Sodium enolate cyclohexanone

Caubere et al. [64, 65] also employed enolates as nucleophiles to intercept the intermediates produced from 32a and the mixture of sodium amide and a sodium enolate. Scheme 6.12 illustrates the results obtained by using the enolates of cyclohexanone and cyclopropyl methyl ketone. The former furnished only the ketone 43 in hexamethylphosphoric triamide as solvent, but almost exclusively the cyclobuta-... 

Robinson annelation. The Robinson annelation of unactivated cyclohexanones with t/ ans -3-pentene-2-one under usual conditions proceeds in low yield, if at all. However, Scanio and Starrett report that the sodium enolate of 2-methylcyclohexa-none (1) in dioxane reacts with 1 eq. of /rom-3-pentene-2-one (2) to give fw-4,10-dimcthyl-l(9)-octalone-2 (3) in 65% yield. If DMSO is used in place of dioxane, the... 

Allylcyclohexanone has been prepared by the direct alkylation of the sodium derivative of cyclohexanone with allyl iodide, sodium amide having been used in the preparation of the sodium enolate, and by ketonic hydrolysis of ethyl l-allyl-2-ketocyclo-hexanecarboxylate, prepared by alkylation of ethyl 2-ketocyclo-hexanecarboxylate. - ... 

An attractive alternative procedure for the preparation of 1-ethynylcyclohcxanol which gives yields of 80-90% employs the potassium salt of ferf.-amyl alcohol to effect the addition of acetylene to cyclohexanone. This condensation has been brought about by a suspension of sodium amide in ether 7.8.9.10.11 and by potassium hydroxide in ether. 1-Ethynylcylclohexanol has also been prepared by the action of acetylene on the sodium enolate of cyclohexanone. The procedure described here is essentially that of Campbell, Campbell, and Kby. ... 

A synthesis of cycloheptanone (5) starts with the base-catalyzed addition of nitromethane to cyclohexanone " the procedure calls for a ratio of 3.25 moles of nitromethane to 2.5 moles of ketone. The sodium enolate (2) separates and is collected and iicldifled to liberate the nitro alcohol (3), which Is hydrogenated to the amino alcohol (4). Nitrous acid then elfects deamlnatlve rearrangement with ring expansion to c) cluheptanone (5). 

Sodium enolates of ketones have been prepared by reaction of these ketones with NaNH2. For example, the alkylation of the sodium enolate of cyclohexanone by allylbromide (Fig. 2) leads to 2-allylcyclohexanone accompanied by a little of the dialkylated product (ref. 14). Dimethyl ethynyl carbinol was obtained by reaction of the enolate of acetone (prepared by reaction of solid NaNH2 in ether) with acetylene. Although a prepared ketone enolate is used, this reaction can also be considered as an aldolisation reaction of the acetylide with acetone (ref. 15). Hauser and coll, react sodioenolates of ketones prepared in ether (ref. 16) with acid chlorides (Fig. 2). 

Solvents can influence the stereochemical outcome of the Robinson annulation. An interesting example is the one-step annulation using the sodium enolate of 49 to give the octalone 54 and 55. The reaction of the sodium enolate of the 2-methyl-cyclohexanone with trans-3-penten-2-one (53) in the presence of dioxane at room temperature for 100 h gives the cis-4,10-dimethyl-A octal-2-one (54) in 65% yield, while the reaction gives the /ra -isomer 55 in 72% yield in 3 h under same conditions. ... 

Although SiCh 57 has been employed, e.g., in the presence of sodium azide to convert ketones into tetrazoles (Section 5.3), to condense cyclopentanone in high yields into 1.2.3.4.5.6-tris(trimethylene)benzene (Section 9.2), or used for the condensation of amino acids to polyamides (Chapter 14) with formation of Si02, enol-trimethylsilyl ethers 107 a of ketones such as cyclohexanone are cleanly converted by SiCh 57 in the presence of Hg(OAc)2 into the trichlorosilylenol ether 116, which adds benzaldehyde in the presence of the asymmetric catalyst 117 to give... 

However, all attempts to activate the a-position of the cyclohexanone ring in order to facilitate a subsequent diazotization, which was to be followed by rhodium carbenoid-mediated aryl C-H insertion onto C-4 [21], were unsatisfactory [22], One of the approaches was based on the generation of the silyl enol ether 35, but attempts to achieve its a-acylation led only to the formation of Paal-Knorr-type cyclization products 36. Chemoselective formylation of 34 to 37 was possible by reaction with ethyl formate in the presence of a large excess of sodium ethoxide, but in situ oxidation of the desired compound 37 to 38, which was the major isolated product, made the reaction impractical (Scheme 6). 

