Conversion of 6-phenylimino-2H-thiopyran-4-amines to 1-phenyl-2,3-dihydro-4(1H)-pyridinones

Summary 6-Phenylimino-3,6-dihydro-2H-thiopyran-4-amines (1) were converted to 1-phenyl-5,6-dihydropyridine-2(1H)-thiones (3). Those were akylated and hydrolyzed, thus yielding 6-methylthio-1-phenyl-2,3-dihydro-4(1H)-pyridinones (5). Finally, the methylthio group was removed withRaney nickel giving the title compounds6. The relative configurations of the formed diastereoisomeric dihydropyridinones have been investigated by NOE measurements.

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Umwandlung von 6-Phenylimino-2H-thiopyran-4-aminen zu 1-Phenyl-2,3-dihydro-4(1H)-pyridinonen

Zusammenfassung 6-Phenylimino-3,6-dihydro-2H-thiopyran-4-amine (1) wurden in 1-Phenyl-5,6-dihydropyridin-2(1H)-thione (3) umgewandelt. Diese wurden alkyliert und zu 6-Methylthio-1-phenyl-2,3-dihydro-4(1H)-pyridinonen (5) hydrolysiert. Zuletzt gelangte man durch selektives Entfernen der Methylthiogruppe mitRaney-Nickel zu den Titelverbindungen6. Die relativen Konfigurationen der gebildeten diastereomeren Dihydropyridinone wurden durch NOE-Messungen aufgeklärt.

     

Cycloaddition reactions of 1-tert-butyl-4-vinylpyrazole

Summary 1-tert-Butyl-4-vinylpyrazole1 a reacts with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate (MP) and N-phenylmaleimide (NPMI) affording the indazole derivatives2,3, and5 as a result of a Diels-Alder ([4 + 2]) cycloaddition. With diethylazodicarboxylate (DEAZD), tetracyanoethylene (TCNE) and 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) the reaction takes place exclusively through the olefinic substituent and the adducts6,7, and9 were isolated. The alkenylpyrazoles1 b–d reacted withDMAD and N-phenylmaleimide to give polymers.

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Cycloadditionen von 1-tert-Butyl-4-vinylpyrazol

Zusammenfassung 1-tert-Butyl-4-vinylpyrazol1 a reagiert mit Acetylendicarbonsäure-dimethylester (DMAD), Propiolsäuremethylester (MP) und N-Phenylmaleimid (NPMI) zu den entsprechenden Indazolderivaten2,3 bzw.5, als Ergebnis einer Diels-Alder-([4+2])-Cycloaddition. Bei der Reaktion mit Azodicarbonsäure-diethylester (DEAZD), Tetracyanethylen (TCNE) und 4-Phenyl-1,2,4-triazol-3,5-dion (PTAD) wird exklusiv die Olefingruppe von1 a angegriffen, wobei die Addukte6,7 bzw.8 isoliert werden. Die Alkenylpyrazole1 b–d reagieren mitDMAD und N-Phenylmaleimid unter Bildung von Polymeren.

     

Synthesis and selected transformations of 1-(5-methyl-1-aryl-1H-1,2,3-triazol-4-yl)ethanones and 1-[4-(4-R-5-methyl-1H-1,2,3-triazol-1-yl)phenyl]ethanones

By cycloaddition of arylazides to acetylacetone are obtained derivatives of 1,2,3-triazole. In the reaction of 1-[5-methyl-1-(R-phenyl)-1H-1,2,3-triazol-4-yl] ethanones (IIa–IIe) and 1-[4-(4-R-5-methyl-1H-1,2,3-triazol-1-yl)phenyl] ethanones (VIIa-VIIe) with isatin are obtained 2-[1-(R-phenyl)-5-methyl-1H-1,2,3-triazol-4-yl]-4-quinolinecarboxylic acids (IIIa–IIIe) and 2-[4-(4-R-5-methyl-1H-1,2,3-triazol-1-yl)phenyl] -4-quinolinecarboxylic acids (IXa, IXb), respectively. We found that 1-[5-methyl-1-(R-phenyl)-1H-1,2,3-triazol-4-yl] ethanones (IIa–IIe) readily transform into [5-methyl-1-(R-phenyl)-1H-1,2,3-triazol-4-yl] acetic acids (IVa–IVc) by the method of Wilgerodt-Kindler. The (5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)acetic acid reacts with 5-phenyl-4-amino-4H-1,2,4-triazol-3-thiol affording 6-[(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl) methyl]-3-phenyl[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazole (VI). Original Russian Text ? N.T. Pokhodylo, R.D. Savka, V.S. Matiichuk, N.D. Obushak, 2009, published in Zhurnal Obshchei Khimii, 2009, vol. 79, no. 2, pp. 320–325.     

