A Metal-Free Strategy for the Synthesis of Symmetrical 2,3,5,6-Tetrasubstituted Pyridines Using Triethyl Orthoformate as a Carbon Source

Abstract

A simple and efficient method for the synthesis of symmetric 2,3,5,6-tetrasubstituted pyridines from enaminones and triethyl orthoformate, catalyzed by pyridinium p-toluenesulfonate, has been established in which triethyl orthoformate was applied as a carbon source. The procedure was smoothly executed, culminating in the synthesis of symmetrical 2,3,5,6-tetrasubstituted pyridines with moderate to exceptional yields across a diverse array of substrates.

Key words

pyridines - triethyl orthoformate - pyridinium toluenesulfonate - metal-free reaction

• References and Notes

• 1a Michael JP. Nat. Prod. Rep. 2005; 22: 627
• 1b Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
• 2a Carey JS, Laffan D, Thomson C, Williams MT. Org. Biomol. Chem. 2006; 4: 2337
• 2b Jayasinghe L, Jayasooriya CP, Hara N, Fujimoto Y. Tetrahedron Lett. 2003; 44: 8769
• 2c Kubota T, Nishi T, Fukushi E, Kawabata J, Fromont J, Kobayashi J.i. Tetrahedron Lett. 2007; 48: 4983
• 3 Wang H, Helgeson R, Ma B, Wudl F. J. Org. Chem. 2000; 65: 5862
• 4 Pavluchenko AI, Petrov VF, Smirnova NI. Liq. Cryst. 1995; 19: 811
• 5 Alstrum-Acevedo JH, Brennaman MK, Meyer TJ. Inorg. Chem. 2005; 44: 6802
• 6 Henry GD. Tetrahedron 2004; 60: 6043
• 7 Savoia D, Alvaro G, Di Fabio R, Fiorelli C, Gualandi A, Monari M, Piccinelli F. Adv. Synth. Catal. 2006; 348: 1883
• 8 Bera MK, Hommes P, Reissig H.-U. Chem. Eur. J. 2011; 17: 11838
• 9a Chen S, Hossain MS, Foss FW. Jr. ACS Sustainable Chem. Eng. 2013; 1: 1045
• 9b Abdel-Mohsen HT, Conrad J, Beifuss U. Green Chem. 2012; 14: 2686
• 9c Nasr-Esfahani M, Karami B, Behzadi M. J. Heterocycl. Chem. 2009; 46: 931
• 10 Zhao M.-N, Hui R.-R, Ren Z.-H, Wang YY, Guan Z.-H. Org. Lett. 2014; 16: 3082
• 11 Zhao M.-N, Yu L, Mo N.-F, Ren Z.-H, Wang Y.-Y, Guan Z.-H. Org. Chem. Front. 2017; 4: 597
• 12 Chang L, Lai J, Yuan G. Chin. J. Chem. 2016; 34: 887
• 13 Yan Y, Li H, Li Z, Niu B, Shi M, Liu Y. J. Org. Chem. 2017; 82: 8628
• 14 Gu Q, He K, Zeng W, Jiang L, Qiao Z, Lin J, Jin Y. Tetrahedron Lett. 2022; 103: 153993
• 15 Sagitullina GP, Garkushenko AK, Atavin EG, Sagitullin RS. Mendeleev Commun. 2009; 19: 155
• 16 Tuengpanya S, Chantana C, Sirion U, Siritanyong W, Srisook K, Jaratjaroonphong J. Tetrahedron 2018; 74: 4373
• 17 Mazloumi M, Shirini F, Goli-Jolodar O, Seddighi M. New J. Chem. 2018; 42: 5742
• 18a Kumar P, Kapur M. Org. Lett. 2020; 22: 5855
• 18b Zine Y, Dems MA, Boulcina R, Boudjada A, Harakat D, Roisnel T, Robert A, Debache A. J. Mol. Struct. 2024; 1300: 137256
• 19 Aydin F, Özen R. J. Chem. Res. 2004; 486
• 20 Symmetric 2,3,5,6-Tetrasubstituted Pyridines; General Procedure The appropriate enaminone 1 (0.6 mmol) was treated with PPTS (20 mol%) in TEM at 60 °C under air for 4 h, then cooled to r.t. The mixture was then extracted with EtOAc, and the combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by chromatography (silica gel). (2,6-Dimethylpyridine-3,5-diyl)bis(phenylmethanone) (3a)¹² Yellow oil; yield: 80.4 mg (82%). ¹H NMR (600 MHz, CDCl₃): δ = 7.77 (d, J = 8.3 Hz, 4 H), 7.61–7.56 (m, 3 H), 7.45 (t, J = 7.0 Hz, 4 H), 2.62–2.57 (m, 6 H). ¹³C NMR (151 MHz, CDCl₃): δ = 195.99, 157.82, 136.57, 136.29, 133.54, 130.28, 129.70, 128.51, 23.26. (2,6-Dimethylpyridine-3,5-diyl)bis[(4-methylphenyl)methanone] (3b)²⁰ Yellow oil; yield: 76.7 mg (78%). ¹H NMR (600 MHz, CDCl₃): δ = 7.69 (d, J = 8.2 Hz, 4 H), 7.57 (s, 1 H), 7.27 (d, J = 7.9 Hz, 4 H), 2.59 (s, 6 H), 2.42 (s, 6 H). ¹³C NMR (151 MHz, CDCl₃): δ = 195.68, 157.41, 144.67, 135.94, 134.10, 130.61, 129.92, 129.24, 23.18, 21.49.
• 21 Zhang XY, Liu K, Li S, Li Y, Wu Y, Li X, Ran X, Liu A, Yuan J. Tetrahedron Lett. 2023; 126: 154623