Methyl and Phenylmethyl 2-Acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate in the Synthesis of heterocyclic systems: Preparation of 3-amino-4H-pyrido-[1,2-a]pyrimidin-4-ones

Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 4 ) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 5 ) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N³-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10 – 12 , 5H-thiazolo[3,2-a]pyrimidin-5-one 13 , 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20 – 23 . Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24 – 26 were prepared from 10 – 12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Synthesis of 7-[4-alkoxy-3-methoxy(hydroxy)phenyl]-10,11-dihydrobenzo[c]acridin-8(7H,9H,12H)-ones and 4-(8-oxo-7,8,9,10,11,12-hexahydrobenzo[c]acridin-7-yl)-2-methoxy(ethoxy)phenyl esters of carboxylic acids

Reactions of azomethines (Schiff bases) prepared from vanillin and vanillal ethers and 1-naphthylamine with cyclohexane-1,3-dione in butanol afforded in 40–64% yields 7-[4-alkoxy-3-methoxy(hydroxy)phenyl]-10,11-dihydrobenzo[c]acridin-8(7H,9H,12H)-ones and 4-(8-oxo-7,8,9,10,11,12-hexahydrobenzo[C]acridin-7-yl)-2-methoxy(ethoxy)phenyl esters of carboxylic acids. The reaction products presumably formed by the rearrangement of the azomethine adduct with the cyclohexane-1,3-dione proceeding by the type of Hofmann-Martius rearrangement. The structure of compounds synthesized was confirmed by the elemental analysis, UV, IR, and ¹H NMR spectra.     

Ring-transformation reactions of 5-hydroxy-2-oxabicyclo[3.2.0]-heptan-4-ones and 5-hydroxy-2-oxabicyclo[3.2.0]hept-6-en-4-ones

Dehydrochlorination of chlorinated 5-hydroxy-2-oxabicyclo[3.2.0]heptan-4-ones, 3a-c, which were obtained from the photo[2+2]cycloadditions between 4-hydroxy-3(2H)-furanone 1 and chloroethylenes, with triethylamine gave 2-ethenyl-3(2H)-furanones 4a,b or 2-(2-cyanoethyl)-3(2H)-furanone 4c. 2-Oxa-bicyclo[3.2.0]hept-6-en-4-ones 7 being [2+2]cycloadducts between 1 and acetylenes gave 2,3-dihydro-3-oxooxepin derivatives 8 by electrocyclic rearrangement.     

Neue Derivate der 2-Acylamino-thiophen-(und-benzo[b]thiophen-)-3-carbonsäure sowie des ([1]Benzo-)Thieno[2,3-d]-pyrimidin-4(3H)-ons

The title substances1 and2 were prepared by acylation of the corresponding ethyl 2-amino-thiophene- (or:-4,5,6,7-tetrahydro-benzo[b]thiophene)-3-carboxylates, in some cases followed by reactions introducing a basic substituent.Additionally a group of 2-aroylamino-thiophene-(or:-4,5,6,7-tetrahydro-benzo[b]thiophene)-3-carboxamides was subjected to ring closure reactions, yielding the corresponding 2-aryl-thieno[2,3-d]pyrimidin-4(3H)-ones and 2-aryl-[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones (both:3).

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Zum Teil unter Mitarbeit vonFerdinand Fuhrmann     

Synthesis of Derivatives of 4-Hydroxy-2-methyl-3-[2-(5-mercapto-1H-1,2,4-triazol-3-yl)ethyl]quinoline and 2-[2-(4-Hydroxy-2-methyl-3-quinolyl)ethyl]-4H-3,1-benzoxazin-4-one

From 4-hydroxy-2-methylquinoline-3-propionyl chlorides hydrochlorides the corresponding thiosemicarbazides were synthesized. The cyclization of the latter both in alkaline and acidic media furnished 4-hydroxy-2-methyl-3-[2-(5-mercapto-1H-1,2,4-triazol-3-yl)ethyl]quinolines. The reaction of the above propionyl chlorides with anthranilic acid afforded the corresponding 2-[2-(4-hydroxy-2-methyl-3-quinolyl)ethyl]-4H-3,1-benzoxazin-4-ones.     

