Ethyl ethoxymethylenemalonate

ETHYL ETHOXYMETHYLENEMALONATE (Malonic acid, ethoxymethylene-, diethyl ester) 

A mixture of 1000 g. (6.75 moles) of ethyl orthoformate, 1260 g. (12.3 moles) of acetic anhydride, 960 g. (6.0 moles) of ethyl malonate, and 0.5 g. of anhydrous zinc chloride is prepared in a 5-1. three-necked flask equipped with a thermometer, a gas inlet tube, and a 12-in. column packed with Berl Saddles (Note 1). The column is attached to a still head and condenser. The contents of the flask are well agitated for 5 minutes by a stream of dry air and then heated (Note 2) as follows 102-115° for lYi hours, 115-127° for 7 hours [after the eighth hour of heating, 250 

The use of this column prevents loss of acetic anhydride during the heating process and permits volatile products formed during the reaction to be removed by distillation. The checkers used a 1 by 12 in. column packed with 6 by 6 mm. glass rings. 

The zinc chloride dissolves, and a chlorine-free crystalline precipitate soon separates. The checkers observed only traces of this precipitate. 

The final heating is necessary to convert unchanged ethyl diethoxymethyhnalonate, an intermediate in the reaction, into ethyl ethox3onethylenemalonate. This intermediate is difficult to separate from ethyl ethoxymethylenemalonate by distillation, and it is important that it be converted as completely as possible during the heating process. 

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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... 

Pyrazino[l, 2-a ]pyrimidines are most commonly prepared from 2-aminopyrazines. Reaction of 2-aminopyrazine (274) with ethyl ethoxymethylenemalonate followed by heating in... 

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... 

The 5-amino-l,2,3-triazoles 8 react with ethyl acetoacetate and ethyl ethoxymethylenemalonate to give 9 and 10, respectively [71JCS(C)2156]. Cyclocondensation of the aminotriazole 8a with isopropyl 2-acetyl-o-fluorocinnamate (11) gave 4,7-dihydro-l,2,3-triazolo[l,5-a]pyrimidine 12 [88JAP(K)63107983]. Condensation of 8b and 8c with acetylacetone in ethanolic piperidine afforded triazolol[l,5-a]pyrimidine derivatives 13a and 13b, respectively. When the reaction with 8b was carried out in glacial ace-... 

Since ethyl diethoxymethyhnalonate is difficult to separate from ethyl ethoxymethylenemalonate by distillation, it is necessary to follow the course of the distillation by observation of the change in refractive index instead of the change in boiling point. After a low-boiling fraction is collected, there is obtained an intermediate fraction ( 1.4142-1.4580), the size of which depends upon the amount of ethyl diethoxymethyhnalonate present. 

The ethyl ethoxymethylenemalonate was collected at 1.4580-1.4623. The checkers used a 5-in. Vigreux column and observed that at the low pressures the boiling point of the distillate in several runs was about 10° lower than that reported by the submitters. For example, in one nm at 0.25 mm. (gauge pressure) the boiling point of the distillate never rose above 97.2° however, the refractive indices of twelve 50-ml. fractions taken in the course of this distillation were all in the proper range, 1.4612-1.4623. 

Ethyl ethoxymethylenemalonate has been prepared by heating ethyl orthoformate, ethyl malonate, and acetic anhydride in the presence of zinc chloride. A higher yield of purer product is obtained by the method described above, which is a modification of the Claisen procedure. 

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