摘要/Abstract

4-喹诺酮结构广泛存在于天然产物和药物分子中. 本工作以易得的N-芳基-O-炔丙基氨基甲酸酯为原料, CO为羰基源, 发展了一种高效、模块化合成4-喹诺酮结构的方法. 氨基甲酸酯底物经2-碘酰基苯甲酸(IBX)氧化产生酰胺氮自由基, 进而发生自由基串联环化反应得到4-喹诺酮结构.
关键词: 自由基, 环化, 4-喹诺酮, 氧化
4-Quinolones are structural motifs prevalent in natural products and biologically active compounds. However, it remains challenging to synthesize 4-quinolones that bears diverse substituents at 2- and 3-positions. Herein we report an efficient and modular method for the synthesis of 4-quinolones from easily available N-aryl-O-propargyl carbamates and CO. The reactions employ 2-iodoxybenzoic acid (IBX) as an oxidant to oxidize the N-H group of the carbamate to generate an amide radical, which undergoes radical cyclization cascade with CO to afford the 4-quinolone product. The reactions provide speedy access to a series of 2,3-disubstituted 4-quinolones by varying the substituents of the carbamate substrate. Late stage functionalization employing Ni-catalysis allows the conversion of an OMe group on the 4-quinonone benzene ring to alkyl substituents, further increasing the diversity of the 4-quinone product. The synthetic potential is further demonstrated by running the synthesis on gram scale and by preparation of an enantiomerically enriched 4-quinolone product. The typical procedure is detailed as follows: A magnetic stirring bar, the carbamate substrate (0.25 mmol), IBX (1.0 mmol), and anhydrous dimethyl sulfoxide (DMSO, 10 mL) were placed in a 50 mL stainless steel autoclave. The autoclave was sealed, vacuumed and purged five times with CO, and finally pressurized with 10 MPa of CO. The reaction vessel was heated at 90 ℃ for 12 h and then cooled to r.t.. Excess CO was released in a fume hood. The reaction mixture was diluted with ethyl acetate (20 mL) and 5% NaHCO₃ (15 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic solution was washed with 5% NaHCO₃ (20 mL) and brine (20 mL). The organic solution was dried over anhydrous MgSO₄, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with ethyl acetate/hexanes to give the desired product.
Key words: radical, cyclization, 4-quinolone, oxidation


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