Potassium Carbonate Catalyzed Intramolecular Post-Ugi Hydroamination Reaction Leading to N-Aryl Piperazine Derivatives

Abstract

N-Arylpiperazines are prominent structures found in natural products and synthetic chemical entities, including therapeutic agents. In this work, we introduce a novel strategy for the effective synthesis of distinctive piperazine compounds through a post-Ugi cyclization under transition-metal-free conditions. This method involves the formation of a four-component Ugi adduct by combining an aldehyde, an isocyanide, a primary propargylamine, and an oxamic acid. Subsequently, an intramolecular alkyne hydroamination reaction occurs, leading to the formation of a piperazine derivative through carbon–nitrogen bond formation. The products have been characterized by ¹H and ¹³C NMR spectroscopy.

Key words

piperazines - hydroamination - post-Ugi modification - catalyst-free reaction - multicomponent reaction

Publikationsverlauf

Eingereicht: 07. Dezember 2024

Angenommen nach Revision: 10. Januar 2025

Artikel online veröffentlicht:
14. April 2025

• References and Notes

• 1a Huang L, Arndt M, Gooßen K, Heydt H, Gooßen LJ. Chem. Rev. 2015; 115: 2596
• 1b Müller TE, Hultzsch KC, Yus M, Foubelo F, Tada M. Chem. Rev. 2008; 108: 3795
• 1c Escorihuela J, Lledós A, Ujaque G. Chem. Rev. 2023; 123: 9139
• 2 Tashrifi Z, Mohammadi Khanaposhtani M, Biglar M, Larijani B, Mahdavi M. Asian J. Org. Chem. 2020; 9: 969
• 3 Lee C, Kang H.-J, Hong S. Chem. Sci. 2024; 15: 442
• 4 Zimin DP, Dar’in DV, Rassadin VA, Kukushkin VY. Org. Lett. 2018; 20: 4880
• 5a Borhanuddin S, Foster D, Dorta R. J. Organomet. Chem. 2024; 1015: 123198
• 5b Liu L.-D, Lei Z.-L, Wang H, Bian M, Liu Z.-J, Liu J.-T, Hu X.-J. Tetrahedron 2018; 74: 4515
• 6 Pham M.-T, Chen S.-R, Liang S.-Y, Cheng Y.-B, Lin H.-C. Org. Lett. 2022; 24: 4064
• 7a Gettys KE, Ye Z, Dai M. Synthesis 2017; 49: 2589
• 7b Reddy Guduru SK, Chamakuri S, Raji IO, MacKenzie KR, Santini C, Young DW. J. Org. Chem. 2018; 83: 11777
• 8 Shaquiquzzaman M, Verma G, Marella A, Akhter M, Akhtar W, Khan MF, Tasneem S, Alam MM. Eur. J. Med. Chem. 2015; 102: 487
• 9 Chauhan N, Pradhan S, Ghorai MK. J. Org. Chem. 2018; 84: 1757
• 10a Patil P, Madhavachary R, Kurpiewska K, Kalinowska-Tłuścik J, Dömling A. Org. Lett. 2017; 19: 642
• 10b Chamorro-Arenas D, Osorio-Nieto U, Quintero L, Hernández-García L, Sartillo-Piscil F. J. Org. Chem. 2018; 83: 15333
• 10c Bana P, Szigetvári Á, Kóti J, Éles J, Greiner I. React. Chem. Eng. 2019; 4: 652
• 10d McManus JB, Onuska NP, Jeffreys MS, Goodwin NC, Nicewicz DA. Org. Lett. 2020; 22: 679
• 10e Gueret R, Pelinski L, Bousquet T, Sauthier M, Ferey V, Bigot A. Org. Lett. 2020; 22: 5157
• 10f Meanwell NA, Loiseleur O. J. Agric. Food Chem. 2022; 70: 10942
• 11 Mittersteiner M, Andrade VP, Zachow LL, Frizzo CP, Bonacorso HG, Martins MA, Zanatta N. J. Org. Chem. 2019; 84: 8976
• 12a Endo A, Yanagisawa A, Abe M, Tohma S, Kan T, Fukuyama T. J. Am. Chem. Soc. 2002; 124: 6552
• 12b Balalaie S, Ramezani Kejani R, Ghabraie E, Darvish F, Rominger F, Hamdan F, Bijanzadeh HR. J. Org. Chem. 2017; 82: 12141
• 12c Tripathi S, Ambule MD, Srivastava AK. J. Org. Chem. 2020; 85: 6910
• 13 Ugi Adducts 5; General Procedure A mixture of the appropriate propargylamine 1 (2.0 mmol), aldehyde 2 (2.0 mmol), isocyanide 3 (2.0 mmol), and acid 4 (2.0 mmol) in MeOH (2.0 mL) was stirred at r.t. for 24 h. When the starting materials were completely consumed (TLC), the product was precipitated and recrystallized from EtOH.
• 14 Dioxopiperazines 6a–o; General Procedure A mixture of the appropriate Ugi adduct 5 (1.0 mmol) and K₂CO₃ (1.0 mmol) in DMSO (1.0 mL) was stirred at 60 °C for 45 min. When the reactant 5 was completely consumed (TLC), the mixture was diluted with H₂O and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na₂SO₄), and filtered. Following the evaporation of the solvent, the product was purified by crystallization (hexane). 2-(4-Chlorophenyl)-N-cyclohexyl-2-(5-methylene-2,3-dioxo-4-phenylpiperazin-1-yl)acetamide (6a) White solid; yield: 416.0 mg (92%); mp 148–150 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.41 (d, J = 7.7 Hz, 1 H), 7.47–7.51 (m, 4 H), 7.42 (d, J = 7.0 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 7.6 Hz, 2 H), 6.21 (s, 1 H), 4.56 (d, J = 14.1 Hz, 1 H), 4.44 (s, 1 H), 3.95 (d, J = 14.2 Hz, 1 H), 3.82 (s, 1 H), 3.59–3.69 (m, 1 H), 1.52–1.83 (m, 5 H), 1.05–1.34 (m, 5 H). ¹³C{¹H} NMR (75 MHz, DMSO-d ₆): δ = 167.1, 156.6, 155.2, 140.3, 138.2, 134.1, 133.6, 131.1, 130.1, 129.3, 128.9, 128.6, 98.1, 59.0, 48.4, 46.4, 32.7, 32.6, 25.6, 25.0, 24.9. Anal. Calcd for C₂₅H₂₆ClN₃O₃: C, 66.44; H, 5.80; N, 9.30. Found: C, 66.57; H, 5.73; N, 9.21.
• 15a Girisha HR, Srinivasa GR, Gowda DC. J. Chem. Res. 2006; 342
• 15b Wolf C, Liu S, Mei X, August AT, Casimir MD. J. Org. Chem. 2006; 71: 3270
• 15c Zhou Q, Du F, Chen Y, Fu Y, Chen G. Tetrahedron Lett. 2019; 60: 1938
• 15d Bhat VS, Lee A. Eur. J. Org. Chem. 2021; 2021: 3382