Sequential Copper-Catalyzed Amidation and Hydroxylation for Acetaminophen Synthesis

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

acetaminophen - paracetamol - amidation - hydroxylation - copper catalysis

• 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%.