A Generalized Approach for Distal C–H Arylation of Organic Building Blocks: Unveiling the Role of Counter Anion

Advanced Science, vol. 13, pp. e19731

Abstract

Aryl-aryl coupling at remote C-H sites remain a formidable challenge in organic synthesis, particularly for electronically biased arenes and heteroarenes. Herein, we report a generalized and versatile protocol for meta-selective C-H arylation using readily available aryl iodides as coupling partners. This strategy overcomes key limitations of prior methods such as reliance on boronic acids and limited substrate scope by employing a Pd(II)/Pd(IV) catalytic cycle assisted by a removable meta-directing group. Importantly, DFT studies revealed that the counter anion critically influences selectivity: trifluoroacetate reduces the activation energy for meta-C-H activation and thereby improving selectivity. This protocol is applicable to a wide array of functional groups and scaffolds, including phenylacetic acids, anilines, phenols, indolines, and pharmaceutical derivatives like Naproxen and Ketoprofen. Moreover, mechanistic investigations via isotope labeling and kinetic studies provide valuable insights into the reaction pathway. Post-arylation transformations, including directing group removal, further underscore the synthetic utility of this method. Overall, this work introduces a practical, mechanistically guided platform for remote C-H arylation, with broad implications for medicinal chemistry and complex molecule construction.

Authors 7

1. Jagrit Grover

   Indian Institute of Technology Bombay

   Affiliation as printed

   Department of Chemistry Indian Institute of Technology Bombay Mumbai India

2. Gaurav Prakash

   Indian Institute of Technology Bombay

   Affiliation as printed

   Department of Chemistry Indian Institute of Technology Bombay Mumbai India

3. Astam Mandal

   Indian Institute of Technology Bombay

   Affiliation as printed

   Department of Chemistry Indian Institute of Technology Bombay Mumbai India

4. Devika Ghosh

   Indian Institute of Technology Bombay

   Affiliation as printed

   Department of Chemistry Indian Institute of Technology Bombay Mumbai India

5. Siddhartha Sankar Maiti

   VIT Bhopal University

   Affiliation as printed

   School of Biosciences, Engineering and Technology VIT Bhopal University Kothrikalan Sehore Madhya Pradesh India

6. Claire Empel corresponding Aachen Institute of Organic Chemistry

   RWTH Aachen University

   Affiliation as printed

   Institute of Organic Chemistry RWTH Aachen University Aachen Germany

7. Debabrata Maiti corresponding

   Indian Institute of Technology Bombay

   Affiliation as printed

   Department of Chemistry Indian Institute of Technology Bombay Mumbai India