Ethoxymethylene ethyl malonate

Step A Ortho-Trif/uoromethy/anilinomethy/ene Ethyl Malonate - A mixture of 54.8 grams of ortho-trifluoromethylaniline and 73.5 grams of ethoxymethylene ethyl malonate was heated to 120°C under an inert atmosphere and maintained for 1 hour at this temperature while distilling off the ethanol formed. The mixture was cooled and the elimination of ethanol was completed by distillation under reduced pressure. The mixture was cooled to obtain 115 grams of ortho-trifluoromethylanilinomethylene ethyl malonate which was used as is for the following stage. A sample of the product was crystallized from petroleum ether (8P = 65° to 75°C) to obtain a melting point of 94°C. 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

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... 

This was later extended to the synthesis of novel pyrimido-[l,3-a]-pyrimidines under solvent-free conditions ethyl-2-armno-4-aryl-l,4-dihydro-6-phenylpyrimidine-5-car-boxylates react regioselectively with 3-formyl chromone or diethyl (ethoxymethylene) malonate, without solvent, to afford pyrimido-[l,3-a]-pyrimidines [92] (Scheme 8.66). 

Reaction of ethyl ethoxymethylene malonate with nitromethane in the presence of amines to afford l-amino-2-nitroethenes [174],... 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

Cyclocondensation of 2-aminoquinoline and diethyl ethoxymethylene-malonate in Dowtherm A at 250°C for 30 min gave ethyl 1-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylate (38, R = Et) (74MIP1). 

Amino-6-methylpyridine Ethoxymethylene malonic acid diethyl ester Sodium hydroxide Ethyl iodide... 

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). 

A good criterion of the purity of the ethyl ethoxymethyl-enemalonate is the refractive index material of > 1.4600 is satisfactory. The checkers redistilled the ethyl ethoxymethylene-malonate through a 1 by 12 in. bead-packed column just before use and employed the fraction boiling at 112-115°/0.1 mm., 1.4604. 

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

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). 

The cyclization of educts with a C-C-C—N pyrimidine structure is similar to the second step of the Gould-Jacobs reaction.194 The reaction of an appropriately substituted pyrimidin-4-amine with diethyl (ethoxymethylene)malonate affords the requisite diethyl [(pyrimidinyl-amino)methylene]malonate. The thermal cyclization of this intermediate, an acylation of the pyrimidine nucleus by one of the ester functions to give ethyl 5-oxopyrido[2,3-t/]pyrimidine-6-carboxylate 1, is effected by heating to 250-320 °C, preferably in mineral oil,195 Dowtherm,196 or diphenyl ether.197 201... 

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]

The reaction of the substituted 4-aminoimidazo[l,2-Z>][l,3,5]triazine (55) with ethoxymethylene malonate afforded ethyl 4-oxo-4/f-imidazo[3,4-c]pyrimido [l,2-a][l,3,5]triazine-3-carboxylate (56) (Equation (4)) <92JCS(P1)2789>. 

The reaction between 3-chloro-4-fluoro aniline and diethyl-ethoxymethylene malonate yields a corresponding imine salt. The resulting produet upon being eyelized thermally gives rise to the formation of ethyl-7-chloro-6-fluoro-4-hydroxyquinoline-3-carboxylate. This undergoes three steps of reaetions sequentially ... 

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. 

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