Über 4-Alkylamino-bzw. 4-Arylamino-5,6-dihydro-2(1H)-pyridinthione

Heating 1-alkyl- or 1-aryldihydro-6-methyl-2(1H)-pyrimidinethiones5, 6 in an inert medium causes rearrangement to 4-alkylamino-(4-arylamino-)-5,6-dihydro-2(1H)-pyridinethiones11, 12, probably via the methylene form29, by thermal heterolysis of the N₁/C₂ bond and exchange of the alkylamino (arylamino) group 1 through the carbon atom of the methylene group 6. The aminodihydropyridinethiones11, which can be regarded as cyclic derivatives of 3-aminothiocrotonamide, react with bistrichlorophenylmalonate under diacylation, and with formaldehyde and primary amines to yield aminodialkylation products of the enamine system, tetrahydro-4-hydroxy-7,7-dimethyl-5-thioxopyrido[4,3-b]pyridine-2(1H)-ones13, 14 and hexahydro-7,7-dimethylpyrido[4,3-d]pyrimidine-5(6H)-thiones18, 19, 21 respectively. H₂O₂ converts11 to the corresponding 4-aminodihydro-2(1H)-pyridones22, which can be reconverted into11 with P₄S₁₀.11 reacts with alkyl halides to 2-alkylthiodihydropyridines23, 24, 25. The mechanism of the methylpyrimidine-pyridine rearrangement is discussed.     

A chemo-enzymatic approach to optically active 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols

With a view to obtaining both enantiomers of 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols, (R)-1 and (S)-1, from the respective racemate, (±)-1, the hydrolysis of its acetate, (±)-2, in the presence of porcine pancreatic lipase (PPL) has been studied. The optical puriry of (R)-1 and (S)-1 thus obtained was unsatisfactory (ee 22–27%), and could not be increased beyondee 33% by repeated enzymatic hydrolysis of the unconverted fraction of the acetate. In contrast with this, the biohydrogenation of 3-(4-methoxycarbonyl)phenyl-2-methyl-2-propen-1-ol (4) with fermentingSaccharomyces cerevisiae afforded (S)-1 of considerably higher optical purity (ee 41–90 %, depending on the strain). The stereochemical correlation of the products obtained in the two biochemical processes under study shows that the PPL-catalyzed hydrolysis of (±)-2 produces preferably (R)-1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 761–766, April, 1995.The authors express their gratitude to the Russian Foundation for Basic Research for financial support (Grant No. 93-03-5893).     

Synthese von 1-Ary1-4-methylthio-2-azetidinonen

TheN-arylthioformimidates4 a-e, which may be obtained byS-alkylation of the thioformanilides3 a-e, react with chloroacetylchloride/triethylamine to yield the (3R,4S/3S,4R)-1-aryl-3-chloro-4-methylthio-2-azetidinones5 a-e and the formanilides6 a-e. Dehalogenation of5 b-e with tri-n-butyltinhydride yield the title compounds7 b-e. Hydrogenolysis of7 b and7 c yields7 f and7 g.

     

über 4-Alkylamino-bzw. 4-Arylamino-5,6-dihydro-2(1H)-pyridinthione

Heating 1-alkyl- or 1-aryldihydro-6-methyl-2(1H)-pyrimidinethiones5, 6 in an inert medium causes rearrangement to 4-alkylamino-(4-arylamino-)-5,6-dihydro-2(1H)-pyridinethiones11, 12, probably via the methylene form29, by thermal heterolysis of the N₁/C₂ bond and exchange of the alkylamino (arylamino) group 1 through the carbon atom of the methylene group 6. The aminodihydropyridinethiones11, which can be regarded as cyclic derivatives of 3-aminothiocrotonamide, react with bistrichlorophenylmalonate under diacylation, and with formaldehyde and primary amines to yield aminodialkylation products of the enamine system, tetrahydro-4-hydroxy-7,7-dimethyl-5-thioxopyrido[4,3-b]pyridine-2(1H)-ones13, 14 and hexahydro-7,7-dimethylpyrido[4,3-d]pyrimidine-5(6H)-thiones18, 19, 21 respectively. H₂O₂ converts11 to the corresponding 4-aminodihydro-2(1H)-pyridones22, which can be reconverted into11 with P₄S₁₀.11 reacts with alkyl halides to 2-alkylthiodihydropyridines23, 24, 25. The mechanism of the methylpyrimidine-pyridine rearrangement is discussed.     

