Synthesis and selected properties of N-substituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

The reactions of methyl α-(2-formyl-1H-pyrrol-1-yl)carboxylates with N-substituted aliphatic 1,2-, 1,3-, and 1,4-diamines afford new pyrrole-containing heterocyclic systems: 1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-ones, 1,3,4,11b-tetrahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a]pyrimidin-6(7H)-ones, and 1,2,3,4,5,12b-hexahydro-pyrrolo[2′,1′:3,4]pyrazino[1,2-a][1,3]diazepin-7(8H)-ones. The reduction of these compounds with different reagents was studied.     

1,2-fused pyrimidines. V. Synthesis of 1-alkyl or phenyl-2H-dipyrido-[1,2-a:2′,3′-d]pyrimidine-2,5(1H)-diones

The reaction of 2-[(N-acyl, N-alkyl or phenyl)amino]-4H-pyrido[1,2-a]pyrimidin-4-ones 8a-g with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier reagent 1 (95°, 90 minutes) afforded 1-alkyl or phenyl-2H-dipyrido[1,2-a:2′,3′-d]pyrimidine-2,5(1H)^?diones, 3-alkyl substituted or not, 10a-g . The starting compounds 8 were prepared by treating 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones N-alkyl substituted 7a,b or N-phenyl substituted 4 with excess anhydrides (130°, 7 hours) when the 2-(alkylamino) derivatives 7 were used in the reaction, compounds 8 were obtained along with very small amounts of 3-acyl-2-(alkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones 9 .     

Nitrogen bridgehead compounds. Part 80 unusual reaction of ethyl 9-bromo-4-oxo-6,7,8,9-tetr ahydro-4h-pyrido[1,2-a]pyrimidine-3-carboxylates and N-Methylaniline

The acid-catalysed intramolecular nucleophilic addition of the phenyl ring to the C(9a) = N(1) double bond of ethyl 9-(N-methyl-N-phenyl)-4-oxotetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates, formed in the reactions of ethyl 9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and N-methylaniline, gave the first examples of a new tetracyclic pyrimido[1′,2′:1,2]pyrido[3,2-b]indole ring system ( 7 ). X-ray diffraction analysis of 7a revealed that the annelation of the pyrimidine and piperidine rings is transoid, while that of the piperidine and pyrroline rings is cis, the piperidine ring adopts an unusual ⁶T₈ twisted boat conformation, while the pyrroline ring has a ⁹T_8a conformation.     

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.     

Studies on ketene and its derivatives. Part 119. Reactions of haloketenes with 2-arylideneaminopyridines

Reactions of haloketenes with 2-arylideneaminopyridines were examined. Reaction of dichloroketene with 2-benzylideneaminopyridines gave 2,2-dichloro-3-phenyl-3-(2-pyridylamino)propanoic acids and 3-chloro-2-phenylpyrido[1,2-a]pyrimidin-4(4H)-ones. Similar reaction of dichloroketene with 2-(2-furfurylideneamino)-pyridines gave 3-chloro-2-(2-furyl)pyrido[1,2-a]pyrimidin-4-(4H)-ones. Chloroketene and chlorophenylketene also reacted with 2-arylideneaminopyridines to give pyrido[1,2-a]pyrimidin-4(4H)-ones. Ring transformations of pyrido[1,2-a]pyrimidin-4-(4H)-ones were carried out to give 1,8-naphthyridin-4(1H)-ones and imidazo[1,2-a]-pyridines.     

