Diethyl Oxomalonate

(R = Et)

[609-09-6]  · C7H10O5  · Diethyl Oxomalonate  · (MW 174.15) (R = Me)

[3298-40-6]  · C5H6O5  · Dimethyl Oxomalonate  · (MW 146.10)

(electron-deficient heterodienophile; Diels-Alder reaction;1-4 heterodipolarophile; [3 + 2] cycloaddition;5 1,3-diyl trapping agent;6 1,4-dipolar cycloaddition;7 [2 + 2] cycloaddition;8 enophile; ene reaction;9,10 electrophilic addition;11-17 Wittig reactions;18-22 condensation with amines;23 Pictet-Spengler reactions24)

Physical Data: bp 95-98 °C/12 mmHg; d 1.144 g cm-3.

Solubility: sol ethanol and diethyl ether.

Form Supplied in: colorless liquid; widely available.

Analysis of Reagent Purity: n20D 1.425.

Preparative Methods: diethyl oxomalonate can be prepared by bromination of Diethyl Malonate to the dibromomalonic ester, exchange of one bromine atom for acetate and a-elimination of acetyl bromide.25 Alternatively, diethyl malonate is condensed with benzaldehyde to afford the Knoevenagel product which is cleaved by ozonolysis.26

Purification: fractional vacuum distillation.

Handling, Storage, and Precautions: diethyl oxomalonate is stable for at least 6 months if stored in the refrigerator.

Diethyl oxomalonate (1) undergoes Diels-Alder reactions as an electron-poor heterodienophile.1a Thus reactions with electron-rich butadienes furnish the gem-diesters (2)1 (eq 1), which can be converted to the monoacid (3) by decarboxylation1d or to the unsaturated d-valerolactones (4) either by a Curtius degradation sequence1b,c or Cerium(IV) Ammonium Nitrate (CAN) oxidation (Scheme 1).7

The reaction is run either at elevated temperature (120-140 °C, MeCN or toluene),1b-d under high pressure conditions (10 kbar)1e,f or under Lewis acid catalysis.1a Chiral Lewis acids have also been applied, but gave only very modest enantioselectivities (<15% ee).2

Azadienes (5) undergo hetero Diels-Alder reactions with diethyl oxomalonate (1) in THF at 80 °C (eq 2).3 2,3-Dihydropyran-4-ones (6) are formed in the reaction with Danishefsky's diene (7) under Lewis acid catalysis at ambient temperature (eq 3).4

Reagent (1) has been used in [3 + 2] dipolar cycloadditions as a heterodipolarophile.5 N-(Silylmethyl)-substituted ketene N,S-acetals (8) are converted to the 1,3-dipolar reagent (9) with Cesium Fluoride in MeCN, which undergoes the cycloaddition with (1) to afford the alkylideneoxazolidines (10) in modest yield, but with complete regioselectivity (eq 4).

Diethyl oxomalonate has been shown to be reactive towards 1,3-diyls.6 Heating the diazene (11) produces the 2-alkylidene-1,3-diyl (12), which is trapped in situ by (1) to form the fused cycloadduct (13) as a sole isomer in good yield (eq 5). Other diyls, however, give mixtures of isomers.

An example of a 1,4-dipolar cycloaddition of (1) with 6-oxo-3,6-dihydro-1-pyrimidinium-4-olate (14) has been described which leads to diazabicyclo[2.2.2]octanediones (15) (eq 6).7

[2 + 2] Cycloadditions of (1) and electron-rich alkenes like 1,1-dimethoxy-2-propene (16) have also been investigated.8 Oxetanes (17) are formed in good yield with complete regioselectivity in a thermal reaction (eq 7). Under photochemical conditions, addition does not take place.

