A Palladium(0)‐Catalyzed C4 Site‐Selective C−H Difluoroalkylation of Isoquinolin‐1(2H)‐Ones

Abstract

Herein, we report a Palladium(0)‐catalyzed C4 site‐selective C−H difluoroalkylation of isoquinolin‐1(2H)‐ones through a radical pathway. The present reaction enables the preparation of 2,2‐difluoro‐2‐(1‐oxo‐1,2‐dihydroisoquinolin‐4‐yl)acetates/acetamides through the direct cross‐coupling reaction of readily available isoquinolin‐1(2H)‐ones with 2‐bromo‐2,2‐difluoroacetates or 2‐bromo‐2,2‐difluoroacetamides. Therefore, this method provides an efficient and convenient approach to install a difluoroacetate or a difluoroacetamide moiety into bioactive molecules. Bioassay results showed that introduction of these difluorinated groups at C4 position was beneficial to improve their antiviral activity and compound 5 ab was found to exhibit similar antiviral activity with commercial Ningnanmycin.

Direct Perfluoroalkylation of C−H Bonds in (Hetero)arenes

“…More recently two examples of palladium-catalyzed processes following a similar radical pathway were reported for the para-selective difluoroalkylation of N-aryloxazolidinones [100] and the C4-selective difluoroalkylation of isoquinolinones. [101]…”

Review and Theoretical Analysis of Fluorinated Radicals in Direct CAr−H Functionalization of (Hetero)arenes

“…Furthermore, the palladium-catalyzed addition of the * CF 2 CO 2 Et radical were proved to be a valuable tool for the late-stage functionalization of aromatic ketones. [151][152][153][154][155] mpg-CN was also employed by König and Antonioetti groups as a recoverable heterogeneous photocatalyst and the applicability of the method was demonstrated through multiple radical transformations, including the direct difluoromethylation of (hetero)arenes through reduction and mesolytic cleavage (I) of FGTR 29. [131] Zhang and coworkers reported that EDA complexes can serve as a versatile tool for direct aromatic functionalization.…”

“…In the pursuit of the development of regioselective difluoromethylation protocols, palladium catalysis has also been harnessed for the addition of the ethyl difluoroacetate radical onto the para ‐position of aromatic ketones. Furthermore, the palladium‐catalyzed addition of the ⋅CF 2 CO 2 Et radical were proved to be a valuable tool for the late‐stage functionalization of aromatic ketones [151–155] . mpg‐CN was also employed by König and Antonioetti groups as a recoverable heterogeneous photocatalyst and the applicability of the method was demonstrated through multiple radical transformations, including the direct difluoromethylation of (hetero)arenes through reduction and mesolytic cleavage ( I ) of FGTR 29 [131] .…”

Palladium‐catalyzed difluoromethylation and difluoroalkylation reactions: An overview

“…A procedure for synthesizing 2,2‐difluoro‐2‐(1‐oxo‐1,2‐dihydroisoquinolin‐4‐yl) acetates (or acetamides), utilizing Pd was disclosed by Zhu et al [ 66 ] Here, isoquinolin‐1( 2H )‐ones were chosen as the substrate and 2‐bromo‐2,2‐difluoroacetates (or 2‐bromo‐2,2‐difluoroacetamides) as the difluoroalkylating agent. 2.5 mol% Pd (PPh 3 ) 4 , 10 mol% Xantphos, and 2 equiv.…”