Synthesis of 2-amino-6,7-dihydrothieno-[3′,2′:5,6]pyrido[2,3-d]pyrimidin-4-one

2-Amino-6,7-dihydrothieno[3′,2′:5,6]pyrido[2,3-rf]pyrimidin-4-one ( 1 ) was prepared in three steps from S-(3-butynyl)thiosemicarbazide hydroiodide ( 3 ) and diethyl ketomalonate. The featured step in this synthetic sequence was an intramolecular Diels-Alder reaction of the in situ generated 3-(3-butynylthio)-6-carboethoxy-5-chloro-1,2,4-triazine ( 9 ) to provide the key intermediate 5-carboethoxy-6-chloro-2,3-dihydrothieno-[2,3-b]pyridine ( 6 ). In the course of studies directed toward the preparation of 1 , thermolysis of 3-(3-butynyl-thio)-6-carboethoxy-1,2,4-triazin-5(2H)-one ( 2 ) was found to involve competitive intramolecular Diels-Alder and intramolecular coplanar cycloamination processes, providing the 2,3-dihydrothieno[2,3-b]pyridin-6(7H)-one ( 4 ) and the 1,3-thiazino[3,2-b]-1,2,4-triazin-3-one (5) derivatives, respectively.     

Acylation of 5-amino-3H-1,3,4-thiadiazolin-2-one

Acylation of 5-amino-3H-1,3,4-thiadiazolin-2-one (2) was undertaken selectively at either the 3-NH position or at 5-amino group depending on reaction conditions. The 3-NH is highly acidic and acylation takes place with acid anhydrides at this position in high yields in the presence of pyridine or triethylamine. The diacylation of both the 3-position and the 5-amino group was only possible via the 5-amino-3-acyl-1,3,4-thiadiazolin-2-one intermediates 4 . Under neutral conditions, acylation only occurs at the 5-amino group with acyl chlorides forming 5-acylamino-3H-1,3,4-thiadiazolin-2-ones 5 . 5-Acetylamino-3H-1,3,4-thiadiazolin-2-one can also be synthesized by the thermal transformation of 5-amino-3-acetyl-1,3,4-thiadi-azolin-2-one in acetic acid.     

Syntheses of 6,8-disubstituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates

A series of 6,8-disubstituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates were prepared employing preformed 9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate precursors. Three synthetic approaches were utilized to accomplish the syntheses. The first approach involved a study of the order of nucleophilic substitution, 6 vs 8, of the intermediate 6,8-dichloro-9-β-D-ribofuranosyipurine 3′,5′-cyclic phosphates ( 2 ) with various nucleophilic agents to yield 8-amino-6-chloro-, 8-chloro-6-(diethylamino)-, 6-chloro-8-(diethylamino)-, 6,8-bis-(diethylamino)- and 8-(benzylthio)-6-chloro-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate (4, 9, 10, 11, 13) respectively and 6-chloro-9-β-D-ribofuranosylpurin-8-one 3′,5′-cyclic phosphate ( 5 ) and 8-amino-9-β-D-ribofuranosylpurine-6-thione 3′,5′-cyclic phosphate ( 6 ). The order of substitution was compared to similar substitutions on 6,8-dichloropurines and 6,8-dichloropurine nucleosides. The second scheme utilized nucleophilic substitution of 6-chloro-8-substituted-9-β-D-ribofuranosylpurine 3′,5′-cyclic, phosphates obtained from the corresponding 8-subslituted inosine 3′,5′-cyclic phosphates by phosphoryl chloride, 6,8-bis-(benzylthio)-, 6-(diethylamino)-8-(benzylthio),8-(p-chlorophenylthio(-6-(diethylamino)- and 6,8-bis-(methyl-thio)-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphates ( 14, 12, 20 , and 21 ) respectively, were prepared in this manner. The final scheme involved N¹-alkylation of an 8-substituted adenosine 3′,5′-cyclic phosphate followed by a Dimroth rearrangement to give 6-(benzylamino)-8-(methylthio)- and 6-(benzylamino)-8-bromo-9-β-D-ribofuranosylpurine 3′,5′-cyclic phosphate ( 24 and 25 ).     

