Alkyl acetoacetates acylation reactions

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

Because of their negligible vapor pressure, thermal stability and easy recyclability, neutral ILs have been referred to as environmentally benign solvents. These ILs have been employed as excellent and recyclable medium for a wide array of reactions e.g., Heck reaction [Park Alper, 2003], Bischler-Napierlaski cyclisation [fudeh et al, 2002], Beckmann rearrangement [Ren et al., 2001], addition of thiols to unsaturated ketones [Yadav et al., 2003], 1-proline catalysed aldol reaction [Loh et al., 2002], and Pechmann condensation of phenols and ethyl acetoacetate (EAA) catalyzed by POCI3 in [bmim]PF6 and [bmim]BF4 ILs [Potdar et al., 2005]. Other examples where ILs have been used as a reaction media include, but not limited to, Diels-Alder reactions [Reinhardt, 2009 Doherty, 2004 Song, 2001], Friedel-Crafts alkylation and acylation reactions [Xiao, 2006 Xiao Malhotra, 2005 ... 

It is this equilibrium which renders difficult the explanation of the course of the reactions which take place when metallic sodium or sodium ethoxide and then alkyl or acyl halide are added to these compounds. At first it was thought that the sodio compound formed with acetoacetic ester was CH3.CO.CHNa.COOC2H5, because the reaction with alkyl and acyl halides always yielded a C-derivative, CH3.CO.CHR.COOC2H5. The first example of a different course of reaction was found in the formation of an O-derivative—/3-carhethoxyhydroxycrotonic ester from sodio-acetoacetic ester and chloroformic ester (J. pr., [2], 37, 473 B., 25,1760 A., 277, 64). This could only be explained by assigning an enol formula to the sodium salt—... 

Alkylation or acylation of ethyl malonate, ethyl acetoacetate, or other compounds containing methylene groups activated by strongly electron-attracting groups are very fruitful preparative methods. Reactions according to the schemes ... 

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. 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

The method of preparation of acyl acetoacetic esters is exemplified in the following. The reaction goes through phases similar to those described for alkyl compounds, but owing to the greater reactivity of the acyl halides, special precautions have to be taken. Unlike the alkyl chlorides, the acyl chlorides give good yields there is no need to use the bromides or the iodides. 

The Reissert reaction would now require a base-catalysed acylation of the methyl group with dimethyl oxalate to give 42. They say All attempts. .. in the presence of various bases to produce intermediate [42] failed. So they used the radical bromination of 43 with NBS (chapter 24) to give 51, alkylated with the anion of methyl acetoacetate to give 52. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

Depending on the respective reaction partner, acetic acid esters can react either as C-H acidic compounds or as acylating agents. Both are illustrated by the self-condensation of ethyl [ 1 acetate in the presence of 0.5 equivalent of sodium ethoxide or triphenymethyl sodium to give ethyl [1,3- C2]acetoacetate (Claisen condensation). In the first case, however, because of the relatively low radiochemical yields (40-45%) obtained by this procedure, it is of minor importance for the preparation of labeled ethyl acetoacetate. The deprotonation of alkyl acetates with LiHMDS followed by acylation with unlabeled or labeled acyl halides to labeled give /3-keto esters is discussed in Section 6.4. Claisen condensation of alkyl [ CJacetates with esters lacking a-hydrogens (i.e. ethyl formate, diethyl oxalate, aromatic/heteroaromatic carboxylic acid esters) proceed unidirectionally and are valuable pathways in the synthesis of ethyl [ C]formyl acetate (521. diethyl [ C]-oxaloacetate (53) and ethyl 3-oxo-3-pyrid-3-yl[2- C]acetate (54). The last example... 

Similar reactions are also possible with ethyl acetoacetate. The electrophiles that work well are primary and secondary alkyl halides and sulfonates. Tertiary halides do not react well— elimination is the main reaction. Acyl halides and unhindered epoxides also react well. An important aspect of these processes is that carboxylic acids with a carbonyl group at the p-position are readily decarboxylated (Figure 17.38). We will see in later chapters that we are using the ester as an activating group so that we can make the enolate more easily, but we can eliminate it later. Some examples of the use of this process in synthesis are given in Figure 17.39. 

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