Ketones enolizations, sodium hydride

Lactams and ketones have been enolized using sodium hydride and have subsequently undergone intramolecular alkylation and acylation on the oxygen atom (eqs 48 and 49). 

The familiar alkylation of -ketoesters followed by decarboxylation is still a useful route to a-alkyl ketones, although the alkylation of enamines is frequently the preferred route. Given below are two examples of alkylation of 2-carbethoxycycloalkanones (prepared in Chapter 10, Section I). In the first case, sodium ethoxide is the base employed to generate the enolate ion of 2-carbethoxycyclohexanone. In the second case, the less acidic 2-carbethoxycyclooctanone requires sodium hydride for the generation of the enolate ion. 

Let US use a systematic approach to consider what product is most likely to result when a mixture of an ester and a ketone, both capable of forming enolate anions, is treated with base. For example, consider an ethyl acetate-acetone mixture treated with sodium hydride in ether solution. 

Sodium hydride and potassium hydride can also be used to prepare enolates from ketones. The reactivity of the metal hydrides is somewhat dependent on the means of preparation and purification of the hydride.5... 

Enolate ions formed from, ketones or aldehydes are extremely important in the synthesis of more complex organic molecules. The ease with which an enolate ion is formed is related to the acidity of the a proton. The pKa of propane (acetone) is 19.3 that means that it is a stronger acid compared to ethane (pKa 60) and a much weaker acid than acetic acid (pKa 4.7), i.e. strong bases like sodium hydride, sodium amide, and lithium diisopropylamide LiN(i-C3H7)2 are needed to form an enolate ion. 

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

The stability of the phosphonium-stabilized enolates also means that, although they react well with aldehydes, their reactions with ketones are often poor, and it is better in these cases to use phos-phonate-stabilized enolates. Being anionic, rather than neutral, these are more reactive. If an ester enolate equivalent is being used, the best base is the alkoxide ion belonging to the ester with a ketone enolate equivalent, use sodium hydride or an alkoxide. 

Just occasionally it is possible to carry out cross-condensations between two different enolizable molecules under equilibrating conditions, A notable example is the base-catalysed reaction between methyl ketones and lactones. With sodium hydride—a strong base that can convert either starting material entirely into its enolate anion—good yields of products from the attack of the enolate of the ketone on the electrophilic lactone can be obtained. 

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

S°C. By contrast, the formylation of ketone enolates with ethyl formate is usually carried out using sodium hydride or sodium ethoxide as base and generally requires 12 to 48 hr at room temperature for complete reaction. 

Methylation of saturated 6-ketones is rather difficult, needing sodium hydride in boiling xylene to generate the enolate anion. With no hindrance to a-face attack in the compound... 

Reduction. Benzophenone and fluorenone are reduced to bcnzhydrol and fluorcnol, respectively, by sodium hydride. The best results (92-97% yields) arc obtained with HMFr, DMF, or pyridine as solvent. Nonenolizable ketones, or ketones which enolize with difficulty, are reduced to the corresponding alcohols in very good yields. Side... 

Sodium hydride removes a proton from the sulfone to give an anion you can represent as enolate. Displacement of mesylate gives an allyl silane converted into an allyl anion with fluor Addition to the ketone gives the 5/5 fused system, necessarily with cis stereochemistry. 

HydroxymethyUttion of ketones. A ketone is treated with sodium hydride for conversion into the enolate and this is alkylated with benzyl chloromethyl ether. Dioxane is the preferred solvent since O-alkylation is minimized. The examples formulated illustrate a high degree of stereoselectivity. The benzyl group should... 

Any equilibrium will produce the thermodynamically most stable enolate. The most stable enolate will have the greatest charge delocalization. In the above example, the thermodynamically favored enolate is conjugated the kinetically favored enolate is not. Common conditions for thermodynamic control are to use average bases (like sodium ethoxide or potassium tert-butoxide, p abH 16 to 19) in alcohol solvents. Proton transfer equilibria rapidly occur among base, solvent, ketone, and enolate. Sodium hydride or potassium hydride in an ether solvent are also thermodynamic reaction conditions that allow equilibration between the ketone and the enolate. Enones have two possible enolates weaker bases give the thermodynamically more stable extended enolate, whereas kinetic conditions produce the cross-conjugated enolate. 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

Enol acetylation. An a-halo-a-arylacetophenone such as (1) cannot be converted into the enol acetate by reaction with isopropenyl acetate, and conversion into the sodium enolate by sodium methoxide followed by treatment with acetyl chloride gives low yields. However, Cooper and Owen28 found that, if the ketone is treated with dry methanol and sodium hydride and the mixture let stand until evolution of hydrogen has ceased and then treated with acetyl chloride, the enol acetate is obtained in yield of50-70%. 

For acylations with reactive esters, such as formate or oxalate (see Section 3.6.4.5), sodium alkoxides are still the bases of choice, but sodium hydride, dimsyl sodium, sodium or potassium amide or sodium metal have all been used for the in situ generation of the enolate anion. A typical example is shown in Scheme 47. Acylation by esters results in the production of 1 equiv. of the alkoxide ion, along with the p-dicarbonyl compound proton transfer then results in the production of the conjugate base of the dicarbonyl compound. This process normally leads to the more stable anion in the acylation of an unsymme-trical ketone. The acyl group thus becomes attached to the less-substituted a-position of the ketone. The less stable 0-acylated products are normally not observed in such reversible base-catalyzed reactions. Methyl alkyl ketones are normally acylated on the methyl group where both a-carbons are substituted to the same extent, acylation occurs at the less-hindered site. Acylation is observed only rarely at a methine carbon as the more stable p-diketone enolate cannot be formed. 

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