Citation: Qian Xiangyang, Xiong Peng, Xu Hai-Chao. Modular Synthesis of Functionalized 4-Quinolones via a Radical Cyclization Cascade Reaction[J]. Acta Chimica Sinica, ;2019, 77(9): 879-883. doi: 10.6023/A19050193 shu

Modular Synthesis of Functionalized 4-Quinolones via a Radical Cyclization Cascade Reaction

College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005

Corresponding author: Xu Hai-Chao, haichao.xu@xmu.edu.cn
Received Date: 25 May 2019
Available Online: 1 September 2019
Fund Project: Project supported by the National Natural Science Foundation of China (No. 21672178) and Fundamental Research Funds for the Central Universitiesthe National Natural Science Foundation of China 21672178

Figures(4)

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.
- radical,
- cyclization,
- 4-quinolone,
- oxidation
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