Ethyl Ethoxymethylenecyanoacetate Research Articles

A Short, Novel, and Practical Synthesis of 3-Alkenylated Indoles

Direct metal-free alkenylation of 2-methylindole via acid-mediated Michael addition–elimination reaction with ethoxymethylenemalononitrile or ethyl ethoxymethylenecyanoacetate affords 3-indolyl-2-cyanoacrylonitrile and ethyl 3-indolyl-2-cyanoacrylate. Behavior of 1H-indole is predictably different.

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate.

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is investigated. At −10 °C reaction takes place on the exocyclic nitrogen atom, giving exclusively ethyl esters of 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)amino]prop-2-enoic acid. The formation of isomeric enamines which may be a theoretical product of the reaction on N3 ring nitrogen atom is not observed. The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the enamines to the temperature of 120–140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.Graphical

Competing transformations of 2-cyanoacetanilides in the reactions with derivatives of ethoxymethylenemalonic acid

Ethoxymethylenemalonodinitrile 1B and ethyl ethoxymethylenecyanoacetate 1C in cyclocondensations with 2-cyanoacetanilides 2 behave as a three-carbon fragment transfer reagent to afford the corresponding 5-cyano- and 5-ethoxycarbonyl-6-amino-1-aryl-3cyanopyridin-2(1H)-one derivatives 7B and 8C. One carbon transfer described earlier for such reactions with a use of diethyl 2-(ethoxymethylene)malonate 1A was observed only as a side process in the case of 1C leading to 2-amino-5-cyano-6-oxo-N,1-diaryl-1,6-dihydropyridine-3carboxamides.

C–C recyclizations of some 2,7-disubstituted 6-ethoxycarbonylpyrazolo[1,5-a]pyrimidines

Condensation of ethyl ethoxymethyleneacetoacetate and ethyl ethoxymethylenecyanoacetate in ethanol with 3-substituted 3-aminopyrazoles and 5-amino-1,2,4-triazole gave the 2-substituted 6-ethoxy- carbonyl-7-methyl- and 7-amino-6-ethoxycarbonylpyrazolo[1,5-a]pyrimidines as well as 7-amino-6-ethoxycarbonyl-1,2,4-triazolo[1,5-a]pyrimidine. In the presence of alkali these rearranged to 2-substituted 6-acetyl-7-hydroxy- and 6-carbamoyl-7-hydroxypyrazolo[1,5-a]pyrimidines respectively and also to 6-carbamoyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine. According to 1 H (including NOESY) NMR spectroscopic data there were formed, along with the cyclization products, noncyclic condensation adducts (as cyano derivatives) from ethyl ethoxymethylenecyanoacetate with 5-aminopyrazoles. In the presence of alcoholic alkaline solution these were also transformed in high yield to 6-carbamoyl-7-hydroxypyrazolopyrimidines. When refluxed for a longer time in 12% aqueous alcoholic alkaline solution the 6-ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine recyclize to give 6-carboxy-2,7-dimethyl- and 2,7-di- methylpyrazolo[1,5-a]pyrimidines.

Synthesis of Pyrazolo[3,4-b]Pyridine and Pyrido[2′,3′:3,4]Pyrazolo [1,5-a]Pyrimidine Derivatives

The synthesis of two series of 1-phenyl and 1 H-pyrazolo[3,4- b]pyridine is described. Thus, reacting 5-amino-1-phenylpyrazole with chalcone analogues gave 4,6-diarylpyrazolo[3,4- b]pyridine derivatives. While, reacting the same starting material with benzylidene derivatives of ethyl cyanoacetate and malononitrile resulted in 4-oxo and 4-aminopyrazolo[3,4- b]pyridine derivatives, respectively. The synthesis of 3-amino-4,6-diarylpyrazolo[3,4- b]pyridines starting from pyridine was also described. Thus, chlorination of 4,6-diarylpyridone derivatives and their subsequent cyclisation with hydrazine hydrate afforded 3-amino-4,6-diarylpyrazolo[3,4 -b]pyridines. Reaction of the latter compounds with acetylacetone, ethyl ethoxymethylenecyanoacetate and chalcone analogue gave the tricyclic pyrido[2′,3′: 3,4]pyrazolo[1,5- a]pyrimidines. The structures of the products were confirmed by spectral data.

Synthesis of some new nitrogen bridge-head pyrido[1,2,4]triazepines

Ring closure reactions of 1,6-diamino-4-(4-chlorophenyl)-2-oxopyridine-3,5-dicarbonitrile with various 1,3-dielectrophiles, namely, diethyl malonate, ethyl ethoxymethylenecyanoacetate, 2-cyano-3,3-bis(methylthio)acrylonitrile, dimethyl acetylenedicarboxylate, dehydroacetic acid, chromone-3-carbonitrile, and 3-formylchromone led to the formation of the target biheterocyclic 1,2,4-triaze-pines. The reactions with 3-phenylazo-2,4-pentadione, ethyl α-cyano-α-phenylazoacetate, and 3,1-benz-oxazin-4-one derivative are also described.

