Pyrimidines. 21. Novel reactions of 5-cyano-1,3-dimethyluracil with carbon nucleophiles. A facile preparation of certain pyrido[2,3-d]pyrimidines

Treatment of 5-cyano-1,3-dimethyluracil ( 8 ) with an activated acetonitrile, such as malononitrile, ethyl cyanoacetate or cyanoacetamide, in base afforded 7-amino-6-cyano-, 7-amino-6-ethoxycarbonyl-, and 7-amino-6-aminocarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18b, 18c and 18d , respectively) in high yields. On the other hand, reaction of 8 with acetonitrile in base gave the Michael adduct, 5-cyano-6-cyanomethyl-5,6-dihydrouracil ( 15 , R = H), and the hydrated product, 1,3-dimethyluracil-5-carboxamide ( 9 ) as the major products, and 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18a ) in only very low yield. Similar reaction with butanone gave 7-ethyl-1,3-dimethyl- and 1,3,6,7-tetramethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 10b and 10c ) in low yields. When 8 was treated with diethylmalonate in base, only a small amount of 6-ethoxycarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione ( 19 ) was obtained together with 1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 20 ) and 18c (also in low yields). Treatment of 8 in ethanolic sodium ethoxide without added carbon nucleophile gave significant amounts (14%) of 20 and a small amount of 18c .     

Synthesis of 1H,3H-imidazo[1,5-c]thiazole-5,7-[6H,7aH]-dione and 7,8-dihydro-5-H-imidazo[1,5-c][1,3]thiazine-1,3-[2H,8aH]-dione and derivatives

1H,3H-Imidazo[1,5-c]thiazole-5,7-[6H,7aH]-dione and the corresponding 7-thione derivatives as well as 7,8-dihydro-5H-imidazo[1,5-c][1,3]thiazine-1,3-[2H,8aH]-dione and the corresponding 3-thione derivatives were synthesized starting from L -cysteine and DL -homocysteine thiolactone, respectively. The second group of bicyclic compounds represents a new heterocyclic ring system. The structures of the compounds were confirmed by spectroscopic studies and elemental analyses.     

Condensation of 2-Alkylcyclohexane-1,3-diones with Cyclic Azomethines

Reaction of 2-acylcyclohexane-1,3-diones with 5- and 6-membered cyclic azomethines (3,4-dihydro-2H-pyrrole and 2,3,4,5-tetrahydropyridine) furnished derivatives of 2,3,3a;,4,8,9-hexahydropyrrolo[1,2-a]quinoline-5,6(1H,5aH)-dione and 3,4,4a,5,9,10-hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-dione respectively. In reaction with 7-membered 3,4,5,6-tetrahydro-2H-azepine we failed to isolate polycyclic nitrogen-containing products.     

Pyrimidines. 20. Novel reactions of 5-cyano-1,3-dimethyluracil. A simple synthesis of pyrido[2,3-d]pyrimidines

A reaction of 5-cyano-1,3-dimethyluracil (1, R = CN) with acetone in base afforded 1,3,7-trimethylpyrido-[2,3-d]pyrimidine-2,4(1H,3H)dione ( 9a ) in a moderate yield. From a reaction mixture of 1 (R = CN) with butanone, 1,3,6,7-tetramethyl- and 7-ethyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 9b and 9c , respectively) were isolated in low yields. When ethyl cyanoacetate or malononitrile was used in place of the ketone in the above reaction, 7-amino-6-ethoxycarbonyl- and 7-amino-6-cyano-1,3-dimethylpyrido[2,3-d]-pyrimidine-2,4(1H,3H)-dione ( 14a and 14b , respectively) were obtained in quantitative yields. A plausible mechanism for the formation of bicyclic compounds is discussed.     

Synthesis of 4,6-disubstituted-7-β-D-ribofuranosyl- and arabinofuranosylpyrazolo[3,4-d]pyrimidines and certain related ribonucleosides

