Ethyl ethoxymethylenecyanoacetate

Condensation of 165 with ethoxymethylenemalononitrile gave 171, and with ethyl ethoxymethylenecyanoacetate or methyl bis(methylmercapto)-methylene cyanoacetate it yielded 172 (80AP108). The reaction of 172 with urea, thiourea, and benzyl nitrile afforded 173 (91PHA98). Treatment of hydrazino derivatives 165 with alkyl, aryl, or aralkyl isothiocyanates yielded (86JHC1731) 3-(/V-substituted-thiocarbamoyl)-hydrazino[l,2,4]triazino[5,6-b]indoles which have been evaluated for in vitro antimicrobial activity (Scheme 36). 

Aminopyrazole has been prepared by a Curtius degradation of pyrazole-3(5)-carboxylic acid hydrazide,2 3 by saponification and decarboxylation of ethyl 3-aminopyrazole-4-carboxy-late 4 obtained from ethyl ethoxymethylenecyanoacetate and hydrazine, and by the present procedure.6,6... 

Cyanouracil — This pyrimidine (XXXV) can be synthesized either by the condensation of pseudoalkylthiourea with ethyl ethoxymethylenecyanoacetate followed by acid hydrolysis [300], or by the treatment of the corresponding cyanoethoxyacrylamide with aqueous ammonia [301,302]. 

A. 2-Mercapto-4-amino-5-carbethoxypyrimidine. A 5-1. threenecked, round-bottomed flask mounted in a heating mantle is fitted with a 250-ml. dropping funnel, an efficient, sealed, mechanical stirrer, and a reflux condenser connected to a calcium chloride drying tube. Absolute ethanol (625 ml.) is placed in the flask, the stirrer is started, and 23 g. (1 g.-atom) of freshly cut sodium is added in portions. After the sodium has dissolved, 76.1 g. (1 mole) of thiourea is added to the warm, stirred solution in one portion. When the bulk of the thiourea has dissolved, 169 g. (1 mole) of liquefied ethyl ethoxymethylenecyanoacetate is added from the dropping funnel to the stirred mixture over a period of 2 hours (Note 1). This rate of addition keeps the reaction mixture warm. The solution is then stirred and gently refluxed for 6 hours. The sodium salt of the carbethoxypyrimidine may precipitate during the course of the reaction. 

Ethyl ethoxymethylenecyanoacetate can be prepared in the laboratory from ethyl cyanoacetate and ethyl orthoformate according to the directions of de Bellemont.2 The submitters and checkers used a commercial product, m.p. 45-50°, obtained from Kay-Fries, Inc., New York. The liquefied product is weighed and poured into the dropping funnel. An infrared heating lamp is used to keep it liquid during the addition. 

Ethyl 2-pyridylacetate + ethyl ethoxymethylenecyanoacetate Na in anhydrous EtgO, stirred 7 hr at 25° 20 26a... 

The sequence for the synthesis of l,3,6-triazacycl[3,3,3]azines (58) is based on the reaction of 2,6-diaminopyridine with ethoxymethylene-malononitrile or ethyl ethoxymethylenecyanoacetate, leading to compounds 56. These on acylation gave 57, which after cyclodehydration yielded the desired cyclazines (58). Small amounts of the unsubstituted parent triazacyclazine (58a) were observed when the cyclization of 57 was carried out in a refluxing mixture of biphenyl and diphenyl ether. Decyanation of 4-cyano-2-methyl-l,3,6-triazacycl[3,3,3]azine (58f) with polyphosphoric acid at 200° yields 2-methyl-l,3,6-triazacycl-[3,3,3]azine (58b).18-80 The synthesis of 58d was carried out by a closely related route.74... 

Aminoisoquinoline and ethyl ethoxymethylenecyanoacetate at 105-110°C for 10 min under nitrogen gave ethyl 4-imino-4//-pyrimido[2,l -a]isoquinoline-3-carboxylate (321) in 67% yield. From the mother liquid, condensation product 322 could also be isolated in 27% yield (78USP4127720). 

The preparation of pyrimidines and hydropyrimidines from thioureas is well established.139,217,218 Since the latest review (1962) covering this reaction,218 several reports of the preparation of heterocyclic compounds by previously reported procedures have appeared in the literature. These involve reactions of thioureas with a,/3-unsaturated ketones,219-224 jS-ketoesters,225-228 aliphatic ketones,229-231 j8-dicar-bonyl compounds,232 and ethyl ethoxymethylenecyanoacetate.233 Selenoureas have also been reported to react with /3-ketoesters to give the analogous 2-selenopyrimidines.234,235 Two reports have appeared of the cyclization of l-/3-carboxyethyl-2-thioureas to hexahydro-pyrimidines in low yields in the presence of acetic anhydride 238,237 however, tetrahydrothiazines are the predominant products in these reactions. 

Seidel28 cyclized compounds (32) derived from the amides (31) with dimethylformamide dimethyl acetal to the 3-substituted 2-oxo-2H-pyrido-[l,2- ]pyrimidines (33) by heating in acetic anhydride. On this basis he corrected the conclusion of Antaki,29 who had assumed that by reacting 2-amino-4-methylpyridine and ethyl ethoxymethylenecyanoacetate, the 2-oxo-2//-pyrido[l,2-a]pyrimidine (33 R = 8-Me, R1 = OEt) was produced. The product was in fact the 4-oxo isomer (36 R = 8-Me, R1 = H, R2 = COOEt). 

