A comparison of nucleophilic reactions of 3-benzenesulfonyloxyalloxazine and its 1-methyl analog

Reactions of 3-benzenesulfonyloxyalloxazine ( 1a ) and its 1-methyl analog 1b with a number of nucleophilic reagents are reported. Relatively small nucleophiles, such as hydroxide ion, methanol, ethanol, methylamine, hydrazine and hydroxylamine converted 1a to 4-carboxy-s-triazolo[4,3-a]quinoxalin-1(2H)-ones and the corresponding esters or amides. As the size of the amine increased from methylamine to ethylamine, dimethylamine, propylamine and isopropylamine, there were obtained 4-(carboxamido)-s-triazolo[4,3-a]quin-oxalin-1(2H)-ones, (1-carboxamido)imidazolo[4,5-b]quinoxalines and 2,3-bis(ureido)quinoxalines. Sodium hydride or potassium cyanide in hot DMF degraded 1a to imidazolo[4,5-b]quinoxaline. However, methylmer-captide and benzylmercaptide ions attacked the sulfonate group of 1a to form 3-hydroxyalloxazine. 1-Methyl-3-benzenesulfonyloxyalloxazine ( 1b ) reacted with methanol, ethanol, 1-propanol, and to some degree 2-propanol, in the presence of triethylamine to furnish anhydro-1-hydroxy-3-methyl-4-(alkoxycarbonyl)-s-triazolo[4,3-a]quinoxalinium hydroxides. However, sodium methoxide in methanol converted this starting material to a mixture of anhydro-1-hydroxy-3-methyl-s-triazolo[4,3-a]quinoxalinium hydroxide and 1-methyl-3-hydroxyflavazole. A saturated aqueous solution of triethylamine transformed 1b to anhydro-1-hydroxy-3-methyl-s-triazolo[4,3-a]quinoxalinium hydroxide, apparently via the corresponding unstable 4-carboxylic acid. The reactions of 1b with a number of aliphatic amines yielded either amides based on the above mesoionic system or on the 3-carboxamido-2-quinoxalyl semicarbazide structure. The reaction of 1b with potassium cyanide furnished 1-methylimidazolo[4,5-b]quinoxaline. Mechanisms to explain all of the degradations are advanced.     

Formycin analogs. I. Model studies in the preparation of an isomer of formyein and related derivatives (s-triazolo[4,3-a] pyrazines)

The synthesis of a number of 8-substituted- and 3-methyl-8-substituted-.s-triazolo[4,3-a]-pyrazines as model molecules for an isomer of formyein (i.e., 8-amino-3-(β-D-ribofuranosyl)-s-triazolo[4,3-a ]pyrazine ( 2 )) and some of its derivatives (including aglycone) is reported. The C-8 subslituents include amino ( 3a and 4a ), chloro ( 3b and 4b ), hydroxy (as the 8 -ones 8a and 9a ), mercapto (as the 8 -thiones 8c and 9c ), hydroxylamino ( 3e and 4e ), selenoxy (as the 8 -selenones 8d and 9d ), metlioxy ( 3g and 4g ), and thiomethoxy ( 3h and 4h ). Also described are 7-methyl-s-triazolo[4,3-a]pyrazin-8(7H) one ( 8b ) and its 3-methyl derivative ( 9b ) together with imidazo[1,2-g]-s-triazolo[4,3-a]pyrazine ( 10a ) and its 3-methyl derivative ( 10b ). Complete spectral data for all of these molecules is presented.     

New polyazaheterocycles. 9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine

9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine have been synthetized from 4-hydrazino-7-methyl-s-triazolo[4,3-c]pyrimidine. Structural assignments based on nmr, ir and chemical manipulations are discussed.     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones

Abstract  

The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species.     