Immunomodulatory and Anticancer Activities of Some Novel 2‐Substituted‐6‐bromo‐3‐methylthiazolo[3,2‐a]benzimidazole Derivatives

Ethyl 6-bromo-3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 2 was prepared by the ambient temperature bromination of ethyl 3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 1. The acid hydrazide 4 was obtained by the reaction of ester 2 with hydrazine hydrate. Treatment of compound 4 with benzaldehyde or 2-thiophenaldehyde yielded the corresponding hydrazones 6a and 6b, respectively, while the reaction of acid hydrazide 4 with ethoxymethylene malononitrile (7a) or with ethyl ethoxymethylene cyanoacetate (7b) in refluxing ethanol afforded pyrazole derivatives 9a and 9b, respectively. Taken together, from the biological investigations compounds 9a and 9b were the most significant inhibitors of LPS-stimulated NO generation from Raw murine macrophage 264.7, and, as another result, compounds 2 and 4 had a weak radical scavenging activity against DPPH radicals. Moreover, 2, 4, and 9a had a concomitant strong cytotoxicity against both colon carcinoma cells (HCT-116) and hepatocellular carcinoma cells (Hep-G2) while 9b showed specific cytotoxicity only against colon carcinoma cells.

Synthesis of Pyridothienopyridines and Arylazothienopyridines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Pyridothienopyridines and Arylazothienopyridines

Treatment of aminothienopyridine 3 with arylidenemalononitrile affords pyridothienopyridine 4. Condensation of 3 with ethyl ethoxymethylene-cyanoacetate affords compound 5, which may be cyclised in diphenyl ether into pyridothienopyridine 6. Thiourea derivative 7 is cyclised using Br2/ AcOH, and ethyl chloroacetate to afford thiazolothienopyridine 8 and thiazolidinylthienopyridine 9 respectively. Compound 15 is condensed with aromatic aldehydes to give the corresponding arylidenethienopyridines 16a–d. The latter compounds undergo Michael addition with malononitrile to produce pyranothienopyridines 17a–d, Compound 15 was coupled with aromatic diazonium chloride to give the corresponding 2-arylazothienopyridine derivatives 20, but when treated with nitrous acids it dimerised to compound 19.

Novel Intramolecular Cyclization of Pyrazolone Ketene S,N‐Acetals for the Construction of Methylsulfanylpyrazolo[4,3‐b]pyridines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of nitrogen‐containing heterocycles 10. Reaction of 2‐amino‐1h‐imidazole derivatives with ethoxymethylene compounds

AbstractThe direct annelation reaction of 4‐substituted 2‐amino‐l‐benzylideneamino‐1H‐imidazoles (1) or 2‐amino‐1‐isopropylideneamino‐1H‐imidazole (8) with ethoxymethylenemalononitrile (I) gave successfully bicyclic imidazo[1,2‐a]pyrimidine compounds 2 and 9 in high yields. The reactions of other ethoxymethylene compounds of lower reactivity, i.e., ethyl ethoxymethylenecyanoacetate (II) and diethyl ethoxymethylenemalonate (III), with 2‐amino‐1H‐imidazoles under similar conditions afforded the corresponding enamines 3, 4 and 10, which, upon heating in the presence of an acid or a base, could readily be cyclized to form imidazopyrimidines except for 1‐isopropylideneamino compound 10. In general, the 3‐phenyl compounds (3b and 4b) did not cyclize to the type 2 compound resulting in a full recovery of the starting enamines.

NOVEL INTRAMOLECULAR CYCLIZATION OF PYRAZOLONE KETENE S,N-ACETALS FOR THE CONSTRUCTION OF METHYLSULFANYLPYRAZOLO- [4,3-b]PYRIDINES

ABSTRACT A novel and efficient method for the synthesis of 6-substituted-7,7a-dihydro-1,7a-dimethyl-7-imino-2-phenyl-1H-pyrazolo[4,3-b]pyridin-3(2H)-ones via the reaction of 4-amino-2,3-dimethyl-1-phenylpyrazolin-5-one with ketene dithioacetals and ethoxy-methylenemalononitrile or ethyl ethoxymethylene-cyanoacetate followed by intramolecular cyclization of the products has been investigated.

Synthesis and Preliminary Pharmacological Evaluation of New 6-cyano-2,3-dihydro-5<I>H</I>-oxazolo[3,2-<I>a</I>]pyrimidin-5-ones and 2-ethyl(methylenecyanoacetate)-2-iminooxazolidines

One-step ring-annulation of 5-substituted 2-amino-2-oxazolines with diethyl ethoxymethy-lenemalonate yielded 2-substituted 6-carboethoxy-2,3-dihydro-5H-oxazolo[3,2-a]pyrimidin-5-ones. Under the same conditions 2-substituted 6-cyano-2,3-dihydro-5H-oxazolo[3,2-a]-pyrimidin-5-ones and the corresponding 2-ethyl(methylenecyanoacetate)-2-iminooxazo-lidines were obtained from ethyl ethoxymethylenecyanoacetate. Some of these compounds were evaluated in mice for antiparasitic activity.