Nitrogen bridgehead compounds VIII . Ring transformations IV . Synthesis and reactions of 2,3-Cycloalkylene-4H-pyrido [1,2-a] pyrimidin-4-ones

By condensing alicyclic β-ketocarboxylates with substituted 2-aminopyridines in polyphosphoric acid or phosphoryl chloride-polyphosphoric acid, numerous 2,3-tri-, tetra-, penta- and hexamethylene-4H-pvrido[1,2-a]pyrimidin-4-ones were synthesized for pharmacological purposes. The stability and several reactions of the title compounds were studied. The 6-substituted-4H-pyrido[1,2-a]pyrimidin-4-ones were transformed into 1,8-naphthyridines in good yields independent of the ring size of ring C . The characteristic differences in the ir and uv spectra of the pyrido-pyrimidines and the corresponding naphthyridines are discussed. Catalytic hydrogenation of the pyrido[1,2-a]pyrimidin-4-ones furnished the corresponding 6,7,8,9-tetrahydropyrido-[1,2-a]pyrimidin-4-one derivatives. It was found that the A and C rings attached to the pyrirnidinone ring in solutions of unsubstituted tetrahydropyrido[1,2-a]pyrimidin-4-ones are flexible, whereas in the 6-methyl derivatives the conformer containing the 6-methyl group in axial position predominates.     

Synthesis of pyrimido[1,2-a]benzimidazoles from ethyl 2-ethoxymethylidene-3-oxo-3-(polyfluoroalkyl)propionates

Cyclization of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with benzimidazol-2-amine in boiling 1,4-dioxane followed two concurrent pathways with participation of fluoroacyl and ethoxycarbonyl fragments and formation of, respectively, ethyl 4-hydroxy-4-polyfluoroalkyl-1,4-dihydropyrimido-[1,2-a]benzimidazole-3-carboxylates and 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols. Dihydropyrimido[1,2-a]benzimidazole derivatives undergo dehydration to give ethyl 4-(polyfluoroalkyl)pyrimido[1,2-a]benzimidazole-3-carboxylates, whereas the hydroxy group in 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols is capable of being replaced by the amino group of the second benzimidazole molecule with formation of 4-(1H-benzimidazol-2-ylamino)-3-polyfluoroacylpyrimido[1,2-a]benzimidazoles.     

1,2-Fused pyrimidines. III. Derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline,a novel heterocyclic system

Reactivities of 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones and 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones, both N,N-dialkyl and (N-alkyl, N-phenyl)substituted, when treated with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier-Haack reagent XII were compared. Starting from 2-[(N-alkyl, N-phenyl)amino] compounds IXa,b , the expected XVIa,b and XVIIa,b were obtained, which are derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline, a novel heterocyclic system. When 2-(phenylamino) compound IXc was used a mixture of 3-formylderivative XVIII and 12H-pyrido-[1′,2′:1,2]pyrimido[4,5-b]quinolin-12-one ( XIX ) resulted from the reaction. On the other hand, 2-(dialkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones IIIa-c plainly afforded high yields of 3-formylderivatives XIVa-c. In contrast, no significant reaction occurred when 4-(dialkylamino) and 4-[(N-alkyl,N-phenyl)amino] compounds IIa-c and VIIIa,b were treated with the reagent XII , under the same as well as more severe conditions. A clear difference in the nucleophilic reactivity of C-3 position between these two classes of isomers is pointed out by the above summarized results.     

Bridgehead nitrogen heterocycles. VI. The reaction of 1-amino- and 1,2-diaminopyridinium salts with β-dicarbonyl compounds

1,2-Diaminopyridinium iodide underwent reaction with ethyl acetoacetate to form 1,4-dihydro-2-methyl-4-oxopyrido[1,2-a]pyrimidin-1-ium iodide, and with acetyl acetone it gave 2,4-dimethylpyrido[1,2-a]pyrimidin-5-ium iodide. Though 2-acetylcyclohexanone gave the corresponding 5-methyl-1,2,3,4-tetrahydropyrido[1,2-a]quinazolin-11-ium iodide, no reaction was observed with 2,6-dimethyl-3,5-heptanedione, 1-benzoylacetone, 1,3-diphenyl-1,3-propanedione and its p-methoxyphenyl derivative. However, 1-aminopyridinium iodide and acetyl acetone in the presence of base gave 3-acetyl-2-methylpyrazolo[1,5-a]pyridine and 1-amino-2-methylpyridinium iodide yielded the corresponding 3-acetyl-2,7-dimethylpyrazolo[1,5-a]pyridine. With ethyl acetoacetate, the latter salt formed 3-ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyridine but with 2,6-dimethyl substituents in the pyridine ring no condensation occurred. Reaction of 1-amino-2-methylpyridinium iodide with benzaldehyde gave N-benzalimino-2-methylpyridinium iodide which, on treatment with base, resulted in the formation of 2-picoline and benzonitrile, providing a convenient method of deamination.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 2

