Ketone enolates acylation

Acylation of ketones (Sec tion 21 4) Diethyl carbo nate and diethyl oxalate can be used to acylate ketone enolates to give p keto esters... 

Oxalic esters (for electronic reasons) and formic esters (because of their low steric hindrance) are reactive esters that can acylate ketone enolates formed with NaOR in equilibrium reactions. Formic esters acylate ketones to provide formyl ketones (for example, see Figure 13.61). It should be noted that under the reaction conditions the conjugate base of the active-methylene formyl ketone is formed. The neutral formyl ketone is regenerated upon acidic workup. 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to p-keto esters by reaction with diethyl carbonate. 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

Ketones are converted to (3-ketoesters by acylation with diethyl carbonate or diethyl oxalate, as illustrated by Entries 4 and 5 in Scheme 2.16. Alkyl cyanoformate can be used as the acylating reagent under conditions where a ketone enolate has been formed under kinetic control.227... 

Acylbenzotriazoles 162 are efficient C-acylation reagents for the regioselective conversion of ketone enolates into P-diketones . Diethyl(l-benzotriazolmethyl)phosphinate (163) was found to be a convenient reagent for the stereoselective preparation of (E)-l-(l-alkenyl)benzotriazoles <00SC1413>. The novel three-carbon synthon 1-(1//-133-... 

Acylation of enol ethers. Reaction of 1 with ethyl vinyl ether in ether provides an intermediate that undergoes dehydrochlorination when heated to provide the trichloromethyl ketone 2, which is converted by base (haloform reaction) to the ester 3 in high yield. 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are all /5-dicarbonyl compounds. They are all rather acidic and can be alkylated by the procedures described in Section 1.4. Reaction of ketone enolates... 

Some /J-heteroatom substituted a,/J-unsaturated acyl silanes react with methyl ketone enolates in a stepwise stereoselective cyclopentannelation process, formally a [3 + 2] annelation, which may proceed through aldol reaction followed by Brook rearrangement and cyclization (Scheme 111)223. 

Thus all that is required is to treat dimethyl 1,2-benzenedicarboxylate and 1,1-diphenylacetone with base. Two successive acylations of a ketone enolate occur the first is intermolecular, the second intramolecular. 

The ring closure of 1,5-keto-acids and their derivatives is a widely used strategy for the synthesis of 2A-pyran-2-ones <1984CHEC, 1996CHEC-II>. The 1,5-keto acid derivatives are typically formed in situ with concomitant ring closure to form 2//-pyran-2-ones. There are three main approaches to access the prerequisite 1,5-keto acid derivatives, namely (i) reaction of an ester enolate with a 2-acyl vinyl cation equivalent, (ii) the reaction of a ketone enolate... 

Fig. 6.21. In situ activation of a carboxylic acid—i.e., the side chain carboxyl group of protected L-aspartic acid—as the mixed anhydride (B) and its aminolysis to a Weinreb amide. How this Weinreb amide acylates an organolithium compound is shown in Figure 6.44. The acylation of an H nucleophile by a second Weinreb amide is presented in Figure 6.42 and the acylation of a di(ketone enolate) by a third Weinreb amide in Figure 13.64. Figure 6.50 also shows how Weinreb amides of carboxylic acids can be obtained by C,C bond formation.

Fig. 12.21. Acylation of an enamine with an acid chloride (—> enaminoketone E), followed by acidic workup (—> /J-diketone B). Since the enamine A is produced from cyclohexanone, the figure shows the second part of a two-step reaction which is an alternative to the one-step acylation of a ketone enolate (cf. Section 13.5.2).

The relative inertness of ketone enolates toward ketones makes it possible to react non-quantitatively obtained ketone enolates with esters instead of with ketones. These esters—and reactive esters in particular—then act as acylating reagents. 

In contrast to ketones, aldehydes easily undergo a base-catalyzed aldol reaction (Figure 13.44), and this reaction may even progress to an aldol condensation (Section 13.4.1). It is therefore not possible to acylate aldehyde enolates that are present only in equilibrium concentrations. Any such enolates would be lost completely to an aldol reaction. 

Most other carboxylic acid derivatives can acylate only ketone enolates that are formed quantitatively. In these reactions, the acylation product is a /J-diketone, i.e., an active-methylene compound. As a consequence it is so acidic that it will be deprotonated quantitatively. This deprotonation will be effected by the ketone enolate. Therefore, a complete acylation of this type can be achieved only if two equivalents of the ketone enolate are reacted with one equivalent of the acylating agent. Of course, proceeding in that manner would mean an unacceptable waste in the case of a valuable ketone. 

Fig. 13.61. Acylation of a ketone enolate with a formic ester to generate a formyl ketone. The ketone enolate intermediate (not shown) is formed in an equilibrium reaction.

Against Wastefulness A Practical Hint Regarding the Acylation of Ketone Enolates... 

The following protocol requires no more than the stoichiometric amount of a ketone eno-late to achieve a complete acylation. An ester is added drop wise to a 1 1 mixture of one equivalent each of the ketone enolate and LDA. The acidic proton of the /3-diketone, which is formed, then is abstracted by the excess equivalent of LDA rather than by the ketone enolate. 

The protocol described also can be used for the acylation of ketone enolates with carbonic acid derivatives (Figure 13.62). Especially good acylating agents are cyanocarbonic acid methyl ester (Mander s reagent, Figure 13.62, top) and dialkyl pyrocarbonates (bottom). Usually it is not possible to use dimethyl carbonate for the acylation of ketone enolates because dimethyl carbonate is a weaker electrophile than cyanocarbonic acid methyl ester or diethyl pyrocarbonates. 

Fig. 13.62. Acylation of ketone enolates with carbonic acid derivatives. Especially good acylation reagents are cyanocarbonic acid methyl ester (top) and dialkyl pyrocarbonates (bottom).

A carbonic acid derivative which, surprisingly, also proves to be suitable for the acylation of ketone enolates, is Stiles reagent, i.e., (methoxymagnesium) monomethyl carbonate. In Section 8.2, you saw how this reagent can be obtained. Ketone enolates are carboxylatedby Stiles reagent to furnish a /3-keto carboxylic acid, as shown by the reaction equation below. As this keto acid is initially obtained as the (methoxymagnesium) carboxylate, such an acylation can easily proceed without the extra equivalents of enolate or base mentioned above. 

Fig. 13.64. Acylation of a bis(ketone enolate) with one equivalent of a Weinreb amide.

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