Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Aliphatic aldehydes in synthesis of 4-alkyl-5-carbamoyl-3-cyano-6-methylpyridine-2(1H)-thiones

Condensation of isovaleric or acetic aldehydes with cyanothioacetamide and acetoacetamide leads to formation of 4-isobutyl(methyl)-5-carbamoyl-3-cyano-6-methylpyridine-2(1H)-thiones. By alkylation of 5-carbamoyl-3-cyano-4,6-dimethylpyridine-2(1H)-thione with 4-methoxyphenacyl bromide, 5-carbamoyl-3-cyano-4,6-dimethyl-2-(4-methoxybenzoyl)methylthiopyridine has been obtained.Lugansk T. G. Shevchenko State Pedagogical Institute, Lugansk 348011, Ukraine. N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 228–229, February, 1999.     

Cyclization of ylidenemalononitriles. X. Synthesis of benzazapropellane derivatives from α-Cyano-β-chloroalkylcinnamonitriles

The reaction of nucleophilic and non-nucleophilic bases wtih 2-carbamoyl-3-(γ-chloropropyl)-1-indenone ( 5 ) have been investigated. Condensation of γ-chlorobutyrophenone with malono-nitrile afforded α-cyano-β-(3-ehloropropyl)cinnamonitrile which was cyclized in concentrated sulfurie acid to produce 5 . Two other products obtained from the cyclization reaction were 2-carbamoyl-3-(γ-ehloropropylidene)-1-indanone ( 4 ) and α-carbamoyl-β-(3-chloropropyl)cinnam-amide. Treatment of a solution of 4 in ethyl acetate with piperidine resulted in cyclization of the γ-chloropropyl side chain to give 2-carbamoyl-3-cycIopropyl-1-indanone. The same compound was obtained in improved yield by the treatment of 4 or 5 with sodium hydroxide solution. The reaction of dirnethylamine with 5 in benzene gave initial Michael addition of the amine followed by internal alkylation of the carbanion so formed to yield 3a-dimethylamino-2,3,3a,8-tetrahydro-8-oxoeyclopent[a]indene-8a(lH)earboxamide ( 7a ). Similarly addition of ammonia, pyrrolidine, piperidine, benzenethiol, p-toluenethiol, 2-naphthalenethiol and nitromethane to the indenone I gave respective analogs of type 7 . Treatment of 5 with sodium cyanide in aqueous t-butyl alcohol resulted in a similar Michael addition followed by internal alkylation. In addition, cyclization between the nitrile and the carbamoyl functions occurred in the same step to give 2-oxo-4-imino-7,8-benzo-3-aza[3.3.3]-propellan-6-one ( 13a ). Hydrolysis of the iminopyrrolido ring in 13a to the corresponding suecin-irnide gave 2,4-dioxo-7,8-benzo-3-aza[3.3.3]propellan-6-one ( 13b ). Reactión of 13b with methyl iodide, allyl bromide, benzyl bromide, and diethyluminoethyl chloride afforded the corresponding N-alkylated products. A similar sequence starling with δ-ehlorovalerophenone led to 5,6-fused ring systems, including a [4.3.3]propellane. 2,9-Dioxo-4-methyl-7,8-benzo-3-aza[4.3.3]propell-4-ene was obtained by the reaction of 5 with acetone in dilute alkali.     

Synthesis of 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones

The reaction of methyl 3-aryl-2-cyano-3-methoxypropenoates 1 with cyanamide and sodium methoxide in methanol afforded after acid hydrolysis the methyl 3-[(aminocarbonyl)amino]-3-aryl-2-cyanopropenoates 4 . By performing the reaction in higher boiling alcohols the 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones 2 were obtained in good yields.     

Synthesis of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3,4′-bipyridine-3′-carboxylic and 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic esters and investigation of their stability. 2. Esters of 6′-carbamoylmethyl-thio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3-carboxylic acids

The stability of solutions of esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoylmethylthio-5′-cyano-4,4′-bipyridine-3′-carboxylic acids,esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H-thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It was established that solutions of the investigated compounds (with mixtures of acetonitrile with phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for one month when the solutions are stored in a place protected against light. It is also necessary to use chromatographic systems in which the aqueous components have pH 3–5 during determination of the purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4, 4′-bipyridine-3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more completely. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 841–848, June, 2007.     

