4-t-Butylcyclohexanone

That the methyl group in the pyrrolidine enamine of 2-methylcyclo-hexanone (7) is in fact axial was demonstrated by Johnson and Whitehead (8). They found that careful hydrolysis of the pyrrolidine enamine of the conformationally more stable system, i.e., 2-methyI-4-t-butylcyclohexanone (13), led to a 1 4 mixture of cis and trans isomers of the ketone (14 and 15), showing that the methyl group in the enamine is largely in the axial orientation. 

Since the conformational inversion of 2c-methylcyclohexanone is the key step in this sequence, the corresponding conformationally more stable system, i.e., cw-2-methyl-4-t-butylcyclohexanone (14), should fail to incorporate any deuterium. This was actually shown to be the case. Treatment of this ketone under identical conditions for d exchange did not show any d incorporation. This evidence also rules out the likelihood of any d incorporation via acid- or base-catalyzed enolization. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The transition metal catalysed addition of a hydridosilane to a multiply-bonded system is known as hydrosilylation (1). Under such conditions, alkynes undergo clear cis-addition, so providing one of the most direct routes to vinylsilanes (Chapter 3). Hydridosilanes also add to the carbonyl group of saturated aldehydes and ketones, to produce alkyl silyl ethers. Fot example, under suitable conditions, 4-t-butylcyclohexanone (2) can be reduced with a high degree of stereoselectivity. 

To a solution of 4-t-butylcyclohexanone (lmmol), tris(triphenylphos-phine)ruthenium(n) chloride (0.05 mmol) and silver trifluoroacetate (0.05 mmol) in toluene (5 ml) was added triethylsilane (1.5 mmol). The mixture was heated under reflux for 20 h, and concentrated under reduced pressure. The residue was diluted with hexane (3 ml), filtered and distilled to give a mixture of triethylsilyl ethers (0.96mmol, 96%), b.p. 70°CI 0.1 mmHg. G.l.c. analysis shows an axial (cis) equatorial (trans) ratio of 5 95—a result comparable to the best LAH results. 

A convenient preparation of a-cyano ketones via ketone enolates has been recently described149. The yields are consistently high when using p-tolylsulfonyl cyanide (264) in THF at — 78 °C. Thus, the addition of the lithium enolates of 4-t-butylcyclohexanone to 2 equivalents of264 at — 78 °C gives a-cyano ketone 265 in 80% yield (equation 158). Use of... 

For simple, conformationally biased cyclohexanone enolates such as that from 4-t-butylcyclohexanone, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Addition of Bu3SnLi or McsSnI.i to 4-t-butylcyclohexanone affords mixtures of trans and cis adducts in ratios that depend on reaction conditions (Table ll)68. In THF, a 93 7 mixture is obtained with both reagents. This ratio is thought to represent the thermodynamic distribution—the axial stannane being favored. In ether, the cis isomer predominates, suggesting a kinetic preference for equatorial addition. Each of the two isomers can be lithiated with BuLi. Subsequent treatment with alkyl halides or carbonyl compounds affords the substituted alkoxy cyclohexanes with retention of stereochemistry. 

Shift reagents have been employed to study the kinetics of catalytic deuteria-tion of 4-t-butylcyclohexanone, and secondary (deuterium) isotopic effects in organic substrates. The n.m.r. study of internal rotation of the methyl groups in MOjNCOR (R = H, Me, or Et) has been facilitated using (1 Ln = Eu or Pr, R = C3F7, R2 = BuV ... 

House, Tefertiller, and Olmstead (127) have found that the treatment of the enolate ion 467 derived from 4-t-butylcyclohexanone with deuterium oxide in deuterioacetic acid yielded a 7 3 mixture of the axial deuterioketone 468 and the equatorial deuterioketone 469. 

In a study combining 2H relaxation-time measurements and use of paramagnetic lanthanide shift reagents, the ratio of the relaxation times of axial and equatorial deuterons in 2,2,6,6-tetradeuterio-4-t-butylcyclohexanone [20]... 

These results on hydrogen-deuterium exchange are also in agreement with the data obtained by House et al. (1968). When the lithium enolate of 4-t-butylcyclohexanone [22] was added to a solution of deuterioacetic acid in... 

The stereoselectivities are not always very high, particularly in the cases of unhindered ketones.154-158 For example, only 78% of the cis (axial) isomer was formed in the hydrogenation of 4-t-butylcyclohexanone over platinum oxide in AcOH-HCl.156... 

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) ... 

To a solution of 4.0 g. (0.012 mole) of iridium tetrachloride (Note 1) in 4.5 ml. of concentrated hydrochloric acid is added ISO ml. of water followed by 50 ml. of trimethyl phosphite (Note 2). This solution is added to a solution of 30.8 g. (0.20 mole) of 4-t-butylcyclohexanone (Note 3) in 635 ml. of 2-propanol contained in a 2-1. flask equipped with a reflux condenser. The solution is heated at reflux for 48 hours (Note 4). At the end of this time the 2-propanol is removed on a rotary evaporator at reduced pressure, and the remaining solution is diluted with 250 ml. of water and extracted with four 150-ml. portions of el her. The ether solution is washed with two 100-ml. portions of wafer which are combined with the aqueous residue (Note 5). Tin ether extract is dried over magnesium sulfate or potassium carbonate and then concentrated on a rotary evaporator at reduced pressure to obtain cis-4-t-butylcyclohexano] as a w hite solid (2ft—31 g. 93-99%). Analysis of the crude product by glpc demonstrates it to contain 95.8-96.2 % eis-alcohol and 12 3 8 % of the trans isomer with essentially no ketone remaining (Note 6). Itecrystallization from 40% aqueous ethanol an nrds greater than 99% pure ri.s-alcohol, m.p. 82-83.5° after Hiihlimulion2 (Nole 7). 

In hydrogenolyses with HAICU, the dimethyl acetals of cyclobutanone and cyclohexanone are cleaved more slowly than that of 3-pentanone, while those of cyclopentanone and cycloheptanone are cleaved more rapidly (Table 1), as would be expected for a carbonium ion process. The differences in rate are small, suggesting that carbonium ion character is not strongly developed in the transition state. With the dimethyl acetal of 4-t-butylcyclohexanone, the hydride addition step occurs with strongly predominating axial addition when HAlCh is used Zn(BH4)2 with TMS-Cl, and TMS-H with TMSO-Tf are less selective (Table 2). Equatorial attack predominates, however, in the reduction of the ketone itself with TBDMS-H and TBDMS-OTf. ... 

Reaction of 1-lithiocyclopropyl phenyl sulphide (123) with 4-t-butylcyclohexanone produces an adduct as a 99 1 mixture of two isomers. By analogy to organometallic addition to this ketone, the stereochemistry is assumed to result from equatorial attack. Treatment of the adduct with one equivalent of anhydrous stannic chloride followed by hydrolysis produces primarily cyclobutanones (equation 94) ... 

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