New method for the annelation of a pyridine ring on derivatives of imidazole and benzimidazole

Abstract

Keywords: γ-bromodypnone, imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, cyclization of azolium ylides.The imidazo[1,2-a]pyridine system has been studied very actively recently, in connection with the introduction into the practice of medicine of preparations of the type of zolpidem [3], fazadinium [4], and others. The basic method for the construction of imidazo[1,2-a]pyridine system consists of the construction of the imidazole part of the bicycle. An alternative possibility is annelation, when the final closing of the imidazo[1,2-a]pyridine or pyrido[1,2-a]imidazole system is carried out during the construction of the pyridine ring, has been insufficiently studied [5][6][7].In the present work a simple variant of the construction of the pyridine ring on the imidazole or benzimidazole structure is proposed, based on the "inversion" of the A. E. Chichibabin reaction [8]. The formation of imidazo[1,2-a]pyridines according to Chichibabin consists of the interaction of α-halo ketones with 2-aminopyridine, which proceeds via the initial formation of a quaternary salt, its deprotonation, and intramolecular attack on the carbonyl group by a nucleophile. The intermediate carbinolamine is readily converted into an imidazo[1,2-a]pyridine by dehydration, but it may be isolated in pure form [9]. Our proposed inverted variant consists, in the first place, in replacing the α-halo ketones by their vinylogs (in this work we refer to γ-bromodypnone) and secondly, in using imidazole or benzimidazole without substitutions in position 2. The sequence of conversions in these reactions is identical to the stages of the Chichibabin reaction.

Interaction of (z)-4-bromo-1,3-di(2-thienyl)- 2-buten-1-one with amines, synthesis of di(2-thienyl)azolo[a]pyridines

“…Under similar conditions, quaternary pyridinium, imidazolium, benzimidazolium, and 1,2,4-triazolium salts were obtained but with higher yields: 1-[(E)-4-oxo-2,4-di(2-thienyl)-2-butenyl]pyridinium (4), 1-R-3-[(E)-4-oxo-2,4-di(2-thienyl)-2-butenyl]-1H-imidazol-3-ium 5a-e, 3-R-1-[(E)-4-oxo-2,4-di(2-thienyl)-2-butenyl]-3H-benzimidazol-1-ium 6a,b, and 1-methyl-4-[(E)-4-oxo-2,4-di-(2-thienyl)-2-butenyl]-1H-1,2,4-triazol-4-ium (7) bromides, respectively. The structure of salts 3-7 was supported by their 1 H NMR and IR spectral data (Tables 4 and 5), which are in accord with the results for the corresponding quaternary salts obtained in the reactions of azoles with -bromodypnones [6,7]. The precise assignment of the signals of the aromatic protons in the 1 H NMR spectra of salts 3-7 was made on the basis of data from the 2D COSY HH spectrum of salt 7.…”

“…1 H NMR spectroscopy indicated the presence of hydroxy derivatives 13 in the product mixture by finding characteristic methylene group signals at 3.61-3.76 ppm as two AB-spin doublets with 2 J = 17.0 Hz. Similar to the corresponding aryl derivatives [7], products 13 are unstable and very readily lose a water molecule. 5a-e, 6a,b, and 7, acetic acid for 8a-e, 9a,b, and 10-12.…”

“…1.324 (3) was determined using their IR and 1 H NMR spectra (Tables 4 and 6), in which a series of analogies was found with the spectra of the corresponding diaryl derivatives [6,7], specifically, the positions of the aromatic (H-5 and H-7 for 8a-e, 10 and H-6 and H-8 for 9a,b and aliphatic protons of the aliphatic substituents at N-1 in the azolopyridinium fragment in the 1 H NMR spectra. Two-dimensional COSY HH, NOESY, HMQC, and HMBC spectra for salt 8a were taken for the precise assignment of the aromatic proton signals and confirmation of the structure of salts 8-10.…”

Synthesis of diarylazolo[a]pyridines from [(Z)-2,4-diaryl-4-oxo-2-butenyl]azolium salts

“…6,8-Diaryl-3-methyl[1,3]thiazolo-[3,2-a]pyridin-4-ium bromides 8a-d and 2,4-diarylpyrido[2,1-b]benzothiazol-10-ium bromides 9a,b were formed in high yields (80-82%) on heating the quaternary salts 6a-d and 7a,b in acetone with triethylamine. The structures of the reaction products 6-9 were established by spectroscopic methods (IR, 1 H NMR), the results of which corresponded with those obtained earlier for derivatives of 1-alkyl-1H-benzimidazoles and -imidazoles 1, 2 [5,6] and 4, 5 (Tables 2 and 3). 3,4]thiadiazolo[3,2-a]pyridine-4-ium bromide (10) was synthesized by the same scheme.…”

“…The presence of the 8-hydroxy-5,8-dihydro-1H-[1,2,4]triazolo[4,3-a]pyridin-4-ium cation in the mixture was confirmed by the signals of the protons of the dihydropyridine fragment: 2H-5 in the 5.64 ppm region as an AB spin system with J = 18.5 Hz, H-7 (s, 6.40), and OH (s, 7.79 ppm). We had observed a similar resonance pattern previously[5,6] for 4-hydroxy-4,5-dihydro-1H-pyrido[1,2-a]benzimidazol-10-ium salts which allowed us to determine the structure of product 13a. Further heating of the quaternary salts 12b-d or the mixture 12a + 13a in acetone in the presence of triethylamine led to the 6,8-diaryl-1R-1H-[1,2,4]triazolo[4,3-a]pyridin-4-ium bromides 14a-d.…”