Ethoxymethylenemalonic acid diethyl acids

Amino-6-methvlPVridine Ethoxymethylenemalonic acid diethyl ester Sodium hydroxide Ethyi iodide... 

Amino-2-methYlthiopyrimidlne EthoxYmethYlenemalonic acid diethyl ester Sodium hydroxide Diethyl sulfate Pyrrolidine... 

Dichloro-3-nitropyridine Acetic anhydride Tetrafluoroboric acid Diethyl ethoxymethylenemalonate Thionyl chloride Ethyl iodide... 

Treatment of 2-aminopyrazine with esters of ethoxymethylenemalonic acid gives the substituted amino compounds 9, which may be cyclized to 4-oxopyrazino[l,2-a]pyrimidines by heating in diphenyl ether at 250°. When the diethyl ester 9 (R = = Et) is cyclized, the 3-ethoxycarbonyl... 

Fluoro-2-methyltetrahydroquinoline Diethyl ethoxymethylenemalonate Poly phosphoric acid Sodium hydroxide... 

In a 50-mL round-bottomed flask were placed 0.265 g 4-aminoindole (2.0 mmol) and 0.405 mL diethyl ethoxymethylenemalonate (2.0 mmol, d = 1.07) the mixture was heated at 130°C for 3 h. Any unreacted diethyl ethoxymethylenemalonate was removed under vacuum, leaving 0.50 g 2-[( 1//-indol-4-ylamino)methylene]malonic acid diethyl ester as a brown solid, in a yield of 83%, m.p., 122°C (ethanol). Then 0.50 g of the solid diester (1.7 mmol) was added to 50 mL boiling diphenyl ether in portions after 20 min of refluxing, the precipitate formed by cooling was collected by flltration, washed many times with diethyl ether, and recrystallized from ethanol, yielding 0.360 g ethyl 4-oxo-4,7-dihydro-lH-pyrrolo[2,3-/z]quinolin-3-carboxylate, in ayieldof83%, m.p.280°C (dec.), Rf = 0.45 (EtOAc/MeOH, 8 2). 

Fluoro-2-methyltetrahydroquinoline (32.2 g,0.2 mol) Is mixed with diethyl ethoxymethylenemalonate, and the mixture is heated at 125°C to 130°C for 3 hours. Polyphosphoric acid (200 g) is added, and the soiution Is gradually heated to 115°C to 120°C in an oil bath with occasional stirring. The temperature is mainteined for 1 hour,then the mixture is poured into 600 ml of water and neutralized with 40% sodium hydroxide solution. The product ester which precipitates is separated by filtration, washed with water and suspended in 2 liters of 10% sodium hydroxide solution. The mixture is heated on the steam bath for 1 hour, treated... 

Alaiz, M., Navarro, J. L., Giron, J., and Vioque, E. (1992). Amino acid analysis by HPLC after derivatization with diethyl ethoxymethylenemalonate. /. Chromatogr. 591,181-186. 

An unexpected reaction occurs when 2-alkyl-4(5)-nitroimidazoles (27 R = alkyl) are reduced in protic solvents [92JCS(P1)2779]. Catalytic hydrogenation of 2-methyl-4(5)-nitroimidazole (27 R = Me) in a solution of acetic anhydride and acetic acid gave 4,4 -diacetamido-2,2 -dimethyl-5,5 -diimidazole (32 yield 10%) in addition to the expected 4-acetamido-l-acetyl-2-methylimidazole (28%). Similarly, reduction of the 2-alkyl-4(5)-nitroimidazoles (27 R = Me, Et, iPr) in ethanol solution in the presence of diethyl ethoxymethylenemalonate [EMME (135)] gives predominantly the 5,5 -diimidazole adducts (33). The formation of these products (33) is believed to involve an electrophilic addition of the starting material (27) to the electron-rich aminoimidazoles (25) [92JCS(P1)2779]. Interestingly, replacement of ethanol by dioxane suppressed diimidazole formation. 

The condensation of 4-aminopyridine (145) with diethyl ethoxymethylenemalonate (EMME) gives 3-ethoxycarbonyl-l,6-naphthyridin-4-one (146) from which compound (2) was obtained by standard procedures (50JOC1224,60JCS1790,58LA(612)153,65JHC393). A recent application of this synthesis is for the preparation of nalidixic acid analogues (147) (82CPB2399). 

Aminopyridazines can also be condensed with /6 -keto esters in the presence of polyphos-phoric acid to give 2ff-pyrimido[l,2-6]pyridazin-2-ones. 3-Ethoxycarbonylpyrimido-[1,2-6 ]pyridazin-4-ones (169) are obtained by the reaction of 3-aminopyridazines (168) with diethyl ethoxymethylenemalonate in the presence of polyphosphoric acid (71JOC2457). 

A suspension of the diazonium salt in toluene was gradually heated and kept at 120°C (bath temp.) for 30 minutes with stirring. After evaporation of the solvent under reduced pressure, the residue was made alkaline with 10% sodium carbonate and then extracted with chloroform. The chloroform extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the crystalline residue was recrystallized from ethyl acetate to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine (mp 132°-133°C). The 3-fluoro derivative was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine. This compound was treated with diethyl ethoxymethylenemalonate at 130°-140°C to give N-[2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (mp 144°-145°C) and then the product was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (mp 279°-281°C). 

Methyl-l-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline Diethyl ethoxymethylenemalonate Acetic anhydride Sulfuric acid... 

To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[l,4]benzoxazine was added 1.58 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130-140°C for 70 min. The reaction mixture was subjected to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[l,4] benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50-60°C for 40 min. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylate. 

Cyclizations of the type (156) - (151) include the conversion of (a) carboxylic acids (218 X = O, S) into diones (219) (34% yield) under acidic conditions <74MI 715-01) (b) pyridine derivative (220) into the pyrano[3,2-c]pyridine (221) (72% yield) via an intramolecular Grignard reaction <82JCS(P1)93> and (c) a 1 1 mixture of diastereoisomers (222) into a 1 1 mixture of diastereoisomeric pyranopyrans (223) via a HSnBu3-mediated free radical cyclization <93LA629>. The diethyl ethoxymethylenemalonate (EMME) synthesis of 3-ethoxycarbonyl-4-naphthyridone derivatives has been discussed in CHEC-I <84CHEC-i(2)58i>. 

Heating equimolar amounts of 5-amino-l-methyIimidazoIe-2(3i/)-thione (391) with diethyl ethoxymethylenemalonate (390) gave the diethyl ester of [(5-amino-2,3-dihydro-l-methyI-2-thioxo-lH-imidazoI-4-yI)methyIene]propanedioic acid (392), which cyclized in 10% aqueous sodium hydroxide to 6-ethoxycarbonyI-3-methyI-2(lH)-thioxoimidazo[4,5-h]pyridin-5(4H)-one (393) (78H(lO)24i). 

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