Diethyl oxomalonate reacts with alkenes that have an allylic hydrogen atom in an ene reaction (eq 8).9 The reaction is run either thermally or under Lewis acid catalysis. Occasionally the ene reaction is followed by a cyclization to form a tetrahydrofuran diester (18), which can be converted to the butyrolactone (19) by CAN oxidation (eq 8).10

Due to the adjacent ester groups, (1) is a highly reactive carbonyl compound which reacts with a variety of nucleophiles. Thus benzoxazinones (20) are formed in the reaction with aminophenols (eq 9).11 Similarly, 6-ethoxycarbonyl-7-oxopyrazinothiadiazines (21) are accessible by the reaction of 3,4,5-triamino-2H-1,2,6-thiadiazine 1,1-dioxide (22) with diethyl oxomalonate (eq 10).12

Enamines (23) react with diethyl oxomalonate to furnish aldol products which can be dehydrated and cyclized to the butenolides (24) by acid catalysis (eq 11).13 N-Methylindole (25) smoothly adds to (1) to afford 3-indolylhydroxymalonate (26) (eq 12).14 In the presence of Ethylaluminum Dichloride a second addition takes place and the 3,3-bisindolyl derivative (27) is formed (eq 12).

The high-pressure addition of 2,5-dialkylfurans (28) to (1) very selectively affords the addition product (29) (eq 13).15 No double addition is observed. The reaction has been shown to proceed through a [1,5]-suprafacial shift of the diethyl oxomalonate moiety.

Diethyl trimethylsilyl phosphite (30) adds to diethyl oxomalonate in a redox process to yield a-hydroxyphosphonic ester (31) (eq 14).16 Only very electron-poor ketones display such a reactivity towards trimethylsilyloxyphosphorus(III) derivatives.

Even aromatic compounds are sufficiently reactive to add to (1). The reaction of p-xylene (32) with (1) is promoted by Tin(IV) Chloride at ambient temperature (eq 15).17

Diethyl oxomalonate has frequently been used in Wittig reactions. Thus the phosphorus ylide (33) of a cephalosporin derivative is smoothly converted to the unsaturated diester (34) (eq 16).18 The ylide (35) of a dithioacetal furnishes the ketene dithioacetal (36) (eq 17).19 An imino-Wittig-type reaction has been used for the construction of the side chain of the mycosporins.20 The iminophosphorane (37), obtained by a Staudinger reduction of the corresponding azide, is condensed with (1); the resulting imine (38) is reduced in situ with Sodium Cyanoborohydride (eq 18).

Reagent (1) has also been applied to a phospha-Wittig reaction with (39) to yield the phospha-alkene complex (40) (eq 19).21 These complexes have been shown to take part in [2 + 2] processes with enol ethers, enamines, and ethoxyacetylene to give phosphetanes.22

Amines can easily be condensed with diethyl oxomalonate by heating at reflux with water removal (Dean-Stark trap). The imines (41) undergo electrophilic cyclization with an internal electron-rich double bond under Lewis acid or Trimethylsilyl Trifluoromethanesulfonate catalysis to produce various nitrogen heterocycles, including piperidines, octahydroisoquinolines, azepines, and pyrrolidines (eq 20).23 Depending on the reaction conditions cis-lactones (42) are formed in a second step very selectively (eq 20).

Reagent (1) has also been used in Pictet-Spengler reactions of tryptamine-2-carboxylic acids (43) (eq 21).24 The reaction is run in refluxing benzene/dioxane/trifluoroacetic acid solution with water removal (Dean-Stark trap). Rearrangement of the initially produced iminium ion gives rise to the 1,2,3,4-tetrahydro-b-carbolin (44).

In addition to the transformations of diethyl oxomalonate described above, several achiral and chiral dialkyl oxomalonates, such as dimethyl oxomalonate,27-40 have been used in related reactions. The esters are best prepared by ozonolysis of the Knoevenagel products of benzaldehyde and the corresponding dialkyl malonates.23,26


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Lutz F. Tietze & Christoph Schneider

Georg-August-Universität zu Göttingen, Germany



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