Later, it was also claimed that 3-(tetrazolyl)-4//-pyrido[ 1,2-u]pyrimidin-4-ones 159 were obtained in an one-step procedure by heating the appropriate 2-aminopyridine, ethyl (l//-tetrazol-5-yl)acetate, and triethyl orthoformate in dimethylformamide at 90°C for 1 hour, or in boiling tetra-hydrofuran for 6 hours followed by treatment with 1N potassium hydroxide at 50°C for 1 hour, or with anhydrous aluminum chloride under reflux for 6 hours (91EUP462834). 9-Methyl-3-( 1 //-tetrazolyl)-4//-pyrido[ 1,2-a]-pyrimidin-4-one 159 (R = 9-Me) could be prepared when 2-amino-3-meth-ylpyridine hydrochloride and sodium azide were suspended and stirred in dimethylformamide for 1 hour at room temperature, followed by the addition of ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalo-nonitrile, ethyl cyanoacetate and triethyl orthoformate, or malononitrile and triethyl orthoformate and stirring at 90°C for 6-12 hours. Then the reaction mixture was treated with 1 N potassium hydroxide at 50°C for 1 hour, phosphoryl chloride at 90°C for 5 hours, or with concentrated hydrochloric acid at 110°C for 4 hours to give 26-62% yields. 

The ethyl (2-pyridylaminomethylene)cyanoacetates 161, prepared from the appropriate 2-aminopyridine and ethyl ethoxymethylenecyanoacetate in refluxing dioxane in the presence of triethylamine, exhibited a triple tautomerism among the E and Z isomers of 161 (E and Z) and the closed-... 

A solution of 2-amino-3-methylpyridine (5.0 g, 0.0462 mole) and ethyl ethoxymethylenecyanoacetate (7.82 g, 0.0462 mole) in toluene (4 ml) was heated for 15 min by means of an oil bath maintained at 100°C. The solution was cooled and the crude product (9.1 g, 85%) collected by filtration. The product was recrystallized from 2-propanol to give an analytical sample of ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate, melting point 144°-146°C. 

Both 2- and 3-nitrothiophenes are reduced by tin and hydrochloric acid to the corresponding aminothiophenes. Reduction of 2,5-dibromo-3,4-dinitrothiophene gives 3,4-diaminothiophene as a stable crystalline solid. 2-Acetamido-furans are prepared by the reduction of 2-nitrofurans in the presence of acetic anhydride. 2-Substituted 5-nitrofurans can be reduced to the S-aminofurans by an electrochemical method. Although catalytic reduction gives 2-aminofurans only in low yields, they can be trapped using ethyl ethoxymethylenecyanoacetate or ethoxymethylenemalononitrile. Benzofuranone 412 and not 2-aminobenzofuran is obtained from tin and hydrochloric acid treatment of 2-nitrobenzo[ ] furan 411. 

A general method for the synthesis of pyrimidines is illustrated by the condensation of ethyl ethoxymethylenecyanoacetate with thiourea in the presence of... 

The parent 2-aminofuran 103 is extremely unstable but when generated in situ, by catalytic reduction of 2-nitrofuran, and immediately reacted with the electrophiles ethoxymethylene malononitrile (EMMN) and ethyl ethoxymethylenecyanoacetate (EMCA) the 5-substitution products 104 were formed in low yield (Eq. (16)) (93JHC113). If the 5-position is blocked as in the case of the 5-methyl derivative 105, or 2-aminobenzo[Z>]furan, then substitution occurs at position 3, e.g. 106 (Eq. (17)) (93JHC113). 

The key intermediates for preparing allopurinol are 3-amino-4-cyanopyrazole (111) or 3-amino-4-carbethoxypyrazole (114), which may be prepared by reacting ethoxymethylenemalononitrile (110) and ethyl ethoxymethylenecyanoacetate (113), respectively, with hydrazine [77,78]. These may be smoothly converted in to al-lopurinol as described in scheme 6. 

Examples of ambident reactivity profile of amin yrazoles in fused-ring pyrazole syntheses was further documented [94JHC(31)239]. The 3-aminopyrazole (41a) reacts with ethyl ethoxymethylenecyanoacetate (EMCA) and ethoxymethylenemalonitrile (EMMN) to afford pyrazolo[l,D-fl]pyrimidines (42), however, the EMCA adducts (43) cyclize to the pyrazolo[l,5-fl]pyrimidin-7(4H)-ones with potassium carbonate. In contrast, the 1-aikyl (aryl) pyrazoles (41b, X = CONH2) and EMMN give pyrazolo[3,4-... 

Ethyl ethoxymethylenecyanoacetate treated with 3 equivalents of acetamidine in ethanol with cooling, then kept overnight in a refrigerator 5-cyano-4-hydroxy-2-methylpyrimidine acetamidinate. Y 85.5%. F. e. and different reaction course s. S. Nishigaki et al., Tetrah. Let. 1969, 247. 

Ethyl ethoxymethylenecyanoacetate (EMCE) followed by a-tetralone added drop-wise to a soln. of Na-ethoxide in dimethoxyethane, and stirred at room temp, overnight ethyl 5,6-dihydro-2-oxo-2H-naphtho[l,2-b]pyran-3-carboxylatc (Y 83%) allowed to react 14 hrs. with ethylene at 200° and... 

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