Synthesis of 1-[3-methyl-2(3H)-benzazolon-5- or 6-yl]-4-{4-[cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methyleneoxyphenyl}piperazines

Reactions of 3-methyl-6-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzoxazolone, 3-methyl-6-[4-(4-hydroxy-phenyl)-1-piperazinyl]-2(3H)-benzothiazolone and 1,3-dimethyl-5-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzimidazolone with cis-{[2-(2,4-dichlorophenyl) -2-(1H-imidazol-1-ylmethyl)]-1,3-dioxolan-4-yl}methyl meth-anesulfonate in the presence of sodium hydride furnish the title compounds.     

Metaboliten der 1,5-Dihydroimidazo[2,1-b]chinazolin-2(3H)-one. Synthese und Reaktionen einiger 1,5-Dihydro-3-hydroxyimidazo[2,1-b]chinazolin-2(3H)-one

Metabolites of 1,5-Dihydroimidazo[2,1-b ]quinazolin-2(3H)-ones. Preparation and Reactions of Some 1,5-Dihydro-3-hydroxyimidazo[2,1-b]quinazolin-2(3H)-ones Hydroxylated 1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-ones 2–4 and 6 were isolated as metabolites of imidazoquinazolinones 1a and 1b , respectively. The synthesis of 1,5-dihydro-3-hydroxy-3-methylimidazo[2,1-b]quinazolin-2(3H)-ones 3 , 4 , and 6 , and the preparation of some derivatives thereof is described.     

Nitrogen bridgehead compounds. Part 88. Synthesis of 3H, 7H-[1,4]diazepino[3,4-b]quinazoline-3,7-diones

3H,7H-[1,4]Diazepino[3,4-b]quinazolone-3,7-diones 9, 11 were synthesized starting from 2-(1-bromo-ethyl)quinazolin-4(3H)-ones 3 and 17 via 2-[1-(4-methoxyphenylamino)ethyl]quinazolin-4(3H)-ones 4 and 18. Cyclization of 3-[2-(1-bromoethyl)-4-oxo-3,4-dihydroquinazolin-3-yl)propionic acid 14 by the action of triethylamine provided the first representative of the tricyclic 7H-[1,4]oxazepino[3,4-b]quinazoline-3,7-dione system, compound 15. The new tricyclic derivatives 9, 11 and 15 are characterized by uv, ir and ¹H nmr spectroscopy.     

Synthesis of pyrimidino[4,5-b][1,5]benzodiazepin-2-ones and pyrimidino[1,6-a]benzimidazol-1-ones from 4-ethoxycarbonylamino-1H-1,5-benzodiazpine-3-carbonitrile via 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles

Reactions of 4-ethoxycarbonylamino-1H-1,5-benzodiazepine-3-carbonitrile (2) with aliphatic primary amines gave 1-substituted 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles 3. Analogous reactions of 2 with aromatic primary amines afforded 2-(2′-anilino-1′-cyanovinyl)benzimidazoles 5 and 6. Upon treatment with triethylamine, 3 underwent intramolecular cyclization to give 3-substituted 5-aminopyrimidino[4,5-b]-[1,5]benzodiazepin-2(3H,11H)-ones 8 . Heating of 3 with p-toluenesulfonic acid in ethanol gave 2-substituted pyrimidino[1,6-a]benzimidazol-1(2H)one-4-carbonitriles 9 . Reactions of 2 with hydrazines were also described. Mechanistic pathways are proposed to account for the products.     

Synthesis of isoxazolopyrroloisoquinolines by intramolecular cyclizations of 5-(2-arylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones

5,8a,11a,11b-Tetrahydroisoxazolo[5′,4′:3,4]pyrrolo[2,1-a]isoquinolin-8(6H)-ones were prepared by intramolecular cyclization of 5-(2-arylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones in the presence of boron trifluoride diethyl etherate.     

