Synthesis of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile by condensation of cyanothioacetamide with acetaldehyde and 1-(prop-1-en-2-yl)piperidine

Three-component condensation of cyanothioacetamide with acetaldehyde and 1-(prop-1-en-2-yl)-piperidine afforded 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile which was alkylated with alkyl halides to obtain substituted 2-alkylsulfanyl-4,6-dimethylpyridine-3-carbonitriles, (3-amino-4,6-dimethylthieno-[2,3-b]pyridin-2-yl)(4-cyclohexylphenyl)methanone, and 2,2′-[ethane-1,2-diylbis(sulfanediyl)]bis(4,6-dimethylpyridine-3-carbonitrile).     

Synthesis of 3-substitued 5-(2-thienyl)isoxazoles

The reaction of 3,4,4-trichloro-1-(2-thienyl)but-3-en-1-one with hydroxylamine gave 3-hydroxyiminomethyl-5-(2-thienyl)isoxazole which was converted into 5-(2-thienyl)isoxazole-3-carbonitrile by the action of acetic anhydride in pyridine. 5-(2-Thienyl)isoxazole-3-carbonitrile reacted with hydroxylamine to produce the corresponding amide oxime. Heterocyclization of its O-acyl derivatives in acetic acid afforded 5-substituted 3-[5-(2-thienyl)isoxazol-3-yl]-1,2,4-oxadiazoles.     

Pyrolysis of aminonitriles,cyanohydrazones, and cyanoacetamides. Part I. Elimination reaction of 1-arylmethyleneamino-1,2-dihydro-4,6-dimethyl-2-oxopyridine-3-carbonitriles and substituted benzaldehyde cyanoacetylhydrazones

Pyrolysis of the Schiff bases of 1-arylmethyleneamino-1,2-dihydro-4,6-dimethyl-2-oxopyridine-3-carbonitriles (1–5) has been studied. These compounds eliminate via a six-membered transition state to produce substituted benzonitriles and 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile. These eliminations are unimolecular first-order reactions. The kinetic data gave a good correlation with σ⁰ values of the substituents on the aryl group with ρ = 0.83 at 520 K. Utilization of the pyrolytic reaction in synthesis of various benzonitriles is considered, and mechanistic information has been obtained by comparing the kinetic data and product analysis of the Schiff bases with their open-chain substituted benzaldehyde cyanoacetylhydrazones (6–9) analogues. © 1996 John Wiley & Sons, Inc.     

Synthesis of some fused heterocycles based on thieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine and their antimicrobial activity

The reaction of 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile with ethylenediamine in the presence of a catalytic amount of carbon disulfide afforded 2-(4,5-dihydro-1H-imidazol-2-yl)-4,6-dimethylthieno-[2,3-b]pyridine-3-amine while its reaction with triethyl orthoformate followed by the reaction with hydrazine hydrate gave 4-imino-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-3(4H)-amine. These two derivatives underwent cyclocondensation reactions with commercially available reactants to afford new heterocycles containing the thieno[2,3-b]pyridine moiety. Some of the synthesized derivatives were tested for antimicrobial and antifungal activity.     

Functional Derivatives of Ethyl 4-(Chloromethyl)-2,6-dimethylpyridine-3-carboxylate

The condensation of ethyl 4-(chloromethyl)-2,6-dimethylpyridine-3-carboxylate with substituted phenols in ethanol in the presence of potassium carbonate afforded the corresponding aryl pyridin-4-ylmethyl ethers. Analogous condensation with substituted anilines gave 2-aryl-4,6-dimethyl-1,2-dihydropyrrolo[3,4-c]- pyridin-3-ones. Esters containing 1,2-azole fragments were synthesized by acylation of hydroxymethylsubstituted ethers with 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carbonyl chlorides.     