Synthesis of 4-β-D-arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide and x-ray diffraction analysis of its 2′,3-anhydro precursor

Reaction of 2-amino-3′,5′-bis(O-tert-butyldimethylsilyl)-β- D -arabinofuran[1′,2′:4,5]-2-oxazoline with 2-chloroethylsulfonyl chloride in the presence of sodium bicarbonate followed by removal of the protecting groups gave 2′,3-anhydro-4-β- D -arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide ( 5 ), which by treatment with ammonia was converted to 4-β- D -arabinofuranosyl-5,6-dihydro-2H-1,2,4-thiadiazin-3-one 1,1-dioxide ( 6 ). The structure of compound 5 was unequivocally established by means of an x-ray diffraction analysis. The compound crystallized in the space group P2₁2₁2₁ with unit cell dimensions a = 5.883(3), b = 9.352(2), c = 18.769(7) Å, Z = 4. Its structure was established by direct multisolution techniques and refined by the full matrix least squares method to a final R value of 0.058 for the 1515 reflections observed.     

Saturated heterocycles. 242. Synthesis of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydro- quinazolin-4(3H)-one Derivatives

In the reactions of the recently synthesized β-ketoesters 1-[(3′-methoxycarbonyl- and 1-[(3′-ethoxycarbonyl-4′-oxo)-1′-cyclohexyl]-3,4-dihydroisoquinoline 4, 5 with amidines or cyclic guanidines, a number of 2-substituted-6-(6′,7′-dimethoxy-3′,4′-dihydro-1′-isoquinolyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one derivatives 6–8 were prepared. The new compounds possess various pharmacological actions.     

8-Aza-7-deaza-2′,3′-dideoxyguanosine: Deoxygenation of its 2′deoxy-β-D-ribofuranoside

The synthesis of 6-amino-1-(2′,3′-dideoxy-β-D -glycero-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( =8-aza-7-deaza-2′,3′-dideoxyguanosine; 1 ) from its 2′-deoxyribofuranoside 5a by a five-step deoxygenation route is described. The precursor of 5a, 3a , was prepared by solid-liquid phase-transfer glyscosylation which gave higher yields (57%) than the liquid-liquid method. Ammonoloysis of 3b furnished the diamino nucleoside 3c . Compound 1 was less acid sensitive at the N-glycosydic bond than 2′,3′-dideoxyguanosine ( 2 ).     

Synthèse et détermination de la structure de la 3H-(indazolyl-3′)-5 oxadiazol-1,3,4-one-2 par RMN 13C et spectrometrie de masse

The 3H-5-(3′-indazolyl)-1,3,4-oxadiazol-2-one was obtained by cyclising the hydrazide of the 3-indazolecarboxylic acid with carbonyl chloride. The structure was assigned by ¹³C nmr and mass spectrometry comparing the 2H, 3H-triazino-1,2,3[4,5-b]indazoledione-1,4. Rearrangement into 3H-5-(3′-indazolyl)-1,3,4-oxadiazol-2-one precedes the fragmentation of 2H,3H-triazino-1,2,4-[4,5-b]indazoledione-1,4 upon electron-impact.     

Synthesis of 5-fluoro-2-methyl-3-(2-trifluoromethyl-1,3,4-thiadiazol-5-yl)-4(3H)-quinazolinone and related compounds with potential antiviral and anticancer activity

The synthesis of ten new substituted 1,3,4-thiadiazolyl-4(3H)-quinazolinones 8–11, 13, 17 , and 20–23 is reported. Compounds 8–11 were prepared by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7. Compound 13 was obtained by condensation of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (3) with DL-α-amino-?-caprolactam (12) . Compound 17 was synthesized by condensation of 6-bromo-2-methyl-3,1-benzoxazin-4-one (16) and 2-amino-5-t-butyl-1,3,4-thiadiazole (5) . Compounds 20–23 were obtained by condensation of 5-chloro-6,8-dibromo-2-methyl-3,1-benzoxazin-4-one (19) and 5-substituted 2-amino-1,3,4-thiadiazoles 4–7, respectively. The substituted 3,1-benzoxazin-4-ones 3, 16, and 19 were obtained in good yield by refluxing the appropriate anthranilic acid, 1,15 , and 18 with acetic anhydride (2) .     

Spirocyclization of 1-(o-aminophenyl)cycloalkanols and 1-(2′-amino-3′-pyridinyl)cycloalkanols

A one-step synthesis of spiro[cycloalkane-1,4′-2H-3′,1-benzoxazin]-2′-ones and spiro[cycloalkane-1,4′-1H-pyrido[2′,3′-d][1,3′]oxazin]-2′-ones, obtained in good yield from the corresponding 1-(o-aminophenyl) and 1-(2′-amino-3′-pyridinyl)cycloalkanols is described using ethyl carbonate in presence of n-butyllithium.     

