Diethyl ethoxymethylenemalonate, reaction with

Another approach involves utilization of the amines for addition of a fused pyridine ring to the benzothiadiazole skeleton. The Gould-Jacobs reaction of 4-amino-2,l,3-benzothiadiazole 60 with diethyl ethoxymethylenemalonate gave the substitution product, and, after thermal cyclization in diphenyl ether, afforded the... 

Pefloxacin (33) is the N-methyl analogue of norfloxacin (58) and is at least partly converted to it by metabolic enzymes in vivo. It has been launched in France for the treatment of a number of infections including those caused by sensitive strains of Pseudomonas aeruginosa. It can be synthesized starting with the Gould-Jacobs reaction of 3-chloro-4-fluoroaniline (28) and diethyl ethoxymethylenemalonate in an addition-elimination sequence leading to 29 which undergoes... 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

With ethoxymethylenemalononitrile (136), C-addition appears to be the only mode of reaction with simple 5-aminoimidazole derivatives. Typically, reaction of 5-amino-1,2-dimethylimidazole (96 R = R2 = Me) with the reagent (136) in dioxane solution gave an 84% yield of the product (144 R = R2 = Me). In contrast, reaction of the same amine with diethyl ethoxymethylenemalonate (135) in dioxane solution gave exclusively an... 

Amino-9-ethylcarbazole and its 6-methyl-homolog underwent the Conrad-Limpach reaction with ethyl acetoacetate, closure occurring at C-4 giving 185 (R = H or Me). 1-Aminocarbazole condensed with diethyl ethoxymethylenemalonate to give 186, which was thermally cyclized... 

Table 13 Reaction of Diethyl Ethoxymethylenemalonate with 2-Methylpyridine Derivatives (Scheme 110)...

Reaction of diethyl ethoxymethylenemalonate or ethyl cyanoethoxy-methylene acetate with l-phenyl-4-aminopyrazole gave esters 187a, which cyclized in boiling Dowtherm to the corresponding pyridones 188a.158 The... 

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). 

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. 

The product from Step 1 (4.48 g) and diethyl ethoxymethylenemalonate (4.25 ml) were heated to 95 °C 2 hours and the reaction cooled. The intermediate solid was treated with 20ml hexanes, filtered, and the product isolated in 83% yield, mp = 138-139 °C. H-NMR, IR, and MS data supplied. 

Reaction with reactive-methylene compounds. Claisen" developed a method for the preparation of diethyl ethoxymethylenemalonate by heating a mixture of triethyl orthoformate, malonic ester, and acetic anhydride with a catalytic amount of zinc chloride. The yield cited is that obtained in a standardized procedure."... 

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