A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

A new, one-pot, multi-component synthesis of imines of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines

An efficient, one-pot, multi-component synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines is described. Heating a mixture of a 2-aminopyridine, 2-aminopyrazine or 2-aminopyrimidine, a benzaldehyde, and imidazoline-2,4,5-trione under solvent-free conditions afforded imine derivatives of the title compounds in excellent yields. Single-crystal X-ray analysis conclusively confirms the structure of these bridgehead bicyclic 5-6 heterocycles.     

Novel heterocyclic β-nitroenamines-based on a one-pot three-component reaction: a facile synthesis of fully substituted 1H-pyrrolo[1,2-a]-fused-1,3-diazaheterocycles

A one-pot multicomponent synthesis of a novel class of 2,3-dihydro-1H-pyrrolo[1,2-a]imidazoles, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidines, and 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepines, starting from simple and readily available inputs including diveres diamines, l,l-bis(methylthio)-2-nitroethen and diaroylacetylene, in excellent yields is described.     

Synthesis of the novel pyrimido[1,6-a]pyrimidine and imidazo[1,2-c]pyrimidine derivatives based on heterocyclic ketene aminals

A concise and efficient route for the synthesis of pyrimido[1,6-a]pyrimidines and imidazo[1,2-c]pyrimidines by simply refluxing a reaction mixture of different heterocyclic ketene aminals and N,N′-bis(arylmethylidene)arylmethane was developed. This protocol provides an alternative method for application in combinatorial and parallel synthesis in drug discovery.     

An investigation of the minimal structural conditions lor the dirnroth-type rearrangement in the polyazaindolizine series

In the imidazo[1,2]diazine series, only the imidazo[1,2-a]- and [1,2-c] pyrimidine systems were found to undergo a Dimroth-type rearrangement under basic aqueous conditions. The electronic and steric factors influencing the rearrangement rates of methyl substituted imidazo-[1,2-a] pyrimidines are discussed.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

Synthesis of 4-trifluoromethylpyrido[1,2-a]pyrimidin-2-ones utilizing activated alkynoates

The synthesis of the biologically relevant, 4-trifluoromethylpyrido[1,2-a]pyrimidin-2-one 7, is reported. Addition of substituted 2-aminopyridines 5 to activated alkynoates leads to the facile formation of a series of metabolically stable trifluoromethyl substituted pyrido[1,2-a]pyrimidines under mild conditions.     

Synthesis and reactions of “biginelli-compounds”. Part I

Various reactions of 2-oxo(or thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid derivatives (Biginelli-compounds) were investigated. The site of methylation and acylation on 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester 1a and its 2-oxo derivative 9a was studied. The synthesis of pyrimido[2,3-b]thiazines and thiazolo[3,2-a]pyrimidines was accomplished by condensation of 1a with 1,3-and 1,2-dielectrophiles. A Dimroth-like rearrangement yielding 6H-1,3-thiazines can be observed when 1a was treated with dimethylformamide and phosphorus oxychloride. The formation of indeno[1,2-d]pyrimidines can be achieved by intramolecular Friedl-Crafts acylation of 9a and 13 , respectively. Finally a route for the preparation of 4,6-disubstituted-pyrimidine-5-carbonitriles is presented, starting with Biginelli-compound 25 .     

Copper oxide nanoparticle catalysed synthesis of imidazo[1,2-a]pyrimidine derivatives,their optical properties and selective fluorescent sensor towards zinc ion

Synthesis of biologically active fused imidazo[1,2-a]pyrimidines were achieved via A³ coupling involving 2-aminobenzimidazole, aldehyde and terminal alkyne, followed by 6-endo-dig cyclization using copper oxide nanoparticles under solvent free condition. Further optical properties of imidazo[1,2-a]pyrimidines were studied which showed the effect of electron-donating and electron-withdrawing substitution on the fluorescence intensities of these compounds. Out of 20 compounds, 2,4-bis(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine can act as a fluorescent sensor for zinc ion with detection limit 4.74?μM, which is much lower than the maximum allowable zinc concentration in drinking water by WHO.     

Synthesis of unsymmetrically tetrasubstituted pyrroles and studies of AIEE in pyrrolo[1,2-a]pyrimidine derivatives

Pyrroles are among the most important heterocycles in pharmaceuticals and agrochemicals. Construction of pyrrole scaffolds with different substituents and a free NH group, however, is challenging. Herein, a metal-free method for the synthesis of unsymmetrically tetrasubstituted NH-pyrroles using a consecutive chemoselective double cyanation is reported. The desired pyrroles were obtained with yields up to 99% and good functional group tolerance. Mechanistic studies identified a reaction mechanism that features a subtle sequence of first cyano-addition and migration, followed by cyano-addition and aromatization to afford the pyrrole skeleton. Pyrrolo[1,2-a]pyrimidines are synthesized as the synthetic applications of NH-pyrroles, and these pyrrolo[1,2-a]pyrimidines exhibit unpredicted time-dependent aggregation-induced emission enhancement (AIEE) properties.

