Cyclohexanone ketal formation

Kinetic studies of acetal/ketal formation from cyclohexanone, and hydrolysis (3 X 0 N HCl/dioxane-H20, 20°), indicate the following orders of reactivity ... 

This ether formation arises from conversion of the phenol to a cyclohexanone, and ketal formation catalyzed by Pd-Hj and hydrogenolysis. With Ru-on-C, the alcohol is formed solely (84). 

Acetal and ketal formation from aldehydes, resp. ketones and alcohols occurs over mordenite and other acidic zeolites [91] slightly above ambient temperatures in the liquid phase. The reaction is not confined to simple alcohols, diols can also be converted (e.g., cyclohexanone reacts with ethylglycol to 1,4, dioxaspiro(4,5)decane [2]). Note that it is likely that desorption controls the rate of such reactions as the product molecules are larger than the reactants and have, hence, a higher adsorption constant. 

The condensation of cyclohexanone (13) and cyclopentanone (14) with formaldehyde produced the corresponding tetrakis-(hydroxymethyl) -ketones in 37 and 90% yields, respectively. When the tetramethylolcyclohexanone was treated with cyclohexanone, a 77% yield of the model keto spiro ketal was formed. In this compound the carbonyl group located between the two quaternary carbon atoms is so hindered that no ketal formation apparently takes place. 

When the oxidation of cyclohexene is carried out in alcoholic solvents, cyclohexanone can undergo subsequent ketal formation with the solvent (Figure 11.1, Table 11.1). Under our mild oxidation conditions, the oxidation of the alcohol solvent Is virtually absent. 

In conclusion, we developed an elegant route for the synthesis of cyclohexanone from cyclohexene. Key achievements were product stability due to protection of the ketone by ketal formation and catalyst stability due to the usage of Na2PdCl4/CuCl2/FeCl3 as a catalyst combination. 

In particular, the dimethyl cyclohexanone ketal also has been reacted with ethyleneglycol to afford a cycHc carbonate and cyclohexanone [112], plus methanol (Scheme 1.16). The use of DCC as water trap deserves comment A detailed study has shown that it is a promoter of the carboxyiation in addition to being a simple water removal agent Combining experimental studies and DFT calculations, the reaction mechanism has been completely elucidated, as shown in Scheme 1.17 [113]. Several carbonates have been produced with very high yields (90-96%) and selectivity (dose to 100%). The latter is highly influenced by the temperature as above 335 K the favored reaction is the formation of carbamate (Scheme 1.17 A). With DCC, using methanol and phenol it has been possible to produce the mixed methyl-phenyl-carbonate, (MeO)(PhO)CO [113]. 

Scheme 1.16 Use of cyclohexanone-ketal in a two-step process for carbonate formation, avoiding the formation of water in the reaction medium containing the carbonate.

The direct formation of a dimethyl ketal by reaction of the ketone with methanol is particularly sensitive to steric effects. Only cyclohexanones react under these conditions.In the steroid series only saturated 3-ketones form dimethyl ketals with methanol and acid although partial reaction of a 2-ketone has been observed in the presence of homogenous rhodium catalyst. ... 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Scheme 1-10. Formation of ketals from glycols and 2-substituted cyclohexanone 22.

For instance, 2-methylpropene reacted with acetic acid at 18°C in the presence of Al-bentonite to form the ester product (75). Ion-exchanged bentonites are also efficient catalysts for formation of ketals from aldehydes or ketones. Cyclohexanone reacted with methanol in the presence of Al-bentonite at room temperature to give 33% yield of dimethyl ketal after 30 min of reaction time. On addition of the same clay to the mixture of cyclohexanone and trimethyl orthoformate at room-temperature, the exothermic reaction caused the liquid to boil and resulted in an almost quantitative yield of the dimethyl ketal in 5 min. When Na- instead of Al-bentonite is used, the same reaction did not take place (75). Solomon and Hawthorne (37) suggest that elimination reactions may have been involved in the geochemical transformation of lipid and other organic sediments into petroleum deposits. 

Cyclohexanone diethyl ketal was prepared according to a procedure by Howard and Lorette see Org. Synth., Collect. Vol. V 1973, 292 bp 80-83°C, 18 mm. The checkers prepared it by keeping cyclohexanone (50 g), triethyl ortho-formate (75 g) and concentrated hydrochloric acid (0.2 mL) in absolute ethanol (30 mL) for 10 hr at room temperature, followed by treatment with sodium hydroxide until the solution is basic. 