Purine analog inhibitors of xanthine oxidase - structure activity relationships and proposed binding of the molybdenum cofactor

A number of new hypoxanthine analogs have been prepared as substrate inhibitors of xanthine oxidase. Most noteworthy inhibitory new hypoxanthine analogs are 3-(m-tolyl)pyrazolo[1,5-a]pyrimidin-7-one ( 47 ), ID₅₀ 0.06 μM and 3-phenylpyrazolo[1,5-a]pyrimidin-7-one ( 46 ), ID₅₀ 0.40 μM. 5-(p-Chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-one ( 63 ) and the corresponding 5-nitrophenyl derivative 64 exhibited an ID₅₀ of 0.21 and 0.23 μM, respectively. 7-Phenylpyrazolo[1,5-a]-s-triazin-4-one ( 40 ) is shown to exhibit an ID₅₀ of 0.047 μM. The structure-activity relationships of these new phenyl substituted hypoxanthine analogs are discussed and compared with the xanthine analogs 3-m-tolyl- and 3-phenyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5-ones ( 90 ) and ( 91 ), previously reported from our laboratory to have ID₅₀ of 0.025 and 0.038 μM, respectively. The presence of the phenyl and substitutedphenyl groups contribute directly to the substrate binding of these potent inhibitors. This work presents an updated study of structure-activity relationships and binding to xanthine oxidase. In view of the recent elucidation of the pterin cofactor and the proposed binding of this factor to the molybdenum ion in xanthine oxidase, a detailed mechanism of xanthine oxidase oxidation of hypoxanthine and xanthine is proposed. Three types of substrate binding are viewed for xanthine oxidase. The binding of xanthine to xanthine oxidase is termed Type I binding. The binding of hypoxanthine is termed Type II binding and the specific binding of alloxanthine is assigned as Type III binding. These three types of substrate binding are analyzed relative to the most potent compounds known to inhibit xanthine oxidase and these inhibitors have been classified as to the type of inhibitor binding most likely to be associated with specific enzyme inhibition. The structural requirements for each type of binding can be clearly seen to correlate with the inhibitory activity observed. The chemical syntheses of the new 3-phenyl- and 3-substituted phenylpyrazolo[1,5-a]pyrimidines with various substituents are reported. The syntheses of various 8-phenyl-2-substituted pyrazolo-[1,5-a]-s-triazines, certain s-triazolo[1,5-a]-s-triazines and s-triazolo[1,5-a]pyrimidine derivatives prepared in connection with the present study are also described.     

A new method for the synthesis of fused 3-amino-s-triazole ring systems

Reaction of 2-methyl-2-thiopseudourea sulfate with 1-hydrazinophthalazine gave 3-amino-s-triazolo[3,4-a] phthalazine in good yield. 1-Amino-4-methyl-s-triazolo[4,3-a]quinoxaline and 1-amino-s-triazolo[4,3-a]quinoxalin-4(5H)one were similarly perpared.     

Preparation of 5-substituted- and 3,5-disubstituted-s-triazolo[4,3-a]pyridines

Cyclization of N-acyl-N′-(6-chloropyrid-2-yl)hydrazines ( 2a-2e ) with phosphorus oxychloride has produced several 5-chloro-s-triazolo[4,3-a]pyridines ( 3a-3e ). Nucleophilic displacement of the chlorosubstituent of 5-chloro-s-triazolo[4,3-a]pyridine ( 3a ) availed the 5-ethoxy ( 4a ) and 5-thioethoxy ( 4b ) derivatives and di(s-triazolo[4,3-a]pyrid-5-yl)sulfide ( 8 ) while reaction of 5-ethylsulfonyl-s-triazolo[4,3-a]pyridine ( 4d ) with potassium hydroxide yielded the 5-hydroxy/5-one system ( 4c or 6 ). Further reaction of 3a with bromine to give 3-bromo-5-chloro-s-triazolo-[4,3-a]pyridine ( 3g ) has provided the corresponding 3-cyano- and 3-carboxamido-5-chloro-s-triazolo[4,3-a]pyridine derivatives ( 3h and 3i ). Treatment of 6-chloro-2-hydrazinopyridine ( 1 ) with cyanogen bromide has provided 3-amino-5-chloro-s-triazolo[4,3-a]pyridine ( 3f ) which, with bromoacetaldehyde dimethyl acetal, transformed into 7-chloroimidazo[1,2-b]-s-triazolo[4,3-a]-pyridine ( 7 ). Finally, attempts at cyclizing N-oxalyl-N′-(6-chloropyrid-2-yl)hydrazine derivatives ( 2g-2i ) with intentions of preparing various 3-acyl-5-chloro-s-triazolo[4,3-a]pyridines for entry into other 3,5-disubstituted systems were unsuccessful.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

