Active Methylene Reagents Research Articles

DBU-Catalyzed, facile and efficient method for synthesis of spirocyclic 2-oxindole derivatives with incorporated 6-amino-4 H-pyridazines and fused derivatives via [3+3] atom combination

3-Cyanomethylidene oxindole derivatives were prepared in excellent yields utilizing DBU-promoted Knoevenagel condensation of isatin derivatives with active methylene reagents. The isolated products were then reacted with azaenamines via a DBU-promoted Michael addition to yield spirocyclic 2-oxindole derivatives with incorporated 6-amino-4 H-pyridazines and their fused derivatives.

Ammonium salt catalyzed multicomponent transformation: simple route to functionalized spirochromenes and spiroacridines

The combination of isatin or acenaphthoquinone, an activated methylene reagent, and 1,3-dicarbonyl compounds in the presence of catalytic ammonium chloride was found to be a suitable and efficient method for the synthesis of the biologically important spirooxindoles.

β‐Oxoanilides in heterocyclic synthesis: An expeditious synthesis of new polyfunctionally substituted pyridine and pyrazole derivatives

Abstractmagnified image3‐Oxo‐N‐{4‐[(pyrimidin‐2‐ylamino)sulfonyl]phenyl}butanamide 3 was condensed with (DMF‐DMA) in refluxing dry dioxane to yield branched structure 4 not its linear isomeric 5. Compound 4 readily reacted with active methylene to yield compounds 8a‐c, 14, 17 and 20 respectively. Also enaminone 4 reacted with phenyl hydrazine giving 24 and 25. In contrast, when compound 4 reacted with hydrazine hydrate in the same experimental conditions pyrazole derivative 27 was obtained. Furthermore, condensation of anilide 3 with triethylorthoformate in refluxing acetic anhydride afforded the ethoxy methylene derivative 28. On the other hand, compound 28 was reacted with active methylene reagents, and hydrazines to afford the products identical in all respects (mp., mixed mp., and spectral data) with those corresponding to compounds 6‐27 respectively. Similarly, compound 3 was reacted with hydrazine hydrate to afford the reaction product 29. Also, compound 3 reacted with cyanoacetamide in refluxing ethanolic pipridine solution to yield the pyridine derivative 30. Finally, 3 reacted with hydroxylamine hydrochloride in refluxing ethanol/sodium acetate solution to yield the acyclic oxime derivative 31.

A Simple and Efficient One-Pot Synthesis of Spirooxindoles in Water Under Microwave Irradiation Conditions

A simple and efficient method for the synthesis of spirooxindoles derivatives by one-pot reactions of isatins, activated methylene reagents and activated carbonyl compounds in water under microwave irradiation was reported. This protocol has the advantages of short reaction time, high yields, easy work-up procedure and environmentally benign characters. Keywords: Spirooxindoles, three-component synthesis, microwave irradiation, aqueous media

Studies with enaminonitriles: Synthesis and chemical reactivity of 2‐phenyl‐3‐piperidin‐1‐yl acrylonitrile under microwave heating

Abstractmagnified imageBenzyl cyanide reacts with triethylorthoformate and piperidine in DMF solution to yield the title compound 2. This reacted with aromatic amines to yield either aminoacrylonitriles or quinoline depending on reaction conditions and substitution pattern on the aromatic amine. The reaction of compound 2 with hydrazine hydrate could only be effected in the microwave oven and resulted in the formation of aminopyrazole 7. Diazotization of 7 and coupling with an active methylene reagent afforded pyrazolo[5,1‐c]‐[1,2,4]triazine derivatives.

