Acetoacetic ester synthons

Diethyl 3-oxoheptanedioate, for example, is clearly derived from giutaryl and acetic acid synthons (e.g. acetoacetic ester M. Guha, 1973 disconnection 1). Disconnection 2 leads to acrylic and acetoacetic esters as reagents. The dianion of acetoacetic ester could, in prin-ciple,be used as described for acetylacetone (p. 9f.), but the reaction with acrylic ester would inevitably yield by-products from aldol-type side-reactions. 

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). 

By far the most TP syntheses are condensations of dinucleophilic 5-amino-1,2,4-triazoles (ATs) with 1,3-bifunctional synthons as shown in the formation of TP 2. A general review covers corresponding reactions of acetoacetic ester with aryl- and heteroarylamines (97CHE499). To the earlier reported list of relevant functionalities described up to 1991 (93AHC(57)81, p. 85) may be added Cl 1S(), R (02S901) and tautomeric =C(SH)NHR (92JSC165). 

Butanoic acid, 3-hydroxy-, esters pr, 176 Frater-Seebach 2-alkylation, 27 —, 3-oxo-, esters (acetoacetic esters) pr., 176 carbon acidity, 10 carboxymethyl da-synthon, 19, 207 dianion 4-alkylation, 24, 207,325-326... 

Cyclopentanones. The synthon reacts with sodium enolates of acetoacetic esters (2) in THF (65°) to form cyclopentenyl sulfides (3), which are hydrolyzed by 20% HCl—dioxane to keto acids (4). 

A convenient way to determine when to apply the acetoacetic ester or malonic ester approach to a synthetic problem is to incorporate the synthon concept into retrosynthetic analysis. A synthon is a structural unit in a molecule that is related to a synthetic operation. A CH2CO2H group is a synthon that alerts us to the possibility of preparing a target by a malonic ester synthesis. Likewise, a CH2C(0)CH3 group is a synthon that suggests an acetoacetic synthesis. 

Phosphorus-based synthons for acetoacetic ester and acetylacetone derivatives are described the phosphonate (78) has been used in the preparation of the /S-ketoester (79), a key intermediate in a synthesis of the fungal sex hormone, trisporic acid B methyl ester (80). Michael addition of an a-methylene ketone to 2,2-diethoxyvinylidenetriphenylphosphorane followed by loss of ethanol gives a valuable reagent (81) for the preparation of 1,3-dioxopent-4-enes by Wittig reaction with aldehydes the intermediate enol ethers (82) can be isolated if desired. 

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. 

We introduced the chemistry of malonate esters in Chapters 21 and 26 as a useful way of controlling the enolization of carbonyl compounds. Alkylation followed by decarboxylation means that we can treat acetoacetate and malonate esters as equivalent for these synthons. 

Perhaps the best known example of the constructive application of a destructive process is the set of classical methods employing acetoacetic and malonic esters. In these methods, a decarboxylation step, the rupture of a C-C bond, is usually required after the initial formation of the new C-C bond by the alkylation. The ease of this step is actually a prerequisite for the nearly universal application of acetoacetic and malonic esters as synthetic equivalents of or Cj synthons. 

Dimethyl oxalate [29SS], diketene [2789], an acetoacetate [3489], 3-amino-crotonic ester [3489] and the Vilsmeicr reagent [2994] have also been demonstrated to be useful synthons. 

The equally easy addition of the activating group is treated in Chapter 20. In this chapter we shall use readily available maionate (12) and acetoacetate (14) esters, reagents for the synthons (13) and (15) respectively, that is activated versions of acetic acid and acetone. 

---