Zur Synthese der 4-Dialkylamino-5,6-dihydro-2(1H)-pyridinthione sowie entsprechender 4-Alkylamino- bzw. 4-Arylaminoverbindungen

The rearrangement of 1-alkyl- and 1-aryldihydro-6-methyl-2(1H)-pyrimidinethiones (1 a) or-ones (1 b) and of methylene compounds (2a, 2b) resp., to 4-alkylamino- and 4-arylaminodihydro-2(1H)-pyridinethiones (4 a) or-ones (4 b) takes place via the corresponding 3-alkylamino- and 3-aryl-amino-3-butenylisothiocyanates (3 a) or-isocyanates (3 b). Dialkylamino-dihydro-2(1H)-pyridinethiones (10) are formed by heating dihydro-6-methyl-2(1H)-pyrimidinethiones (6 a) and 3,4-dihydro-6-methyl-1,3-thiazin-2-thiones (6 b) with dialkylformamides and by the reaction of secondary amines with tetrahydro-6-hydroxy-6-methyl-1,3-thiazin-2-thiones (5 a), with N,N-dialkyl-N-(3-oxobutyl)-thioureas (7) and 3-oxobutyl isothiocyanates (8). A general method for the preparation of10 is the reaction of dialkylammoniumrhodanides12, N,N-dialkylthioureas13 and dialkylammonium chlorides and KCNS, resp., with 3-alken-2-ones14 and 4-hydroxy-2-alkanones15, resp. Methyl ketones such as acetone, which readily undergo the aldol condensation, behave analogously. The reactions described take place via the intermediate aminoalkenyl isothiocyanates (9).     

Synthesis of 2-(p-Toluenesulfonamido)-4-phenyl-4, 5-dihydro-1H-1, 3, 4-diazaphosphole 4-oxides

Some novel unsaturated five-membered organophosphorus heterocyclic compounds, 2-(p-toluenesulfonamido)-4-phenyl-4, 5-dihydro-1H-1, 3, 4-diazaphosphole 4-oxides 8 have been synthesized by Mannich-type reaction of p-toluenesulfonylguanidine with phenyldichlorophosphine and ketones.     

A comparative study of the synthetic paths from 1-butyne to 2E,4Z-heptadien-1-ol

2E,4Z-Heptadien-1-ol (1), the key intermediate in the synthesis of the grapevine moth sex pheromone, was obtained from 1-butyne by a number of alternative procedures, including various variants of the stereocontrolled building of the conjugatedE,Z-diene system (Cadiot—Chodkiewicz cross-coupling, alkyne—vinyl halide cross-coupling catalyzed by palladium complexes, anionotropic allylic rearrangement, partialcis- andtrans-reduction of the triple bond). None of them could provide for configurational uniformity of1. The most acceptable path to obtain1 in multigram amounts appears to be that which proceeds via the conjugated diynol and enynol intermediates with subsequent catalyticcis-hydrogenation.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 769–772, April, 1993.     

新型3-取代-6-(4-氯苯基)-7-(1H-1,2,4-三唑-1-基)-1',2',4'-三唑[3,4-b]-1",3",4"-噻二嗪衍生物的合成及抗菌活性

通过3-取代-4-氨基-5-巯基-1,2,4-三唑(3a～3m)和2-溴-2-(1H–1,2,4-三唑-1-基)-4′-氯代苯乙酮(2)的缩合反应, 合成了13个新型3-取代-6-(4-氯苯基)-7-(1H-1,2,4-三唑-1-基)-1',2',4'-三唑[3,4-b]-1",3",4"-噻二嗪衍生物4a～4m. 化合物结构经元素分析, ¹H NMR, IR和MS进行了表征. 抗菌试验表明所合成的化合物对细菌表现出中等程度的抑制活性.     

A facile synthesis of 4-aryl-2H-1-benzopyran-2-ones

Reaction of 2-hydroxybenzophenones (1,3,7,8) with ethoxycarbonyl-methylenetriphenylphosphorane affords 4-aryl-2H-1-benzopyran-2-ones (2,4–6) in excellent yields.

