gem‐Difluoromethylene Alkyne‐Enabled Diverse C−H Functionalization and Application to the on‐DNA Synthesis of Difluorinated Isocoumarins

• Published in: Angewandte Chemie International Edition 2021-01, Vol.60 (4), p.1959-1966
• Main Authors: Gao, Hui, Lin, Shuang, Zhang, Shuning, Chen, Weijie, Liu, Xiawen, Yang, Guang, Lerner, Richard A., Xu, Hongtao, Zhou, Zhi, Yi, Wei
• Format: Article
• Language: English
• Subjects: Alkynes; Benzoic acid; Catalysis; chemodivergence; C−H functionalization; Deoxyribonucleic acid; Divergence; DNA; DNA biosynthesis; DNA-encoded libraries; Fluorine; gem-difluoromethylene alkynes; Rh/Ir catalysis; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202013052

Using gem‐difluoromethylene alkynes as effectors, unprecedented diverse C−H activation/[4+2] annulations of simple benzoic acids are reported. The chemodivergent reaction outcomes are well‐tuned by Rh/Ir‐catalyzed system; in the RhIII catalysis, 3‐alkenyl‐1H‐isochromen‐1‐one and 3,4‐dialkylideneisochroman‐1‐one skeletons are afforded in a solvent‐dependent manner whereas difluoromethylene‐substituted 1H‐isochromen‐1‐ones are generated under the IrIII‐catalyzed system. Mechanistic studies revealed that unusually double β‐F eliminations and fluorine effect‐induced regioselective reductive elimination are independently involved to enable distinct reaction modes for divergent product formations. Besides, synthetic application in both the derivatization of obtained diene products and the on‐DNA synthesis of DNA‐tagged difluorinated isocoumarin have been demonstrated, which manifested great potential for synthetic utility of the developed protocols. An unprecedented divergent C−H functionalization of simple benzoic acids with gem‐difluoromethylene alkynes was realized in a controllable and chemoselective manner, which is tuned by RhIII/IrIII‐catalyzed system. The derivatization of obtained diene products and synthetic applicability on‐DNA synthesis were feasible.