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Abstract
A metal-free strategy has been developed for the α-arylation of carboxylic acids, secondary amides, and esters employing arenes as key reagents. This process entails the Lewis-acid catalyzed reductive Friedel–Crafts alkylation of aromatic and heterocyclic arenes with α-ketoacids, facilitated by silane as a reductant in HFIP solvent. The transformation is highly efficient and mild, providing significant advantages over existing protocols. Notably, the method exhibits exceptional tolerance towards various functional groups, enabling late-stage functionalization of pharmaceutical compounds and natural products such as Thymol, and Sesamol. The reaction mechanism has been studied through control experiments, providing valuable insight. This one-step reductive Friedel–Crafts type protocol has been successfully used in the synthesis of various commercially available drugs, such as Adiphenine, Piperidolate, derivatives of Ketoprofen, Ibuprofen, and Flurbiprofen, and Bromopropylate pesticide. Furthermore, after the gram-scale synthesis, the solvent (HFIP) was recovered, demonstrating the method's suitability for industrial applications.
Supplementary materials
Title
Silylium Ion-Catalyzed α-Arylation of Carboxylic Acids, Amides, and Esters: Efficient Synthesis of Anesthetic and Anti-inflammatory Drugs
Description
A metal-free strategy has been developed for the α-arylation of carboxylic acids, secondary amides, and esters employing arenes as key reagents. This process entails the Lewis-acid catalyzed reductive Friedel–Crafts alkylation of aromatic and heterocyclic arenes with α-ketoacids, facilitated by silane as a reductant in HFIP solvent. The transformation is highly efficient and mild, providing significant advantages over existing protocols. Notably, the method exhibits exceptional tolerance towards various functional groups, enabling late-stage functionalization of pharmaceutical compounds and natural products such as Thymol, and Sesamol. The reaction mechanism has been studied through control experiments, providing valuable insight. This one-step reductive Friedel–Crafts type protocol has been successfully used in the synthesis of various commercially available drugs, such as Adiphenine, Piperidolate, derivatives of Ketoprofen, Ibuprofen, and Flurbiprofen, and Bromopropylate pesticide. Furthermore, after the gram-scale synthesis, the solvent (HFIP) was recovered, demonstrating the method's suitability for industrial applications.
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