Diethyl malonate derivatives, reaction synthesis

Although heating benzene-1,2-diamine with malonic acid in aqueous hydrochloric acid affords the parent dione 26 (R = H) in 62% yield,277 the method cannot be extended to substituted malonic acids because decarboxylation intervenes however, the reaction of benzene-1,2-diamines with diethyl malonate and its derivatives constitutes a general procedure for the synthesis of l,5-benzodiazepine-2,4-diones 26 selected examples are given.278... 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

Treatment of diethyl malonate and related compounds with 1,2-dihaloethane in the presence of base constitutes a classical method of cyclopropane synthesis296"300. The reaction can be conveniently carried out under PTC conditions. An improved method utilizing solid-liquid phase transfer catalysis has been reported298. The reaction of dimethyl or diethyl malonate with 1,2-dibromoalkanes except for 1,2-dibromethane tends to give only low yields of 2-alkylcyclopropane-l, 1-dicarboxylic esters. By the use of di-tm-butyl malonate, their preparations in satisfactory yields are realized (equation 134)297. The 2-alkylcyclopropane derivatives are also obtained from the reaction of dimethyl malonate and cyclic sulfates derived from alkane-1,2-diols (equation 135)301. Asymmetric synthesis... 

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... 

Acylaminomalonic esters and related reagents are widely used for the synthesis of a-amino acids. The method differs from those syntheses already discussed in that the amino group is incorporated into the system from the outset. A popular reagent is diethyl acetamidomalonate (35). The acetamido group can readily be introduced into the reactive methylene position in diethyl malonate by first converting the latter into the hydroxy-imino derivative (33) by reaction with nitrous acid or an alkyl nitrite (cf. Section 4.2.7, p. 413). This derivative is then reduced catalytically to diethyl aminomalonate (34) which is acetylated using acetic anhydride. 

The last step in the synthesis of pentobarbital is the reaction of the appropriately substituted derivative of diethyl malonate with urea. 

A spectacular application allowed the synthesis of fenestranes by a three-step sequential action of cobalt nanoparticles and a palladium catalyst [131]. The cascade reaction started with a PKR of enyne 105, accomplished by the cobalt catalyst giving 106, followed by the formation of allyl-7r3 palladium complex 107 which reacted with a nucleophile derived from diethyl malonate, to give enyne 108. The final step was a second PKR that gave 109 in good yield. They used cobalt nanoparticles as with Co/charcoal the third step did not take place, apparently due to damage in this catalyst after the allylation step (Scheme 31). 

This reaction can be adapted to the synthesis of a-amino acids by using a commercially available derivative of diethyl malonate as starting material. This compound, diethyl acetamidomalo-nate, has a nitrogen atom on the a carbon, which ultimately becomes the NH2 group on the a carbon of the amino acid. 

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>. 

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 reaction of 2-amino-3-nitrosopyridines with compounds containing an activated methylene group permits unambiguous synthesis of various derivatives of pyrido[2,3-b]pyrazine. For example, the pyridine 58 reacts in the presence of sodium ethoxide with a variety of arylacetonitriles and cyanoacetic acid derivatives to provide various 2-substituted 3-amino compounds (59). " " Diethyl malonate reacts similarly to give the 2-carboxylic acid 60, its ester being presumably hydrolyzed in the alkaline reaction conditions. Ethyl acetoacetate yields the 2-acetyl-3-oxo compound 61, and acetylacetone ° provides the 2-acetyl-3-methyl compound 62. The latter condensation proceeds poorly in ethanolic sodium ethoxide, but heating the nitroso compound with acetylacetone under reflux in pyridine gives a 59% yield of the product 62. °... 

Synthesis of the T-methoxy derivative 484 commenced with the alkylation of the anion of diethyl malonate with a suitable bromoacetal, followed by reduction to give 482, which upon acetylation and then reaction with acetyl chloride and thionyl chloride gave the a-chloroether 483. Reaction of 483 with the trimethylsilylated 2-A-acetylguanine using tin (IV) chloride... 

Dihydrazide 231 was also used in the synthesis of thienothiophenes containing triazole substituents. For example, the reaction with phenyl isothiocyanate in ethanol produces di(A -phenylthiocarbamoyl)carbohydrazide 238, whose treatment with KOH followed by acidification affords compound 239. Diazotization of dihydrazide 231 with 10% sodium nitrite in acetic acid gives diazide 240. The reactions of the latter with compounds containing the active methylene group, viz., ethyl cyanoacetate, malononitrile or diethyl malonate, in the presence of sodium ethoxide, yield the corresponding ditriazole derivatives 241-243. 

Malonic ester synthesis (Section 20.11) Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl malonate, followed by saponification and decarboxylation. 

Ester enolates undergo alkylation reactions. When ethyl 3-methylpentanoate (110) reacts with sodium ethoxide in ethanol and then with bromoethane, the product is 111. Alkylation of malonate derivatives leads to an interesting sequence of reactions that are useful in synthesis. The reaction of diethyl malonate (90) and NaOEt in ethanol, followed by reaction with benzyl bromide, gives 112. In a second reaction, 112 reacts with NaOEt in ethanol and then with iodomethane to give 113. Saponification of 113 (see Chapter 20, Section 20.2) gives the dicarboxylic acid, 114, and heating leads to decarboxylation (Section 22.8) and formation of acid 115. This overall sequence converted malonic acid via the diester to a substituted carboxylic acid, and it is known as the malonic ester synthesis. 

Another example to illustrate the synthesis of proline derivatives 78 was published by Vicario and coworkers in 2013 [48]. Starting from aromatic aldehydes, diethyl malonate, and a,p-unsaturated aldehydes upon catalysis of unprotected diphenylprolinol, the synthesis of polysubstituted pyrrolidines was achieved in a one-pot condensation and [3+2] cycloaddition reaction in aqueous medium. 

The reaction of cyclic oxonium derivatives of polyhedral boron hydrides with acetamido diethyl-malonate (glycine anion equivalent for amino acid synthesis), a variation of the classical Sdrensen synthesis of amino acids, followed by acidic hydrolysis and decarboxylation was proposed as a route to boron hydride-based aminoacids (Figure 24.10) [31,51]. 

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