Facile Synthesis of Nicotinic Acid Derivatives with Unsymmetrical Substitution Patterns

Abstract

Two novel methods for synthesis of nicotinic acid derivatives with unsymmetrical substitution patterns were presented via ketene dithioacetals. The ketene N,S-acetals 2 reacted with β-ketoesters or β-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthio-nicotinic acid derivatives 3 or 2,4-diamino-5-cyano-6-methylthio-nicotinic acid ethyl ester 4. However, 6-amino-5-cyano-2-alkyl-4-methylthio-nicotinic acid esters 6 were obtained by the reaction of the ketene dithioacetals 1 and β-amino-crotonates.     

Reactions of 4-dicyanomethylenepyrans with hindered primary amines

The reaction of 2,6-dimethyl- and 2,6-diphenyl-4-dicyanomethylene-4H-pyran with hindered primary amines such as isopropylamine and cyclohexylamine gave 1-alkyl-2-amino-3-cyano-6-rnethyl(or phenyl)-4-acetonylidene (or phenacylidene)-1,4-dihydropyridine derivatives. The 6-methyl-4-acetonylidene examples underwent a facile thermal rearrangement to give 1-alkyl-2,6-dimethyl-4-dicy anomethy lene-1,4-dihydropy ridines. Several reactions of the acylidene derivatives are described.     

Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells

Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino- 6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1- pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2- yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl S-nucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Imidazo[1,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole derivatives: XXVIII. Syntheses and heterocyclizations on the basis of 1-allyl-2-aminobenzimidazole

Addition of hydrogen bromide at the double bond of 1-allyl-2-amino-1H-benzimidazole and 3-alkyl-(benzyl)-1-allyl-2-amino-1H-benzimidazolium halides was studied. The resulting 1-(2-bromopropyl) derivatives were subjected to thermolysis under different conditions, and the structure of dehydrobromination products was determined and proved by independent synthesis via prototropic isomerization of the allyl group by the action of bases.     

The reactions of some ortho-substituted anilines with various α,β-acetylenic ketones. A route to substituted quinolines

The reactions of some ortho-substituted anilines with various α,β-acetylenic ketones were investigated as a route to 4-alkyl-, 4-aryl-, 4-hydroxy-, and 4-amino-3-quinolyl ketones. The anilines examined were 2-aminoacetophenone ( 1 ), 2-aminobenzophenone ( 2 ), anthranilonitrile ( 3 ), methyl anthranilate ( 4 ), and ethyl anthranilate ( 5 ). The acetylenic ketones used were 1,4-diphenyl-2-butyne-1,4-dione ( 6 ), 3-butyn-2-one (7), 1,3-diphenyl-2-propyn-1-one ( 8 ), and 4-phenyl-3-butyn-2-one ( 9 ). The acetylenic ketones typically reacted with the anilines to give enamines; however, exceptions were found. Acetylene 6 reacts with 3 to give the enamine ( 13 ) along with a small amount of 2,3-dibenzoyl-4-quinolamine ( 14 ). The reactions of 1 or 2 with 6 give the respective quinoline derivatives directly. Acetylene 8 reacts with 2 to give 3-benzoyl-2,4-diphenylquinoline ( 22 ) directly, whereas no reaction occurs between 8 and 1 or 3 . Acetylene 9 does not react with 1, 2 , or 3 . The enamines exist as the intramolecularly hydrogen bonded isomers and usually undergo cyclization with 5 molar equivalents of methanolic sodium methoxide to give quinoline derivatives. The 4-quinolinols exist predominantly as the 4-quinolinone tautomer.     

Nanosized magnesium oxide as a highly effective heterogeneous base catalyst for the rapid synthesis of pyranopyrazoles via a tandem four-component reaction

A four-component reaction of hydrazine hydrate or phenyl hydrazine, ethyl 3-alkyl-3-oxo propanoate, aldehydes and malononitrile has been achieved in the presence of nanosized magnesium oxide as a highly effective heterogeneous base catalyst to produce of 6-amino-3-alkyl-4-aryl-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole derivatives in excellent yields and in a short experimental time. This method is simple and rapid for focusing a pyrano ring with a pyrazole ring.     