The chemistry of 4-hydrazino-7-phenylpyrazolo[1,5-a] -1,3,5-triazines

The reaction of 4-hydrazino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 4 ) with nitrous acid gave 8-phenyltetrazolo[1,5-e]pyrazolo[1,5-a]-1,3,5-triazine ( 5b ), which was determined by pmr and ir spectra to be in equilibrium with 4-azido-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 5a ). The equilibrium between the tetrazolo ( 5b ) and azido ( 5a ) forms was studied by pmr and an attempt was made to determine if substituents in the pyrazole nucleus could sufficiently stabilize the tricyclic tetrazolo form ( 5b ) over the bicyclic azido form ( 5a ). Thermal degradation of 5 (a ? b) in an aprotic solvent gave 4-amino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 7 ), indicating the probability of a nitrene mechanism involved in the decomposition. Heating 5 in aqueous base gave both 7 and the “hydroxy” analog, 7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4(3H)one ( 6 ), further substantiating the existence of a nitrene intermediate with a competing nucleophilic displacement of the azido group by a hydroxyl group. Cyclization of 4 with diethoxymethylacetate (DEMA) gave 8-phenyl-s-triazolo[4,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 8 ), which underwent thermal rearrangement to 8-phenyl-s-triazolo[2,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 9 ). Acid catalyzed ring opening of 9 with formic acid gave 3-N-formamido-5-phenyl-2(2-s-triazolyl)pyrazole ( 10 ). The failure of 10 to recyclize to 9 with the resultant loss of water, supported the theory that the rearrangement of 8 to 9 might occur simply as a concerted, thermally induced “anhydrous” rearrangement rather than via a covalently hydrated intermediate or a Dimroth type mechanism (in the base catalyzed rearrangement).     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-<Emphasis Type="Italic">d</Emphasis>]-1,2,4-triazolo[4,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5-ones

Abstract  The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species. Graphical abstract        

On triazoles XXIII [1]. The reaction of 5-amino-1,2,4-triazoles with thiacyclohexane β-oxo esters [2]

Six novel isomeric ring systems, namely the thiopyrano[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,4-e]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[4,3-e]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine and the thiopyrano[2,3-e]-1,2,4-triazolo[1,5-a]pyrimidine were synthesised. Spectroscopical evidence was given for the structure of compounds obtained.     

Synthèse et étude physicochimique des 1,2,4-triazolo[4,3-a]-pyridines et des 1,2,4-triazolo[2,3-a]pyridines

The synthesis of 1,2,4-triazolo[4,3-a] and [2,3-a]pyridines 7, 8 was achieved by cyclization of 2-hydrazino-8-nitropyridine 3a with formic acid. The 4,5,6,7-tetrahydro-1,2,4-triazolo[2,3-a]pyridine 13 and 8-amino-1,2,4-triazolo[2,3-a]pyridine 9 were obtained by catalytic hydrogenation. The reduction of triazolo pyridine 8 using stannous chloride led to the intermediate compound 10 which with acetic anhydride afforded 8-acetylamino-5-chloro-1,2,4-triazolo[2,3-a]pyridine 10a . The structure of the derivatives was determined by ¹H-nmr (DMSO-d₆).     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

Synthesis and antimalarial effects of 2-(3,4-dichloroanilino)-7-[[[(dialkylamino)alkyl]amino]]-5-methyl-s-triazolo[1,5-a]pyrimidines

3,4-Dichlorophenylisothioeyanate ( 10 ) was allowed to react with 2-methy1-2-thiopseudourea to give methyl 4-(3,4-dichlorophenyl)(dithioaltophanimidate ( 11 ) (41%), which upon treatment with hydrazine afforded 3-amino-5-(3,4-dichloroanilino)-s-triazole ( 12 ) (54-91%). Ring-closure with ethyl acetoacetale in acetic acid afforded 2-(3,4-dichloroanilino)-5-methyl-s-triazolo[ 1,5-α ]-pyrimidin-7-ol ( 13 ) (81%). Chlorination with phosphorus oxychloride gave 7-chloro-2-(3,4-dichloroanilino)-5-methyl-s-triazolo[1,5-α ]pyrimidine ( 14 ) (98%), which was condensed with various amines to yield the desired 2-(3,4-diehloroanilino)-7-¶[(dialkylamino)alkyl]arnino¶-5-methyl-s-triazolo[ 1,5-α]pyrimidines ( 6 a-d). The structures of the s-triazolo[ 1,5-α ]pyrimidines were based on nmr spectroscopy and ring stability considerations. Several of the amino-s-triazolo[ 1,5-α ]pyrimidines possessed antimalarial activity against P. berghei in mice.     

