Ch. 21 Ester Enolates. The Claisen Condensation & Malonic Ester Syntheses. 21.

1 We are now in a position to propose some fairly useful synthetic schemes. We have emphasized in past chapters those reactions in which new C-C bonds are made. Now we will encounter a few more of great utility. The Claisen Condensation. Remember the Aldol Condensation (self-Aldol: aldehydes with "-H, PT to the enolatewhich is a kind of carbanion, then AdN to another aldehyde carbonyl; product is a $hydroxyaldehyde)? Well, aldehydes and some ketones are not the only compound types that have "Hs. Consider an ester like ethyl propanoate. Are the Hs " to the ester function more easily removable than the typical Hs on C (that is, are they enolizable)? The answer is yes, but one must select carefully the base to accomplish it. Esters will saponify with aqueous sodium hydroxide, the base used often in Aldol condensations. The appropriate base to remove "-Hs from esters is the alkoxide related to the ester function (in this case, ethanolate or ethoxide).

As in enolates of aldehydes and ketones, the resulting carbanion is stabilized by resonance. Ka for estere
"-Hs is about 10-24, or not very different from the acidities of the "-Hs of aldehydes (10-18). The "-C

must be 4 sp3 hybridized, and have 2 or 3 Hs to form an ester enolate. What happens next is precisely what you might expect. The carbanion form of this enolate can attack a carboxyl carbon of another ester molecule (AdN ) in the self-Claisen reaction, followed by E$ . The product is a $-keto ester, in this case ... ethyl 2-methyl-3-oxypentanoate

21.2 Note that since this attack by carbanion on an ester, we may expect reduction at the site of nucleophilic attack. Indeed, the product is a $-ketoester (ethyl 2-methyl-3-oxopentanoate). The dashed line goes throught the C-C bond which has just been made. Note that there are three carbons (in the chains) on each side, and, once again, it is the ",$-bond which has been made. The reaction requires only a caralytic amount of alkoxide, since it is used to make the enolate, then produced in the E$ . Note also that since the product still has an "-H, the alkoxide removes it at the end of the reaction, but there is no problem with another condensation occurring since the new enolate is that from a $-ketoester, and it is stabilized by three resonance structures. It remains only to neutralize the reaction by addition of aqueous acid (H3O+) to generate the $-ketoester product in excellent yield. Using ethyl ethanoate (ethyl acetate), we show the outline synthesis from ethanol of the Claisen product ethyl acetoacetate or acetoacetic ester; actually ethyl 3-oxobutanoate.

The reaction can be done intramolecularly between two esters in the same molecule; the reaction is known as the Diekmann reaction. Of course, 5- and 6-membered rings are especially likely products.

Brief review. Not all esters can undergo self-Claisen reactions. Q? How many "-Hs are there in ethyl 2-methyl propanoate; in ethyl benzoate; in ethyl pentanoate; in diethyl oxalate?

21.3 The Mixed Claisen reaction. As with the Aldol condensation, the Claisen will have limited utility if we can only make $-ketoesters from two indentical (self) esters. If we include two different esters each with "-Hs, we may expect four possible products from the crossed-Claisen or mixed-Claisen reaction. For example, suppose we use the ethyl esters of a C3 and C4 acid. Wed get the $-ketoesters from the ketoacids with C3 + C3, C3 + C4, C4 + C3, and C4 + C4, that is, a mixture which we would then have to separate. Not very useful. Can it be made useful by some strategy? Yes. As before, include one ester which has NO "-Hs to react with one that does. That way, only the self-Claisen interferes, and that we can handle by using an excess of the ester without "-Hs (like oxalates, benzoates, formates and carbonates). An example: ethyl ethanoate (with "-Hs) and ethyl benzoate (without "-Hs).

