No abstract

BackgroundThe proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type.ResultsTheoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction.ConclusionComputational calculations predicted correctly the conformational preferences in angular 3-π-EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift.

No abstract

A systematic study of electrophilic substitution reactions of 3-nitroso-2-arylimidazo[l,2-a]pyridine confirmed that the nitroso group may be /pio-substituted by bromine (NBS in DMF) and that bromine in turn may be substituted by the nitroso group. Electronic influence of the aryl sustituent at the Imidazopyridine 2-position during the ipsoelectrophilic process was experimentally assessed and confirmed by molecular orbital calculations. An ipso electrophilic substitution of bromine in 3-bromo-2-phenylimidazo[l,2-a]pyridine by a nitro group gave different nitro substituted imidazo[l,2-a]pyridine derivatives depending on the nitric acid concentration.Brought to you by | Purdue University Libraries Authenticated Download Date | 5/27/15 9:12 AM

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...