3-甲基-2(1H)-喹喔啉系列衍生物的电子轰击质谱

用电子轰击质谱（EI－MS）研究了1－烷基－3－甲基－2（1H）－喹喔啉－2－酮（烷基为H，CH3，Et,n-C5H11),1-烷基－3－甲基－6－硝基－2（1H）－喹喔啉－2－酮（烷基为CH3，Et)和1－甲基－3－甲基－6－胺基－2（1H）－喹喔啉－2－酮，结合其结构特征总结出一些裂解规律。讨论了不同取代基对这类化合物熔点的影响，结果表明：在同类喹喔啉化合物中，随着烷基链的增长，样品熔点通常会有所降低，而硝基及胺基的引入会使其熔点升高。     

Condensed isoquinolines. 38*. Azolo[<Emphasis Type="Italic">b</Emphasis>]isoquinolines from 2-(halomethyl)benzoic acid derivatives

On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with 1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of which with bases (K₂CO₃, Et₃N) led to the intramolecular acylation products, 1-alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium halides, 5-alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium halides, or 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate halides.     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with amines and hydrazines. A new and efficient synthetic approach to 3-amino-5,8-dichloroflavazoles

Reactions of 5,8-dichloro-2,3-dicyanoquinoxaline with primary amines and hydrazines under different experimental conditions were investigated. Alkylamines provided novel 3-alkylamino-5,8-dichloro-2-cyanoquinoxalines and N-alkyl-(5,8-dichloro-3-alkylamino-2-quinoxalinyl)carboxamidines in high yields. Alkylhydrazines and lithium arylhydrazinides gave previously unattainable 1-alkyl-3-amino-5,8-dichloroflavazoles and 3-amino-1-aryl-5,8-dichloroflavazoles in good to near quantitative yields whose molecular structure was confirmed by X-ray crystallography of 3-[N,N-bis(4-chlorobenzoyl)amino]-5,8-dichloro-1-phenylflavazole. Reaction with hydrazine gave 5,8-dichloro-3-hydrazino-2-quinoxalinylcarboxamidrazone quantitatively, which was converted to the parent compound of this class of flavazoles, 3-amino-5,8-dichloroflavazole, in high yield by a pyrolytic process involving loss of hydrazine.     

Syntheses and reactions of some 1-substituted-7-alkyl-2-thioxopurines: X-Ray structure of 6-methylamino-7-nonyl-2-thioxopurine

Several 1-substituted-7-alkyl-2-thioxopurines 8,9,10 were synthesized by the reaction of isothiocyanates with 1-alkyl-4-amino-5-cyanoimidazoles 3 . Treatment of 3 with methyl isothiocyanate gave the Dimroth rearranged product 6-methylamino-7-alkyl-2-thioxopurines 11 . The structure of 11 was unambiguously defined by X-ray crystallography.     

General and modular synthesis of isomeric 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides bearing diverse alkyl, aryl, hetaryl, amino, carbamoyl, and hydroxy groups

A general modular and practical methodology for preparation of diverse 5-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-ribonucleosides was developed. Regioselective lithiation of 2,5-dibromopyridine proceeded at position 5 or 2 depending on the solvent, and the resulting bromopyridyl lithium species underwent additions to TBS-protected ribonolactone and follow-up transformations to corresponding acetylated hemiketal intermediates 7 and 10 that were diastereoselectively reduced to give either 5-bromopyridin-2-yl or 6-bromopyridin-3-yl silyl-protected C-ribonucleosides 8 or 11 in 68% and 77% overall yields as pure β-anomers. These bromopyridyl C-nucleoside intermediates were then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, aminocarbonylations, and hydroxylations to give a series of protected 1β-(5-alkyl-, 5-aryl-, 5-amino-, 5-carbamoyl-, and 5-hydroxypyridin-2-yl)-C-ribonucleosides 13a-i and β-(6-alkyl-, 6-aryl-, 6-amino-, 6-carbamoyl-, and 6-hydroxypyridin-3-yl)-C-ribonucleosides 15a-i. Deprotection of silylated nucleosides by Et(3)N·3HF, TBAF, or TFA gave a series of free C-nucleosides 14a-i and 16a-i.     