Novel synthesis and reactions of 5,7-dialkyl-4,6-dioxo-4,5,6,7-tetrahydro- isothiazolo[3,4,-d]pyrimidine-3-carbonitriles and 6-methyl-4-oxo-4H-1-aza-5-oxa-2- thiaindene-3-carbonitrile

[reaction: see text] 5,7-Dialkyl-4,6-dioxo-4,5,6,7-tetrahydroisothiazolo[3,4-d]pyrimidine-3-carbonitriles 4, prepared from 6-amino-1,3-dialkyluracils 3 and 4,5-dichloro-5H-1,2,3-dithiazolium chloride (Appel's salt) 1, are utilized for the preparation of new derivatives of 4 bearing amino, alkylthio, amido, thioamido, tetrazolyl, and carboximidic acid ethyl ester groups at position 3. Similarly, the reactions of 6-methyl-4-oxo-4H-1-aza-5-oxa-2-thiaindene-3-carbonitrile 8, prepared from 4-amino-6-methyl-2-pyrone 6 and 1, with alkyl- and arylamines in DMF at 50 degrees C and reflux afforded different isothiazole derivatives 11 and 17, respectively. On the other hand, treatment of 8 with 1,3-diaminopropane in THF at room temperature, followed by chromatography on silica gel, gave 3-(2-oxopropyl)-6,7,8-trihydro-4H-1-thia-2,5,9-triazacyclopentacyclononene-4,10-dione 12 in 59% yield.     

Isothiazoles. III. Synthesis of isothiazolo [5,4-d] pyrimidines

5-Amino-3-methylisothiazole-4-carbonitrile 2 was prepared by oxidation of 3-amino-2-cyano-thiocrotonamide 1 . A series of 4-amino-3-methylisothiazolo[5,4-d]pyrimidines 6 was derived from 2 by reaction with orthoesters followed by cyclization with primary amines. Hydrolysis of 2 to the corresponding amide 10 followed by cyclization with orthoesters gave the corresponding 5H-isothiazolo[5,4-d]pyrimidin-4-ones 11 . Reactions of 2 and 10 with sodium methyl xanthate gave the corresponding pyrimidinethione derivatives 12 and 13.     

Some Reactions with 3-(2-Chloro-7-Methylquinolinyl) Chalcone Derivatives

The preparation of some new 3-quinolinylchalcone derivatives was described. Their reaction with hydrazines, hydroxylamine hydrochloride, malononitrile and ethyl cyanoacetate gave the corresponding pyrazoline, isoxazoline, cyanopyridine and cyanopyridone derivatives, respectively. The biological activity of some of the products was evaluated.     

Synthesis and Some Chemical Transformations of Adamantyl-Substituted Pyrazolones

1-Substituted 3-(1-adamantyl)-4,5-dihydro-1H-pyrazol–5-ones and 3-(1-adamantyl)-4,5-dihydroiso-xazol-5-one were synthesized by reaction of ethyl 3-(1-adamantyl)-3-oxopropanoate with various hydrazine derivatives and hydroxylamine hydrochloride. Nitrosation of adamantyl-substituted pyrazolones with sodium nitrite in acetic acid gave the corresponding 4-hydroxyimino derivatives. Reactions of 3-(1-adamantyl)-4,5-di-hydro-1H-pyrazol–5-ones and 3-(1-adamantyl)-4,5-dihydroisoxazol–5-one with aromatic and heterocyclic aldehydes led to the formation of condensation products at position 4 of the heteroring.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Synthesis of derivatives of 2-aminoimidazole and 2-iminoimidazolidine by cyclization of 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines with α-bromocarbonyl compounds

Cyclization of 1-aryl-2-(4,6-dimethylpyrimidin-2-yl)guanidines with α-bromoacetophenone and ethyl bromoacetate gave derivatives of 1,4-diphenyl-1H-imidazole-2-amine and 2-amino-1-phenylimidazolidin- 4-one respectively. The mechanism of the reaction was determined on the basis of quantum-chemical calculations, NOESY NMR spectroscopy, and X-ray crystallography.     

