Diethyl ethoxymethylenemalonate

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... 

Cyclocondensation of 3,4-dihydro-2//-l,4-benzothiazines and diethyl ethoxymethylenemalonate in PPA at 120-160°C yielded ethyl 7-oxo-2,3-dihydro-7//-pyrido[l,2,3- fc]benzothiazine-6-carboxylates (97MI3,... 

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... 

Fluoro-2-methyltetrahydroquinoline Diethyl ethoxymethylenemalonate Polyphosphoric acid Sodium hydroxide... 

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... 

A mixture of 27 parts by weight of 3,4-methylenedioxyaniline and 43 parts by weight of diethyl ethoxymethylenemalonate is heated at 80° to 90°C for 3 hours. The mixture is then heated at 80° to 90°C for 1 hour under about 15 mm pressure to remove the byproduct ethyl alcohol formed. The residue is recrystallized from ligroin (BP 60° to 90°C) to give diethyl [(3,4-methylenedioxyanilino)methylene] malonate as a yellow solid melting at 100° to 102°C. The analytical sample from ligroin melts at 101° to 102°C. 

With a similar approach, Dave and Shah have developed a simple, fast, solvent-free and high-yielding, variant of the Gould-Jacob type synthesis of thieno[3,2-e]pyrimido[l,2-c]pyrimidines. In this example the conventional condensation between 4-aminothieno-2,3-dyrimidines and diethyl ethoxymethylenemalonate via acyclic intermediates (usually performed in 5-6 h) was compared with a solvent-free single-step microwave procedure (7-10 min) applying a multimode microwave oven (BPL 700T, Mumbai, India) [7], Scheme 6. 

C,9H2x07) see Tetroxoprim ethoxyiiiethylenemalonic add diethyl ester see under diethyl ethoxymethylenemalonate ethoxymethylenemalononitrile... 

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. 

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... 

When 3-amino-5-methylthio- 1,2,4-triazole was reacted with diethyl ethoxymethylenemalonate (EMME) in aqueous ethanol at ambient temperature for two days, an addition product (24) was obtained in 38% yield instead of a condensation product (62JCS2222). 

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)...

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). 

Diethyl ethoxymethylenemalonate reacts with 3-amino-1-phenylpyrazole to yield 53, which cyclizes to 54. The latter (54) affords amides upon treatment with amino heterocycles (82GEP3309432). Pyrazolo[l,5-a]pyrimidines are produced by cyclization of aminopyrazoles with 3-ethoxycrotonate (82S673). 

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