Acid catalyzed α-alkylation of β-aminothiophenes with aldehydes. synthesis of 2-alkyl 3-thiophenamines,bis(3-amino-2-thienyl)-methane derivatives and dithieno[3,2-b:2′,3′-e]pyridines

The acid catalyzed reaction of 3-thiophenamines with aldehydes in the presence of selenophenol as the reducing agent, gives 2-alkyl-3-miophenamines. Without reduction, bis(3-amino-2-thienyl)methane derivatives have been obtained and transformed into dithieno[3,2-b:2′,3′-e]pyridines by thermal and acidic treatment when the substrates are primary amines. These new tricyclic heterocycles can be synthesized in a one-pot procedure from 3-thiophenamine.     

Amidrazones 9. Convenient Syntheses of 1-Alkyl-1-Phenylhydrazines and α,β-Unsaturated Amidrazones Via Base-Promoted Reactions of 1,1-Disubstituted-3-Amino-4,5-Dihydro-1H-Pyrazolium Salts

A simple, efficient procedure for the conversion of phenylhydrazine to 1-alkyl-1-phenylhydrazines via base-promoted hydrolysis of 1-alkyl-3-amino-4,5-dihydro-1-phenyl-1H-pyrazolium iodides (2) is described. N¹, N¹-disubstituted hydrazones of trans-cinnamamide and acrylamide are obtained by Hofmann-type ring openings of 1,1 -disubstituted-3-amino-4,5-dihydro-5-phenyl (or 5-unsubstituted) -1H-pyrazolium halides (5, 7).     

Synthesis and properties of symm-triazines. 3. Reactions of 2-alkyl-4,6-bistrichloromethyl-symm-triazines containing higher alkyl groups with ammonia and aliphatic amines

The reaction of 2-alkyl-4,6-bistrichloromethyl-symm-triazines containing higher alkyl groups with ammonia or aliphatic amines results, depending on the reaction conditions, in the replacement of one or both trichloromethyl groups. On heating these symm-triazines with aqueous ammonia or dimethylamine, 2-oxo-4-amino-6-alkyl-1(3)H-symm-triazines are obtained.For communication 2, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1557–1563, November, 1985.     

<Emphasis Type="Italic">N</Emphasis>-acylimino-substituted 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes in the synthesis of 3-(1<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazol-3-yl)-3<Emphasis Type="Italic">H</Emphasis>-pyrrole-4-carbonitriles

Reaction with phenylhydrazine of 3Н-pyrroles spirobound to a furan ring, N-acylimino-substituted 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes, occurs with a diasteroselective formation of previously unknown derivatives of 1,2,4-triazole: 5-amino-3-(5-alkyl-1-phenyl-1H-1,2,4-triazol-3-yl)-2-morpholin-4-yl-3H-pyrrole-4-carbonitriles.     

Reaction of 1-(tetracyanocyclopropyl)alkanones with sodium and potassium hydroxides

Enolizable 1-(tetracyanocyclopropyl)alkanones reacted with aqueous alkali metal hydroxides to give, depending on the alkali concentration, 2-(5-amino-2-alkylidene-4-cyano-2,3-dihydrofuran-3-ylidene)-propanedinitriles or 2-(4-alkyl-3-amino-2-cyano-5-oxo-cyclopent-2-en-1-ylidene)propanedinitriles.     

Synthesis of new liquid-crystalline compounds from the 3-aryl-5-alkylpyrazole series

A method was developed for the preparation of new liquid-crystalline substances, pyrazole derivatives, through the corresponding 2-isoxazolines and isoxazoles. The hydrogenolysis of the heterocycle in 3-(4-hydroxyphenyl)-5-amylisoxazole afforded 1-amino-1-(4-hydroxyphenyl)-1-octen-3-one. The acid hydrolysis of the compound followed by treating with hydrazine hydrate resulted in 5-amyl-3-(4-hydroxyphenyl)-1H-pyrazole, whose benzylation and esterification with the corresponding mesogenous benzyl chlorides and benzoyl chlorides provided liquid-crystalline 5-alkyl-3-aryl-1H-pyrazoles.     

Novel Approaches to Synthesis of 4-Alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles

We have obtained 4-alkyl-6-amino-5-cyano-3-methyl(propyl, phenyl)-2H,4H-pyrano[2,3-c]pyrazoles by reaction of 4-alkylmethylene-3-substituted 5-pyrazolones with malononitrile or cyanothioacetamide. We have used X-ray diffraction to study the structure of 6-amino-5-cyano-4-isopropyl(hexyl)-3-phenyl-2H,4H-pyrano[2,3-c]pyrazoles.