Synthesis of Benzofurans Modified by Coumarin and Pyrazole Heterocycles
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SYNTHESIS OF BENZOFURANS MODIFIED BY COUMARIN AND PYRAZOLE HETEROCYCLES
T. V. Shokol,1* N. V. Gorbulenko,1 M. S. Frasinyuk,2 and V. P. Khilya1
Reactions of 7-hydroxy-2-methyl-8-formylisoflavone with 4-chloromethylcoumarins synthesized 8-(coumarin4-yl)furo[2,3-h]chromones, which reacted with 2-bromoacetylbenzofuran to produce 8-(benzofuroyl)furo [2,3-h]chromone. Recyclization of the corresponding furochromones through the action of hydrazine hydrate gave 4-hydroxybenzofurans with pyrazole and coumarin or benzofuroyl substituents. Keywords: benzofurans, 2-bromoacetylbenzofuran, 7-hydroxy-8-formylisoflavone, pyrazoles, recyclization, 4-chloromethylcoumarins, furo[2,3-h]chromones. Oxygen-containing heterocycles are basic structures in many natural compounds. Coumarins are the most numerous class of natural benzopyrans with broad spectra of pharmacological activity [1]. Benzofuran derivatives occurring in plants of the families Asteraceae [2], Fabaceae [3], and Styracaceae [4] and their synthetic analogs possess fungicidal, antimicrobial, antiviral, anti-inflammatory, antihyperglycemic, antidepressant, antioxidant, and anticancer activity [4–8]. 2-Coumarinylsubstituted benzofurans obtained via condensation of 4-bromomethylcoumarins with ortho-hydroxyacetophenones or benzaldehydes exhibited antimicrobial, anti-inflammatory, and analgesic activity [9–11]. 3-Pyrazolylbenzopyrans were reported to have antimicrobial activity [12]. 5-Pyrazolylbenzopyrans (reaction products of the natural β-hydroxychalcone pongamol and arylhydrazines) turned out to be CYP1A1 inhibitors [13]. Benzofurans condensed with a γ-pyrone core, i.e., furo[2,3-h]chromones pongapin and lanceolatin B, were isolated from Pongamia pinnata and possessed antibacterial, fungicidal, and cytotoxic activity, blocked the cell cycle and induced senescence in CYP1A1-overexpressing breast cancer cells, and were potential chemopreventive anticancer agents [13, 14]. 2-(Coumarin-4-yl)furo[3,2-g]chromones exhibited anti-inflammatory and analgesic activity [10]. The goal of the present work was to synthesize benzofurans modified by coumarin or benzofuran and pyrazole heterocycles via recyclization of furo[2,3-h]chromones through the action of hydrazine hydrate. The starting compound for synthesizing furo[2,3-h]chromones was 7-hydroxy-2-methyl-8-formylisoflavone (1), which was obtained from the natural isoflavone via a Duff reaction [15]. Reaction of 1 with 2-bromoacetylbenzofuran (2) in DMF in the presence of potash at 100°C for 5 h afforded 8-benzofuroylfuro[2,3-h]chromone 3. The lack of weak-field singlets for the CHO protons (10.56 ppm) and OH groups (12.24 ppm) characteristic of 1 and the presence of an H-9 singlet at 8.22 ppm and resonances for the methyl and aromatic protons of both starting heterocycles in the PMR spectrum of 3 indicated that the furan ring was annelated to the chromone core. Use of 4-chloromethylcoumarins 4a,b and their benzoannelated analogs 4c,d in this reaction synthesized coumarin-yl furo[2,3-h]chromones 5a–d. PMR spectra of 5a–d showed reson
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