9-Deazapurine nucleosides. The synthesis of certain N-5-β-d-ribofuranosylpyrrolo[3,2-d]pyrimidines

Several N-5 ribofuranosyl-2,4-disubstituted pyrrolo[3,2-d]pyrimidine (9-deazapurine) nucleosides were prepared by the single phase sodium salt glycosylation of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine ( 3 ) using 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dirnethylsilyl-α-D-ribofuranose ( 2 ). Use of 2 for the glycosylation avoided the formation of “orthoamide” products 1 and provided an excellent yield of the β nucleoside, 2,4-dichloro-5-[2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-β-D-ribofuranosyl]-5H-pyrrolo[3,2-d]pyrimidine ( 4 ), along with a small amount of the corresponding α anomer, 5 . Compound 4 served as the versatile intermediate from which the N-7 ribofuranosyl analogs of the naturally-occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, controlled amination of 4 followed by sugar deprotection and dehalogenation yielded the adenosine analog, 4-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidine ( 8 ) as the hydrochloride salt. Base hydrolysis of 4 followed by deprotection gave the 2-chloroinosine analog, 10 , and subsequent dehalogenation provided the inosine analog, 5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]-pyrimidin-4(3H)-one ( 11 ). Amination of 10 furnished the guanosine analog, 2-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one ( 12 ). Finally, the α anomer in the guanosine series, 16 , was prepared from 5 by the same procedure as that used to prepare 12 . The structural assignments were made on the basis of ultraviolet and proton nmr spectroscopy. In particular, the isopropylidene intermediates 9 and 14 were used to assign the proper configuration as β and α, respectively, according to Imbach's rule.     

A simple one pot synthesis of 1-(s-triazolo[4,3-x]azinyl-3)-substituted polyols

Open-chain C-nucleosides, 1-(s-triazolo[4,3-x]azinyl-3)polyols 13–18 were prepared by one-pot synthesis from hydrazinoazines 20a,c and various D-aldoses 1–6. No protective groups were required for these transformations. 1-(s-Triazolo[4,3-b]pyridazinyl-3)-D-xylo-tetritol (15a) was isolated and characterised in the form of its 4-O-triphenylmethyl derivative 19. Reaction of hydrazinopyridazines 20a,b with methyl 2,3-di-O-acetyl-L-threuronate ( 22 ), followed by treatment with bromine, gave the corresponding (2R,3S)-2,3-diacetoxy-3-(s-triazolo[4,3-b]pyridazinyl-3)propanoic acid methyl esters 24a,b. Acetonisation of 1-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-D-gluco-pentitol ( 17a ) gave a mixture of isomeric bis-acetonides 25 and 26 , while acetonisation of 1-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-D-manno-pentitol ( 18a ) gave acetonide 27 as a single isomer.     

A convenient synthesis of 1,2,4-triazolo[4,3,2-o,p]-[1,3]diazocino[4,5-b]quinoxalines via a 1,3-dipolar cycloaddition reaction and a ring transformation

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 5 with triethyl orthoformate gave 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 6. The reaction of compound 6 with phenyl isocyanate afforded 7-chloro-4-phenylamino-1,2,4-triazolo[4,3-a]quinoxaline 7 , while the reaction of compound 6 with phenyl isothiocyanate resulted in deoxygenation to provide 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 8. However, the reaction of compound 6 with allyl isothiocyanate effected the 1,3-dipolar cycloaddition reaction, but not deoxygenation, to furnish 9-chloro-4,5-dihydroisoxazolo[2,3-a][1,2,4]triazolo[3,4-c]quinoxalin-5-ylmethylisothiocyanate 9. Moreover, the reduction of compound 9 with iron/acetic acid resulted in ring transformation to give 11 -chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2- o,p][1,3]diazocino[4,5-b]quinoxaline 10 , whose acetylation afforded 5-acetyl-11-chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2-o,p][1,3]diazocino[4,5-b]quinoxaline 11.     