Synthesis and hydrazinolysis of β-(1,3,4-oxadiazol-2-yl)pyridines

Cyclization of the hydrazide of 5-ethoxycarbonyl-2,6-dimethylpyridine-3-carboxylic acid by acylation with aromatic or aliphatic acid chlorides with subsequent boiling in POCl₃ or heating in orthoformic acid gave the corresponding ethyl 2,6-dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate. The cyclization of the reaction products with hydrazine hydrate has been studied. Cyclization of the dihydrazide of 2,6-dimethyl-3,5-pyridinedicarboxylic acid under analogous conditions gave only 3,5-bis-(5-R-1,3,4-oxadiazol-2-yl)-2,6-dimethylpyridines, containing R = 2-FC₆H₄, H.     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Synthesis of 2-substituted 3,4-bis(diethoxyphosphorylmethyl)furans

Bromination of ethyl 4-(diethoxyphosphorylmethyl)-5-methylfuran-2-carboxylate and 4-(diethoxyphosphorylmethyl)-5-methylfuran-2-carbonitrile with N-bromosuccinimide followed by phosphorylation via the Arbuzov reaction have yielded the corresponding 2-substituted 4,5-bis(diethoxyphosphorylmethyl)furans. Synthesis and transformations of bisphosphorylated 2-furoic acid and its derivatives are described.

     

Synthesis of bromodifluoromethyl substituted pyrazoles and isoxazoles

Bromodifluoromethyl substituted β-diketone 3a-3d, prepared from corresponding ketones and ethyl bromodifluoroactate in the presence of sodium methoxide, reacted with aryl hydrazine derivatives affording bromodifluoromethyl substituted pyrazoles in high regioselectivity. The reaction of 3a-3d with hydroxylamine hydrochloride gave dihydroisoxazoles, which afforded bromodifluoromethyl substituted isoxazoles through dehydration by PPA or concentrated sulfuric acid.     

Synthesis of new condensed and cyclized coumarin derivatives

Condensation of 4-chloro-2-oxo-2H-chromene-3-carbonitrile with selected heteroarylamines in acetonitrile containing a catalytic amount of triethylamine, followed by intramolecular cyclization, gave the new coumarin derivatives with yields ranging from 43 % to 78 %. The novel compounds were subjected to acid hydrolysis giving the corresponding oxo derivatives in 66–70 % yield. The structural assignments of the synthesized compounds were based on elemental, IR, ¹H and ¹³C NMR analyses.     

Reduction and diazotization of ethyl 7-amino-3-<Emphasis Type="Italic">tert</Emphasis>-butyl-4-oxo-4,6-dihydropyrazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazine-8-carboxylate

The ester group in ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate was converted for the first time to methyl by the action of lithium tetrahydridoborate in the presence of boron trifluoride–diethyl ether complex. This reaction has almost no analogies among other classes of organic compounds. New difficultly accessible 7-chloro and 7-azido derivatives were synthesized via diazotization of the reduction product, and treatment of the latter with acetic anhydride afforded the exhaustively acetylated derivative. Diazotization of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo-[5,1-c][1,2,4]triazine-8-carboxylate, followed by reaction with sodium azide, gave the corresponding azide, and the product of azo coupling with ethyl acetoacetate failed to undergo intramolecular cyclization to tricyclic pyrazolo[3,2-c: 5,1-c′]bis[1,2,4]triazine system.     

Synthesis of new mesogens of the 3-arylisoxazolone and 3-arylpyrazolone series

Acylation of ethyl acetoacetate with mesogenic para-substituted benzoyl chlorides, followed by cleavage of ethyl aroylacetoacetates thus obtained under basic conditions, gave the corresponding ethyl 3-aryl-3-oxopropanoates which were brought into condensations with hydroxylamine and hydrazine to obtain mesogenic 3-arylisoxazolones and 3-arylpyrazolones, respectively.     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

Synthesis of 2-methylthioindolizine-3-carbonitriles using nitro ketene dithioacetal

The reaction of 1-cyanomethylpyridinium chloride or bromide, 1a-i , with 1,1-bis(methylthio)-2-nitroethylene ( 2 ) in the presence of triethylamine as a base in ethanol gave the corresponding 2-methylthioindolizine-3-carbonitrile 3 and 2-methyl-thio-1-nitroindolizine-3-carbonitrile 4 in good yields, respectively. Compounds 3a,f were key intermediates for the synthesis of cycl[3.2.2]azine derivatives.