Antimicrobial Activities of some Synthesized Pyridines, Oxazines and Thiazoles from 3-Aryl-1-(2-naphthyl)prop-2-en-1-ones

3-Aryl-1-(2-naphthyl)-prop-2-en-1-ones were reacted with ethyl cyanoacetate to produce 4-aryl-6-(2-naphthyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles, which were treated with ethyl chloroacetate to give the corresponding ester. Treatment of the latter ester with hydrazine hydrate or anthranilic acid afforded hydrazides and benzoxazines. The hydrazides were reacted with benzaldehyde or phenylisothiocyanate to afford the corresponding hydrazone and thiosemicarbazide derivatives, which were cyclized with chloroacetic acid or thioglycolic acid to the corresponding thiazole derivatives. 3-Aryl-1-(2-naphthyl)-prop-2-en-1-ones were either condensed with malononitrile under different conditions to produce carbonitrile derivatives or treated with active methylene reagents to afford the substituted cyclohexene derivatives. The structure assignment of the new compounds is based on chemical and spectroscopic evidence. Some of these compounds exhibited antimicrobial activities comparable to Ampicillin® as reference drug.

Unprecedented One‐Pot Stereoselective Synthesis of Knoevenagel‐Type Derivatives via in situ Condensation of N‐Methyleniminium Salts of Ethylenethiourea and Ethyleneurea with Active Methylene Reagents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Phenylacetone as Building Blocks in Heterocyclic Synthesis: Synthesis of Polyfunctionally-Substituted Pyridines, and fused Pyridines

Many pyridinethiones are biologically active. In view of our interest in developing efficient syntheses of polyfunctionally substituted heteroaromatics utilizing the readily obtainable enaminone 3 as starting materials. So, treatment of enaminone 3 with cyanothioacetamide or cyanoacetamide afforded the pyridinethione 5a and pyridone 5b. compound 5a reacted with α -halo- ketones in refluxing sodium ethoxide to give the thienopyridine derivatives 9a – e . Compound 5a reacted with methyl iodide to give 2-methylthiopyridine 10. Condensation of pyridinethione 5a with dimethylformamide-dimethylacetal gave the adduct 11 and with hydrazine hydrate afforded 12 . Compound 5a reacted with arylidenemalonitrile to give styryl derivatives 14a – d . Compound 14a – d also prepared from the condensation of 5a with the aromatic aldehydes under the same condition. Reflux of thienopyridine derivatives 9a – d with triethylorthoformat, acetic anhydride, carbon disulfide and sodium nitrite to give compounds 19 – 23 , respectively. The aminopyrazole 12 reacted with dimethylaminopropiophenone hydrochloride 24 or enaminone 30 in refluxing DMF to yield compound 26a – d . Treatment of 12 with 32 afforded 34 . Compound 34 can be also prepared from the reaction of 37 with aroylacetonitrile 31. Compound 12 reacted with DMF-DMA to give 37 , which reacted with compound 1 to give 38 prepared directly from reaction of 12 with enaminone 2 . Diazotization of 12 with nitrous acid followed by coupling with different active methylene reagents afforded the pyridothienotriazines 42a , b . Reaction of benzylideneacetophenone with 12 yielded the pyridopyrazolopyrimidine 44. Also, compound 12 reacted directly with active methylene to give the pyridopyrazolopyrimidine derivatives 46a , b .

Pyrazolo[3,4-b]pyridine in heterocyclic synthesis: synthesis of new pyrazolo[3,4-b]pyridines, imidazo[1',2':1,5]pyrazolo[3,4-b]pyridines, and pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines

Pyrazolo[3,4-b]pyridine derivatives 7 and 9 were synthesized via the reaction of 3-amino-1H-pyrazolo-[3,4-b]pyridine derivative 2 with ω-bromoacetophenones. Reaction of 7 and 9 with Ac2O afforded the imidazo[1',2':1,5]py razolo[3,4-b]pyridine derivative 8 and pyrazolo[3,4-b]pyridine derivative 10, respectively. Reaction of 2 with chloroacetonitrile followed by DMF-DMA gave imidazo[1',2':1,5]pyrazolo[3,4-b]pyridines 4 and 5, respectively. Acetyl acetone and 1,1-dicyano-2,2-dimethylthioethene were reacted with 2 to afford the pyrido[2',3':3,4]pyrazolo-[1,5-a]-pyrimidines 11 and 14, respectively. Also, 2 reacted with DMF-DMA to yield the formamidine 15, which in turn, reacted with active methylene reagents, yielding the corresponding pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines 18 and 23a-23d.Key words: 1H-pyrazolo[3,4-b]pyridines, imidazo[1',2':1,5]pyrazolo[3,4-b]pyridines, pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines.