A series of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-6-ones was obtained by reaction of ammonium acetate with ethyl 7-dimethylaminovinylpyrazolo[1,5-a]pyrimidine-6-carboxylates and these had been prepared from ethyl 7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylates by reaction with dimethylformamide dimethylacetal. Under these conditions the compounds bearing a 2-hydroxy group were also O-alkylated. During the preparation of the ethyl 2-hydroxy-7-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate the corresponding 5-methyl isomer was isolated and identified.     

Synthesis of Substituted Indolo[1,2- a ]quinoxalines

Abstract

1-(2-Nitrophenyl)indole-2-carboxylates 5, obtained by the N-arylation of indole-2-carboxylates 4, on catalytic reductive cyclization afford indolo[1,2-a]quinoxalino-6(5H)-ones 6. These compounds on reduction with LAH in ether/THF yielded indolo[1,2-a]quinoxalines 7.     

Povarov Reaction of Glyoxylate Imines Derived from 12-Aminodehydroabietic Acid

Glyoxylate and arylglyoxal imines based on 12-aminodehydroabietic acid undergo hetero-Diels—Alder (Povarov) reaction with ethyl vinyl ether, cyclopentadiene, and indene to give, respectively, methyl (8aR,9R,12aS)-3-aroyl-5-isopropyl–9,12a-dimethyl–7,8,8a,9,10,11,12,12a-octahydronaphtho[1,2-f]quinoline-9-carboxylates, methyl (7R,10aS,10dR,13aS)-1-aroyl–3-isopropyl–7,10a-dimethyl–2,5,6,6a,7,8,9,10,10a,10d,13,13a-dodecahydro-1H-naphtho[1,2-f]cyclopenta[c]quinoline-7-carboxylates, and methyl (6aS,11bS,11eS,15R,15aR)-6-aroyl–4-isopropyl–11e,15-dimethyl–2,5,6,6a,7,11b,11e,12,13,14,15,15a-1H-dodecahydroindeno[2,1-c]-naphtho[1,2-f]quinoline-15-carboxylates.     

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.     

A Convenient Synthesis of NovelDerivatives of Pyrido[2,3- d ][1,2,4]triazolo[4,3- a ]pyrimidine-5,6-dione

 Reaction of 6-Amino-2-thiouracil with hydrazonoyl halides yielded regioselectively 7-amino-1,3-disubstituted-1,2,4-triazolo[4,3-a]pyrimidine derivatives. Upon treatment with methyl (Z)-2-benzoylamino-3-dimethylaminopropenoate, the corresponding methyl (Z)-2-benzoylamino-3-([1,2, 4]triazolo[4,3-a]pyrimidin-7-yl)-amino propenoates were obtained which cyclized in the presence of sodium ethoxide to afford novel derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5,6-(1H,8H)-diones.     

Reaction of 4-Aryl-1-(4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidin-2-yl)thiosemicarbazides with Dimethyl Acetylenedicarboxylate

4-Aryl-1-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thiosemicarbazides react with dimethyl acetylenedicarboxylate in methanol to give the corresponding methyl {3-aryl-4-oxo-2-[(4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-yl)hydrazono]-1,3-thiazolidin-5-ylidene}acetates, whereas in dioxane methyl 5-aryl-amino-2-methoxycarbonylmethyl-3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2,3-dihydro-1,3,4-thiadiazole-2-carboxylates are mainly formed.     

