Diethyl ethoxymethylene malonate

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 antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

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). 

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). 

An equimolar mixture of 3,4,5-trimethoxy phenyl iodide 157, lithium propargyl alkoxide 158, and diethyl ethoxymethylene malonate 159 was stirred at room temperature in the presence of a palladium catalyst. Then, to the resulting intermediate 161 potassium t-butoxide was added, and the ensuing base-promoted decarboxylative aromatization afforded tetrahydrofuran MCR adduct 162 in good yield. The ester was first reduced and the furan ring was hydrogenated with Raney nickel to furnish a diastereomeric mixture of products 163 in high yield. Further synthetic manipulations then provided a known precursor to the natural product. 

A solution of 108 g. (0.5 inole) of diethyl ethoxymethylene-malonate (Note 1) in 100 ml. of commercial absolute alcohol is placed in an apparatus for high-pressure hydrogenation together with 10 g. of Raney nickel catalyst (Note 2). The pressure in the bomb is raised to 1000-1500 lb. with hydrogen, and the temperature is adjusted to 45° (Note 3). The bomb is shaken, and the reaction is allowed to proceed for 12-20 hours, during which time 0.5 mole of hydrogen is absorbed. 

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). 

Agata et al. reacted caprolactim ethers with diethyl ethoxymethylene-malonate in the presence of ammonium acetate and obtained 4-oxopyrimido[l,2-a]azepine-3-carboxylate 415 (R = R = H, R = COOEt) (73JAP(K)34897 76MIP10021). The reaction of caprolactim methyl ether with diethyl aminomethylenemalonate also gave 4-oxopyrimido[l,2-o]-azepine-3-carboxylate 415 (R = H, R = COOEt, R = H). 

An impressive alternate approach to the synthesis of furans beginning with alkynols was developed by Balme [160, 161] and subsequently applied in a total synthesis by Morimoto [162]. Balme discovered that a three-component coupling reaction between a propargylic alkoxide, a conjugate addition acceptor, and an unsaturated halide yields a variety of di- and trisubstituted furans. In one example, propargyl alcohol, diethyl ethoxymethylene malonate (193), and iodobenzene combine to furnish disubstituted furan 194 in... 

Reactions with diethyl(ethoxymethylene)malonate or 3-formylchromone gave pyrimidine... 

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). 

Less vigorous conditions than those described above converted diethyl (ethoxymethylene)malonate 205 and (3,4-dimethylphenyl)hydra-zine monohydrochloride 206 into pyrazol-3-one 208 (01JMC3730, 04H2537) (Scheme 46). The reaction took place in ethanol or methanol containing aqueous potassium carbonate via conjugate substitution of ethoxide ion, intramolecular acyl substitution and tautomerization of intermediate pyrazol-3-one 207. 

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... 

The original Gould-Jacobs reaction, i.e. the reaction of an aniline or naphthylamine with diethyl (ethoxymethylene)malonate followed by cyclization of the intermediate at ca. 250 °C to give quinolinone derivatives (see Houben-Weyl, Vol. E 7a, p 345),194 has been extended to the synthesis of pyridopyrimidines. The method of first preparing the intermediate (pyrimidiny-lamino)methylene compound and its subsequent thermal cyclization has been discussed (vide supra). 

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]

An example of the normal Gould - Jacobs pathway is the reaction of 6-amino-2-methoxypyrim-idin-4(3//)-ones with diethyl (ethoxymethylene)malonate in ethanolic sodium ethoxide to give the corresponding pyrido[2,3-d]pyrimidine-2,4,5(l//,3/7,8/7)-trione in low yield together with the diethyl [(pyrimidinylamino)methylene]malonate.223... 

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 ... 

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