Synlett, Table of Contents Synlett 2025; 36(06): 674-678DOI: 10.1055/a-2384-7081 letter Thieme Chemistry Journals Awardees 2024 Sequential Copper-Catalyzed Amidation and Hydroxylation for Acetaminophen Synthesis Authors Author Affiliations Youngran Seo a Department of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea Dongwon Yoo ∗ a Department of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea b Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea Young Gyu Kim∗ a Department of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) 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%. Key words Key wordsacetaminophen - paracetamol - amidation - hydroxylation - copper catalysis Full Text References References and Notes 1 Jóźwiak-Bebenista M, Nowak JZ. Acta Pol. Pharm. 2014; 71: 11 2 Joncour R, Ferreira A, Duguet N, Lemaire M. Org. Process Res. Dev. 2018; 22: 312 3 Faizullabhoy M, Wani G. Acetaminophen Market . Global Market Insights; Selbyville: 2023. https://www.gminsights.com/industry-analysis/acetaminophen-market (accessed Jun 2, 2023) 4 Rode CV, Vaidya MJ, Chaudhari RV. Org. Process Res. Dev. 1999; 3: 465 5 Rode CV, Vaidya MJ, Jaganathan R, Chaudhari RV. Chem. Eng. Sci. 2001; 56: 1299 6 Nadgeri JM, Biradar NS, Patil PB, Jadkar ST, Garade AC, Rode CV. Ind. Eng. Chem. Res. 2011; 50: 5478 7 Park J, Maier JS, Evans C, Hatzell M, France S, Sievers C, Bommarius AS. Green Chem. 2024; 26: 4079 8 Yao C, Wu J, Pan L, Yu L, Luo J, Shan J, Liu J, Lu C, Feng F, Xu X, Lin L, Yue Y, Wang Q, Zhao J, Zhang Q, Li X. Chem. Eng. J. (Amsterdam, Neth.) 2024; 486: 150329 9 Luo J, Yao C, Ma D, Chen Y, Tian M, Xie H, Chen R, Wu J, Zhen Y, Pan L, Lu C, Feng F, Xu X, Wang Q, Zhang Q, Li X. Appl. Catal., A 2023; 660: 119198 10 Joncour R, Duguet N, Métay E, Ferreira A, Lemaire M. Green Chem. 2014; 16: 2997 11 Mane SN, Gadalkar SM, Rathod VK. Ultrason. Sonochem. 2018; 49: 106 12 San BH, Ravichandran S, Park K.-s, Subramani VK, Kim KK. ACS Appl. Mater. Interfaces 2016; 8: 30058 13 Nishii Y, Ikeda M, Hayashi Y, Kawauchi S, Miura M. J. Am. Chem. Soc. 2020; 142: 1621 14 de Almeida LS, de Mattos MS, Esteves PM. Synlett 2013; 24: 603 15 Hossain MD, Oyamada J, Kitamura T. Synthesis 2008; 690 16 Bhunia S, Pawar GG, Kumar SV, Jiang Y, Ma D. Angew. Chem. Int. Ed. 2017; 56: 16136 17 Klapars A, Huang X, Buchwald SL. J. Am. Chem. Soc. 2002; 124: 7421 18 Toto P, Gesquière J.-C, Cousaert N, Deprez B, Willand N. Tetrahedron Lett. 2006; 47: 4973 19 Sheppard TD. Org. Biomol. Chem. 2009; 7: 1043 20 Yanagisawa S, Ueda K, Taniguchi T, Itami K. Org. Lett. 2008; 10: 4673 21 Barham JP, Coulthard G, Emery KJ, Doni E, Cumine F, Nocera G, John MP, Berlouis LE. A, McGuire T, Tuttle T, Murphy JA. J. Am. Chem. Soc. 2016; 138: 7402 22 Cristau H.-J, Cellier PP, Spindler J.-F, Taillefer M. Chem. Eur. J. 2004; 10: 5607 23 Wang Y, Zhou C, Wang R. Green Chem. 2015; 17: 3910 24 Lefèvre G, Tlili A, Taillefer M, Adamo C, Ciofini I, Jutand A. Dalton Trans. 2013; 42: 5348 25 Mehmood A, Leadbeater NE. Catal. Commun. 2010; 12: 64 26 Ren Y, Cheng L, Tian X, Zhao S, Wang J, Hou C. Tetrahedron Lett. 2010; 51: 43 27 Paul R, Ali MA, Punniyamurthy T. Synthesis 2010; 4268 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%. Supplementary Material Supplementary Material Supporting Information (PDF)
