Diethyl malonate: acylation

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

Both diethyl malonate and ethyl acetoacetate can be acylated by acyl chlorides using magnesium chloride and pyridine or triethylamine.223... 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

The 4-amino group of 145 is readily monoacylated with acyl or sulfonyl chlorides and isocyanates or isothiocyanates ethyl acetoacetate and diethyl malonate yield, respectively, 159 and 160. Hydrazides 161 undergo a re-... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonate[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7]. Deformylation and reduction leads to 2-sub-stituted indoles. 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

One preparative procedure for achieving this reaction involves the acylation of the magnesium enolate of diethyl malonate with an acid chloride in benzene solution (cf. Expt 5.96), and the resulting aclymalonic ester is then heated to 200 °C with an arylsulphonic acid to effect the decarbethoxylation step. An illustrative example is the preparation of ethyl 3-oxopentanoate (ethyl propionyl-acetate, Expt 5.177). 

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

IV-Alkyl-substituted phthalimides 9 were easily transformed into mono-, di- or trisubslituted pyrazoles 10 via a one-pot addition/decyclization/cyclocondensation sequence <02JCS(P1)207>. 5-Silylpyrazoles can be prepared from condensation of silylalkynones with hydrazines <02T4975>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted pyrazolin-5-ones <02T3639>. 

The malonic ester synthesis makes substituted derivatives of acetic acid. Malonic ester (diethyl malonate) is alkylated or acylated on the more acidic carbon that is a to both carbonyl groups, and the resulting derivative is hydrolyzed and allowed to decarboxylate. 

Alkylation or acylation of malonic ester (diethyl malonate), followed by hydrolysis and decarboxylation, to give substituted acetic acids, (p. 1079)... 

The first is the acylation of the magnesium derivative of diethyl malonate. The magnesium atom prevents 0-acylation with acid chlorides, and decarboxylation (p. 678) removes the redundant ester group. 

A convenient method for preparing alicyclic or aromatic methyl ketones consists in the acylation of the ethoxymagnesium derivative of diethyl malonate with the appropriate acyl chloride, followed by acid hydrolysis and decarboxylation of the resulting /3-keto diester. The last step is Carried out like the ketonic cleavage of /3-keto esters. The over-all yields are 60-85%. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Mixed anhydride synthesis. A method widfely used for the synthesis of peptides provides a general method of acylation, illustrated by the benzoylation of diethyl malonate. Benzoic acid is converted into the triethylamine salt in toluene, and the solution is treated at 0 with ethyl chloroformate to form the mixed benzoic-carbonic anhydride, with precipitation of triethylamine hydrochloride. The second component, ethoxymagnesium malonic ester, is prepared from diethyl malonate in ethanol-ether... 

The acid chloride of tetra-fluoro benzoic acid 203 acylated the magnesium enolate 204 of diethyl malonate to give 205. The chelated magnesium enolate avoids O-acylation. Condensation with ethyl orthoformate puts in the masked aldehyde group and 206 is ready for a succession of aromatic nucleophilic substitutions.39... 

The amidation of one of the ester functions of diethyl malonate by 5-amino-l,3-dimethyluracil requires fusion at 200 C. At that temperature the initial product readily partially cyclizes by intramolecular acylation to yield 8-hydroxy-l,3-dimethylpyrido[3,2-t/]pyrimidine-2,4,6(1 HfH, 5//)-trione (3) 443... 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

The N -substituted N-imines can be prepared by the reaction of the N-aminoazonium salts, in the presence or absence of base, with anhydrides or acyl halides,8,13-17,20,21,45,46 diketene,47 diethyl malonate,48 sulfonyl chloride,8,15,49,50 /i-halovinyl ketones and esters,51-54 diethyl ethoxymeth-ylenemalonate and related compounds,53,55-57 isocyanates,17,58 thioiso-cyanates,17,58 imidoyl chlorides and imidates,59,60 nitro acetate,8,61 and active halobenzenes.62,63 Some representative pyridine -(substituted imines) prepared in this way are shown in Scheme 1. 

The preparation of diethyl benzoylmalonate (entry 12) represents the use of an acid anhydride, a function in which it is much more reactive than an ester, as the acylating agent. The reaction must be carried out in nonnucleophilic solvents to prevent solvolysis of the anhydride from competing with the desired reaction. Other limitations on the use of highly reactive acylating agents, such as acid anhydrides and acid chlorides, in reactions with enolates derive from the fact that O-acylation may be the dominant reaction. The magnesium salt of diethyl malonate (entries 12 and... 

I c + ester (diethyl malonate) is alkylated or acylated on the carbon that is a to both... 

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