Ethoxy methylene malonates

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

Finally less common routes are by reaction between an aniline and diethyl ethoxy methylene malonate followed by cyclisation... 

SYNS DIETHYL EMME DIETHYL (ETHOXY-METHYLENE)MALONATE MALONIC ACID, (ETHOXYMETHYLENE)-, DIETHYL ESTER TL 1483... 

The key intermediate for synthesizing chloroquine, amodiquine and other 4-aminoquinoline drugs is 4,7-dichloroquinolihe (91), which can be prepared by reacting m-chloroaniline (83) with diethyl oxaloacetate (EtO-CO-CH2-CO-COOEt) or ethoxy methylene malonic ester [EtO-CH=C(CCXDEt)2] as shown in scheme 1 [8,128-133]. 

An interesting application of the lithiation route for coumarin synthesis is the Michael addition of the aromatic lithio compound to ethoxy methylene malonic ester. 3-Carboxy coumarins are directly obtained by this method. The linear benzocoumarin is also accessible by this method... 

Interaction of 3-chloro-4-fluoroaniline with diethyl ethoxy-methylene malonate yields the corresponding imine salt, which on being thermally cyclized gives rise to the formation of ethyl-7-ehloro-6-fluoro-4-hydroxyquinoline-3-carboxylate. The resulting produet on being subjected to N-alkalation, followed by the nucleophilic displacement of the 7-chloro moiety with N-methylpiperazine, and finally hydrolysis of the ester yields the desired product ofloxacin. 

In the reaction of EMME and the potassium salt of pyrrole in tetrahydro-furan (THF) at 0°C for 30 min, an addition product, ethoxy(l-pyrrolyl)-methylmalonate (115), could be isolated in 85% yield (82CB714). This ester (115) was hydrolyzed with potassium hydroxide in aqueous ethanol at reflux temperature to yield 95% dipotassium ethoxy( 1 -pyrrolyI)methylene-malonate (116), from which 1-pyrrolylmethylenemalonic acid (118) was... 

Anions of methylene-active compounds (1,3-dione enolates and ester enolates), ketene acetals, and even electron-rich five-membered heterocycles comprise another group of nucleophiles that attack triazine rings, preferably in the form of l,2,3-triazin-2-ium salts. 4,6-Disubstituted-2-methyl-l,2,3-triazinium iodides add malonic ester anion at the C-5 position to form 4,6-disubstituted-2-methyl-5-bis(ethoxy-carbonyl)methyl-2,5-dihydro-l,2,3-triazines in 57-76% yield <1992CPB2283, 1996CHEC-II(6)483>. The following cases have been published more recently. 

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