N‐N migration of a carbamoyl group in a pyrazole derivative revealed by NMR

During a synthesis of 5‐amino‐4‐(6‐methoxy‐2‐methylpyridin‐3‐yl)‐3‐methyl‐1H‐pyrazole‐1‐carboxamide (see Scheme 1), a side‐reaction produced 3‐amino‐4‐(6‐methoxy‐2‐methylpyridin‐3‐yl)‐5‐methyl‐1H‐pyrazole‐1‐carboxamide as a by‐product that forms an equilibrium with the target‐compound. The structure of the by‐product was elucidated by the interpretation of 1D and 2D (HMQC, HMBC) NMR data where ¹H‐¹⁵ N HMBC correlations revealed the position of carbamoyl group attachment on the pyrazole. Comparison of structures of the target‐compound and the by‐product showed that the latter resulted from N‐N migration of the carbamoyl group in the target‐compound. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of N-vinyl derivatives of 2-methyl- and 4(5)-methylimidazoles

Conclusions The reaction of 2-methyl and 4(5)-methylimidazoles with acetylene in the presence of Gu₂Cl₂ leads to the corresponding N-vinyl derivatives. 1-Vinyl-4(5)-methylimidazole is formed as a mixture of two isomers differing in the position of the methyl group.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2122–2124, September, 1987.     

Structures of abnormal- and normal-addition 1-pyrazolines produced from 2-cyano-3,3-di-(or mono-)-substituted-acrylates with diazoalkanes

Reactions of methyl 2-cyano-3-methyl-3-(p-substituted-phenyl)acrylates ( 1 ) with 1-phenyldiazoethane ( 2 ) produced the stable abnormal-addition 1-pyrazolines, AP, 4 [1]. The structure of cis-syn- 4a (X = NO₂) was determined by X-ray crystallography. Thermal decomposition of 4 results in “true cycloreversion” to the starting materials. Stereochemistry and decomposition of the normal-addition 1-pyrazolines, NP , produced in situ from 2-cyano-3-(p-substituted-phenyl)acrylates and diazoalkanes, are also discussed.     

Studies on imidazole derivatives and related compounds. I. Synthesis of novel antineoplastic derivatives of 4-carbamoylimidazolium-5-olate

Acylation of 4-carbamoylimidazolium-5-olate ( 2 ) with a variety of acid chlorides produced 4(5)-carbamoyl-1H-imidazol-5-(4)yl acid carboxylates ( 3a-j ). Treatment of esters 3a,c with sodium hydroxide gave imides, 4a,c . Methylation of 3a and 2 with diazomethane gave the N-3 methyl derivative ( 6 ) and a mixture of the N-3, O-dimethyl derivative ( 9 ), the N-1, N-3-dimethyl derivative ( 10 ) and the O-methyl derivative ( 11 ), respectively. 5-Carbamoyl-1-methylimidazolium-4-olate ( 7 ) and its 4-carbamoyl isomer ( 16 ) were prepared from 2-aminopropanediamides 8 and 15 , respectively. Treatment of the imidazolium compound ( 10 ) with aqueous potassium hydroxide gave the recyclized product, 1-methyl-5-methylcarbamoylimidazolium 4-olate ( 18 ). Methyl derivatives 6, 7 , and 9 except 16 demonstrated the complete lack of antitumor activity against Lewis lung carcinoma or sarcoma 180 in mice.     

Synthesis and Photoisomerization of 3-Cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-2-one

The condensation of 4-nitrobenzaldehyde with 3-cyano-4,6,6-trimethyl-5,6-dihydropyran-2-one leads to the formation of a crotonization product and a compound of the Michael adduct type. The main product of the photochemical conversion of (E)-3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-2-one is the Z-isomer. Investigation of the photoisomerization of 3-cyano-6,6-dimethyl-4-(4-nitrophenylvinyl)-5,6-dihydropyran-2-one by the semiempirical AM1 method showed that in the ground state the E-isomer was thermodynamically more stable than the E-isomer. E-Z-photoisomerization is effected most probably through the lowest excited singlet state S₁.     