To a solution of the silyl enol ether (2.21 g, 12 mmol) in dry dichloromethane (50 ml) was added HTI (3.92 g, 10 mmol), at room temperature. After 2 h stirring the reaction mixture was washed with aqueous sodium bicarbonate solution (3 x 50 ml), then the organic phase was dried and concentrated to give an oil. Addition of hexane followed by decantation of the hexane phase removed iodobenzene and some ketone pure 2-methyl-6-tosyloxy-cyclohexanone was obtained by crystallization from ether (2.25 g, 80%), m.p. 112-114°C. 

He adds sodium ethoxide to cyclohexanone (in ethanol solution) to make the enolate ion then he adds benzyl bromide to alkylate the enolate ion, and heats the solution for half an hour to drive the reaction to completion. 

The stereoselective chelation-controlled aldol reaction of unsubstituted lithium ester enolates with (7 s)-2-(p-tolylsulfinyl) cyclohexanone A (Figure 16) led to a high enantio-face differentiation (> 90 < 10), while the simple diastereoselection was rather low for prochiral enolates567. The role of the lithium cation acting as a template is here essential, since sodium, potassium, HMPA or even added ZnCl2 resulted in decreased yield and selectivity. 

The a-arylation of ketones, such as cyclohexanone, can be achieved using different methods. A convenient route by Pinhey et al.89), reacts cyclohexanone-2-carboxylic esters with aryllead triacetates in pyridine. The protection of the P-carboxylic ester prevents a,a-di- or even higher arylations in a -positions. The ester group can be removed by basic hydrolysis and mild thermal decarboxylation or by heating in wet dimethylsulfoxide with sodium chloride (120-180 °C)90). Barton et al. 91) have found a similar a-arylation route using the less electrophilic triphenylbismuth carbonate. In both cases probably the lead- or bismuth-enolates, respectively, are the first inter-... 

Hence, the first clearcut evidence for the involvement of enol radical cations in ketone oxidation reactions was provided by Henry [109] and Littler [110,112]. From kinetic results and product studies it was concluded that in the oxidation of cyclohexanone using the outer-sphere one-electron oxidants, tris-substituted 2,2 -bipyridyl or 1,10-phenanthroline complexes of iron(III) and ruthenium(III) or sodium hexachloroiridate(IV) (IrCI), the cyclohexenol radical cation (65" ) is formed, which rapidly deprotonates to the a-carbonyl radical 66. An upper limit for the deuterium isotope effect in the oxidation step (k /kjy < 2) suggests that electron transfer from the enol to the metal complex occurs prior to the loss of the proton [109]. In the reaction with the ruthenium(III) salt, four main products were formed 2-hydroxycyclohexanone (67), cyclohexenone, cyclopen tanecarboxylic acid and 1,2-cyclohexanedione, whereas oxidation with IrCl afforded 2-chlorocyclohexanone in almost quantitative yield. Similarly, enol radical cations can be invoked in the oxidation reactions of aliphatic ketones with the substitution inert dodecatungstocobaltate(III), CoW,20 o complex [169]. Unfortunately, these results have never been linked to the general concept of inversion of stability order of enol/ketone systems (Sect. 2) and thus have never received wide attention. 

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

Exo cycloalkylations have been used to synthesize ct5-1-decalones. For example, treatment of 2-methyl-3(4-tosyloxybutyl)cyclohexanone with sodium t-pentylate in benzene gave c/j-9-methyl-l-deca-lone (50) in 60% yield. Also, as shown in Scheme 28, conjugate addition-cycloalkylation was employed to synthesize a cw-fused decalone related to the sesquiterpene, ( )-valerane. Apparently, in these cases, the enolate intermediate adopts a conformation having the 4-bromobutyl side chain quasi-axial, and C—C bond formation occurs via equatorial attack to give initially a twist-boat conformation of the product. 

Their stability at low temperature means that lithium enolates are usually preferred, but sodium and potassium enolates can also be formed by abstraction of a proton by strong bases. The increased separation of the metal cation from the enolate anion with the larger alkali metals leads to more reactive but less stable enolates. Typical very strong Na and K bases include the hydrides (NaH, KH) or amide anions derived from ammonia (NaNH2, KNH2) or hexamethyldisilazane (NaHMDS, KHMDS). The instability of the enolates means that they are usually made and reacted in a single step, so the base and electrophile need to be compatible. Here are two examples of cyclohexanone alkylation the high reactivity of the potassium enolate is demonstrated by the efficient tetramethylation with excess potassium hydride and methyl iodide. 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Sato and co-workers in 1991 showed the utilization of organotin triflate as the Lewis acid catalyst for the Michael addition step. Synthesis of octalone 30 is a good example in which silyl enol ether of cyclohexanone and MVK (1.3 1 ratio) reacts in DCM in the presence of 0.05 equivalent of Bu2Sn(OTf)2 at -78 C. After alkylation was complete, sodium methoxide in methanol was added, and the mixture was stirred at room temperature to give 30 in an excellent 89% yield. ... 

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