Unprecedented One-Pot Stereoselective Synthesis of Knoevenagel-Type Derivatives­ via in situ Condensation of N-Methyleniminium Salts of Ethylenethiourea­ and Ethyleneurea with Active Methylene Reagents

A facile stereoselective synthesis of Knoevenagel-type compounds 8 and 9 was accomplished through a one-pot two-step procedure. The reaction of ethylenethiourea ( 1) and ethyleneurea ( 2) with benzoyl chloride- N, N-dimethylformamide complex in N, N-dimethylformamide gave the corresponding isolable ternary N-methyleniminium chlorides 3 and 4, along with benzoic acid ( 5) as a byproduct. Hydrolysis of salts 3 and 4 yielded the N-formyl derivatives 6 and 7, thus confirming the N-methyleniminium structure. Salts 3 and 4 condensed in situ at 120 °C with a variety of acyclic active methylene reagents Y-CH 2 -Z (Y = or ≠ Z), in the presence of 5 (Procedure A) or of 5 and triethylamine (1.5 equiv) (Procedure B), afforded α,β-unsaturated compounds 8 and 9. The overall yields ranged from poor to good. Mechanistic hypotheses concerning the formation of 3 and 4 and the origin of the stereoselectivity are also discussed.

A simple and clean procedure for three-component synthesis of spirooxindoles in aqueous medium

A simple and efficient one-pot three-component synthesis of the biologically important spirooxindoles scaffold was carried out by the reaction of isatin, activated methylene reagent, and 1,3-dicarbonyl compounds in aqueous medium. This method is of great value because of its environmentally benign character, high yield processing, and easy handling.

Uses of 2-Amino-3-cyano-5,5-dimethyl-7-oxocyclohexano[b]thiophene in Heterocyclic Synthesis

The reaction of 2-diazo-3-cyano-5,5-dimethyl-7-oxocycloheneno-[b]thiophene ( 4 ) with the active methylene reagents 2 , 5 , 12a, or 12b gave the hydrazo derivatives 6a,b and 13a,b , respectively. The reactivity of the latter products towards different reagents was studied to give pyrazole, pyridazine, 1,2,4-triazine, and thieno[3,4-d]pyridazine derivatives. The antimicrobial and antifungal activities of the newly synthesized products were measured against the three bacterial isolates (Bacillus Subtillis, Escherichia Coli, and Pseudomonas Aeruginosa) and the three fungal isolates (Candida Albicans, C. Glabrata, and A. Fumigatus).

A Facile and Simple Synthesis of Some New Pyridobenzothiazepine and Pyrimidobenzothiazepine Derivatives

2-Amino-3-cyano-4-(2-thienyl)[1,5]benzothiazepine 5 has been synthesized and reacted with some active methylene and nucleophile reagents to yield new pyrido[6,5-b][1,5]benzothiazepine and pyrimido[6,5-b][1,5]benzothiazepine derivatives.

Novel Synthesis of Dihydroquinoxalinylpyridazine Derivatives

AbstractMethylquinoxaline derivative 1 undergoes bromination to give bromomethyl quinoxaline 2, which could be transferred to cyanomethyl quinoxaline 3. The latter compound 3 readily coupled with arene diazonium salts to give hydrazone derivatives 5a‐c. Compounds 5a,b reacted with active methylene reagents to give the target ring system, quinoxalinylpyridazine derivatives 8a‐c. Compound 1 reacted with DMFDMA to give the enamine derivative 9, which coupled with arene diazonium salts to give the aldehydic hydrazone derivatives 10a‐c. Compound 10 reacted with active methylene compounds to give quinoxalinylpyridazine derivatives. UV characterization of some of the prepared compounds was reported.