[1,2,4]Triazines. 4. Regiospecific ring closure reactions involving 6-amino-5-hydrazino[1,2,4]triazin-3(2H)-ones and orthoesters

6-Amino-5-hydrazino[1,2,4]triazin-3(2H)-one, 3 , was treated with a variety of orthoesters and concentrated acid forming mixtures of ring-closed and open-chain derivatives. These mixtures were converted in warm aqueous acid to the Mriazolo[5,1-d][1,2,4]triazin-3(2H)-ones, 11b, 14b , and 15b by a regiospecific ring closure at N-4 of the [1,2,4]triazine ring and subsequent Dimroth-like rearrangement of the initially formed s-triazolo[4,3-d][1,2,4]triazin-3(2H)-ones ( 11a, 14a, 15a ).     

Synthesis of some 5H,12H-[1]benzoxepino[4,3-b]indol-6-ones. A new heterocyclic ring system

The synthesis of the title compounds 5H,12H-[1]benzoxepino[4,3-b]indol-6-ones 10 was effected by the Fischer indole cyclization of some 2,3-dihydro-4-phenylhydrazono[1]benzoxepin-5-ones 9 , obtained from the 3,4-dihydro-4-hydroxymethylene[1]benzoxepin-5(2H)-ones 7 by the Japp-Klingemann reaction. The structure of these new heterocyclic compounds was supported by ir, ¹H nmr and ms spectral data.     

Synthesis of [1,5]benzothiazepine derivatives

Various derivatives of 2,3-dihydro[1,5]benzothiazepin-4(5H)-ones were synthesized. Alternative route for the synthesis of 5-dimethylaminoethyl-2,3-dihydro[1,5]benzothiazepin-4(5H)-ones and 4-dimethylaminopro-poxy-(2H,5H)-[1,5]benzothiazepines are described.     

Synthesis and antimicrobial activity of some 2-alkyl-2H-1,4-benzothiazin-3(4H)-ones and 2-alkylbenzo[d]imidazolo[2,1-b]-thiazolidin-3-ones

Summary Sodium 2-aminothiophenoxide (1) reacts with ethyl 2-bromoalkanoates (2) under direct cyclization to form 2-alkyl-2H-1,4-benzothiazin-3(4H)-ones (3). Reaction of the sodium salt of 2-mercaptobenzimidazole (4) with2 or 2-bromoalkanoic acids (5) affords only S-alkylated products (6 or7, respectively). The cyclization products — 2-alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-ones (8) — can be obtained only from the corresponding 2-(2-benzimidazolylthio)alkanoic acids (7) by the action of acetic anhydride. Both compounds3 and8 exhibit only moderate antimicrobial activity against some gram-positive bacteria.

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Synthese und antimikrobielle Wirkung von einigen 2-Alkyl-2H-1,4-benzothiazin-3(4H)-onen und 2-Alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-onen

Zusammenfassung Bei der Reaktion von Natrium-2-aminothiophenolat mit 2-Bromoalkansäure-ethylestern (2) entstehen als Cyclisierungsprodukte 2-Alkyl-2H-1,4-benzothiazin-3(4H)-one (3). Die Umsetzung von Natriumbenzimidazol-2-thiolat mit2 oder mit 2-Bromoalkansäuren (5) liefert nur S-Alkylierungsprodukte (6 oder7). Die Cyclisierungsprodukte — 2-Alkylbenzo[d]imidazolo[2,1-b]thiazolidin-3-one (8) — sind nur durch Umsetzung von entsprechenden 2-(2-Benzimidazolylthio)-alkansäuren (7) mit Acetanhydrid erhältlich. Die Verbindungen3 und8 weisen nur mäßige antimikrobielle Wirkung gegen einige gram-positive Bakterien aus.

