Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles.
Fluorinated heterocycles play an important role in pharmaceutical and agrochemical industries. Herein, we report on the synthesis of four types of fluorinated heterocycles via rhodium(III)-catalyzed C-H activation of arenes/alkenes and versatile coupling with 2,2-difluorovinyl tosylate. With N-OMe benzamide being a directing group (DG), the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones and 5-fluoropyridin-2(1H)-ones. When N-OPiv benzamides were used, however, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones. Synthetic applications have been demonstrated and the ready availability of both the arene and the coupling partner highlighted the synthetic potentials of these protocols. Mechanistically, these two processes share a common process involving N-H deprotonation, C-H activation, and olefin insertion to form a 7-membered rhodacycle. Thereafter, different reaction pathways featuring β-F elimination and C-N bond formation are followed on the basis of density functional theory (DFT) studies. These two pathways are DG-dependent and led to the open chain and cyclization products, respectively. The mechanistic rationale was supported by detailed DFT studies. In particular, the origins of the intriguing selectivity in the competing β-F elimination versus C-N bond formation were elucidated. It was found that β-F elimination is a facile event and proceeds via a syn-coplanar transition state with a low energy barrier. The C-N bond formation proceeds via a facile migratory insertion of the Rh-C(alkyl) into the Rh(V) amido species. In both reactions, the migratory insertion of the alkene is turnover-limiting, which stays in good agreement with the experimental studies.
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Jia-Qiang
JQ
Wu
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Shang-Shi
SS
Zhang
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Hui
H
Gao
Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
Zisong
Z
Qi
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Chu-Jun
CJ
Zhou
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Wei-Wei
WW
Ji
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Yao
Y
Liu
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Yunyun
Y
Chen
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Qingjiang
Q
Li
Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
Xingwei
0000-0002-1153-1558
X
Li
School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
Honggen
0000-0002-9648-6759
H
Wang