Synthesis and crystal structure of a covalently hydrated 8-thia-1,4-diazacycl[3.3.2]azine

Condensation of ethyl 4-chloroacetoacetate with 4-amino-6-hydroxy-2-pyrimidinethiol produced ethyl 3-hydroxy-5-amino-7-oxothiazolino[3,2-a]pyrimidin-3-acetate ( 7a ) on crystallization. Subsequent ring closure of 7a produced the tricyclic 6a-hydroxy-5,6,6a,7-tetrahydro-8-thia-1,4-diazacycl[3.3.2]azin-2,5-dione ( 8 ). The structure of 8 was confirmed by crystal x-ray diffraction analysis.     

Structure and reactions of a thiazolino[3,2-a]pyrimidine carbinolamine

Ethyl 4-chloroacetoacetate condenses with 4-amino-6-hydroxy-2-pyrimidinethiol to yield ethyl 3-hydroxy-5-oxo-7-aminothiazolino[3,2-a]pyrimidin-3-acetate ( 3 ), and not ethyl 3-hydroxy-5-amino-7-oxothiazolino[3,2-a]-pyrimidin-3-acetate, as previously reported. This compound reacts with ammonia to produce ethyl 4-(6′-amino-4′-oxo-2′-pyrimidinethiol)-3-aminocrotonate ( 8 ), the open chain structure of which accounts for the cyclization of 3 to the poly-cyclic lactam, 6a-hydroxy-5,6,6a,7-tetrahydro-8-thia-1,4-diazacycl[3.3.2]azine-2,5-dione, rather than the sterically more favorable lactone, when 3 was treated with triethylamine. Some other reactions of 3 are described, and the structures of 3 and 8 were comfirmed by single crystal X-ray diffraction analysis.     

7-Amino-5-imino-8(5H)-quinolones, 6-Amino-8-imino-5(8H)-quinolones and 7-Alkyl-4,6-dihydroxy-5,8-quinolinediones as potential antiprotozoal agents

Oxidation of 7-amino-8-hydroxyquinoline-5-sulfonic acid with silver oxide in dimethylformamide and in the presence of arylamines provided a series of 7-amino-5-arylimino-8(5H)-quinolones (VIIIb). Reaction of 8-dialkylamino-5,6-quinolinediones with triethyloxonium tetrafluoborate gave a series of unstable but synthetically useful enol ethers. These reacted with amines to give 6-amino-8-imino-5(8H)-quinolones, isolated and characterized as tetrafluoborate salts (XIa). Proton magnetic resonance studies showed these to be vinylogous amidinium salts, analogous to those previously obtained with 2-amino-1,4-naphthoquinone imines. 4,6-Dihydroxy-5,8-quinolinedione underwent free radical alkylation to give a 7-alkyl-4,6-dihydroxy-5,8-quinolinedione. Evaluation of the new compounds against various Plasmodium species in rodents, birds and mosquitoes revealed no significant antimalarial activity.     

Cyclization reactions of 1,3-dibromopropan-2-ol, 2,3-dibromopropan-1-ol and 1-bromomethyloxirane with 6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone

The cyclization reactions, carried out in strongly- or weakly-basic media, are described. Sometimes, 7-amino-2,3-dihydro-3-hydroxymethyl-5H-thiazolo[3,2-a]pyrimidin-5-one is separated out, together with 8-amino-3,4-dihydro-3-hydroxy-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, as the principal product. A mechanism of reaction, during which the cyclizating agents are changed into oxirane derivatives, is proposed. The results of single-crystal X-ray investigations on 8-amino-3,4-dihydro-3-hydroxy-7-nitroso-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (R = 0.035 for 1013 reflections), and on 7-hydroxymethyl-6,7-dihydrothiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one (R = 0.027 for 1607 reflections) are reported.     

The synthesis of 1,4-diazacycl[3,2,2]azine

The diazaanalog of “cycl[3,2,2]azine”, “1,4-diazacycl[3,2,2]azine” (1,4,7b-triazacyclopent-[cd]indene) and its 2-methyl derivative were prepared. These compounds are subject to facile acid-catalyzed hydrolysis affording substituted imidazo[1,2-a]pyridines.     

Coupling to the pyrimido[4,5-b][1,4]oxazine ring system: Synthesis of potential antifolates

The ability of 2-amino-4-hydroxy-7H-pyrimido[4,5-b][1,4]oxazine derivatives to inhibit dihydrofolate reductase led to a search for means of synthesizing new side chain substituted analogs of this marginally stable pyrimidooxazine system. A study of the synthesis and use of 6-functionalized pyrimido[4,5-b][1,4]oxazines for coupling side chains was begun and has now revealed methods for coupling p-aminobenzoic acid with 2-amino-4-hydroxy-6-carboxy-7H-pyrimido[4,5-b][1,4]oxazine and hydrolyzed 2-amino-4-hydroxy-6-carbe-thoxymethylene-6,7-dihdyro-5H-pyrimido[4,5-b][1,4]oxazine. The products are of interest for evaluation as potential antifolates.     

