Synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,4]diazepine-6,8-diones

The sodium ethoxide catalyzed condensation of 4,5-diaminopyrimidine ( 3 ) with diethyl malonate afforded 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ). Methylation of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) using sodium hydride and two equivalents of iodomethane gave 5,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 5 ) which on further methylation using sodium hydride and one equivalent iodomethane yielded 6,7,8,9-tetrahydro-5,7,9-trimethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 6 ). Reaction of 6,7,8,9-tetrahydro-5H-pyrirnido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) with 4.2 equivalents of sodium hydride and 4.1 equivalents of iodomethane afforded 6,7,8,9-tetrahydro-5,7,7, 9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ). 6,7,8,9-Tetrahydro-5,7,7,9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ) exhibited weak anticonvulsant activities in the subcutaneous pentylenetetrazole and maximal electroshock anticonvulsant screens indicating it is a partial bioisostere of the anticonvulsant drug clobazam ( 2 ).     

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.     

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.     

Reaction of 4,5-diaminopyrimidine and ethyl acetoacetate: Synthesis and chemistry of isomeric dihydropyrimido[4,5-b][1,4] diazepinones

Depending upon reaction conditions, 4,5-diaminopyrimidine and acetoacetic ester gave a variety of condensation products, including the two isomeric dihydropyrimido[4,5-b][1,4]-diazepinones. Under conditions leading to bicyclic products, the formation of 1,5-dihydro-4-methyl-2H-pyrimido[4,5-b][1,4]diazepin-2-one ( 2 ) was strongly favored. The isomeric 3,5-dihydro-2-methyl-4H-4-one compound ( 4 ) was best obtained by cyclization of ethyl 3-(4-amino-5-pyrimidylamino)crotonate ( 3 ) under base catalysis. Thermal rearrangement of 2 and 4 proceeded, in each instance, with loss of the isopropenyl moiety and gave 8-purinone. Compound 4 underwent ring contraction under the influence of alkoxide to yield a product which was shown to be the 7-isopropenyl-8-purinone ( 6 ).     

Synthesis of 2,3-dihydropyrido- and 2,3-dihydropyrimido-[1,4]diazepines from triaminopyridine and triaminopyrimidine

The reaction of 2,3,6-triaminopyridine 1 and 4,5,6-triaminopyrimidine 2 with one equivalent of the chal-cones 3, in acetic acid, leads to the formation of the 8-amino-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepine and 6-amino-2,3-dihydro-1H-pyrimido[4,5-b][1,4]diazepine derivatives 4 and 5 . The products were characterized by NMR techniques such as ¹³C, ¹H, and DEPT including selective ¹³C{¹H} decoupling experiments.     

Synthesis of 2-aryl-2,3-dihydro-4-styrylpyrimidodiazepines in the reaction of 4,5,6-triaminopyrimidine and 2,4,5,6-tetraaminopyrimidine with diarylidenacetones

New 6-amino and 6,8-diamino-2-aryl-2,3-dihydro-4-styryl-1H-pyrimido[4,5-b][1,4]diazepines were obtained in the reaction of 2,4,5,6-tetraaminopyrimidine 1a and 4,5,6-triaminopyrimidine 1b with one equivalent of the diaryli dene acetones 2 in absolute ethanol with acetic acid as the catalyst. Structure analysis of 6-amino and 6,8-diamino-2-aryl-2,3-dihydro-4-styryl-1H-pyrimido[4,5-b][1,4]diazepines 3a-i, determined by detailed nmr measurements, reveals a high regioselectivity of this reaction.     

Synthesis of 4-hydrazino-5H-pyrimido[5,4-b]indole and related compounds

This paper describes the synthesis of two 4-amino-5H-pyrimido[5,4-b]indoles 5 , 4-hydrazino-5H-pyrimido[5,4-b]indole 6 , two 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 , and tetrazolo[4,5-c]pyrimido[5,4-b]indole 10 . Starting with ethyl 3-aminoindole-2-carboxylate 1 , 5H-pyrimido[5,4-b]indol-4-one 2 was obtained (80%) by condensing with formamide. Reactions of 2 with phosphorus oxychloride and phosphorus pentasulfide gave respectively, 4-chloro-5H-pyrimido[5,4-b]indole 3 (70%) and 5H-pyrimido[5,4-b]indole-4-thione 4 (80%). Compound 3 reacted with amines (morpholine, piperidine) to give the respective 4-amino-5H-pyrimido[5,4-b]-indoles 5 , and compound 4 reacted with hydrazine to give 4-hydrazino-5H-pyrimido[5,4-b]indole 6 (80%). Two hydrazones of 6 (benzylidene, isopropylidene) 7 were also prepared (90%). Compound 6 reacted with formic and acetic acids to give (65–75%) the respective 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 and with nitrous acid to give tetrazolo[4,5-c]pyrimido[5,4-b]indole 9 (85%). All the new compounds 2 to 9 were characterized by elemental analysis and spectral data (ir, nmr).     

Synthesis of novel imidazo[1,2-a][3,1]benzothiazines 4, imidazo[1,2-a]-[1,2,4]benzotriazines 5, and 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazines 6

Starting from the readily available 2-aminobenzhydrols ( 7 ), 3-amino-1,2,4-benzotriazine ( 11 ) and 2-amino-3-pyridinol ( 12 ), novel derivatives of 5-phenyl-5H-imidazo[1,2-a][3,1]benzothiazine-2-carboxylic acid, ethyl ester ( 4 ), imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester ( 5 ) and 4H-imidazo[2,3-c]pyrido-[2,3-e][1,4]oxazine ( 6 ) were prepared.     

