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Transition metal–catalyzed cross-coupling reactions are some of the most widely used methods in chemical synthesis. However, despite notable advantages of iron (Fe) as a potentially cheaper, more abundant, and less toxic transition metal catalyst, its practical application in multicomponent cross-couplings remains largely unsuccessful. We demonstrate 1,2-bis(dicyclohexylphosphino)ethane Fe–catalyzed coupling of α-boryl radicals (generated from selective radical addition to vinyl boronates) with Grignard reagents. Then, we extended the scope of these radical cascades by developing a general and broadly applicable Fe-catalyzed multicomponent annulation–cross-coupling protocol that engages a wide range of π-systems and permits the practical synthesis of cyclic fluorous compounds. Mechanistic studies are consistent with a bisarylated Fe(II) species being responsible for alkyl radical generation to initiate catalysis, while carbon-carbon bond formation proceeds between a monoarylated Fe(II) center and a transient alkyl radical.
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Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability
Abstract The scarcity of precious metals has led to the development of sustainable strategies for metal‐catalyzed cross‐coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron‐catalyzed cross‐couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field‐tested as highly effective base‐metal catalysts in practical, kilogram‐scale industrial cross‐couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross‐coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.
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- Award ID(s):
- 1650766
- PAR ID:
- 10064569
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 57
- Issue:
- 35
- ISSN:
- 1433-7851
- Page Range / eLocation ID:
- p. 11116-11128
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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