A Convenient Synthesis of NovelDerivatives of Pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5,6-dione

Summary.  Reaction of 6-Amino-2-thiouracil with hydrazonoyl halides yielded regioselectively 7-amino-1,3-disubstituted-1,2,4-triazolo[4,3-a]pyrimidine derivatives. Upon treatment with methyl (Z)-2-benzoylamino-3-dimethylaminopropenoate, the corresponding methyl (Z)-2-benzoylamino-3-([1,2, 4]triazolo[4,3-a]pyrimidin-7-yl)-amino propenoates were obtained which cyclized in the presence of sodium ethoxide to afford novel derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5,6-(1H,8H)-diones. E-mail: mosselhi@chem-sci.cairo.eun.eg Received February 8, 2002; accepted (revised) March 18, 2002     

Cycloaddition of Carbodiimides with a Heteroaromatic Substituent to Allenic Acids

Cycloaddition of the allenic acid 3 with the N -cyclohexyl-N′ -heteroaromatic carbodiimides 2a and 2b gave the isomeric pyrido[1,2-a]pyrimidinones 4 and 5 and thiazolo[3,2-a]pyrimidinones 6 and 7 , respectively, instead of the expected Diels-Alder adducts analogous to 1 . The compounds of the latter type, i.e. 8 and 9 , were formed from 3 and carbodiimides 2c and 2d , respectively, containing an N′-(pyrazin-2-yl) or N′-(pyrimidin-2-yl) substituent.     

On triazoles XXIV . Synthesis of cycloalka[1,2,4]triazolo[1,5-a]pyrimidinones

The uv and nmr spectral data of some 6,7,8,9,10,11-hexahydrocyclohepta[d][1,2,4]triazolo[1,5-a]pyrimidin-5-one, 5,6,7,8,9,11-hexahydrocyclohepta[e][1,2,4]triazolo[1,5-a]pyrimidin-10-one, 6,7,8,9,10,11-hexahydrocycloocta[d][1,2,4]triazolo[1,5-a]pyrimidin-5(12H)-one, 5,6,7,8,9,10-hexahydrocycloocta[e][1,2,4]triazolo[1,5-a]-pyrimidin-11(12H)-one, 6,7,8,9,10,11,12,13,14,15-decahydrocyclododeca[d][1,2,4]triazolo[1,5-a]pyrimidin-5(16H)-one and 5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[e][1,2,4]triazolo[1,5-a]pyrimidin-15(16H)-one as well as their N-benzylated derivatives representing six novel ring systems were compared to prove their structure. The N-benzylation of the highly insoluble cyclic amides to yield the isomeric N-benzyl derivatives 3/1, 3/2 and 3/3 distinguished by INAPT was performed through their readily soluble tetrabutylammonium salts.     

Synthesis of Heterocyclic Compounds Using Amidines as Their Ene-1,1-diamine Tautomers,IV: Synthesis of N-Bridged Heterocycles 1,2,3,4-Tetrahydropyrido[1,2-a]pyrimidin-6-ones and Methyl 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrimidin-7-ylideneacetates

2-Benzyl-1,4,5,6-tetrahydropyrimidines 1 (as ene-1,1-diamine N,C-tautomers) in diglyme reacted with ethyl benzoylacetate at 160 °C in an oil bath to give 1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-6-ones 3 and with dimethyl acetylenedicarboxylate in methanol at room temperature, leading to methyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-7-ylideneacetates 5, respectively.      

Design,synthesis, and toward a side-ring optimization of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and their effect on melanin synthesis in murine B16 cells

Abstract

Herein, we report the synthesis of 48 novel 3-sulfonylamides containing a tricyclic thieno[2,3-d]pyrimidin-4(3H)-one moiety, and their influence on melanin synthesis in murine B16 cells. All target sulfonylamides were synthesized through key intermediate 3-nitro-thieno[2,3-d]pyrimidin-4(3H)-ones using three types of ipso-nitration reactions. In this case, we converted the pyrido[1,2-a]- fragment of the thieno[2,3-d]pyrimidine moiety to pyrrolo[1,2-a]- and azepino[1,2-a]- side-rings in order to evaluate the bioactivities of the synthesized derivatives for a structure activity-relationships point of view. The obtained results suggest that some of the selected compounds revealed a promising influence on melanin synthesis in murine B16 cells and may serve as lead compounds for further drug discovery and development.