The product as expected is a $-ketoester, ethyl 3-phenyl-3-oxopropanoate, the ester of a C9 acid. The ethyl benzoate has served as a source of a benzoyl group, hence we may think about this reaction as the acylation [R-C(=O)-] of ethyl ethanoate. These same non-enolizable esters (ones without "-Hs) can also be used to acylate ketones (with "Hs). The reaction is related to the mixed Claisen condensation. An example: acetophenone (ketone with "-Hs) and ethyl benzoate (no "-Hs)

The product is now a $-diketone (in this case, 1,3-diphenyl-1,3-propandione). These can be especially useful in other syntheses, since they too have "-Hs which can be removed to make stabilized carbanions. In general, ketones with "-Hs (and not aldehydes) can condense with esters. Try these: acetone + diethyl oxalate; 3-pentanone + ethyl formate; cyclohexanone + ethyl benzoate

21.4 Conversion of $-ketoesters to ketones. (Via the decarboxylation of the $-ketoacid.) One of the more useful reactions that can be accomplished with the products of the Claisen and Diekmann reactions is their conversion into ketones. You might recall that $-ketoacids are unusually easy to decarboxylate (by heating to 80-130oC). That is how this conversion takes place. Example: take the $-ketoester ethyl 2-methyl-3-oxopentanoate we made above by the self Claisen of ethyl propanoate. First, we saponify and acidify to retrieve the acid, then heat.

The decarboxylation is clean and high yield, producing 3-pentanone. This now sets the stage for a very useful sequence of reactions. These have been collected into the scheme usually called the Acetoacetic Ester Synthesis. It is a method to make substituted acetones (that is, substituted ketones related to propanone). We havent paid much attention to the other kinds of reactions that the enolate carbanions can do, but they are either AdN or SN2. We will focus on the latter one just now. Beginning with ethyl acetoacetate (ethyl 3-oxobutanoate), we make the enolate with ethoxide. Then we can alkylate the carbanion by reaction with 1o or 2o alkyl, allyl or benzyl halides. This can be done once or twice! Then, we can isolate the $-ketoester, and after conversion to the $-ketoacids, decarboxylate it to the ketone. Examine the synthesis of 3-methyl-2-pentanone by this method.

The product can be thought of as a substituted acetone (note the two C-C bonds formed) with the substituents coming from the alkyl halides used in the two alkylation steps.

21.5 A closely related reaction to the Acetoacetic Ester Synthesis is the Malonic Ester Synthesis. It has essentially the same things working in it. We begin with diethylmalonate (malonic ester), and use it as the starting material for makeing substituted acetic acids. An example: Examine the synthesis of 2-methyl-3-phenylpropanoic acid.

Note that diethyl malonate is the source of only two carbons in the final acid, all the others came from the alkyl groups. In the example above, benzyl bromide provides 7, methyl iodide 1, so the final acid is a C10, 1+7+2. Another example. Malonic ester and 1,3-dibromopropane. Here, in the second alkylation, we close the four-membered ring, and the product is cyclobutanecarboxylic acid.

Malonic esters (before saponification) can also be condensed with urea to produce the class of sedativehypnotics and anti-seizure medications called barbiturates. The synthesis of veronal is shown.

Two remaining subjects of interest. 21.6 The Michael Addition. Enolates can add (as nucleophiles) to the $-position of ",$-unsaturated carbonyl compounds. You will remember that is called conjugate nucleophilic addition.

Heres a relevant example. 4-Hydroxycoumarin (think about how this might be made) has an enolate that can be formed from its keto form. This can then add to E-4-phenyl-3-buten-2-one (think about how this can be made) in a Michael-type addition to give a complicated molecule the trade name for which is warfarin (a potent oral anti-coagulant commonly used in treating thrombophlebitis, etc.). Work out the Michael addition of acetoacetic ester and methyl vinyl ketone. Lithium Enolates. You might be wondering whether we can access the "-Hs of an acid (other than in the HVZ reaction). Unfortunately, no, we cant since the acidic proton is more easily removed first, and the resulting carboxylate is an anion, which cant be easily deprotonated (at the "-position) a second time. But, we can remove "-Hs from esters (as we have seen), and it is possible to directly alkylate them. Enolates of Esters are sources of carbanions after all. If the base is strong enough, then it is possible to convert an ester completely to is enolate. The suitable base is LDA (lithium di-isopropylamide), a very strong amide base, but the bulky isopropyl groups keep it from being a good nucleophile. So, it deprotonates an "-H, resulting in an ester enolate, which can be used as a carbanion to react by SN2 with alkyl halides to form esters, and by (AdN) with aldehydes and ketones to form $hydroxy esters.

The lithium enolate reaction can also make aldehyde and ketone enolates, and therefore to react with other (mixed) aldehydes and ketones to form Aldols ($-hydroxy aldehydes and ketones) (Ch. 18).