Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine

The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e,f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.     

A study of the products of the reduction of the antibiotic reumycin (6-methylpyrimido [5,4-e][1,2,4]triazine-5,7-dione)

The structures of the products of the reduction of the antibiotic reumycin (I), which is a specific autooxidizable acceptor of reducing equivalents from certain flavin dehydrogenases of the respiratory chain of the mitochondria of yeast and animal tissues, have been established with the aid of physicochemical methods (UV, IR, and PMR spectroscopy and mass spectrometry). In the determination of the structures of five reduction products of reumycin effective use has been made of high-resolution mass spectrometry and a consideration of the spectra of metastable ions (the DADI technique). It has been shown that only the asym-triazine ring in the initial (I) undergoes reduction and ring-opening.All-Union Scientific-Research Institute of Antibiotics, Moscow Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 85–95, January–February, 1981.     

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.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Regioselective alkylation of 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole

Alkylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole using different alkylating agents leads regioselectively to 1-N-alkylated products. The hydrolysis-decarboxylation of 1,6-dimethyl-7-ethoxycarbonyl-pyrazolo[5,1-c][1,2,4]triazole yields a compound identical with that obtained by the direct methylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole. The 1-N-alkylation is confirmed by NMR spectroscopy and mass spectrometry.     

A tandem multi-component synthesis of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones

The five-component reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, aromatic aldehydes, and ammonium acetate affords two diastereomers of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones via a novel tandem Mannich-enamine-substitution sequence. Presumably, they are generated from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]acetates. During the formation of the trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]acetates, the configuration at the carbon bearing an aryl group adjacent to the enamide CC double bond is inverted via ring opening and closure. When o-substituted benzaldehydes were employed in this reaction, 5,7-diaryl-5,6-dihydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones were obtained via air oxidation, along with trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones.     

Microwave-assisted one-pot synthesis of benzo[b][1,4]oxazin-3(4H)-ones via Smiles rearrangement

An efficient method for the synthesis of benzo[b][1,4]oxazin-3(4H)-ones via Smiles rearrangement using a microwave-assisted one-pot, three-step reaction has been developed. Various benzo[b][1,4]oxazin-3(4H)-ones are obtained in good yields (55-86%) from the corresponding substituted 2-chlorophenols and primary amines in short reaction time (18-40 min).     

Microwave-assisted one-pot synthesis of benzo[b][1,4]thiazin-3(4H)-ones via Smiles rearrangement

The synthesis of benzo[b][1,4]thiazin-3(4H)-one derivatives in a simple and efficient method from the one-pot reaction of substituted 2-chlorobenzenthiols, chloroacetyl chloride, and primary amines via Smiles rearrangement under microwave irradiation gave high yields (65-92%) of the products with short reaction time (15-20 min).     

Regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by radical cyclization

5-Hydroxy uracils or 4-hydroxy[1]benzopyran-2-ones were refluxed with 2-bromobenzyl bromides in acetone in the presence of anhydrous potassium carbonate to afford a number of 5-(2′-bromobenzyloxy) pyrimidine-2,4-dione (80-92%) or 4-(2′-bromobenzyloxy) benzopyran-7-ones (70-82%) respectively. These were then refluxed with tri-n-butyltin chloride and sodium cyanoborohydride in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) for 3-4 h to give 1H,3H,6H [2]benzopyrano[4,3-d]pyrimidine-2,4-diones (75-85%) or 12H-benzopyrano[3,2-c][1]benzopyran-5-ones (70-85%) respectively.     

Solid-phase synthesis of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine derivatives

We have developed an efficient solid-phase synthetic approach for the synthesis of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine derivatives. The methodology is of value for high throughput synthesis of these potentially bioactive molecules.     

Niementowski-type synthesis of pyrido[3,2-e][1,2,4]triazines: potent aza-analogs of pyrido[2,3-b]pyrazine fungicides

Novel trisubstituted pyrido[3,2-e][1,2,4]triazines have been found to possess similar biological activity to the corresponding pyridopyrazine fungicides against important phytopathogens such as Mycosphaerella graminicola (wheat leaf blotch), Magnaporthe grisea (rice blast), and Rhizoctonia solani (rice sheath blight). They have been prepared for the first time from a monocyclic triazine by Niementowski-type ring condensation.     

A novel synthesis of substituted 3-amino and 3-thio pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

Fervenulin is a natural product that has been extensively studied due to its molecular features and breadth of biological activities. Published studies have reported the generation of numerous analogues of the bicyclic pyrimidotriazinodione core. One underrepresented subclass are compounds with electron releasing atoms bonded directly to the C-3 position. We report an efficient and straightforward synthesis of compounds with substituted amino and thio functionality attached to the C-3 position. These are derived from a common 3-chloro precursor that is made in six steps in 15.8% overall yield from a starting chlorouracil. Our methodology should be applicable to the synthesis of C-3 ether congeners also, and through previously described chemistry be expandable to incorporating diversity at the N-6 position of the pyrimidotriazinodione core. The chemistry reported herein expands possibilities for the generation of diverse libraries of substituted pyrimidotriazinediones for future studies.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

Metal-free synthesis of chromeno[4,3-c]pyrazol-3(2H)-one derivatives

An unprecedented metal-free synthesis of 4-(methylthio)chromeno[4,3-c]pyrazol-3(2H)-one is reported via sequential one-pot desulfitative [5+1] hetero-annulation. The present strategy consists of one-pot sequential, base catalysed dithioketene formation from active methylene of pyrazolone followed by methylation and [5+1] heteroannulative cyclization. The resulting substrate undergoes facile nucleophilic substitution with various amines to yield 4-(substituted-amine)-chromeno[4,3-c]pyrazol-3(2H)-one derivatives under metal free condition.     

Synthesis of 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazines by Sonogashira/copper(I)-catalyzed heteroannulation

A Sonogashira/copper(I)-catalyzed heteroannulation sequence was developed to convert 3,5-diamino-6-chloro-1,2,4-triazines to the corresponding 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazine derivatives in good yields.     

Design,two-directional synthesis,DFT study of new pyrimido[5,4-d]pyrimidine-2,8-dione derivatives

A facile two-directional synthesis of new pyrimido[5,4-d]pyrimidine-2,8-dione was reported via an efficient reaction of premade bis-aldehydes and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea in the presence of triethylamine as the base and Cu (II) as catalyst. As there is controversy about the formation of two types of products, that is, purine or pyrimidine ring containing compounds in the reaction of diaminomaleonitrile with isocyanates and aldehydes, the computational model chemistry has been employed to obtain new insight about this reaction and determining the dominant pathway of the process. Using DFT model, two alternative pathways have been explored and geometrical isomerization of central double bond has been considered. Accordingly, the evaluated energy barriers affirm the formation of six-membered pyrimidine ring as the major product in the presence of CuCl₂ as the catalyst and MeOH as solvent.