     

Nitrogen bridgehead compounds. Part 86. Synthesis and reactivity of 7,12-dihydropyrimido[1′,2′;1,2]pyrido[3,4-b]indol-4(6H)-ones. Debenzologues of rutaecarpine alkaloids

A series of 7,12-dihydropyrimido[1′2′:1,2]pyrido[3,4-b]mdole-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrirmdin-4-ones. Quantum chemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indole-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-tetrahydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indol-4(6H)-one 16 with bromine afforded 3-bromo derivative 25 , which was reacted with cyclic amines to give 2-ammo-7,12-dihydropyrirmdo[1′2′:1,2]pyrido[3,4-b]indol-4(6H)-ones 26–30 in an addition-elimination reaction. Vielsmeier-Haack formylation of compound 16 gave 12-formyl 31 and 3,12-diformyl 32 derivatives (an N-formyl-1-deaza derivative of nauclefidine alkaloid 34 ) at 60° and 100°, respectively. 3,12-Diformyl compound 32 was oxidized to 3-carboxyl derivative 33 with potassium permanganate. The quaternary salt 35 , obtained from compound 16 with dimethyl sulfate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, ¹H nmr and in some cases by ¹³C ruler, CD spectra and X-ray investigations.     

Reactions with pyrrolidine-2,4-diones,II: New approaches to the synthesis of substituted 5,6-dihydropyrrolo[3,4-d][1,2,3]triazol-4(2H,4H)ones

Summary Approaches leading to 5,6-dihydro-5,6-diphenyl-2-substituted-pyrrolo[3,4-d][1,2,3]-triazol-4(2H,4H)-ones (10) are described. The first approach consists of cyclodehydrating 3(or 4)-hydroxyimino-1,5-diphenyl-4(or 3)-(4-substituted phenylhydrazono)pyrrolidin-2-ones (4,7) with boiling acetic anhydride. The second approach involves cyclization of 3(or 4)-acetoxyimino-1,5-diphenyl-4(or 3)-(4-substituted phenylhydrazono)pyrrolidin-2-ones (8,9) with elimination of acetic acid upon treatment with sodium hydroxide.Part of the work has been presented at the 8^th International Congress of Heterocyclic Chemistry (August 1981), Graz, Austria     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVII. Synthesis of 2H-[1]benzothiepino[5,4-b]pyran derivatives

1,4-Cycloaddition of dichloroketene to a number of N,N-disubstituted (E)-4-amino methylene-3,4-dihydro-[1]benzothiepin-5(2H)-ones gave in excellent yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-[1]benzothiepino[5,4-b]pyran-2-ones III, which are derivatives of the 2H-[1]benzothiepino[5,4-b]pyran system. Dehydrochlorination of III with DBN afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-[1]-benzothiepino[5,4-b]pyran-2-ones, generally in excellent yield.     

Reaction of 2-dimethylaminomethylene-1,3-diones with Dinucleophiles. IV. Synthesis of 5,7-dihydrothiopyrano[3,4-c]pyrazol-4(1H)-ones, 5H-Thiopyrano[4,3-d]isoxazol-4(7H)-one and 6H-Thiopyrano[3,4-d]pyrimidin-5(8H)-ones

The reaction of 2H-thiopyran-3,5(4H,6H)-dione with N,N-dimethylformamide dimethyl acetal gave in good yield 4-dimethylaminomethylene-2H-thiopyran-3,5(4H,6H)dione (II), which afforded 1-substituted 5,7-dihydrothiopyrano[3,4-c]pyrazol-4(1H)-ones with aliphatic and aromatic hydrazines, 5H-thiopyrano[4,3-d]isoxazol-4(7H)-one (IV) with hydroxylamine hydrochloride and 2-substituted 6H-thiopyrano[3,4-d]pyrimidin-5(8H)-ones with amidines and guanidines, generally in satisfactory yields. 4-(t-Butylhydrazonoformyl)-2H-thiopyran-3,5(4H,6H)-dione was isolated as an intermediate in the reaction of II with t-butylhydrazine, whereas formamidine gave with II 4-iminoformyl-2H-thiopyran-3,5(4H,6H)-dione as the sole product. The isoxazole IV isomerized easily with sodium methoxide to 3,4,5,6-tetrahydro-5,5-dihydroxy-3-oxo-2H-thiopyrano-4-carbonitrile.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.