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Copper-Catalyzed Enantioselective Three-Component Carboamidation of Styrenes with Alkanes and Amides

09 July 2025

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As a distinguished academician of the Chinese Academy of Sciences and a professor at the School of Chemistry of Nankai University, Professor Qi-Lin Zhou has made remarkable contributions to the field of asymmetric catalytic synthesis. His research encompasses the intricate structural design and synthesis of chiral catalysts, as well as in-depth exploration of various asymmetric synthesis reactions and the creation of chiral drug molecules. These catalysts have demonstrated exceptional catalytic activity and enantioselectivity in key reactions, including asymmetric catalytic hydrogenation and the formation of carbon-carbon and carbon-heteroatom bonds. His groundbreaking work has been widely recognized through publications in top-tier international journals such as Science, Nature Chemistry, and JACS.

The efficient assembly of valuable chiral molecules from readily available and low-cost chemical feedstocks remains one of the most challenging tasks in synthetic chemistry today. Radical-mediated three-component carboamination of alkenes offers an attractive strategy for addressing this challenge. However, most existing reports focus on racemic examples and are largely limited to activated alkenes, preactivated alkylation reagents, or sufficiently active nucleophiles. Herein, the authors report a highly enantioselective three-component carboamidation of styrenes with unactivated alkanes and weakly nucleophilic amides. Enantioselective control is achieved by using chiral cationic copper catalysts. This method enables the synthesis of various optically active amides with excellent enantioselectivity. Mechanistic studies reveal that the reaction proceeds via hydrogen atom transfer from the alkane, followed by radical addition to the olefin.

The authors began their study by exploring the reaction conditions for the carboamidation of styrene (1a) with 4-methoxybenzamide (2a) and cyclohexane (3a) (Figure 1). The investigation revealed that CuBArF, generated in situ from CuCl and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]-borate (NaBArF), produced the best results. A comparison of ligands demonstrated that the bisoxazoline ligand with 4-tert-butylbenzyl groups on the bridging carbon (L3) outperformed other bisoxazoline ligands. Among the HAT reagents tested, DTBP provided a higher yield and better enantioselectivity than other HAT reagents. Screening solvents revealed that PhCl was the optimal solvent, affording a good yield and high enantioselectivity.

Figure 1. Cu-Catalyzed Enantioselective Three-Component Carboamidation of Styrenes

The authors propose the reaction pathway outlined in Figure 2. The complexation of the chiral BOX-type ligand with copper, in the presence of NaBArF, forms the active catalyst I. Catalyst I promotes the homolytic cleavage of DTBP, leading to the formation of an alkoxy copper(II) intermediate II and a tert-butoxy radical. The tert-butoxy group of intermediate II undergoes ligand exchange with the amide substrate to generate the copper(II) intermediate III. Additionally, the tert-butoxy radical abstracts a hydrogen atom from cyclohexane via a HAT process, producing a cyclohexyl radical. The addition of cyclohexyl radical to styrene generates a benzyl radical, which is subsequently trapped by intermediate III to form copper(III) species IV. Intermediate IV undergoes reductive elimination, yielding the amidation product and regenerating the copper(I) catalyst I.

Figure 2. Mechanism of the catalytic cycle of carbonamidation

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References

[1]Huang L., Arndt M., Gooßen K., et al. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 2015, 115, 2596−2697.

[2]Lin J. S., Dong X. Y., Li T. T., et al. A dual-catalytic strategy to direct asymmetric radical aminotrifluoromethylation of alkenes. J. Am. Chem. Soc. 2016, 138, 9357−9360.

[3]Chen Y. Y., Dai L., Zhang X. G., et al. Copper-Catalyzed Enantioselective Three-Component Carboamidation of Styrenes with Alkanes and Amides. J. Am. Chem. Soc. 2025, 147(15), 12397–12404.

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