Ethoxymethylenemalonate cyclizations

In 1939, Gould and Jacobs reported the condensation of aniline with acetyl malonic ester (AME) and ethoxymethylenemalonate (EMME), respectively, followed by cyclization of anilinomethylenemalonic ester 13 and 14 in mineral oil to afford the esters 15 and 16. Saponification of the esters gave the known acids 17 and 18, respectively. 

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... 

Replacement of one of the ethereal oxygen atoms by a methylene group is compatible with anticoccidial activity. For example, condensation of substituted aniline 35 with dimethyl ethoxymethylenemalonate affords aminoacrylate 36. Thermal cyclization in diphenyl ether gives neguinate (37).11... 

The 4-hydroxypyridine (or 4-pyridone) derivatives are obtained by the use of ethoxymethylenemalonate and acetoacetate (59NKZ534) or acetylenedicarboxylate (78USP4130649). In analogy to these reactions, cyclizations starting from 5-aminotropolone ethers (83USP4382088) or 2-aminotropones (83USP4381304) were claimed. 

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... 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

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). 

A few extensions of the Conrad-Limpach synthesis have been applied to the synthesis of 4,7-phenanthrolines. Unlike o-phenylenediamine, which gives a quinoxaline derivative, p-phenylenediamine reacts with excess of ethyl ethoxalylpropionate to give an intermediate bisanil, which cyclizes in hot diphenyl ether to afford 3,8-dicarboethoxy-l,10-dihydroxy-2,9-dimethyl-4,7-phenanthroline in high yield.237 With diethyl ethoxymethylenemalonate as condensing agent, 6-amino-8-methoxy-quinoline has been converted into 2-carboethoxy-l-hydroxy-6-methoxy-4,7-phenanthroline.238 A related condensation affording 1-... 

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... 

Ethyl acetoacetate, ethyl ethoxymethylenemalonate, ethyl acetoacetate, and ethyl cyanoacetate afford 2-(ethoxycarbonylvinylamino)-l,8-naph-thyridines (84). Some of these compounds have been successfully cyclized to pyrimido [ 1,2-u]-1,8-naphthyridines (85).4 5... 

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). 

Reaction of lithiated 3-enaminophosphonj tes of aniline and isocyanates with subsequent cyclization of the resulting amides with triphenylphosphine/triethylamine leads to the 3-phosphonyl-4-aminoquinolines (Equation 92) <1999T5947>. Aniline reaction with /3-diketones < 1999H(51 )2171 > and ethoxymethylenemalonates <1999JFC(94)7> also leads to quinoline formation. The Vilsmeier reaction conditions can also be applied to the synthesis of quinolines with the use of a-oxoketene /V -anilinoacetals (Equation 93) <2003JOC3966>. 

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>. 

Thermal cyclization was also the route employed to prepare 9-hydroxy-7-methyl-l/f-pyrazolo[3,4-/]quinoline (74) from the 6-aminoindazole/ethyl acetoacetate condensation adduct shown in Equation (41) <92JMC4595>. The hydroxyl substituent of compound (74) was then converted (POCl3, DMF) to a chloro, which in turn was displaced by treatment with aryl amines to give tricyclics with potent in vivo immunostimulatory activity like that noted for regioisomeric l//-imidazo[4,5-/]quinolines but unlike the inactive pyrazolo[4,3-/]quinolines. Although it was noted with some interest that none of the linear tricyclic isomer had been isolated, this finding actually parallels that reported earlier for the similar condensation of 1- and (V(6)-alkyl and unsubstituted 6-amino-indazoles with diethyl ethoxymethylenemalonate <83JHC1351>. 

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