Synthesis of some new imidazo[1,2‐a]pyrimidin‐5(1H)‐ones as potential antineoplastic agents

AbstractSome substituted imidazo[1,2‐a]pyrimidin‐5(1H)‐ones have been synthesized via the reaction of 2‐aminoimidazole sulfate with some β‐keto esters, diethyl ethoxymethylenemalonate and ethyl ethoxymethylenecyanoacetate. Several compounds were screened for their in vitro antineoplastic and anti‐HIV activity but were inactive.

Synthesis of 2H‐pyrazolo[3,4‐b]pyridin‐3‐oles via cyclization of pyrazolacrylonitriles

AbstractThe reaction of 1‐acyl‐3‐amino‐5‐pyrazolones 1 with ethyl ethoxymethylenecyanoacetate and ethoxymethylenemalononitrile 2 is described. Thermal cyclization in phenyl ether of the obtained pyrazol‐acrylonitriles 3 provides good yields of pyrazolopyridin‐3‐ol derivatives 4.

Annulation reactions of 3‐aminoisoquinolin‐l(2H)‐one. Synthesis of pyrimido[1,2‐b]isoquinolines, pyrido‐[2,3‐c]isoquinolines and pyrrolo[2,3‐c]isoquinolines

AbstractReactions of the title compound with the malonic acid derivatives diethyl ethoxymethylenemalonate (EMME), ethyl ethoxymethylenecyanoacetate (EMCA) and ethoxymethylenemalononitrile (EMMN) are reported. Condensations occur at the amino group or C‐4, depending on conditions and the former intermediate was successfully cyclized to the pyrimido[1,2‐b]isoquinoline system. Reactions with 2,4‐pentanedione and p‐bromophenacyl bromide gave only the angular systems, pyrido[2,3‐c]isoquinoline and pyrrolo[2,3‐c]isoquin‐oline, respectively.

Reaction of 5‐aminopyrazole derivatives with ethoxymethylene‐malononitrile and its analogues

AbstractA one‐pot synthesis using 5‐aminopyrazole derivatives 1 with ethoxymethylenemalononitrile (EMMN), ethyl ethoxymethylenecyanoacetate (EMCA) or diethyl ethoxymethylenemalonate (DEMM) gave pyrazolo‐[1,5‐a]pyrimidine compounds 2,4,8. Also, the one step reaction of EMCA with hydrazine hydrate afforded ethyl(4‐ethoxycarbonyl‐5‐pyrazolyl)aminomethylenecyanoacetate 3c. On the other hand, the reaction of 1‐substituted 5‐aminopyrazole‐4‐carboxamide 9 with EMMN afforded pyrazolo[3,4‐d]pyrimidine compounds 10.

A study of 2‐aminofurans

AbstractCatalytic reduction of 2‐nitrofurans 2 gives low yields of 2‐aminofurans 1 which are not isolated but are trapped using ethyl ethoxymethylenecyanoacetate (6) or ethoxymethylenemalononitrile (7). In these reactions 2‐aminofuran (1a) behaves like a dieneamine with substitution occurring at position 5 of the ring. When the 5‐position is substituted reaction takes place at position 3 and thermal cyclisation of the product gives furo‐[2,3‐b]pyridine derivatives 16. An AM1 calculation of the properties of 2‐aminofuran (1a) is reported and the results are consistent with observed properties.

Heterocyclization of Acetamidrazones. I. Synthesis of 1,2,4‐triazolo[4,3‐a]pyridines via ring closure of 6‐(2‐acylhydrazino)pyridine intermediates

AbstractThe reaction of N1‐acyl‐2‐ethoxycarbonylacetamidrazones with ethyl ethoxymethylenecyanoacetate (EMCA) has been examined. The acetamidrazone 1a reacts with EMCA in boiling dimethyl sulphoxide to give the 1,2,4‐triazolo[4,3‐a]pyridin‐3(2H)‐one 2 in excellent yield. Similarly from the amidrazones 1b‐h the 1,2,4‐triazolo[4,3‐a]pyridines 3b‐h were obtained. When the reaction between the amidrazones and EMCA was performed in ethanolic solution, the 6‐(2‐acylhydrazino)‐pyridines 4 were isolated. Ring closure of 4 afforded the 1,2,4‐triazolo[4,3‐a]pyridines.

Synthesis and Biological Activities of Some New Pyridazine Derivatives

AbstractThe reactions of 4‐carboxyhydrazide‐5,6‐diphenyl‐3(2H)‐pyridazinone (I) with aromatic aldehydes, phenyl isothiocyanate, β dicarbonyl compounds, ethyl ethoxymethylenecyanoacetate, ethyl cyanoacetate and acylating agents have been investigated. Oxadiazolines (III) and thiazolidinones (IV) were synthesized from arylidenehydrazides (II) through appropriate routes. The thiosemicarbazide derivative (V) on reaction with malonic acid and acetyl chloride gave VII, and on treatment with monochloroacetic acid and sodium acetate afforded IX. Some reactions with 3‐amino‐4,5‐diphenylpyrazolo [3,4‐b] pyridazine (XIVa) were also reported.