A novel method for the challenging synthesis of unsymmetrically tetrasubstituted NH-pyrroles from chalcone derivatives is reported. The pyrrolo[1,2-a]pyrimidine derivatives that were synthesized from NH-pyrroles exhibit AIE and AIEE property.     

One-pot synthesis of 6H-2,2a1,3-triazaaceanthrylen-6-ones and 6H-2,2a1,4-triazaaceanthrylen-6-ones via tandem cyclization strategies

Two operationally simple one-pot protocols have been developed for the synthesis of 6H-2,2a¹,3-triazaaceanthrylen-6-ones and 6H-2,2a¹,4-triazaaceanthrylen-6-ones. The first Pd-catalyzed tandem cyclization of imidazo[1,2-a]pyrimidines/imidazo[1,2-a]pyrazines with 2-chlorobenzaldehydes could proceed in aqueous medium under air, affording the desired products in moderate to good yields. The molecular structures of products 3i and 5b were confirmed by X-ray crystallographic analysis.     

A new approach to synthesis of 2-sulfonylamino-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidines

A procedure for synthesis of 2-sulfonylamino-1,2,4-triazolo[1,5-a]pyrimidines by sulfonylation of 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines, followed by oxidation of intermediate 2-sulfonylamino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines, was suggested.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

The synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines from a vinyl ether

A new method has been developed for the synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines. 2-Chloro-6-[(Z)-2-ethoxyethenyl]pyrazine was treated with N-bromosuccinimide in dioxane-water to generate the 2-bromo-2-(6-chloropyrazin-2-yl)-1-ethoxyethanol intermediate. In a subsequent one-pot step, optional treatment with various 2-aminopyridines provided the cyclized 3-pyrazinyl-imidazo[1,2-a]pyridines in 31-76% yields.     

Pyrazolo[1,5-a]pyridines: synthetic approaches to a novel class of antiherpetics

Synthesis of a novel class of 7-amino-3-pyrimidinyl-pyrazolo[1,5-a]pyridine antiherpetic compounds is described. The synthetic methodology is designed to allow for rapid analog synthesis around the C-3 and C-7 positions of the pyrazolo[1,5-a]pyridine. The 7-chloropyrazolo[1,5-a]pyridine D, produced through an azirine rearrangement, served as a key building block. Two complementary methodologies for construction of the C-3 pyrimidine are described. These methods include the development of a novel cyclization utilizing alkynyl ketones or enones to give highly substituted pyrimidines. The outlined strategies facilitated late stage manipulation of either the C-3 or C-7 positions providing flexibility for rapid analog synthesis.     

Pd/C-catalyzed heterocyclization during copper-free Sonogashira coupling: synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water

An efficient synthesis of 2-benzylimidazo[1,2-a]pyrimidines in water is accomplished via Pd/C-catalyzed reaction of 2-imino-1-(2-propynyl)pyrimidine with various aryl iodides in the presence of K₂CO₃ as the base.     

Synthesis of amino derivatives of triazolopyrimidine

Heterocyclization of 1-(4,6-dimethylpyrimidin-2-yl)-4-R-thiosemicarbazides by the action of methyl iodide in ethanol in the presence of sodium acetate is accompanied by Dimroth rearrangement leading to the formation of 5,7-dimethyl-2-R-amino[1,2,4]triazolo[1,5-a]pyrimidines. Analogous heterocyclization of 4-aryl-1-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thiosemicarbazides gives 3-arylamino-7-methyl-5-oxo-[1,2,4]triazolo[4,3-a]pyrimidines. The presence in the pyrimidine ring of a carbonyl group capable of forming hydrogen bond with protons of the amino group stabilizes the molecule, thus hampering the Dimroth rearrangement.     

NBS mediated protocol for the synthesis of N-bridged fused heterocycles in water

A facile and environmental friendly protocol for the synthesis of N-bridged fused bicyclic compounds such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[2,1-b]thiazole, from commercially available starting materials has been developed. The reaction proceeds via NBS mediated in situ formation of α-brominated intermediate of corresponding aromatic ketones, 1,3-diketones, β-keto esters, followed by trapping with suitable nucleophiles to provide these versatile imidazole fused bicyclic heterocycles in good yields under metal-free conditions.     

Cyclisation of 3-alkenylpyrido[1,2-a]pyrimidines to furo[2,3-d]pyrido[1,2-a]pyrimidines

3-Alkenylpyrido[1,2-a]pyrimidines react under mild conditions to give novel tricyclic furo[2,3-d]pyrido[1,2-a]pyrimidines in high yields. The cyclisation takes place in the presence of an acid catalyst. The product yield is affected by the type and the strength of the acid used. Exceptionally high yields were obtained when an organic acid like trifluoromethanesulfonic acid and trifluoroacetic acid were used. On the other hand, sulfuric acid gave the best results of the inorganic acids examined.     

One step synthesis of 6,7-dimethyl-2-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a][1,3]pyrimidines

A one-step synthesis of substituted pyrrolo[1,2-a][1,3]pyrimidines from acetyl methyl carbinol, 3-aminopropionic acid, and substituted acetonitriles is reported.