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Eine einfache Synthese für 4-Aryl-2H-1-benzopyran-2-one

Zusammenfassung Die Reaktion der 2-Hydroxybenzophenone1,3,7 und8 mit Ethoxycarbonyl-methylentriphenylphosphoran ergab die 4-Aryl-2H-1-benzopyran-2-one2 und4–6 in ausgezeichneten Ausbeuten.

     

Transformations of 1-(2-chloropyridyl-3)-4-ethoxycarbonyl-and 1-(2-chloropyridyl-3)-4-ethoxycarbonylmethyl thiosemicarbazides. Attempts to prepare pyrido[3,2-e]-1,2,4-thiadiazine

2-Chloro-3-hydrazinopyridine (2) was converted with ethoxycarbonyl and ethoxycarbonylmethyl isothiocyanates into 1,4-disubstituted thiosemicarbazides3 and4, while with phenyl isothiocyanate directly 1H-pyrido[3,2-e]-1,3,4-thiadiazine7 was formed. Attempts to cyclize the thiosemicarbazides3 and4 into pyridothiadiazine derivatives5 and6 failed. In the reaction of3 with hydrazine 2-aminothiazolo[5,4-b]pyridine (9) was formed, while4 gave only the corresponding hydrazide10. The cyclization of the side chain occurred in compound4 by heating in aqueous hydrochloric acid to give11, which was further transformed with N,N-dimethylformamide dimethyl acetal (DMFDMA) into12, while with diethyl acetylene dicarboxylate the thiazolidone derivative13 was produced.

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Transformationen von 1-(2-Chlorpyridyl-3)-4-ethoxycarbonyl- und 1-(2-Chlorpyridyl-3)-4-ethoxycarbonylmethylthiosemicarbaziden. Versuche zur Synthese von Pyrido[3,2-e]-1,2,4-thiadiazinen

Zusammenfassung 2-Chlor-3-hydrazinopyridin (2) wurde mit Ethoxycarbonyl- und Ethoxycarbonylmethylisothiocyanaten zu 1,4-disubstituierten Thiosemicarbaziden3 und4 umgesetzt, mit Phenylisothiocyanaten wurden direkt die 1H-Pyrido[3,2-e]-1,3,4-thiadiazine7 erhalten. Versuche zur Cyclisierung der Thiosemicarbazide3 und4 zu den Pyridothiadiazinderivaten5 und6 gelangen nicht. Bei der Reaktion von3 mit Hydrazin entstand 2-Aminothiazolo[5,4-b]pyridin (9),4 gab nur das entsprechende Hydrazid10. Die Cyclisierung der Seitenkette von4 gelang durch Erhitzen in wäßriger HCl unter Bildung von11, das seinerseits mit N,N-Dimethylformamiddimethylacetal (DMFDMA) weiter zu12 umgesetzt wurde, währenddessen mit Diethylacetylendicarboxylat die Thiazolidonderivate13 entstanden.

     

Synthesis and antiemetic activity of 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives

5-HT₃ receptor antagonists, such as Ondansetron, are used for anti-emesis after chemotherapy, radiotherapy and operations. Some Ondansetron analogs possessing piperazine ring as side chains were synthesized in our lab. Thus, one of the two carbonyl groups of starting material 1,3-cyclohexandione (1) was condensed with phenylhydrazine hydrochloride to form monophenylhydrazone (2). 1,2,3,9-Tetrahydro-4H-carbazol-4-one (3) was prepared from 2 via cyclization and rearranged in the presence of ZnCl₂. Through a methylation reaction, compound 3 was converted to 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (4). 3-Dimethylaminomethyl substituted compound (5) was synthesized from 4 by a Mannich reaction in glacial acetic acid. Nine novel 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4H-carbazol-4-one derivatives (6a–6i) were synthesized through nucleophilic substitution reaction of 5 with piperazines. The structures of all the target compounds were determined by elemental analysis, IR, MS, ¹H NMR and ¹³C NMR spectra. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control Ondansetron. __________ Translated from Chinese Journal of Organic Chemistry, 2008, 28(2) (in Chinese)     

Synthesis of partially saturated N-substituted 4H-3,1-benzothiazine-2(1H)-thiones

Summary Acid-catalyzed reaction of 2-arylidenecyclohexanones1 with N-substituted dithiocarbamic acids2 gave open-chain addition products3 and4. Dehydration of3 and4 afforded only one of the three possible isomeric N-substituted 4H-3,1-benzothiazine-2(1H)-thiones5 and6.