Several disubstituted pyrazolo[3,4-d]pyrimidine, pyrazolo[1,5-a]pyrimidine and thiazolo[4,5-d]pyrimidine ribonucleosides have been prepared as congeners of uridine and cytidine. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[3,4-d]pyrimidine-4,6(1H,5H,7H)-dione ( 4 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 5 ) in the presence of TMS triflate afforded 7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo-[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 6 ). Debenzoylation of 6 gave the uridine analog 7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 3 ), identical with 7-ribofuranosyloxoallopurinol reported earlier. Thiation of 6 gave 7 , which on debenzoylation afforded 7-β-D-ribofuranosyl-6-oxopyrazolo[3,4-d]pyrimidine-4(1H,5H)-thione ( 8 ). Ammonolysis of 7 at elevated temperature gave a low yield of the cytidine analog 4-amino-7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-6(1H)-one ( 11 ). Chlorination of 6 , followed by ammonolysis, furnished an alternate route to 11 . A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride ( 12 ) gave mainly the N7-glycosylated product 13 , which on debenzylation provided 7-β-D-arabinofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 14 ). 4-Amino-7-β-D-arabinofuranosyl-pyrazolo[3,4-d]pyrimidin-6(1H)-one ( 19 ) was prepared from 13 via the C4-pyridinium chloride intermediate 17 . Condensation of the TMS derivatives of 7-hydroxy- ( 20 ) or 7-aminopyrazolo[1,5-a]pyrimidin-5(4H)-one ( 23 ) with 5 in the presence of TMS triflate gave the corresponding blocked nucleosides 21 and 24 , respectively, which on deprotection afforded 7-hydroxy- 22 and 7-amino-4-β-D-ribofuranosylpyrazolo[1,5-a]pyrimidin-5-one ( 25 ), respectively. Similarly, starting either from 2-chloro ( 26 ) or 2-aminothiazolo[4,5-d]pyrimidine-5,7-(4H,6H)-dione ( 29 ), 2-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-5,7(6H)-dione ( 28 ) has been prepared. The structure of 25 was confirmed by single crystal X-ray diffraction studies.     

Studies on the chemistry of 5-propynyloxy- and 5-propynylthiopyrimidines: New syntheses of furo- and thieno[3,2-d]pyrimidines

The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.     

Plant coumarins: V. Palladium-catalyzed amination of 2-(1,3-dibromopropan-2-ylidene)oreoselone

Palladium-catalyzed amination of 2-(1,3-dibromopropan-2-ylidene)-7H-furo[3,2-g]chromene-3,7(2H)-dione with various amines and amino acid derivatives led to the formation of the corresponding 2-(1,3-diaminopropan-2-ylidene)-substituted oreoselones. The yields depended on the catalytic system, base, and amine structure. Di- and polyazamacrocyclic furocoumarin derivatives were obtained by reactions of 2-(1,3-dibromopropan-2-ylidene)-7H-furo[3,2-g]chromene-3,7(2H)-dione with linear di- and polyamines (hexamethylenediamine, spermine, spermidine, and 3,6-dithiaoctane-1,8-diamine), catalyzed by palladium complexes.     

Efficient and facile synthesis of 5-arylindeno[2′,1′:5,6]pyrido[2,3-d] pyrimidine-2,4(3H)-dione and 7-arylbenzo[h]pyrimido[4,5-b]quinoline-8,10(5H,9H)-dione under mild conditions

An efficient and facile method for the synthesis of 5-arylindeno[2′,1′:5,6]pyrido[2,3-d] pyrimidine-2,4(3H)-dione and 7-arylbenzo[h]pyrimido[4,5-b]quinoline-8,10(5H,9H)-dione derivatives from the reactions of 2-arylidene-2,3-dihydroinden-1-one (or 2-arylidene-3,4- dihydronaphthalen-1(2H)-one) and 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione under mild conditions was described. This is a simple, efficient, and very rapid synthetic method, which is believed to provide a useful process for the synthesis of these fused heterocyclic compounds. The products were confirmed by infrared, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry.     

The synthesis of methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino-2H-pyran-2-ones,fused 2H-pyran-2-ones and 4H-pyridin-4-ones

Methyl 2-(benzyloxycarbonyl)aimno-3-dimemylaminopropenoate ( 2 ) was prepared from methyl N-(benzyloxycarbonyl)glycinate ( 1 ) and t-butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6 , ?2H-pyran-2-ones 17–19 , ?2H-1-benzopyran-2-ones 28–31 , and -naphthopyrans 32–35 , ?2H-pyrano[3,2-c]pyridine-2,5-dione 46 , -pyrano-[4,3-b]pyran-2,5-dione 47 , -pyrano[3,2-c]benzopyran-2,5-dione 48 , -pyrano[2,3-c]pyrazol-6-ones 49 and 50 , -pyrano[2,3-d]pyrirnidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubsti tuted pyrroles 14–16 were formed. Selective removal of benzyloxycarbonyl group was achieved by cat alytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3-amino compounds 7 , 8 , 20 , 36–38 and 53–57 in yields better than 80%.     

