Malonic Ester and Acetoacetic Ester Syntheses

Chapter 26

Carbanions II Malonic Ester and Acetoacetic Ester Syntheses 

Carbanions in organic synthesis

• We have already seen something of the importance to organic synthesis of the formation of carbon-carbon bonds: it enables us to make big molecules out of little ones. In this process a key role is played by negatively charged carbon. Such nucleophilic carbon attacks carbon holding a good leaving group in alkyl halides or sulfonates, usually or carbonyl or acyl carbon. Through nucleophilic substitution or nucleophilic addition, a new carbon -carbon bond is formed.

• Nucleophilic carbon is of two general kinds, (a) There are the carbanion-like groups in organometallic compounds, usually generated through reaction of an organic halide with a metal: Grignard and organocadmium reagents, for example; the lithium dialkylcopper reagents used in the Corey-House synthesis of hydrocarbons; the organozinc compounds that are intermediates in the Reformat sky reaction, (b) There are the more nearly full-fledged carbanions generated through abstraction of -hydrogens by base, as in the aldol and Claisen condensations and their relatives.

• The difference between these two kinds of carbon is one of degree, not kind. There is interaction --just how much depending on the metal and the solvent even between electropositive ions like sodium or potassium or lithium and the anion from carbonyl compounds. These intermediates, too, could be called organometallic compounds; the bonding is simply more ionic than that in, say, a Grignard.

• In this chapter we shall continue with our study of carbanion chemistry, with emphasis on the attachment of alkyl groups to the a-carbons of carbonyl and acyl compounds. Such alkylation reactions owe their great importance to the special nature of the carbonyl group, and in two ways. First, the carbonyl group makes a-hydrogens acidic, so that alkylation can take place. Next, the products.

• Of the very many alkylation methods that have been developed, we can look at only a few: first, two classics of organic synthesis, the malonic ester synthesis and the acetoacetic ester synthesis', and then, several newer methods. In doing this we shall be concerned not only with learning a bit more about how to make new molecules from old ones, but also with seeing the variety of ways in which carbanion chemistry is involved.

Malonic ester synthesis of carboxylic acids 

• One of the most valuable methods of preparing carboxylic acids makes use of ethyl malonate (malonic ester), CH2 (COOC2 H 5 ) 2 , and is called the malonic ester synthesis. This synthesis depends upon (a) the high acidity of the -hydrogens of malonic ester, and (b) the extreme ease with which malonic acid and substituted malonic acids undergo decarboxylation. (As we shall sec, this combination of properties is more than a happy accident and can be traced to a single underlying cause.)

• Like acetoacetic ester (Sec. 21.11), and for exactly the same reason, malonic ester contains a-hydrogens that are particularly acidic: they are alpha to two carbonyl groups. When treated with sodium ethoxide in absolute alcohol, malonic ester is converted largely into its salt, seismologic 

• In planning a malonic ester synthesis, our problem is to select the proper alkyl halide or halides; to do this, we have only to look at the structure of the acid we want. Isocaproic acid, for example, (CH3)2CHCH2CH2COOH, can be considered as acetic acid in which one hydrogen has been replaced by an isobutyl group. To prepare this acid by the malonic ester synthesis, we would have to use isobutyl bromide as the alkylating

 

• w-propyl group and a second hydrogen has been replaced by a methyl group; we must therefore use two alkyl halides, w-propyl bromide and methyl bromide. The basic malonic ester synthesis we have outlined can be modified. Often one can advantageously use: different bases as, for example, potassium Ter butoxide; alkyl sulfonates instead of halides; polar aprotic solvents like DMSO or DMF.

• In place of simple alkyl halides, certain other halogen-containing compounds may be used, in particular the readily available a-bromo esters (why can a-bromoimides not be used ?), which yield substituted succinic acids by the malonic ester synthesis. For example:

Acetoacetic ester synthesis of ketone

• One of the most valuable methods of preparing ketones makes use of ethyl acetoacetate (acetoacetic ester), CH3COCH2COOC2H5 , and is called the acetoacetic ester synthesis of ketones. This synthesis closely parallels the malonic ester synthesis of carboxylic acids.

• Acetoacetic ester is converted by sodiunuethexitfe into the sodioacetoacetic ester, which is then allowed to react with aa^ alkyjjialidejo form an alkyl acetoacetic ester (an ethyl alkyl acetoacetate), CH3COCHRCOOC2H5 ; if desired, the alkylation can be repeated to yield a dialkylacetoacetic ester, CH3COCRR'COOC2H5 . All allylations are conducted in absolute alcohol.

• When hydrolyzed by dilute aqueous alkali (or by acid), these monoallelic dialkylacetoacetic esters yield the corresponding acids, CH3COCHRCOOH or CH3COCRR'COOH, which undergo decarboxylation to form ketones* CH3COCH2R or CH3COCHRR'. This loss of carbon dioxide occurs even more readily than from malonic acid and may even take place before acidification of the hydrolysis mixture.

• In planning an acetoacetic ester synthesis, as in planning a malonic ester synthesis, our problem is to select the proper alkyl halide or halides. To do this, we have only to look at the structure of the ketone we want. For example, 5-methyl-2-hexanone can be considered as acetone in which one hydrogen has been replaced by an isobutyl group. In order to prepare this ketone by the acetoacetic ester synthesis, we would have to use isobutyl bromide as the alkylating 

 

Decarboxylation of j8-keto acids and malonic acid

• The acetoacetic ester synthesis thus depends on (a) the high acidity of the a-hydrogens of -keto esters, and (b) the extreme ease with which -keto acids undergo decarboxylation. These properties are exactly parallel to those on which the malonic ester synthesis depends.