Synthesis of 3- and 5-amino-5-(3)-(pyrrol-2-yl)isoxazoles

5-Amino-3-(pyrrol-2-yl)isoxazoles were selectively prepared by the reaction of 2-(2,2-dicyano-1-ethylthioethenyl)pyrroles with hydroxylamine in methanol. Under analogous conditions, 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl) pyrroles with hydroxylamine gave 5-aminoisoxazoles and their structural isomers, 3-aminoisoxazoles (3-5% yield). The latter were selectively prepared by reacting 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles with hydroxylamine in the presence of aqueous NaOH and from the products of intramolecular cyclization of 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles, 1-ethylthio-3-iminopyrrolizines and hydroxylamine.     

Stereoselective synthesis and structure of 3,4-trans-6-amino-4-aryl-3-carbamoyl-5-cyano-1,2,3,4-tetrahydropyridin-2(1H)-thiones

Condensation of thiocarbamoylacetamide with arylidenemalononitrile or the three-component condensation of thiocarbamoylacetamide with aldehydes and malononitrile in the presence of triethylamine occurred regioselectively to give triethylammonium-6-amino-4-aryl-3-carbamoyl-5-cyano-1,4-dihydropyridine-2-thiolates. Protonation of the latter occurred stereoselectively to give 3,4-trans-6-aryl-3-carbamoyl-5-cyano-1,2,3,4-tetrahydropyridin-2(1H)-thiones. The¹H NMR spectrum and single x-ray crystallography indicate that the dihydropyridine ring has he sofa conformation with trans-pseudodiaxial orientation of the Ar and CONH₂ groups and trans-pseudoequatorial orientation of atoms 3-H and 4-H.N. D. Zelinskii Organic Chemistry Institute, Russian Academy of Sciences, Moscow, 117913. A. N. Nesmeyanov Institute of Elementoorganic Chemistry, Russian Academy of Sciences, Moscow, 117813. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1376–1382, Octoberm 1996. Original article submitted June 10, 1996.     

Synthesis of Ammonium 5-Arylcarbamoyl-4-heteryl-6-methyl-3-cyano-1,4-dihydropyridine-2-thiolates and 4-Heteryl-5-carbamoyl-6-methyl-3-cyano-1,4-dihydropyridine-2-selenolates

The condensation of enamines derived from acetoacetanilides, heterocyclic aldehydes, and cyanothioacetamide yielded ammonium 5-arylcarbamoyl-5-heteryl-6-methyl-3-cyano-1,4-dihydropyridine-2-thiolates, which were subsequently used for the synthesis of substituted 2-alkylthio-1,4-dihydropyridines, 2-alkylthiopyridines, and thieno[2,3-b]pyridines. The reaction of acetoacetamide with heteroaromatic aldehydes and cyanoselenoacetamide in the presence of N-ethylmorpholine yielded N-ethylmorpholinium 4-heteryl-5-carbamoyl-6-methyl-3-cyano-1,4-dihydrolyridine-2-selenolates, from which substituted 2-alkylseleno-1,4-dihydropyridines were prepared.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 3, 2005, pp. 483–492.Original Russian Text Copyright © 2005 by Dyachenko.     

Reactions 1-acetyl-3-oxo-2,3-dihydroindole with alkyl 2-cyano-3-alkoxypropenoate and alkyl 2-alkoxycarbonyl-3-alkoxy-propenoate. Synthesis of 9-acetoxypyrrolo[1,2-a]indol-3-one derivatives

1-Acetyl-3-oxo-2,3-dihydroindole reacted with methyl 2-cyano-3-methoxypropenoate and ethyl 2-cyano-3-ethoxypropenoate in the presence of sodium hydride, affording compounds 3 (2-(2-cyano-2-alkoxycarbonyl-vinyl)-3-hydroxyindole). Methyl 2-methoxycarbonyl-3-methoxypropenoate gave compounds 4 or compounds 5 (in the presence of Triton B). Heating compounds 3 or their acetylated derivatives in acetic anhydride at reflux afforded 9-acetoxy-(3H)-pyrrolo[1,2-a]indol-3-one 8 .     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Synthesis of pyrimidine derivatives by the reaction of ketene dithioacetals with amides