Preparation of novel tricyclic ring systems containing the pyridazinone ring

Novel tricyclic ring systems, irmdazo[3,4-d]pyridazino[4,5-b][1,4]thiazines 3 , imidazo[2,1-b]pyridazino[4,5-e][1,3,4]thiadiazines 15 and 18 were prepared by the reaction of 5-amino-4-chloropyridazin-3(2H)-ones 1 and 5(4)-(1-methylhydrazino)-4(5)-chloropyridazin-3(2H)-ones 13 (16) with isothiocyanates 2 and 7 .     

The reaction of aromatic α,β-unsaturated ketones with 4,5-diamino-1,6-dihydropyrimidin-6-ones

The reaction of 4,5-diamino-1,6-dihydropyrimidin-6-ones 1 with one equivalent of the chalcones 2 leads in an acidic medium to the formation of the 2,4-diaryl-2,3,6,7-tetrahydro-1H-pyrimido[4,5-b][1,4]diazepin-6-ones 3a-m . The structure elucidation of the products is based on detailed nmr investigations including selective ¹³C[¹H] decoupling experiments.     

The Synthesis of pyrimido[4,5-b][1,4]diazocines and pyrido[2,3-b][1,4]diazoeines

The reaction conditions for the preparation of 7H,8H-1,3-dimethyl-2,4,6,9-tetraoxopyrimidino[4,5-b][1,4]-diazocine ( 9 ), 1,3-dimethy 1–2,4,6,11-tetraoxobenzo[f]pyrimidino[4,5-b][1,4]diazocine ( 10 ), 7H,8H-1,3-dimethyl-2,4,6,10-tetraoxopyrimidino[4,5-b][1,4]diazonine ( 16 ), and 7H,8H-6,9-dioxopyridino[2,3-b][1,4]diazocine ( 19 ) were determined. The mechanism of the formation of these compounds was established. The scope of these reactions was found to be general for eight and nine ring formation from 2,3-diamino-N-heterocycles.     

One-pot three component isocyanide-based reaction: Synthesis of novel tetracyclic fused furo[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole

A rapid, efficient and benign protocol has been developed for the construction of potentially biologically active furo[2′,3′:4,5]pyrimido[2,1-b][1,3]benzothiazole derivatives as major products along with (3E)-3-[(alkylamino)methylene]-2H-pyrimido[2,1-b][1,3]benzothiazole-2,4(3H)-dione derivatives as minor products using a one-pot, multi-component reaction of isocyanides, aromatic aldehydes and 2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one. The significant features of this protocol are the readily available and low-cost starting materials, short reaction time, mild reaction conditions, high yield of products and avoidance of toxic solvents and catalysts. Structures of compounds 4b and 5a were confirmed from single crystal X-ray studies.     

Synthesis of novel imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines

Several 1 1-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines have been used as starting material to prepare a number of derivatives of 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and 10H-pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines. The imidazole nucleus was built by reaction of amidines with ethyl bromopyruvate or aminoacetaldehyde dimethylacetal. Several derivatives of imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine have been prepared by formylation of the pyrrole ring followed by formation of thioamides. Condensation of 11-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines with diethyl ethoxymethylenemalonate afforded intermediate diesters which were transformed into the corresponding 10H-pyrimido[1,2-a]pyrrolo[2,1-c]-benzodiazepines.     

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.     

Bischler-Napieralski cyclocondensation in the synthesis of new 11H-pyrimido[4,5-b][1,4]benzodiazepines

A synthetic strategy based on nitrosation-aminolysis-nitroso reduction and Bischler-Napieralski cyclocondensation has been developed for the synthesis of a family of 2-amino-4-methoxy-11H-pyrimido[4,5-b][1,4]benzodiazepines.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole with oxalic acid derivatives

Refluxing 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with diethyl oxalate ( 2a ) in a 2:1 molar ratio in dry pyridine provided 2,2′-binaphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 3 ). On the other hand, when 1 was treated with excess amount of 2a in dimethylformamide, it afforded ethyl naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole-2-carboxylate ( 4a ) on heating and ethyl N-(2-iminonaphtho[1,2-d]thiazol-3-yl)oxamate ( 5 ) by stirring at room temperature. Cyclization of 5 upon fusion led to the formation of 3-hydroxy-2H-naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazin-2-one ( 6 ). Compound 6 could also be prepared directly from 1 by refluxing either with 2a neatly, in glacial acetic acid or with oxalic acid ( 2b ) in the same medium. The acid form of 4a might be obtained from 1 and 2b on heating in dimethylformamide, but it was decarboxylated to naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 4b ) during the reaction.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

The Mannich reaction in the synthesis of N,S-containing heterocycles

Reactions of 6-aryl-5-cyano-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidines with formaldehyde and primary amines gave earlier unknown 3,4-dihydro-2H,6H-pyrimido[2,1-b]-[1,3,5]thiadiazine derivatives in 58–94% yields. In boiling AcOH, these pyrimidothiadiazines underwent the retro-Mannich reaction leading to the starting pyrimidine-2-thiones. The structure of 3-(4-ethoxyphenyl)-6-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazine-7-carbonitrile was studied by X-ray diffraction analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1384–1387, July, 2007.     

Substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates as synthons for novel heterocycles

The triethylamine-catalyzed reaction of 4-substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates IIIa-h with 2,2,6-trimethyl-4H-1,3-dioxin-4-one IV gave 4-substituted ethyl 3-acetyl-2-hydroxy-7-methylthieno[2,3-b:4,5-b′]dipyridine-9-carboxylates Va-h. Some of the thienodipyridines ( V ) reacted with excess IV to give 5-substituted ethyl 3-acetyl-4,8-dimethyl-2-oxo-2H-pyrano[2,3-b]-pyrido[3′,2′:4,5]thieno[2,3-e]pyridine-10-carboxylates VI .