Cyclic condensations of 2-amino-1,3,4-thiadiazole with 1,3-dicarbonyl compounds

The reactions of 2-amino-1,3,4-thiadiazole with 1,3-dicarbonyl compounds are described. 2,4-Pentanedione gave 2-thiocyanato-4,6-dimethylpyrimidine while diethylmalonate and ethyl acetoacetate yielded 5-hydroxy-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-one and 7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, respectively. The structure of the latter compound was confirmed by a synthesis of the alternative isomeric structure (5-methyl-7H-1,3,4-thiadiazolo[3,2-a]pyrirnidin-7-one) from 2-amino-1,3,4-thiadiazole and α-bromocrotonic acid.     

Fused sulfur-containing pyridine systems. 1. Synthesis and structures of tetrahydropyridothienopyridinone and tetrahydropyridothiopyranopyridinone derivatives

The reactions of N-methylmorpholinium 4-aryl(hetaryl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates with malononitrile and acetone in ethanol afforded substituted tetrahydropyridothienopyridinones. In the absence of acetone, tetrahydropyridothiopyranopyridinones were isolated as the major reaction products. The latter were also synthesized independently by the reactions of the above-mentioned thiolates with 2-amino-1,1,3-tricyanopropene. The structure of 2,4-diamino-10-(2-chlorophenyl)-3-cyano-5-imino-8-oxo-7,8,9,10-tetrahydro-5H-pyrido[2",3":2,3]thiopyrano[4,5-b]pyridine was established by X-ray diffraction analysis.     

Synthesis of 2-amino-3-hydroxy- and of 2,3-diamino-3H-1,4-benzodiazepines

A new synthesis of 7-chloro-2,3-diamino-5-phenyl-3H-1,4-benzodiazepines is described, which allows for the preparation of compounds bearing the same or different substituents at the 2 and 3 positions, starting from 2-amino-7-chloro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepines.     

New heterocyclic structures. [1,2,5]Thiadiazolo[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazine and thiazolo[3,2a][1,2,5]thiadiazolo[3,4-d]pyrimidine

Derivatives of two new molecular structures, namely, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one and 6,7-dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo[3,4-d][pyrimidin-9-one, and derivatives of N-substituted sulfamic acid, namely, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl)sulfamic acid and (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, were separated out as by-products in the reduction reaction of 8-amino-3,4-dihydro-7-nitroso-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one and 7-amino-2,3-dihydro-6-nitroso-5H-thiazolo[3,2-a]pyrimidin-5-one derivatives, respectively, with sodium hydrosulfite. A mechanism of reaction, which hypothesizes the action of sodium hydrosulfite in an asymmetic form, is proposed. The results of single-crystal X-ray investigation on 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one (R = 0.032 for 863 reflections) and (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b]- [1,3]thiazin-6-on-7-yl)sulfamic acid, sodium salt (R = 0.028 for 3507 reflections) are reported.     

Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.     

Reactions of ethyl 4-amino-6-(ethoxycarbonylmethyl)-2-phenylpyrimidine-5-carboxylate with hydrazines

New substituted 4,6-diamino-7-hydroxypyrido[4,3-d]pyrimidin-5(6H)-ones were synthe-sized by treatment of ethyl 4-amino-6-(ethoxycarbonylmethyl)-2-phenylpyrimidine-5-car-boxylic acid with hydrazine hydrate and phenylhydrazine. In the case of methylhydrazine, the reaction proceeded in an unusual way and afforded a product identified, relying on NMR data, as functionally substituted 8-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-7-ylidene)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine comprising two amineimide fragments. A diacetyl derivative of this compound was obtained.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

Synthesis of 5-Oxo and 7-Oxopyrido[2,3-d]pyrimidines

The synthesis of 4-amino-2-methylthio-5-oxopyrido[2,3-d]pyrimidine 4 and its isomer, 4-amino-2-methyl-thio-7-oxopyrido[2,3-d]pyrimidine 6 is described. The regiochemistry of the reaction of 4,6-diamino-2-methyl-thiopyrimidine 9 and diethyl ethoxymethylene malonate 12 is discussed.     

Synthesis of 10-thia-5-deazafolic acid and 2-desamino-2-oxo-10-thia-5-deazafolic acid

The folate analogue, 10-thia-5-deazafolic acid, was obtained via a multistep synthetic sequence beginning with the known intermediate, 2,4-diaminopyrido[2,3-d]pyrirnidine-6-carboxaldehyde. Reduction of this aldehyde with sodium borohydride gave 2,4-diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine, which when heated in base gave 2-amino-3,4-dihydro-6-(hydroxymethyl)-4-oxopyrido[2,3-d]pyrimidine. Treatment of the latter compound with phosphorus tribromide in tetrahydrofuran afforded 2-amino-6-(bromomethyl)-3,4-dihydro-4-oxopyrido[2,3-d]pyrimidine, thus constituting the first successful synthesis of this elusive intermediate. The aforementioned bromomethyl compound reacted smoothly with the sodium salt of ethyl 4-mercaptobenzoate, and the resulting ester was saponified to give 10-thia-5-deazapteroic acid. Conventional peptide bond coupling to di-tert-butyl L-glutamate followed by treatment with trifluoroacetic acid afforded the target compound in respectable yield. Attempts to prepare its 5,6,7,8-tetrahydro derivative by catalytic hydrogenation were unsuccessful.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Investigation of nitrogen- and sulfur-containing heterocycles

The reaction of 5-amino-4-chloro- and -4-methoxy-6~mercaptopyrimidines with 4-methoxy-, 4-amino-, and 2,4-diethoxyphenacyl chlorides has yielded 5-amino-4-chloro- and -4-methoxy-6-phenacylthiopyrimidines. The reaction of 2, 5-diamino-4-methyl-6-mercaptopyrimidine with 4-methoxyphenacyl chloride has yielded 2-amino-6-hydroxy-6-(4-methoxyphenyl)-4-methyl-5, 6-dihydropyrimido[4, 5-b]-1,4-thiazine, and that with 4-aminophenacyl chloride has yielded the corresponding 7H-pyrimido[4, 5-b]-1,4-thiazine.For part IV, see [1].     

Synthesis and Properties of Unsymmetrical Phenyl-substituted Porphyrazines

3-Amino-1,1-dichloro-5/6-phenyl-1H-isoindole hydrochloride was reacted with 5-amino-2-imino-3,4-diphenyl-2H-pyrrole or 5-amino-2-imino-3,4-ethylenedithio-2H-pyrrole to obtain unsymmetrical phenyl-substituted porphyrazines.     

Reactions of 6-Amino-5-Cyano-3-Methyl-1,4-Diphenyl-1H 4H-Pyrano[2,3-C]Pyrazole and its Methanimidate

Reaction of 6-amino-5-cyano-3-methyl-1,4-diphenyl- 1H,4H-pyrano[2,3-c]pyrazole 1 with triethyl orthoformate in acetic anhydride gave its methanimidate 2, which reacts with primary aliphatic and aromatic amines to give 4,6-dihydro-3-methyl-1,4-diphenyl-6- (alkyl)pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5(lH)- imine 3 and the starting compound 1 , respectively. Treatment of 1 with o-aminophenol gave 5-(2-benzoxalyl)- 1,4-dihydro-3-methyl-1,4-diphenylpyrano[2,3-c]pyrazol- 6-amine 9.     

Thermal decomposition of 2-amino-3-aziridino-1,4-naphthoquinones

The course of the thermal decomposition of various 2-amino-3-substituted aziridino-1,4-naphthoquinones (Ia-g) was investigated. In all the cases, the thermal decomposition gave variable amounts of 2,3-diamino-1,4-naphthoquinone (II) and of substituted 1,2,3,4,5,10-hexahydrobenzo[g]quinoxaline-5,10-diones (IIIa-g) with complete stereospecificity. The decomposition of the aziridines Ib,f also gave significative amounts of 2-amino-3-allylamino-1,4-naphthoquinones (IVb,f). In the case of 2-amino-3-(2′-phenyl-3′-ethylaziridino)-1,4-naphthoquinone (Ig), the formation of trans-1-phenyl-1-butene (V), 2-(1-phenylpropyl)-1H-naphtho-imidazole-4,9-dione (VI), 2-phenyl-3-ethyl-3,4,5,10-tetrahydrobenzo[g]quinoxaline-5,10-dione (VII), 2-phenyl-3-ethyl-5,10-dihydrobenzo[g]quinoxaline-5,10-dione (VIII), and a mixture of cis- and trans-4H-2,3,5,6-tetra-hydro-2-phenyl-3-ethyl-5-iminonaphtho[1,2-b]oxazin-6-one (IX) also occurred. Hypotheses concerning the mechanism and the steric course of this reaction are given. The reaction is a general method for the stereospecific synthesis of 2,3-disubstituted 1,2,3,4,5,10-hexahydrobenzo[g]quinoxalines.