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Synlett 2025; 36(06): 674-678
DOI: 10.1055/a-2384-7081
DOI: 10.1055/a-2384-7081
letter
Thieme Chemistry Journals Awardees 2024
Sequential Copper-Catalyzed Amidation and Hydroxylation for Acetaminophen Synthesis
Authors
The work was supported by SK Chemicals (Y.G.K.) and the National Research Foundation of Korea (NRF-2022M3E5F1081320 and RS-2024-00398065) (D.Y.).
Abstract
A sequential Cu-catalyzed amidation and hydroxylation of p-dihalobenzenes is applied to synthesize acetaminophen. This method allows the direct introduction of acetamido and hydroxy groups under acid-free conditions without forming other regioisomers. By using a one-pot process, acetaminophen can be prepared with an overall yield of up to 74%.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2384-7081.
- Supporting Information (PDF)
Publication History
Received: 15 June 2024
Accepted after revision: 12 August 2024
Accepted Manuscript online:
12 August 2024
Article published online:
10 September 2024
© 2024. Thieme. All rights reserved
Georg Thieme Verlag KG
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- 28 Acetaminophen (1); One-Pot Procedure A pressure tube was backfilled with N2 and then charged with p-bromoiodobenzene (1 mmol), acetamide (62 mg, 1.05 mmol), CsF (608 mg, 4.0 mmol), and CuI (3.8 mg, 0.02 mmol). Argon-sparged THF (2 mL) and DMEDA (22 μL, 0.2 mmol) were added and the tube was carefully sealed. The mixture was vigorously stirred at 130 °C for 24 h, then cooled to r.t. Argon-flushed H2O (6 mL) was added to the mixture and the pressure tube was resealed. The mixture was then heated at 180 °C for 24 h, cooled to r.t., and diluted with EtOAc (30 mL). The aqueous solution was saturated with NH4Cl and the saturated aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The organic residue was purified by chromatography [silica gel, hexane–EtOAc (1:4)] to give a white solid; yield: 74%.