• We have seen that the higher acidity of the cc-hydrogens is due to the ability of the keto group to help accommodate the negative charge of the acetoacetic ester anion. The ease of decarboxylation is, in part, due to exactly the same factor. (So, too, is the occurrence of the Claisen condensation, by which the acetoacetic ester is made in the first place.)

• Decarboxylation of j9-keto acids involves both the free acid and the carboxylate ion. Loss of carbon dioxide from the anion yields the carbanion I. This carbanion is formed faster than the simple carbanion (R: ~) that would be formed from a simple carboxylate ion (RCOO~) because it is more stable. It is more stable, of course, due to the accommodation of the negative charge by the keto group.

Direct and indirect alkylation of esters and ketones

• By the malonic ester and acetoacetic ester, we make ^-substituted acids and a-substituted ketones. But why not do the job directly? Why not convert simple acids (or esters) and ketones into their carbanions, and allow these to react with alkyl halides? There are a number of obstacles: (a) self-condensation aldol condensation, for example, of ketones; (b) polyalkylation; and (c) for unsymmetrical ketones, alkylation at both a-carbons, or at the wrong one. Consider self-condensation. A carbanion can be generated from, say, a simple ketone; but competing with attack on an alkyl halide is attack at the carbonyl carbon of another ketone molecule. What is needed is a base-solvent combination that can convert the ketone rapidly and essentially completely into the carbanion before appreciable self-condensation can occur. Steps toward solving this problem have been taken, and there are available methods so far, of limited applicability for the direct alkylation of acids and kantars.

• A tremendous amount of work has gone into the development of alternatives to direct alkylation. Another group is introduced temporarily to do one or more of these things: increase the acidity of the a-hydrogens, prevent self-condensation, and direct alkylation to a specific position. The malonic ester and acetoacetic ester syntheses are, of course, typical of this approach. In the acetoacetic ester synthesis, for example, the carboethoxy group, Coat, enhances the acidity ex-hydrogens, but only those on one particular a-carbon, so that allegation will take place there. Then, when alkylation is over, the carboethoxy group is easily removed by hydrolysis and decarboxylation.

• In the biosynthesis of fats (Sec. 37.6), long-chain carboxylic acids are made via a series of what are basically malonic ester syntheses. Although in this case reactions are catalyzed by enzymes, the system still finds it worthwhile to consume carbon dioxide to make a malonyl compound, then form a new carbon-carbon bond, and finally eject the carbon dioxide.

• To get some idea of the way problems like these are being approached, let us look at just a few of the other alternatives to direct alkylation.

Synthesis of acids and esters via 2-oxazoline

• Reaction of a carboxylic acid with 2-amino-2-methyl-l-propanol yields a heterocyclic compound called a 2-oxazoline (1). Firor. this compound the acid can be regenerated, in the form of its ethyl ester, by Ethan lysis.

Organoborane synthesis of acids and ketones

• Hydroboration of alkenes yields alkylboranes, and these, we have seen (Sec. 15.9), can be converted through oxidation into alcohols. But oxidation is only one of many reactions undergone by alkylboranes. Since the discovery of hydroboration in 1957, H. C. Brown and his co-workers (p. 507) have shown that alkylboranes are perhaps the most versatile class of organic reagents known. In the presence of base, alkylboranes react with bromoacetone to yield alkyl acetones, and with ethyl bromoacetate to yield ethyl alkyl acetates. 

• combines (2) with the (Lewis) acidic alkylborane to give II. Intermediate II now rearranges (3) with loss of halide ion to form III. Finally, HI undergoes (4) proton lysis (a Lowry-Bronsted acid-base reaction this time) to yield the alkylated ketone. The key step is (3), in which a new carbon-carbon bond is formed. In II, boron carries a negative charge. Made mobile by this negative charge, and attracted by the adjacent carbon holding a good leaving group, an alkyl group migrates to this carbon taking its electrons along and displaces the weakly basic halide ion.

Alkylation of carbonyl compounds via enamines

• As we might expect, amines react with carbonyl compounds by nucleophilic addition. If the amine is primary, the initial addition product undergoes dehydration (compare Sec. 19.14) to form a compound containing a carbon-nitrogen.

• imine rather than the enamine (ene for the carbon-carbon double bond, amine for the amino group). If some enamine should be formed initially it rapidly tautomerizes into the more stable amino form.

• The system is strictly analogous to the keto-enol one (Sees. 8.13 and 21.4). The proton is acidic, and therefore separates fairly readily from the hybrid anion ; it can return to either carbon or nitrogen, but when it returns to carbon, it tends to stay there. Equilibrium favors formation of the weaker acid.

• Now, a secondary amine, too, can react with a carbonyl compound, and to yield the same kind of initial product. But here there is no hydrogen left on nitrogen; if dehydration is to occur, it must be in the other direction, to form a carbon carbon double bond. A stable enamine is the product.

• Best yields are obtained with reactive halides like benzyl and allyl halides, -halo esters, and -halo ketones. For example: