Carboxylic esters, acetoacetic compounds

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

Plant. In plants, mevinphos is hydrolyzed to phosphoric acid dimethyl ester, phosphoric acid, and other less toxic compounds (Hartley and Kidd, 1987). In one day, the compound is almost completely degraded in plants (Cremlyn, 1991). Casida et al. (1956) proposed two degradative pathways of mevinphos in bean plants and cabbage. In the first degradative pathway, cleavage of the vinyl phosphate bond affords methylacetoacetate and acetoacetic acid, which may be precursors to the formation of the end products dimethyl phosphoric acid, methanol, acetone, and carbon dioxide. In the other degradative pathway, direct hydrolysis of the carboxylic ester would yield vinyl phosphates as intermediates. The half-life of mevinphos in bean plants was 0.5 d (Casida et ah, 1956). In alfalfa, the half-life was 17 h (Huddelston and Gyrisco, 1961). 

Among procedures for the synthesis of 1,7-naphthyridines, four-component condensation of l-benzyl-3-hydroxy-5-piperidone 101 with 2,3-dichloro-6-fluorobenz-aldehyde, acetoacetic esters and ammonium acetate giving rise to 1,4,5,6,7-hexahydro-l,7-naphtyridin-5-one-3-carboxylic esters 102 attracts attention due to its simplicity. The compounds 102 and their N-debenzylation products 103 exhibit hypotensive activity (1985USP4596873, 1985USP4618678). 

The compound containing the active methylene group is first converted in tetrahydrofuran solution into its sodium salt by means of sodium hydride, then a two- to three-fold excess of acetone cyanohydrin nitrate is added and the whole is boiled for 2 h under reflux. Substituted acetoacetic and malonic esters thus give good yields of a-nitro carboxylic esters. 

DONORS. Acetoacetates Aldehydes Carboxylic esters Cyanoacetates Ketones Malonates Nitriles Nitro compounds and Sulfones. 

In 1991, Wright et al. reported a procedure for the preparation of substituted 1-benzyl-1//-1,2,3-triazoles 21 and 23 from benzyl azides 20 under very mild conditions (Scheme 4.7) [9]. Benzyl azides 20 reacted with active methylene compounds in DMSO induced by potassium carbonate at 35-40 C to give 1-benzyl-1//-1,2,3-triazoles 21 and 23 usually in good yield. Acetonitrile derivatives 10 gave 5-amino-l-benzyl-l//-l,2,3-triazoles 21, whereas diethyl malonate gave 5-hydroxy-l-benzyl-l//-l,2,3-triazoles. l//-l,2,3-Triazole-4-carboxylate esters and l//-l,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and P-diketones, respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-l//-l,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds that did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate, and ethyl nitroacetate. 

These substances, as well as the parent compound, are p-keto esters and undergo hydrol3rtio cleavage in two directions. One type of cleavage, ketonlc hydrolysis, is effected by the action of dilute caustic alkali in the cold, followed by acidification and boiling the free acetoacetic acid produced has a carboxyl and carbonyl group on the same carbon atom and therefore readily undergoes decarboxylation to yield a ketone, for example ... 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The first step is formation of a pyrrole ring system from two identical aminoketones. It is actually a Knorr pyrrole synthesis, but we do not need to identify it as such, just approach it logically. In fact, if we look back at the Knorr pyrrole synthesis, we shall see that, under chemical conditions, the reagents used here are not sufficiently reactive for the pyrrole synthesis we need a more activated compound, like ethyl acetoacetate. Furthermore, we could not possibly proceed without masking the carboxyls as esters. This underlines how a biosynthetic sequence might differ somewhat from a purely chemical synthesis. 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

The self-condensation of /3-keto esters and related compounds occurs under the influence of either acidic or basic catalysts and constitutes one of the earliest syntheses of pyran-2-ones (l883LA(222)l). It exemplifies a synthesis of type (ii) (Scheme 85). Ethyl acetoacetate, for instance, gives a mixture of 4,6-dimethyl-2-oxopyran-5-carboxylic acid and its ethyl ester other esters behave similarly (59RTC364). Decarboxylation of the pyrancarboxylic acid occurs at 160 °C in sulfuric acid. The formation of the pyranone proceeds through a 5-keto ester which is considered to result from attack of the enolic form of the ester on protonated ethyl acetoacetate (51JA3531). A detailed synthesis of the pyran-5-carboxylic acid is available <630SC(4)549). 

The extra ester group is not normally added to the preformed ketone as ethyl acetoacetate 41 is available and the diester is available diethyl malonate 59. If it is necessary to make the 1,3-dicarbonyl compound, this can be done by methods described in chapters 19 and 20. The carboxylic acid 56 can be disconnected at the branchpoint to an alkyl halide and the synthon 58 that could be realised as the anion of diethyl malonate 59 or the lithium enolate of ethyl acetate. 

If the reaction between the enol and the electrophile proceeds extremely fast, the enol tautomer of a carbonyl or carboxyl compound might be consumed completely. The generation of enol becomes the rate-determining step. This situation occurs with the enol titration of ace-toacetic ester, (Figure 12.4). In this process, bromine is added to an equilibrium mixture of the ketone form (B) and the enol form (iso-B) of an acetoacetic ester. Bromine functionalizes the enol form via the intermediacy of the carboxonium ion E to form the bromoacetic ester D. The trick of conducting the enol titration is to capture the enol portion of a known amount of acetoacetic ester by adding exactly the equivalent amount of bromine. From the values for... 

As was the case in the decarboxylation that occurs in the acetoacetic ester synthesis, it is the presence of a carbonyl group at the /3-position of the carboxylic acid that allows carbon dioxide to be lost when the compound is heated. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Carboranyl acid halides can be very easy prepared. We have studied the acylation of malononitrile and acetoacetic ester by methylcarboranyl carboxylic acid chloride (15). The reaction with malononitrile leads to the compound 17a, which exists also as a enol form, similar to compound 13. Compound 17a can be methylated to give compound 17b, a novel synthon for the preparation of wide range of heterocyclic compounds (Scheme 7). 

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