Malonic acid, ethoxymethylene

SYNS DIETHYL EMME DIETHYL (ETHOXY-METHYLENE)MALONATE MALONIC ACID, (ETHOXYMETHYLENE)-, DIETHYL ESTER TL 1483... 

ETHYL ETHOXYMETHYLENEMALONATE (Malonic acid, ethoxymethylene-, diethyl ester)... 

Ethoxymethylene malonic acid diethyl ester Diethyl sulfata... 

The starting material may be produced by reacting 6-amino-2-methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. The intermediate thus produced is converted by boiling in diphenyl ether to 6-ethoxycarbonyl-2-methylthio-5-oxo-5,B-dihydropyrido-[2,3-d]pyrimidine. That is hydrolyzed by sodium hydroxide to cleave the ethoxy group and then ethylated with diethyl sulfate to give the starting material. 

Nit ropheny I) pyridine Ethoxymethylene malonic acid diethyl ester Ethyl iodide Sodium hydroxide... 

The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethylene-malonic acid diethyl ester and then reacting that product with sodium hydroxide. 

From malonic acid or diethyl (ethoxymethylene)malonate. Malonic acid 201 underwent nucleophilic acyl substitution with N-acetyl-3,4-dimethylphenylhydrazine 202 and phosphorus trichloride via in situ generated malonyl dichloride to afford pyrazoline-3,5-dione 203 which then underwent acid-catalyzed condensation with ethanol over molecular sieves to give 4-ethoxyrazol-3-one 204 (01JMC3730) (Scheme 45). 

Treatment of compound 270 with 1 equiv of ethoxymethylene malonate provides 271 and heating with acetic acid leads to the cyclized product 133 (Scheme 34) <2003MI1>. 

Ethyl 2-pyridylacetate reacts with diethyl ethoxymethylene malonate to give cyclic compound 64, which, on refluxing in hydrochloric acid, affords 4-quinolizone (65) (51JA3681). The 40% contribution of the betaine form 66 to the resonance hybrid was estimated on the basis of the H-NMR spectrum of 65 (73JOC4391). 

Af -2,2-Bis(ethoxycarbonyl)vinyl-protected amino acids are prepared by reaction of commercially available diethyl 2-(ethoxymethylene)malonate (127) with the respective amino acid in methanolic KOH. This rapid reaction is complete within 5 minutes and leads to the potassium salts. Subsequent acidification with 1M HCl yields the amino acid derivative in 75-90% yield.f This intermediate enamine-type N-protection is of particular interest in chemistry to be performed on the carboxy groups of the amino acids such as esterification with alkyl bromides in the presence of a base. Since cleavage of the enamine entity is achieved by treatment with bromine in chloroform at room temperature, it cannot be used for amino acids sensitive to halogenation such as tyrosine, tryptophan, and methionine (Scheme 61). Based on the experience gained with the enamine-type protection the Al-2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) and N-2-(4,4-dimethyl-2,6-dioxocyclohex-ylidene)isovaleryl derivatives were developed as specific side-chain protecting groups (see Section 2.1.2.2.5.2). 

Annulation of a nuclear amino group with a side-chain hydrazone function [as in (51.2)] proceeds in moderate yield on heating the compound with sodium acetate-acetic acid for 10-20 h under anhydrous conditions. Ethoxymethylene-malonates also convert imino- -amines into triazoles with a similar loss of carboxyl-derived functions. 

A variation on the cyclization of a-cyanomethylpyridines with a malonic ester (p. 566) is the ring closure of the acetate (104.7) with ethoxymethylene-malononitrile and of the quinolinone (104.8) with ethyl (ethoxymethylene)cya-noacetate. A methylene group in the succinic acid (104.9) readily forms an anion which attacks the electron-rich pyrrole ring on heating the compound in piperidine. COOEt... 

From 3(5)-hydroxypyrazoles. 5-Hydroxy-l-phenyl-lH-pyrazole-4-carboxylic acid ethyl ester 303, derived from diethyl (ethoxymethylene)-malonate and phenylhydrazine hydrochloride, when methylated with dimethyl sulfate in aqueous sodium hydroxide solution afforded pyrazole 304 together with pyrazol-3-one 305 in 16% and 33% yield, respectively (95JHC1341) (Scheme 68). 

It is, however, possible to obtain either pyrido[2,3-rf]pyrimidine-2,4,7(1/7,377,8//)-triones or, to a lesser extent, py rido[2,3-acetic acid 99 affords ethyl 1,3-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carboxylate. Further examples of this pathway are the reaction of diethyl (ethoxymethylene)malonate with 6-amino-165 or 6-(methylamino)-l,3-dimethyluracil 222 neat at 220-230 °C, or with 6-amino-2-methoxypyrimidin-4(3/7)-one223 in acetic acid to yield the corresponding ethyl 2,4,7-trioxo-l, 2,3,4,7,8-hexahydropyrido[2,3-[Pg.118]

Equimolar amounts of 4-ethylaniline and diethyl (ethoxymethylene)-malonate were heated together at 120°C for 1 h and then heated under reflux in Dowtherm A to effect cyclization. The resulting crude ester was saponified to give 6-ethyl-4(l//)-quinolone-3-carboxyUc acid in an overall yield of 81%, m.p., (DMF) 257°C (dec.). This acid was decarboxylated in benzophenone at 275°C to give 6-ethyl-4(l//)-quinolone, in a yield of 77%, m.p (H2O) 197.5-198.5°C. 

In one of the Vertex s process approaches, the original synthesis of ester 12 was improved where POCI3 was used to facilitate the Friedel-Crafts acylation. " The conditions to carry out the condensation between aniline and diethyl ethoxymethylene-malonate (10) were similar to those of the discovery route except with somewhat elevated temperature (150 °C vs 110 °C). The greater improvement was to carry out the Friedel-Crafts acylation in the presence of POCI3 and phosphoric acid at 70 °C. The overall yield for converting 10- 12 was 70%, more than doubled the yield for the discovery route. 

Masked P-dicarbonyl systems (Mke (alkoxymethylene)malonates or -cyanoacetates) can also be used as 1,3-biselectrophiles in the Pinner cyclocondensation. As the reaction of (ethoxymethylene)cyanoacetate and acetamidine demonstrates, the cycHzation of the primary product 21 can be directed by the reaction medium Acid medium favors... 

Orthoformates such as HC(OEt)3, in the presence of acetic anhydride and catalytic amounts of an appropriate Lewis acid (e.g. ZnCl2), react with diethyl [ C]malonates to provide dialkyl ethoxymethylene[ C]malonate (3391 which serve as highly valuable intermediates... 

PhSSPh with retention/ or photochemically/ Methyl phenyl N-methyl-sulphoximide gives adducts with ketones after conversion into its carban-ion, from which either tertiary alcohols are obtained by Al-Hg reduction under neutral conditions, or alkenes by reduction in aqueous acid, thus providing an alternative to the Wittig methylenation reaction/ Oxosul-phonium ylides formed by N-dimethylation followed by carbanion formation with NaH are useful as alkylidene-transfer reagents/ Uses of sulphoximides in heterocyclic synthesis have been reported methyl phenyl sulphoximide reacts through N with ethoxymethylene malonate esters. ... 

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