Synthesis of azolo[a]pyridines from 5-(bromomethyl)hept-4-en-3-one and 5-bromopent-3-en-2-one derivatives

Abstract

Keywords: 5-(bromomethyl)hept-4-en-3-one, 5-bromopent-3-en-2-one, imidazo[1,2-a]pyridine, pyrido-[1,2-a]benzimidazole, thiazolo[3,2-a]pyridine, [1,2,4]triazolo [4,3-a]pyridine.γ-Halo-substituted unsaturated ketones are highly reactive compounds and are the synthetic equivalents of 1,4-dielectrophilic synthons. On account of their relatively poor availability they were used predominantly for the production of pyrroles in reactions with primary amines [1][2][3][4][5]. We recently found convenient methods for the synthesis of the azolo[a]pyridine system derivatives on the basis of (2Z)-4-bromo-1,3-diphenyl-2-buten-1-one (γ-bromodypnone) and its derivatives [6][7][8]. While continuing investigations in this direction we turned to γ-halo ketones of the aliphatic series.The structural features of (4Z)-5-(bromomethyl)-2,2,6,6-tetramethylhept-4-en-3-one (1) make it possible to regard it as an analog of γ-bromodypnone; there are nonenolizing groups at the carbonyl group and at the C=C double bond, and their volume leads to configurational stability for the molecule in the form of the (Z)-isomer [9]. Properties of this compound have hardly been studied at all, and only the formation of a quaternary triphenylphosphonium salt [9] and intramolecular cyclization to 2,4-di-tert-butylfuran [10] are known.We have established that compound 1, like γ-bromodypnone, forms quaternary azolium salts 2 with high yields when a mixture of the bromo ketone 1 and azole is kept in benzene at room temperature for several days (Scheme 1), as described in [7,8] (Table 1). Difficulties in the isolation of the alkylation products 2b,e in pure form only arose in the case of reactions with 1-benzyl-1H-imidazole and 1-methyl-1H-1,2,4-triazole. When the reaction is conducted under standard conditions (benzene, 25°, 2-3 days) the reaction mixture still contains the initial azole as impurity (15-20%), which subsequently initiates cyclization of the salts 2b,e during