Facile Synthesis of 2′-Deoxyisoguanosine and Related 2′,3′-Dideoxyribonucleosides

The 2′-deoxyisoguanosine ( 1 ) was synthesized by a two-step procedure from 2′-deoxyguanosine ( 5 ). Amination of silylated 2′-deoxyguanosine yielded 2-amino-2′-deoxyadenosine ( 6 ) which was subjected to selective deamination of the 2-NH₂ group resulting in compound 1 . Also 2′,3′-dideoxyisoguanosine ( 2 ) was prepared employing the photo-substitution of the 2-substituent of 2-chloro-2′,3′-dideoxyadenosine ( 4 ). The latter was synthesized by Barton deoxygenation from 2-chloro-2′-deoxyadenosine ( 3 ) or via glycosylation of 2,6-dichloropurine ( 12 ) with the lactol 13 . Compound 1 was less stable at the N-glycosylic bond than 2′-deoxyguanosine ( 5 ). The dideoxynucleoside 2 was deaminated by adenosine deaminase affording 2′,3′-dideoxyxanthosine ( 17 ).     

Aroylation of 5-amino-2H-1,2,4-thiadiazolin-3-one

2-Aroyl-5-aroylamino-1,2,4-thiadiazolin-3-ones 2 have been synthesized through aroylation of 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1 ) as an analog of cytosine. The aroylation was carried out with a substituted aroyl chloride in pyridine at 56–58°. It has been established that the intermediates of the reactions are 2-aroyl-5-amino-1,2,4-thiadiazolin-3-ones 3 on the basis of the spectral data, additional experimental information and ab initio molecular orbital calculations.     

(±)-5′-Nor ribofuranoside carbocyclic guanosine

The synthesis of the guanine derivative (±)-2-amino-1,9-dihydro-9-[(1′α,2′β,3′β,4′α)-(2′,3′,4′-trihydroxy-1′-cyclopentyl]-6H-purin-6-one ( 2 ) is described. This compound is viewed as the carbocyclic ribofuranoside guanine nucleoside analogue lacking the 5′-methylene.     

Synthesis and conversions of 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline

The reaction of the hydrazone 3a with hydrazine hydrate in DBU/ethanol conveniently gave 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 6 . The reactions of 6 with an equimolar and 2-fold molar amount of nitrous acid afforded 3-(α-hydroxyimino-4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 9 and 3-(α-hydroxyimino-5-methyl-2H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 10 , respectively, which were converted into the 3-heteroarylisoxazolo[4,5-b]quin-oxalines 13a,b and 11 , respectively. Compound 9 was also cyclized into the 8-quinoxalinyl-1,2,4-triazolo-[3,4-f][1,2,4]triazines 14a,b .     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

Synthesis and properties of 5-(1,2-dihaloethyl)-2′-deoxyuridines and related analogues

The regiospecific reaction of 5-vinyl-3′,5′-di-O-acetyl-2′-deoxyuridine ( 2 ) with HOX (X = Cl, Br, I) yielded the corresponding 5-(1-hydroxy-2-haloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines 3a-c . Alternatively, reaction of 2 with iodine monochloride in aqueous acetonitrile also afforded 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with DAST (Et₂NSF₃) in methylene chloride at -40° gave the respective 5-(1-fluoro-2-chloroethyl)- ( 6a , 74%) and 5-(1-fluoro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6b , 65%). In contrast, 5-(1-fluoro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6e ) could not be isolated due to its facile reaction with methanol, ethanol or water to yield the corresponding 5-(1-methoxy-2-iodoethyl)- ( 6c ), 5-(1-ethoxy-2-iodoethyl)- ( 6d ) and 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with thionyl chloride yielded the respective 5-(1,2-dichloroethyl)- ( 6f , 85%) and 5-(1-chloro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6g , 50%), whereas a similar reaction employing the 5-(1-hydroxy-2-iodoethyl)- compound 3c afforded 5-(1-methoxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6c ), possibly via the unstable 5-(1-chloro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine intermediate 6h . The 5-(1-bromo-2-chloroethyl)- ( 6i ) and 5-(1,2-dibromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6j ) could not be isolated due to their facile conversion to the corresponding 5-(1-ethoxy-2-chloroethyl)- ( 6k ) and 5-(1-ethoxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 61 ). Reaction of 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with methanolic ammonia, to remove the 3′,5′-di-O-acetyl groups, gave 2,3-dihydro-3-hydroxy-5-(2′-deoxy-β-D-ribofuranosyl)-furano[2,3-d]pyrimidine-6(5H)-one ( 8 ). In contrast, a similar reaction of 5-(1-fluoro-2-chloroethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6a ) yielded (E)-5-(2-chlorovinyl)-2′-deoxyuridine ( 1b , 23%) and 5-(2′-deoxy-β-D-ribofuranosyl)furano[2,3-d]pyrimidin-6(5H)-one ( 9 , 13%). The mechanisms of the substitution and elimination reactions observed for these 5-(1,2-dihaloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines are described.     

