A convenient synthesis of novel pyrido(1′,2′:1,2)imidazo[5,4‐d]‐1,2,3‐triazinones from imidazo[1,2‐a]pyridines

Abstract

The imidazo[1,2-a]pyridine system was investigated as a synthon for the building of very attractive fused triazines, a planar, angular tri-heterocycle with potential biological activity. Thus ethyl 3-nitroimidazo[1,2-a]pyridine-2-carboxylate was treated with ammonia or with an excess of primary amines to generate the corresponding substituted nitro carboxamidoimidazopyridines. The nitro substituent in the latter products, was reduced to yield 3-amino-2-carboxamidoimidazo[1,2-a]pyridine derivatives, which in turn were treated with nitrous acid to furnish 1-oxo-2-substituted pyrido(1',2':1,2)imidazo [5,4-d] We were interested in preparing triazinones fused to the imidazopyridine nucleus and evaluate their potential affinity of binding to dopaminergic and adrenergic receptors. The planar fixed geometry of these heterocycles makes them attractive candidates for screening in relation to other biological activities.A fine research on the formation of triazines from anthranylate esters is available [6]. We then sought for an appropriately 2,3-substituted imidazo[1,2-a]pyridine and found compound 1 a suitable candidate. In this study, we present the results of the investigation carried out on the imidazopyridine nucleus as a synthon for the construction of a rigid geometry t r i-heterocycle system containing a 1,2,3-triazine ring.The synthetic approach shown in scheme 1 was followed. A c c o r d i n g l y, the readily available ethyl imidazo[1,2-a] p y r idine-2-carboxylate 1, [7] was easily nitrated at low temperature with concentrated nitric acid in sulfuric acid. The ease of electrophilic substitution at position 3-in these systems allowed the formation of 3-nitro imidazo[1,2-a] p y r i d i n e -2 -carboxylate 2 in good yield (80 %).Formation of the amide was preferred over preparation of the corresponding anthranylate ester, which would have been less reactive towards ammonia. Thus, nitro ester 2 was treated with ammonium hydroxide saturated with ammonia at room temperature and from the heterogeneous mixture, the corresponding amide 3a was isolated in good yield. Other primary amines were heated with compound 2 in the absence of solvent (an excess of the amine was required) to yield the corresponding crude 3-nitro-2-carboxamido imidazo[1,2-a]pyridines 3. These products were recrystallized either from water or ethyl alcohol. In order to improve the reaction time (4-5 h) of the latter process, experiments were carried out using an alternative source of energy such as IR radiation [8]. Indeed the reaction time dropped dramatically under these conditions, a maximum of 40 min were required to complete the reaction. In spite of this result, conventional heating was preferred since it allowed the use of larger quantities of reactants.The nitrocarboxamido substituted imidazo[1,2-a]pyridines 3 were fully characterized through conventional spectroscopic methods. The numbering of the structures in Scheme 1 was based on early reports dealing with 1 H nmr assignments [9] on these systems. The nitroamides 3 were then reduced to th...

Structure−Activity Relationship of Triazafluorenone Derivatives as Potent and Selective mGluR1 Antagonists

“…This intermediate was then treated with potassium t -butoxide in a mixture of methanol and pyridine to give the cyclized product 12 in quantitative yield. The amino amide, 5-amino-4-dimethylaminothieno[8,9- b ]pyridine-6-carboxylic acid amide ( 12 ), was oxidized with sodium nitrate at 0 °C to form the tricyclic heterocycle, 9-dimethylamino- 3H -5-thia-1,2,3,6-tetraazafluoren-4-one ( 13 ) (91%) . With this tetraazafluorenone intermediate 13 in hand, the 3-substituted tetraazafluorenone 14 could be made by reaction of the corresponding alkyl halide using sodium hydride in dimethylformamide (DMF) with moderate chemical yield (Scheme ) accompanied by small amounts of O -alkylation product …”