Degradative ring opening of pyrido and pyrazino 3-benzenesulfonyloxyuracils and their conversion to condensed pyrazolones and triazolones

Ring opening, followed by an immediate Lossen rearrangement, of 3-benzenesulfonyloxypyrido[3,2-d, 3,4-d and 4,3-d]pyrimidine-2,4(1H,3H)diones with sodium methoxide in methanol furnished good yields of the methyl esters of 3-[2-(methoxycarbonyl)hydrazino]-2-, 3-[2-(methoxycarbonylhydrazino]-4- and 4-[2-(methoxycarbonyl)hydrazino]-3-pyridinecarboxylic acids, respectively. These hydrazino esters were cyclized to the corresponding pyridopyrazolones. However, the reaction of 3-benzenesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)dione with sodium methoxide produced 8-methoxycarbonyl-s-triazolo[4,5-a]pyridin-3(2H)one. In similar fashion, sodium methoxide converted 3-benzenesulfonyloxylumazine to 8-methoxycarbonyl-s-triazolo[4,3-a]pyrazin-3(2H)one.     

Reactions with 2-mercaptopyrimidines. Synthesis of some new thiazolo[3,2-a]- and triazolo[4,3-a]pyrimidines

Alkylation of 5-cyano-4-oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine I with methyl iodide, chloroacetic acid or 3-chloro-2,4-pentanedione, afforded the S-alkyl derivatives IIa-c. 2-Carboxymethylthio and 2-(2′,4′-dioxopentan-3-ylthio) derivatives IIb and IIc could be cyclised by acetic anhydride or polyphosphoric acid to give 6-cyano-3,5-dioxo-5H-7-phenylthiazolo[3,2-a]pyrimidine III and 2-acetyl-6-carboxamido-5H-3-methyl-7-phenylthiazolo[3,2-a]pyrimidine-5-one IX , respectively. Benzoylation of 2-hydrazinopyrimidine derivative XII , in anhydrous dioxan, afforded the N-benzoyl derivative XIII , which could be cyclised by heating in dimethylformamide to give 5-amino-6-cyano-3,7-diphenyl-s-triazolo[4,3-a]pyrimidine ( XIV ). The 2-hydrazinopyrimidine derivatives XII and XV reacted with benzoyl isothiocyanate in dioxane to yield 4-benzoylthiosemicarbazide derivatives XVI and XVII , which were converted into the 2-s-trizolopyrimidine derivatives XVIII and XIX , respectively. Also, XVI and XVII reacted with 2,4-pentanedione and 3-chloro-2,4-pentanedione to yield 2-pyrazolopyrimidine derivatives XX and XXI , respectively.     

The Donor-Acceptor-Acceptor Purine Analog: Transformation of 5-aza-7-deaza-1H-isoguanine (=4-aminoimidazo-[1,2-a]-1,3,5-triazin-2(1H)-one) to 2′-deoxy-5-aza-7-deaza-isoguanosine using purine nucleoside phosphorylase

A new synthesis is reported for 4-aminoimidazo[1,2-a]-1,3,5-triazin-2(1H)-one ( =5-aza-7-deaza-isoguanosine; 8 ), a purine analog that, when incorporated into an oligonucleotide chain, presents a H-bond donor-acceptor-acceptor pattern to a complementary pyrimidine analog. A protected ribose derivative was coupled to 8 to yield 4-amino-8-(β-D -ribofuranosyl)imidazo[1,2-a]-1,3,5-triazin-2(8H)-one ( =5-aza-7-deaza-isoguanosine; 11 ) after deprotection, Alternatively, direct synthesis of both the ribo derivative 11 and the corresponding deoxyribo derivative 17 as the β-D -anomers was achieved using the enzyme purine nucleoside phosphorylase in a one-pot reaction. This adapts a known synthetic approach to yield a new strategy for obtaining diastereoisomerically pure deoxyribonucleoside analogs on 1-gram scales.