The formation of the dimethylketal of cyclohexanone is an equilibrium reaction according to Figure 9.12. Complete conversion to the ketal is most simply achieved by working in methanol as a solvent and thus shifting the equilibrium to the ketal side. Whose principle is in action in this case ... 

As described in Chapter 12, hydrogenation of cyclohexanone or related cyclic ketones over pre-reduced palladium hydroxide or palladium oxide in alcoholic solvents gave the ether as the primary product.35 The mechanism put forth for this reaction involved the intermediate formation of a ketal which was then hydrogenolyzed to the ether (Eqn. 18.12) 6 Evaporated platinum and palladium blacks, which have no basic impurities, promoted facile acetal formation. Further hydrogenation over palladium gave the ether as the almost exclusive product at a rate four times faster than that observed when reduced palladium hydroxide was used as the catalyst. Over the evaporated platinum catalyst only moderate amounts of the ether were formed. The primary product was the alcohol accompanied by some alkane.36 Ether formation was also observed on hydrogenation of cyclic ketones over Pt02 in ethanolic-HCl at room temperature and atmospheric pressure. Acetal formation occurred on... 

In a similar vein, 3 equiv. of trimethylsilyldimethylamine have been used at room temperature to form the enamine from cyclohexanone, conditions under which the water is presumably consumed as hexa-methyldisiloxane (equation 5). This method has been extended to the formation of IVA -dimethyl-enamines from unsaturated aldehydes. Alternatively, enamines have also been obtained by converting the carbonyl compound to a ketal before reaction with the amine. The first process is endothermic but can be readily driven to completion and provides the driving force for formation of the enamine. 

The synthesis involves the formation of a ketal of 4-tert-butyl cyclohexanone with racemic 3-chloro-1,2-propanediol, and substitution of the chlorine with ethyl-propylamine, as described by W. Kramer and coworkers (Scheme 17.20). 

Scheme 8.52. The formation of, first, a hemiketal and, second, a (cyclic) ketal as a result of the acid-catalyzed addition of 1,2-dihydroxyethane (ethylene glycol, HOCH2CH2OH) to cyclohexanone.

The formation of hemiketals and ketals from alcohols and ketones is exactly analogous (with somewhat more difficulty as ketones are generally less reactive than aldehydes Chapter 9). In the reaction of a ketone, such as cyclohexanone (Table 8.6, item 12) with a 1,2-diol, such as 1,2-dihydroxyethane (ethylene glycol [HOCH2CH2OH]) (Scheme 8.52), the second equivalent of alcohol is part of the initial alcohol substrate and the cyclic product results. 

In general it may be stated that ease of formation of dioxolans and other acetals and ketals is rou ly in the order aldehydes > acyclic ketones and cyclohexanones > cyclopentanones > o , 3-unsaturated ketones > a-mono- and di-substituted ketones > aromatic ketones, though variations in this order may be experienced as a result of additional steric or electronic factors. Use of this general principle, and judicious choice of experimental conditions, generally makes possible selective dioxolan formation in polycarbonyl compounds this subject has been extensively reviewed in the steroid field (Ref. l,pp. 3-17). 

The synthesis continued with reduction of the cyclohexanone to the alcohol oxidation state, taking it out of play for a series of reactions that constructed the sidechain (49 54). The sidechain ketone was then protected as an acetal, and the cyclohexanone was reinstalled by deprotection and oxidation of the cyclohexanol. Regioselective acylation of 55 under conditions of thermodynamic control, followed by reduction of the intermediate /3-ketoester, gave 56 (for comparison see 3 —> 14 on Steroids-3). Formation of the tosylate, a /3-elimination, and ketal hydrolysis completed the synthesis of 14. 

Many chemical reactions are catalyzed by acids but on a large-scale can generate significant amoimts of acid waste, which requires neutralization and/ or disposal. In principle, CO dissolved in water is mildly acidic, due to formation of carbonic acid and should be capable of catalyzing a range of reactions. Simple pressure release at the end of the reaction brings the pH back to levels, which require minimal neutralization. Hydrolysis of ketal to cyclohexanone and ethylene glycol and epoxides to diols are a few examples where CO in presence of water have been used as a catalyst [322]. 

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