Reaction of Anthranilonitrile with Some Active Methylene Reagents: Synthesis of Some New Quinoline and Quinazoline Derivatives.

Abstract Anthranilonitrile (1) reacts with ethyl cyanoacetate and its dimer, malononitrile, cyanothioacetamide and N‐arylidene cyanoacetohydrazides 12a–c to afford pyrano[2,3‐b]quinoline 5, cyanomethyl‐quinazoline 10, pyrazolo[2,3‐a]quinazoline 12 and triazolo[4,3‐a]‐quinoline derivatives 16a–c, respectively. Structures and conceivable mechanisms are discussed.

Pyrazoles as Building Blocks in Heterocyclic Synthesis: Synthesis of Some New Substituted 1‐Triazinylpyrazolo[3,4‐d]pyrimidine and 1‐Triazinylpyrazolo[3,4‐b]pyridine Derivatives.

Several new pyrazolo[3,4-d]pyrimidines and pyrazolo[3,4-b]pyridine derivatives were prepared by condensation of 5-amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-1H-pyrazole-4-carbonitrile with succinic anhydride, acetic anhydride, γ-chlorobutyl chloride, succinyl chloride, formic acid—formamide mixture, formamide, and active methylene reagents such as malononitrile, ethyl cyanoacetate, and ethyl acetoacetate under different reaction conditions.

Heterocyclic Synthesis with 4‐Hydrazinopyridothienopyrimidines: Synthesis of Pyridothienotriazolopyrimidines and Heterocyclylpyridothienopyrimidines with Biological Interest.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Reaction of Anthranilonitrile with Some Active Methylene Reagents: Synthesis of Some New Quinoline and Quinazoline Derivatives

Anthranilonitrile (1) reacts with ethyl cyanoacetate and its dimer, malononitrile, cyanothioacetamide and N‐arylidene cyanoacetohydrazides 12a–c to afford pyrano[2,3‐b]quinoline 5, cyanomethyl‐quinazoline 10, pyrazolo[2,3‐a]quinazoline 12 and triazolo[4,3‐a]‐quinoline derivatives 16a–c, respectively. Structures and conceivable mechanisms are discussed.

Synthesis of Some New Azole, Azepine, Pyridine, and Pyrimidine Derivatives Using 6‐Hydroxy‐4H‐4‐oxo[1]‐benzopyran‐3‐carboxaldehyde as a Versatile Starting Material.

Condensation of 3-formyl chromone 1 with hydroxylamine hydrochloride afforded the corresponding oxime 2 that was converted to nitrile 3. Refluxing of oxime 2 and/or nitrile 3 with aceturic or hippuric acid gave 16 and 17. Treatment of 1 with semicarbazide hydrochloride and thiosemicarbazide afforded the corresponding carbazones 5–6 that underwent cyclization with ethyl bromoacetate and/or chloroacetone yielding 7–8. Also 1 reacted with acyclic active methylene reagents, e.g. malononitrile, ethyl cyanoacetate, and ethyl acetoacetate to form compounds 11, 12, and 13. Reaction of 1 with bifunctional reagents, e.g. benzil, o-phenylenediamine, o-aminophenol, and o-aminothiophenol yielding the corresponding imidazolyl bezopyranone and azepine derivatives 14–20. Condensation of 1 with acyclic or heterocyclic compounds containing active methylene group, e.g. hippuric acid forming the condensed products 21–27. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:20–27, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20048

The Condensation of Active Methylene Reagents with Salicylaldehyde: Novel Synthesis of Chromene, Azaanthracene, Pyrano[3,4‐c]chromene and Chromeno[3,4‐c]pyridine Derivatives.

On heating of the cyanoacetic acid cyclopentylidene hydrazide 1 with salicylaldehyde in the presence of bases the azaanthracene derivative 6 was formed. Also, reaction of 3 with malononitrile and ketones 10a,b afforded the pyrano[3,4-c]chromene 9 and chromeno[3,4-c]pyridine 11 respectively. A mechanism for these reactions is proposed.