Diethyl malonates, oxidation

The use of epoxides as alkylating agents for diethyl malonate provides a useful route to y lactones Wnte equations illustrating such a sequence for styrene oxide as the starting epoxide Is the lactone formed by this reaction 3 phenylbutanohde or is it 4 phenylbutanohde ... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

The reaction of pyrido[2,3-c/]pyrimidine-3-oxide (415) and diethyl malonate in the presence of sodium ethylate in ethanol at 0°C for 10 min led to the formation of Af-[3-(l,2,4-oxadiazol-3-yl)-2-pyridyl]aminomethylene-malonate (416) in 73% yield, but at ambient temperature for 1.5 hr, the product was diethyl N-(3-cyano-2-pyridyl)aminomethylenemaIonate in 61% yield (83JOC4132). 

Di(methyIthio)-l,2,5-thiadiazole 1-oxide reacted readily with the carbanion of diethyl malonate to yield (1,2,5-thiadiazol-3-ylidene)malonate (482) in high yield [81H( 16)1561]. 

The reaction of diethyl malonate and 2-aryl-4-methylthioquinazoline-3-oxides (1295) in boiling acetonitrile, in the presence of potassium tert-butoxide for 24 hr under nitrogen, afforded isoxazolo[2,3-c]quinazolines (1297, via 1296, in 57-61% yields (87SC1449). 

When ethyl acetoacetate was employed instead of diethyl malonate in a similar solid-state reaction, dihydrofuran-fused Cgo derivative 47 was obtained in 22% yield (49% based on consumed Cgo). Again, the initially formed anion is supposed to be oxidized by oxygen to the corresponding radical, which undergoes intramolecular cyclization with release of a hydrogen radical as shown in Scheme 22 [52]. 

Carbanions derived from hydrocarbons or substituted hydrocarbons with pKa values in the range of 10 may—e.g., 2-nitropropane—or may not (diethyl malonate) be oxidizable. When oxidation does occur, it is generally solely by the radical-chain mechanism. 

The same zwitterions can give pyrid-2-ones (798) when treated with dimethyl acety-lenedicarboxylate (71AG(E)925). Quaternary pyrimidinium salts are attacked by the anions from diethyl malonate or malononitrile to produce pyrid-2-ones (799) or 2-aminopyridines (800) respectively (74RCT233). Quinazoline Af-oxide (801) reacts with ketones on heating to give quinolines the reaction is assumed to be initiated by attack at C-4, with subsequent... 

Ferrocenylacetonitrile, 40, 4S Ferrous sulfate, oxidation ferf-butyl alcohol to a,a,a, a -tetramethyl tetra-methylene glycol by hydrogen peroxide and, 40, 90 Fluoboric acid as catalyst for diazomethane etherifications, 41, 9,10 Formaldehyde, reaction with diethyl malonate to form diethyl bis-(hydroxymethyl)malonate, 40, 27... 

Frequently the basic conditions used cause the initial Michael adduct to undergo intramolecular transformations, as for example in the synthesis of dimedone (Expt 7.11). This involves a Michael reaction between mesityl oxide and diethyl malonate followed by an internal Claisen ester condensation. 

Equip a dry 1-litre three-necked flask with a dropping funnel, a sealed stirrer unit and an efficient double surface condenser. Place 11.5 g (0.5 mol) of sodium in the flask, cool in an ice bath and add 200 ml of absolute ethanol in one portion. When the initial vigorous reaction has subsided, remove the ice bath and allow the reaction to proceed until all the sodium has reacted warming on a water bath is sometimes necessary to dissolve the last traces of sodium. Place a calcium chloride guard-tube at the top of the condenser. Introduce 85 g (0.53 mol) of diethyl malonate, and then add through the dropping funnel 50 g (0.51 mol) of freshly distilled mesityl oxide (Expt 5.213)... 

A Cr(VI)-catalyst complex has been proposed as the reactive oxidizing species in the oxidation of frans-stibene with chromic acid, catalysed separately by 1,10-phenanthroline (PHEN), oxalic acid, and picolinic acid (PA). The oxidation process is believed to involve a nucleophilic attack of the olefinic bond on the Cr(VI)-catalyst complex to generate a ternary complex.31 PA- and PHEN-catalysed chromic acid oxidation of primary alcohols also is proposed to proceed through a similar ternary complex. Methanol- reacted nearly six times slower than methanol, supporting a hydride transfer mechanism in this oxidation.32 Kinetics of chromic acid oxidation of dimethyl and diethyl malonates, in the presence and absence of oxalic acid, have been obtained and the activation parameters have been calculated.33 Reactivity in the chromic acid oxidation of three alicyclic ketoximes has been rationalized on the basis of I-strain. Kinetic and activation parameters have been determined and a mechanism... 

Styrene oxide will be attacked by the anion of diethyl malonate at its less hindered ring position. 

Dimedone has a trivial name because its preparation is so easy that it was discovered early in the history of organic chemistry. The first step is a conjugate addition of diethyl malonate to the unsaturated ketone mesityl oxide (4-methylpent-3-en-2-one given a trivial name for the same reason). Ethoxide ion is the base for the usual reason that nucleophilic substitution at the ester group simply regenerates starting material. 

Another procedure utilizes oxides of nitrogen. An example is the oxidation of diethyl malonate to diethyl oxomalonate, CO(COjCjH5)j, with nitrous anhydride (76%). Synthesis of alkyl aryl a-diketones has been accomplished under similar conditions (30-40%). ... 

Huebner et al. studied the stoichiometry and approximate rates of oxidation of a number of compounds containing an active methylene group. They found that not all such compounds are oxidised by periodate, and that in general one of the activating groups must be -CHO or -COOH for oxidation to occur. Thus diethyl malonate, ethyl acetoacetate, and cyanoacetic acid are not oxidised. Acetylacetone and other acyclic 1,3-diketones are oxidised very slowly, but cyclic 1,3-diketones are readily oxidised (Wolfrom and Bobbitt ). The first step in the oxidation of a compound containing an active methylene group is hydroxylation, then this is followed by further oxidation, e.g. malonic acid and 1,3-cyclohexanedione react as follows... 

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