Trifluoromethyl Rhodium‐Carbynoid in [2+1+2] Cycloadditions

• Published in: Angewandte Chemie International Edition Vol. 63; no. 13; pp. e202318887 - n/a
• Main Authors: Zhao, Wen‐Wen, Tian, Meng‐Yang, Zhou, Yi‐Lin, Liu, Lu‐Jie, Tian, Shao‐Fang, He, Chun‐Yang, Yang, Xing‐Zhi, Chen, Yong‐Zheng, Han, Wen‐Yong
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.03.2024; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Anticancer properties; Antitumor activity; Antitumour agents; Carbyne; Cations; CD3 antigen; Chemistry; Chemistry, Multidisciplinary; Cycloadditions; Metals; N-heteroarenes; Nitriles; Physical Sciences; Rhodium; Science & Technology; Sulfonium salts; Trifluorodiazoethane; Trifluoromethyl Rh-carbynoid; DRUG; DESIGN; Trifluorodiazoethane; Cycloadditions; LIGANDS; AMINO-ACIDS; HIGHLY POTENT; Trifluoromethyl Rh-carbynoid; N-heteroarenes; DISCOVERY
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202318887

Trifluoromethyl cationic carbyne (CF3C+:) possessing dual carbene‐carbocation behavior emulated as trifluoromethyl metal‐carbynoid (CF3C+=M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α‐diazotrifluoroethyl sulfonium salt was prepared and used in Rh‐catalyzed three‐component [2+1+2] cycloadditions for the first time with commercially available N‐fused heteroarenes and nitriles, yielding a series of imidazo[1,5‐a] N‐heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh‐carbynoid (CF3C+=Rh) into C=N bonds of N‐fused heteroarenes was involved. This strategy demonstrates synthetic applications in late‐stage modification of pharmaceuticals, construction of CD3‐containing N‐heterocycles, gram‐scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5‐a] N‐heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry. A novel α‐diazotrifluoroethyl sulfonium salt was prepared, and it was applied in Rh‐catalyzed three‐component [2+1+2] cycloadditions for the first time, affording various imidazo[1,5‐a] N‐heterocycles under mild conditions. This strategy involved a unique trifluoromethyl Rh‐carbynoid (CF3C+=Rh), wherein three new chemical bonds were forged at the α‐carbon of trifluoromethyl in a single step.