Microwave assisted synthesis of ethyl 2,2-bis(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-furo[3,2-c]chromene-3-carboxylate via manganese(III) acetate mediated radical cyclization reaction

Research Article EMUJPharmSci ISSN 2651-3587 https://dergipark.org.tr/emujpharmsci Microwave assisted synthesis of ethyl 2,2-bis(4-fluorophenyl)-4-oxo-3,4dihydro-2H-furo[3,2-c]chromene-3-carboxylate via manganese(III) acetate mediated radical cyclization reaction Negar Khezri, E. Vildan Burgaz* Eastern Mediterranean University, Faculty of Pharmacy, Famagusta, North Cyprus, Mersin 10 Turkey. Abstract “Ethyl 2,2-bis(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-furo[3,2-c]chromene-3-carboxylate” is dihydrofuran-fused monocyclic heterocycles containing dihydrofurocoumarin framework. Compounds that include these core structures are especially important for drug discovery. Manganese(III) acetate has been used as an efficient oxidizing agent for the preparation of “ethyl 2,2bis(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-furo[3,2-c]chromene-3-carboxylate” by the multi-steps reaction of ethyl 3,3-bis(4-fluorophenyl)acrylate and 4-hydroxycoumarin under microwave irradiation to perform faster heating times, significantly reduce reaction times, and the efficient solubilization of manganese(III) acetate in acetic acid. The cyclization reaction was achieved using reactivity of the carbonyl group within the molecule. Keywords Dihydrofuran, manganese(III) acetate, microwave irradiation, radical cyclization reaction. Article History Submitted: 02 August 2020 Accepted: 14 October 2020 Published Online: October 2020 Article Info *Corresponding author: E. Vildan Burgaz email: Research Article: Volume: 3 Issue: 2 October 2020 Pages: 80-85 ©Copyright 2020 by EMUJPharmSci – Available online at dergipark.org.tr/emujpharmsci. 81 INTRODUCTION Heterocycles are generally important in the the most commonly-used types of these field of medicinal chemistry for drug metal salts (Bar et al., 2001; Kajikawa et al., discovery. Drugs containing heterocycles 2001). are used in a number of therapies, including Reaction those for cancer, ulcer, metabolic and manganese(III) acetate are known as cardiovascular diseases, infections, and suitable central (CNS)-related irradiation, despite being considered in a illnesses. Furan, thiophene, and pyrrole are limited number of publications (Mu et al., among the most popular five-membered 2005). heterocycles with a single heteroatom and potentially facilitate the rapid heating, are of great importance for the discovery of efficient solubilization, and significantly novel drugs (Riddell, 1980; Li, 2013). reduce the reaction time of Mn(OAc)3 in The salts of transition metal (Mn3+, Co3+, acetic Cu2+, Ce4+) that are capable of transferring Consequently, it has widely been used as a single electrons are known to produce α- controllable, yet powerful method of carbon radicals with enolizable functional heating groups, which can generate new carbon- reactions typically result in higher yields, carbon bonds when added to unsaturated better selectivities, and shorter reaction systems (Iqbal et al., 1994; Ozgur et al., times (Larhed and Hallberg, 2001; Larhed 2019; Akpinar et al., 2018; Aslan et al., et al., 2002; Wathey, 2002; Kappe, 2002; 2014; Yilmaz et al., 2008). Manganese(III) Kappe and Stadler, 2005; Eycken, 2006; acetate, cerium(IV) ammonium nitrate are Kappe et al., 2009). nervous system mixtures that candidates Microwave acid for microwave irradiation (Curti organic include et could al., reactions. 2009). Microwave MATERIALS AND METHODS Triethyl phosphonoacetate (1), bis (4- As shown in Figure 1, conjugated ester (3) fluorophenyl) was methanone (2) and 4- synthesized by using hydroxycoumarin (4) were obtained from phosphonoacetate (1) and Sigma Aldrich. Because the purity of these fluorophenyl) compounds was more than % 99, no other tetrahydrofuran (THF) and sodium hydride purification step was applied. (NaH) (Pinna et al., 2003; Burgaz et al., Synthesis of starting material: “Ethyl 2011). methanone triethyl bis (4- (2) in 3,3-bis(4-fluorophenyl) acrylate (3)” Khezri N et al. EMUJPharmSci 2020; 3(2):80-85. 82 Figure 1: General mechanism for the synthesis of ethyl 3, 3-bis (4-fluorophenyl) acrylate. A solution of triethyl phosphonoacetate layer was dried by sodium sulfate and (120 mmol, 21 mL) in THF (50 mL) was vaporized. The crude product was purified added dropwise to a solution of NaH (120 by silica gel column chromatography mmol, 60% dispersion in mineral oil, 4.8 g) eluting with n-hexane/ethyl acetate (5:1). in THF (200 mL) within ice bath. Half an Synthesis hour later, the suitable ketone (100 mmol) fluorophenyl)-4-oxo-3,4-dihydro-2H- was added to the reaction mixture and was furo[3,2-c]chromene-3-carboxylate” stirred for 2-3 days at room temperature. General mechanism for the synthesis of When the reaction was finished, THF was ethyl subjected dihydro-2H-furo[3,2-c]chromene-3- to decreased pressure and vaporized. The remainder was extracted of “ethyl 2,2-bis(4- 2,2-bis(4-fluorophenyl)-4-oxo-3,4- carboxylate is shown in Figure 2. with diethyl ether. Afterwards, the organic Figure 2: General mechanism for the synthesis of ethyl 2,2-bis(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-furo[3,2c]chromene-3-carboxylate. 4-hydroxycoumarin (4) (1 mmol, 0.163 g) a magnet inside the vessel for mechanical and stirring. The vial was placed inside the subsequently ethyl 3,3-bis(4- fluorophenyl) acrylate (3) (0.5 mmol, 0.145 microwave machine. g) were added to a test tube containing Optimization of the reaction manganese(III) acetate dihydrate (3 mmol, In 0.804 g) and mixed well. Acetic acid was optimization was carried out. To produce added into the tube and the mixture was the higher amount of the product with the poured into a microwave reaction vial with minimum waste, the percentage yield is Khezri N et al. EMUJPharmSci 2020; 3(2):80-85. order to maximize performance, 83 extremely remarkable and is useful as an Mechanism of reaction indicator that the strategy is productive and In the synthesis of the product (8), the very accurate. Therefore, various factors such as early reaction is the generation of the temperature, and radical form of 4-hydroxycoumarin (5) due concentrations were arranged to obtain the to the addition of MAH (Figure 3). The highest-yield of the product. Finally, the unpaired electrons positioned on secondary microwave machine was adjusted at 80˚C radical 4-hydroxycoumarin (5) make the for 5 minutes. After the reaction was compound highly reactive. Thus, the π- completed, water was added and extraction bond of 2,3-diene chain belonging to ethyl was done with chloroform. The organic 3,3-bis(4-fluorophenyl)acrylate layer was dried over sodium sulfate and captured by the radical during the addition then evaporated. The product was purified of acetic acid, being broken down forming by silica gel column chromatography benzyl radical (because benzyl radical is eluting with hexane/ethyl aceta (...truncated)