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Synthese von partiell gesättigten N-substituierten 4H-3,1-Benzothiazin-2-(1H)-thionen

Zusammenfassung Die säurekatalysierte Reaktion von 2-Arylidencyclohexanonen1 mit N-substituierten Dithiocarbaminsäure2 ergab die offenkettigen Additionsprodukte3 und4. Die Dehydratation von3 und4 führte ausschließlich zu einem der drei möglichen N-substituierten 4H-3,1-Benzothiazin-2(1H)-thion-Isomeren5 und6.

     

Novel Synthesis of 1-(1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea,an Anti-inflammatory Agent

Abstract

A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl] urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.     

Stereospecific Transformation of Terpinen-4-ol to Dihydropinol

A simple transformation of terpinen-4-ol (1) to dihydropinol (4) is described. S-Terpinen-4-ol was stereospecifically oxidized with vanadyl diacac to cis-terpinen-4-ol-epoxide (2). Reduction with LiAlD₄ afforded the unexpected 1R-deutero-2S,4S-dihydroxy menthane (3) which was cyclized in acid to 4.     

4-Amino-1-arylpyrazole durchThorpe-Cyclisierung

-Arylhydrazononitriles1 react with -halogen carbonyl compounds in presence of K₂CO₃ to yield substituted4-amino-1-aryl-pyrazoles3. Pyrazolo[4,3-d]pyrimidines, pyrazolo[4,3-d]oxazinones and substituted 4-aminopyrazolecarboxylic acids can be obtained from3; the carboxyl group in the 5-position can be removed.     

Synthesis of 4-hydroxy-2(1H)-pyridones from azomethines and substituted dialkylmalonates

Summary The reaction of azomethines4 with substituted dialkyl malonates5 leads to the formation of 3-substituted 4-hydroxy-2(1H)-pyridones6 in moderate yields. The azomethines4 are preparedvia arylaminopropionitriles3 or in the conventional way by acid catalyzed condensation of ketones1 with anilines2. Chlorination of pyridones6 with sulfuryl chloride leads to compounds8–10.

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Synthese von 4-Hydroxy-2(1H)-pyridonen aus Azomethinen und substituierten Dialkylmalonaten

Zusammenfassung Umsetzung der Azomethine4 mit den substituierten Dialkylmalonaten5 ergibt die in 3-Stellung substituierten 4-Hydroxy-2(1H)-pyridone6 in mäßigen Ausbeuten. Die Azomethine4 werden entweder über dieStrecker-Verbindungen3 oder konventionell über durch Säuren katalysierte Kondensation der Ketone1 mit den Aminen2 hergestellt. Chlorierung der Pyridone6 mit Sulfurylchlorid führt zu den Verbindungen8–10.

     

Über N1- und N2-substituierte 2-Amino-5,6-dihydro-4(1H)-pyrimidinone

The reactions of the monosubstituted guanidines2 b-h with methyl acrylate in dimethylformamide or ethanol as solvent preferentially afford 1-substituted 2-amino-5,6-dihydro-4(1H)-pyrimidinones6 b-h. The structures of 1-hexyl- and 1-benzyl-4-pyrimidinones6 c, e and of the picrate of 1-phenylpyrimidinone6 g were proved by comparison with authentic samples, which were prepared from N-substituted ethyl 3-amino-propionates14 c, e andg and cyanamide. Accordingly,6 g is not identical with authentic 2-phenylaminopyrimidinone7 g (prepared from 2-methylthio-4-pyrimidinone10 and 2-thioxo-4-pyrimidinone12 respectively, compare¹⁰).N,N-Disubstituted guanidines2 i-m react with methyl acrylate in dimethylformamide as solvent to afford N²,N²-disubstituted 2-amino-5,6-dihydro-4-(1H)-pyrimidinones7 i-m. Action of morpholine-4-carboxamidine (21) on methyl acrylate in ethanol yields 2-morpholinopyrimidinone71 as byproduct and 3-ethoxy-N-[morpholino(amino)methylene]propionamide (91) as mainproduct.

Herrn Prof. Dr.Robert Ott mit den besten Wünschen zum 60. Geburtstag gewidmet.