Easy Access to N-(Pyridin-2-yl)benzamides through Electro-oxidative Ring Opening of 2-Arylimidazo[1,2-a]pyridines

Abstract

An electro-oxidative method for the ring opening of imidazopyridine derivatives is reported. This mild protocol offers a sustainable alternative to the existing harsh reaction conditions and unleashes an efficient approach to produce N-(pyridin-2-yl)amide derivatives with good tolerance of different functional groups. Systematic mechanistic studies provided insight into the reaction pathway and revealed that the residual water of DMSO is the source of oxygen atoms in the products.

Key words

electrosynthesis - C–C bond cleavage - imidazopyridine - oxidative ring opening - radicals

Publication History

Received: 31 August 2022

Accepted after revision: 07 October 2022

Accepted Manuscript online:
07 October 2022

Article published online:
07 November 2022

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• 18 General Procedure (GP) for Electro-oxidative Ring-Opening2-Arylimidazo[1,2-a]pyridines 1 (0.25 mmol, 1.0 equiv), HClO₄ (25 μmol, 10 mol%), and lithium perchlorate (53 mg, 0.1 M) were taken in an oven-dried undivided cell and dissolved in 5 mL of DMSO solvent. Thereafter graphite (3.0 cm × 0.8 cm × 0.2 cm) and platinum plate (3.0 cm × 0.8 cm × 0.025 cm) electrodes were dipped into the reaction mixture and connected with an AXIOMET AX-3003P power supply. The electrolysis was conducted along with continuous stirring for 2.5 h at 10 mA of constant current under air atmosphere at room temperature. After electrolysis, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dried with Na₂SO₄ and evaporated under reduced pressure. Purification of the product by column chromatography using 8–24% ethyl acetate in hexane yielded N-(pyridin-2-yl)benzamide derivatives 2.Analytical Data
  N-(Pyridin-2-yl)benzamide (2a)The GP was followed using 2-phenylimidazo[1,2-a]pyridine (1a, 48 mg, 0.25 mmol), HClO₄ (1.5 μL, 10 mol%). After 2.5 h, purification by column chromatography in silica gel (100–200 mesh) using 10% ethyl acetate in hexane yielded 2a (40 mg, 80%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 9.60 (br, 1 H), 8.43 (d, J = 8.4 Hz, 1 H), 8.11 (d, J = 8.3 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 2 H), 7.73 (t, J = 7.9 Hz, 1 H), 7.53 (t, J = 7.3 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.00 (t, J = 5.7 Hz, 1 H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ = 166.0, 151.2, 147.6, 139.0, 134.3, 132.4, 129.0, 127.5, 120.1, 114.6.4-Methyl-N-(pyridin-2-yl)benzamide (2b)The GP was followed using 2-(p-tolyl)imidazo[1,2-a]pyridine (1b, 52 mg, 0.25 mmol), HClO₄ (1.5 μL, 10 mol%). After 2.5 h, purification by column chromatography in silica gel (100–200 mesh) using 8% ethyl acetate in hexane yielded 2b (36 mg, 68%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.75 (br, 1 H), 8.36 (d, J = 8.4 Hz, 1 H), 8.24 (d, J = 4.4 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 2 H), 7.75–7.70 (m, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 7.05–7.01 (m, 1 H), 2.39 (s, 3 H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ = 165.8, 151.8, 147.8, 143.0, 138.7, 131.5, 129.6, 127.4, 119.9, 114.4, 21.7.4-Methoxy-N-(pyridin-2-yl)benzamide (2c)The GP was followed using 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (1c, 56 mg, 0.25 mmol), HClO₄ (1.5 μL, 10 mol%). After 2.5 h, purification by column chromatography in silica gel (100–200 mesh) using 20% ethyl acetate in hexane yielded 2c (42 mg, 73%) as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ = 9.13 (br, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 8.29–8.23 (m, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 7.76 (t, J = 8.8 Hz, 1 H), 7.10–7.03 (m, 1 H), 6.98 (d, J = 8.8 Hz, 2 H), 3.87 (s, 3 H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ = 165.6, 163.0, 152.0, 147.5, 138.9, 129.5, 126.5, 119.8, 114.6, 114.1, 55.6. N-[5-(4-Methoxyphenyl)pyridin-2-yl]benzamide (2p)The GP was followed using 6-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine (1p, 75 mg, 0.25 mmol), HClO₄ (1.5 μL, 10 mol%). After 2.5 h, purification by column chromatography in silica gel (100–200 mesh) using 22% ethyl acetate in hexane yielded 2p (44 mg, 59%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.75 (br, 1 H), 8.48–8.44 (m, 2 H), 7.97–7.91 (m, 3 H), 7.61–7.45 (m, 5 H), 7.01 (d, J = 8.7 Hz, 2 H), 3.86 (s, 3 H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ = 165.7, 159.8, 150.3, 145.7, 136.6, 134.4, 133.0, 132.4, 130.0, 129.0, 128.0, 127.4, 114.73, 114.1, 55.6. N-(5-Cyanopyridin-2-yl)benzamide (2q)
  The GP was followed using 2-phenylimidazo[1,2-a]pyridine-6-carbonitrile (1q, 54 mg, 0.25 mmol), HClO₄ (1.5 μL, 10 mol%). After 3.5 h, purification by column chromatography in silica gel (100–200 mesh) using 12% ethyl acetate in hexane yielded 2q (40 mg, 72%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 9.05 (s, 1 H), 8.60–8.54 (m, 2 H), 8.01 (dd, J = 8.8, 2.3 Hz, 1 H), 8.01–7.90 (m, 2 H), 7.66–7.57 (m, 1 H), 7.54 (dd, J = 8.4, 7.0 Hz, 2 H). ¹³C NMR{¹H} (126 MHz, CDCl₃): δ = 166.0, 154.3, 151.7, 141.9, 133.5, 133.1, 129.2, 127.6, 116.8, 114.0, 105.4.