A Unified Approach to Decarboxylative Halogenation of (Hetero)aryl Carboxylic Acids
Tiffany Q. Chen, P. Scott Pedersen, Nathan W. Dow, Remi Fayad, Cory E. Hauke, Michael C. Rosko, Evgeny O. Danilov, David C. Blakemore, Anne-Marie Dechert-Schmitt, Thomas Knauber, Felix N. Castellano and David W. C. MacMillan*
*Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States,
Email: dmacmill
princeton.edu
T. Q. Chen, P. Scott Pedersen, N. W. Dow, R. Fayad, C. E. Hauke, M. S. Rosko, E. O. Danilov, D. C. Blakemore, A.-M. Dechert-Schmitt, T. Knauber, F. N. Castelano, D. W. C. MacMillan, J. Am. Chem. Soc., 2022, 144, 8296-8305.
DOI: 10.1021/jacs.2c02392
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Abstract
A catalytic decarboxylative halogenation of (hetero)aryl carboxylic acids accommodates an exceptionally broad scope of substrates. The generated aryl radical intermediate enables divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes.
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Details
The article presents a unified approach for the decarboxylative halogenation of (hetero)aryl carboxylic acids, enabling the synthesis of aryl halides, which are crucial in synthetic chemistry and drug discovery. The method leverages ligand-to-metal charge transfer (LMCT) to generate aryl radicals, which can then undergo atom transfer or copper-mediated bond formation to produce bromo-, iodo-, chloro-, and fluoroarenes. This strategy addresses the limitations of existing halodecarboxylation methods, which often suffer from poor selectivity and limited substrate scope. The authors demonstrate the method's broad applicability across various electron-rich and electron-deficient substrates, including complex heterocycles. The protocol is operationally simple, mild, and scalable, making it suitable for late-stage functionalization of bioactive molecules. Spectroscopic studies support the proposed LMCT mechanism, highlighting the method's potential to expand the utility of (hetero)aryl carboxylic acids in synthetic chemistry. The research was supported by several institutions, including the National Institute of General Medical Sciences and the Princeton Catalysis Initiative. The authors anticipate that this approach will enable new scaffolds and strategies for late-stage functionalization, enhancing the synthetic utility of aryl carboxylic acids.
Key Words
bromination, decarboxylation, DBDMH, photochemistry
ID: J48-Y2022