The synthesis of lin-benzoreumycin,lin-benzo-1-methylxanthine,and lin-benzo-1,9-dimethylxanthine

Commencing with 7-chloro-3-methylquinazoline-2,4(1H,3H)-dione ( 9a ), a five step synthesis of 7-methylpyrimido[5,4-g]-1,2,4-benzotriazine-6,8(7H,9H)-dione (lin-benzoreumycin, 6 ) has been accomplished. A synthesis of 1,7-dimethylpyrimido[5,4-g]-1,2,4-benzotriazine-6,8(1H,7H)-dione (lin-benzotoxoflavin, 5 ) employing an intermediate from the preparation of 6 (i.e., 7-chloro-3-methyl-6-nitroquinazoline-2,4(1H,3H)-dione, 9b ) was attempted but could not be accomplished beyond the dihydro precursor of 5 (i.e., 12 ). Compound 9b did lead to successful preparations of 7-methylimidazo[4,5-g]quinazoline-6,8(5H,7H)-dione (lin-benzo-1-methylxanthine, 7 ) and 3,7-dimethylimidazo[4,5-g]quinazoline-6,8(5H,7H)-dione (lin-benzo-1,9-dimethylxanthine, 8 ) by first reacting 9b with ammonia (for 7) or methylamine (for 8 ) followed by reductive cyclization in formic acid.     

[3,4]-annulated pyrroles 1. Polynuclear heterocyclic systems based on pyrrolo[3,4-d]pyrimidine-2,4-dione

The intramolecular electrophilic substitution in 6-functionalized 1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-diones was used for the synthesis of pyrimido[4′,5′:3,4]-pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione, pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,2,4]benzo-triazine-8,10(7H,9H)-dione, and 2H-pyrimido[4′,5′:3,4]pyrrolo[1,2-a]indole-2,4,11(1H, 3H)-trione derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2180–2185, December, 2006.     

NMR study on the tautomeric equilibria between the hydrazone imine and diazenyl enamine forms in side chained quinoxalines: Solvent effects and temperature dependence

The reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazonium chloride gave 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)-ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8b , respectively, while the reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 7 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazomum chloride provided 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9b , respectively. Compounds 8a,b and 9a,b showed the tautomeric equilibria between the hydrazone imine C and diazenyl enamine D forms in dimethyl sulfoxide and/or trifluoroacetic acid, and the effects of solvent and temperature on the tautomer ratios of C to D were studied by the nmr measurements in a series of mixed trifluoroacetic acid/dimethyl sulfoxide media (compounds 8a,b and 9a,b ) and at various temperatures (compounds 8a,b ).     

Die photochemische Reduktion von 4,6-Dimethyl-2-pyrimidinol

π,π*-Excitation of 4,6-dimethyl-2-pyrimidinol in methanol leads to an addition product 5 whereas in 2-propanol a dihydrodimer 3 is formed. By acid catalysis the dihydrodimer gives the 5, 9-methano-2H-pyrimido[5,6-e] [1,3]diazepine-2,7(1H)-dione 7 which with stronger acids rearranges to the 2H-cyclopentapyrimidin-2-one 8 . Nitrous acid reacts with the dihydrodimer yielding the dioxime of 2-hydroxy-4,6-pyrimidinedicarbaldehyde.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.     

Reaction of 2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-carbaldehyde with naphthalen-1-amine,quinolin-8-amine,and 1,3-diketones

Condensation of 2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-carbaldehyde with naphthalen-1-amine and cyclohexane-1,3-dione, methyl 2,2-dimethyl-4,6-dioxocyclohexane-1-carboxylate, or dimedone gave the corresponding 7-(2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-yl)-7,8,9,10,11,12-hexahydro-12H-benzo[c]acridin-8-ones. The reaction of 2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-carbaldehyde with naphthalen-1-amine and indan-1,3-dione produced 7-(2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-yl)-8H-benzo[h]indeno[1,2-b]quinolin-8-one. 7-(2′-Hydroxy-1,1′: 3′,1″-terphenyl-5′-yl)-7,8,9,10,11,12-hexahydrobenzo[b][1,10]phenanthrolin-8-ones were obtained by three-component condensation of 2′-hydroxy-1,1′: 3′,1″-terphenyl-5′-carbaldehyde with quinolin-8-amine and cyclohexane-1,3-dione, methyl 2,2-dimethyl-4,6-dioxocyclohexane-1-carboxylate, or dimedone.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

New [f]-fused xanthines: Synthesis of 1,3-dipropyl-1H,3H-pyrazino,pyrido, pyrimido and pyrrolo[2, 1-f]purine-2,4-diones

Synthesis of 1,3-dipropyl-1H,3H-pyrazino, pyrido, pyrimido and pyrrolo[2,1-f]purine-2,4-diones, starting from 5,6-diamino-1,3-dipropylpyrimidine-2,4-dione 1 and 6-chloro-1,3-dipropylpyrimidine-2,4-dione 14 is described. A new synthetic approach to 1,3-dipropyl-1H,3H-pyrido(or pyrazino)[1′,2′-1,2]pyrimido[4,5-d]pyrimidine-2,4,5-triones 19 e, f, h has been also developed.     