Reactions of methyl 2-cyano-3,3-bis(methylthio)acrylate ( 1a ) with carboxamides 2a-g in the presence of sodium hydride in a mixture of benzene and N,N-dimethylacetamide took place displacement with the methylthio group to give the corresponding methyl 3-N-acylamino-2-cyano-3-(methylthio)acrylates 3a-g which were readily converted to the corresponding pyrimidine derivatives at reflux in methanol in good yields. Reactions of 2-cyano-3,3-bis(methylthio)acrylonitrile ( 1b ) with the carboxamides 2a-f gave directly pyrimidine-5-carbonitrile derivatives 7a-f . Ketene dithioacetals 1a,b smoothly reacted with thioamide 2g or urea 2h,i to give the expected pyrimidine derivatives 9,10a,b . Polyfunctionalized pyrimidines, thus obtained, were also used for the synthesis of fused pyrimidine derivatives.     

Structures and fluorescence of secondary products produced from the cope-knoevenagel reaction of 2-phenylpropionaldehyde with methyl cyanoacetate

The Cope-Knoevenagel reaction of 2-phenylpropionaldehyde ( 7 ) with methyl cyanoacetate ( 8 ) produced methyl (E)-2-cyano-4-phenylpent-2-enoate ( 9 ) and the two highly fluorescent secondary products, 2-amino-3-carbomethoxy-6-phenyl-4-(1-phenylethyl)pyridine ( 10 ) and 3-cyano-6-phenyl-4-(1-phenylethyl)-2-pyridone ( 11 ). The structure of 10 was determined by X-ray crystallography while the structure of 11 was confirmed by the conversion of 9 into 11 . The mechanism of their formation is discussed. Fluorescence of 10 and 11 and the related compounds are also described.     

Organocatalytic clean synthesis of densely functionalized 4H-pyrans by bifunctional tetraethylammonium 2-(carbamoyl)benzoate using ball milling technique under mild conditions

A green and simple method has been developed for efficient preparation of diverse annulated 2-amino-3-cyano-4H-pyran derivatives in the presence of a low loading of tetraethylammonium 2-(carbamoyl)benzoate (TEACB), as a bifunctional organocatalyst, under solvent-free conditions using the ball milling technique. This procedure is a clean, transition-metal-free, and environmentally friendly approach that offers many advantages including short reaction times, high to quantitative yields, low cost, and straightforward work-up.     

Reactions of 3-oxo-2,3-dihydrobenzofuran with alkyl 2-cyano-3-alkoxypropenoate and alkyl 2-alkoxycarbonyl-3-alkoxypropenoate. Synthesis of pyran derivatives

3-Oxo-2,3-dihydrobenzofuran reacted with ethyl 2-cyano-3-ethoxypropenoate, methyl 2-cyano-3-methoxy-propenoate affording compounds 3 (2-(2-cyano-2-alkoxycarbonylvinyl)-3-hydroxybenzofuran) obtained as a mixture of Z + E isomers. Methyl 2-methoxycarbonyl-3-methoxypropenoate gave compound 4 . Malonic compounds added on 2-dimethylaminomethylene-3-oxo-2,3-dihydrobenzofuran 6 for giving compound 3 or 2-oxo-3-methoxycarbonyl-2H-pyrano[3,2-b]benzofuran 8 . Compound 8 was also obtained by heating compound 4 in xylene.     

Reaction of 2-methylquinoline with 3-phenylprop-2-ynenitrile in the KOH—H<Subscript>2</Subscript>O system

The reaction of 2-methylquinoline with 3-phenylprop-2-ynenitrile in the presence of water (0—25 °C, 20 mol.% KOH, 5 equiv. H₂O) is accompanied by the loss of aromaticity of the quinoline nucleus and results in double functionalization of the molecule at the nitrogen atom and the methyl group. Two 2-cyano-1-phenylethenyl groups were introduced into the molecule to form (2E,4E)-4-{1-[(Z)-2-cyano-1-phenylethenyl]quinolin-2(1H)-ylidene}-3-phenylbut-2-enenitrile in 59—67% yield. This reaction is stereoselective: the N-2-cyano-1-phenylethenyl-substituent has the Z-configuration, while the 1,3-diene moiety at the methyl group has the E,E-configuration. (2E)-3-Phenyl-4-(quinolin-2-yl)but-2-enenitrile that formed as a by-product (0—24% yields) is formally the addition product of the methyl group of the quinoline substrate at the acetylenic bond.