dimethyl sulfide and chlorine (this volume) for oxidation of primary and secondary alcohols the formation of hydrogen chloride is avoided and yields are generally higher. The procedure is illustrated for the oxidation of 4-/-butyl-cyclohexanol (2) to 4-r-butylcyclohexanone (4). The complex (1) is prepared by addition of dimethyl sulfide (4.1 mmole) to a stirred solution of NCS (3.0 mmole) in toluene at 0° under argon. The mixture is cooled to -25° and a solution of 4-r-butylcyclo-hexanol (2.0 mmole, mixture of cis and trans) in toluene is added dropwise. The stirring is continued for 2 hr. at — 25° and then triethylamine (3.0 mmole) in toluene is added dropwise. The ketone (4) is obtained in almost quantitative yield. As in oxidation with the complex of dimethyl sulfide and chlorine, an intermediate sulfoxonium complex (3) is involved. 

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