Synthesis of representative 10-aryl-, 10-aralkyl- and 10-heteraryl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b]- [1,2,4]triazin-9-ones as potential anti-HIV agents

To prepare the title compounds, cyclocondensation of 1-amino-2-iminonaphtho[1,2-d]thiazole ( 2 ) with some representative glyoxylic acid derivatives was investigated. Heating 2 with methyl phenylglyoxylate ( 3a ) in methanol afforded only the open chain intermediates 4a,b . However, when this reaction was performed in re-fluxing glacial acetic acid, the expected compound, 10-phenyl-9H-naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]- triazin-9-one ( 5a ) was produced in 27% yield. Similar treatment of 2 with benzyl-, 2-furyl- and 2-thienylgly-oxylic acids 3b-d gave the corresponding 10-benzyl-, 10-(2-furyl)- and 10-(2-thienyl)-9H-naphtho[1′,2′:4,5]thi-azolo[3,2-b][1,2,4]triazin-9-ones 5b-d in 48–67% yields. As by-products, 9-benzoyl- and 9-(2-thenoyl)naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazoles 6a,d were also isolated. Compound 5a was selected for in vitro anti-HIV evaluation but found to be inactive.     

A method for the synthesis of racemic and optically active 2-substituted 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines

Several 9-(2′,3′-O-isopropylidene)- and 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines were synthesized by a “one pot” method starting from the acetonide of racemic or (S)-1-azido-2,3-dihydroxypropane, obtained from D-mannitol. 9-(2′,3′-Dihydroxypropyl)-8-azapurines were tested as adenosine deaminase inhibitors.     

Acid-catalysed,nucleophile-catalysed and thermal decomposition of 2-amino-3-(2′,2′-dimethylaziridino)-1,4-naphthoquinone

The course of the thermal, acid-catalysed and iodide-catalysed decomposition of 2-amino-3-(2′,2′-dimethylaziridino)-1,4-naphthoquinone (III) was investigated. Thermal and iodide-catalysed decompositions gave mainly 2,3-diamino-1,4-naphthoquinone (VI) and 2-amino-3-(2′-methylallylamino)-1,4-naphthoquinone (V) together with low amounts of 2,2-dimethyl-1,2,3,4,5,10-hexahydrobenzo[g]quinoxaline (IV) and 2-isopropyl-1H-naphthoimid-azole-4,9-dione (VII). The acid catalysed isomerization of the aziridinonaphthoquinone III with halohydric acids or with acetic acid readily gave the opening of the aziridine ring; the corresponding salts of 2-amino-3-(2′-haloisobutylamino)-1,4-naphthoquinones (VIIIa-c) and 2-amino-3-(2′-acetoxyisobutylamino)-1,4-naphthoqunone (X) were formed by cleavage of the carbon-nitrogen bond at the substituted carbon atom. Hypotheses on the mechanism of these reactions are given.     

5-(α-Fluorovinyl)tryptamines and 5-(α-Fluorovinyl)-3-(N-methyl-1′,2′,5′,6′,-tetrahydropyridin-3′- and -4′-yl)indoles—5-(α-Fluorovinyl)tryptamines

5-(α-Fluorovinyl)tryptamines 4a, 4b and 5-(α-fluorovinyl)-3-(N-methyl-1′,2′,5′,6′-tetrahydropyridin-3′- and -4′-yl) indoles 5a, 5b were synthesized using 5-(α-fluorovinyl)indole ( 7 ). The target compounds are bioisosteres of 5-carboxyamido substituted tryptamines and their tetrahydropyridyl analogs.