Studies in spiroheterocycles. Part XVII. synthesis of novel fluorine containing spiro[indole-pyranobenzopyran] and spiro[indenopyran-indole] derivatives

An elegant one-step synthesis of two novel spiro ring systems viz: spiro[3H-indole-3,4′-(2′-amino-3′-carbonitrile-[4′H]-pyrano[3,2-c]benzopyran)]-2,5′(1H)-dione8 and spiro[(2-amino-3-carbonitrile-indeno[1,2-b]pyran)-4(5H)>3′-[3H]indole]-2′,5(1′H)-diones in 80–85% yields is described. The spiro heterocycles were prepared by the reactions of fluorine containing 3-dicyanomethylene-2H-indol-2-ones with 4-hydroxy-2H-1-benzopyran-2-one and 1H-indene-1,3(2H)-dione respectively. The synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral data.     

Synthesis of 5,7-disubstituted-4-β-D-ribofuranosylpyrazolo[4,3-d]-pyrimidines and 2,4-disubstituted-1-β-D-ribofuranosylpyrrolo[3,2-d]-pyrimidines as congeners of uridine and cytidine

The synthesis of the congeners of uridine and cytidine in the pyrazolo[4,3-d]pyrimidine and pyrrolo[3,2-d]-pyrimidine ring system is described. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[4,3-d)pyrimidine-5,7(1H,4H,6H)-dione (4) with either 1-bromo- or 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose 5 and 6 , respectively in the presence of a Lewis acid catalyst gave the protected nucleoside 7 , which on debenzoylation afforded the uridine analogue 4-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidine-5,7(1H,6H)-dione (8). Thiation of 7 gave 13 , which on deprotection yielded 4-β-D-ribofuranosyl-5-oxopyrazolo[4,3-d]pyrimidine-7(1H,-6H)-thione (14). Ammonolysis of 13 gave a low yield of the cytidine analogue 15. A chlorination of 7 , followed by amination furnished an alternative route to 15. A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride (16) gave mainly the N4 glycosylated product 17 , which on debenzylation furnished 4-β-D-arabinofuranosylpyrazolo[4,3-d]pyrimidine-5,7(1H,6H)-dione (18). 7-Amino-4-β-D-arabinofuranosylpyrazolo[4,3-d]pyrimidin-5(1H)-one (23) was prepared from 17 via the pyridinium chloride intermediate 21. Condensation of the TMS derivative of pyrrolo[3,2-d]pyrimidine-2,4(1H,3H,5H)-dione (24) with 6 , followed by deprotection of the reaction product gave 1-β-D-ribofuranosylpyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (26). Similarly, TMS-24 was reacted with 16 to give a mixture of the blocked nucleosides 31 and 32 , which on debenzylation afforded a mixture of two isomeric compounds 34 and 35. 1-β-D-Arabinofuranosylpyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (34) was converted to the ara-C analogue 38 via the 3-nitrotriazolyl intermediate 36. The structure of 38 was confirmed by single crystal X-ray diffraction studies.     

Directed regiospecificity of 1,3-dipolar cycloaddition of 2-diazopropane to 4- and 5-substituted pyridazin-3(2H)-ones

6-Methoxy-2-methylpyridazin-3(2H)-one ( 1 ) gave with 2-diazopropane ( 8 ) a mixture of 3H-pyrazolo[3,4-d]-pyridazin-4(5H)-one derivative 12 , as the main product, and -7(6H)-one derivative 10 , as the minor product. On the other hand, 4-substituted pyridazin-3(2H)-ones 2, 3 , and 4 gave 3H-pyrazolo[3,4-d]pyridazin-7(6H)-one 10 , exclusively, while 5-substituted pyridazin-3(2H)-ones 5, 6 , and 7 produced only the isomeric 3H-pyrazolo[3,4-H]pyridazin-4(5H)-one 12 . The 5-phenylsulfonyl derivative 13 gave with 8 by elimination of a molecule of nitrogen, followed by rearrangement, 1,2-diazepine derivative 15 and with an excess of 8 3H-pyrazolo[3,4-d][1,2]diazepine derivative 16. 1 ,2-Dimethylpyridazine-3,6-(1H,2H)-dione and its derivatives 18 and 19 produced 3H-pyrazolo[3,4-d]pyridazine-4,7(5H,6H)-dione derivative 23 , while from 17 and 1-diazoindane ( 24 ) the spiro compound 27 was obtained. The 1,2-dihydro and 3a,7a-dihydro intermediates 21 and 25 were isolated.