Synthesis of 2-Acylated Indoles through Palladium-Catalyzed Dehydrogenative Coupling of N-Pyrimidine-Protected Indoles with Aldehydes and Ethyl Glyoxylate

Abstract

C2-Acylated indoles have been synthesized in good yields through palladium-catalyzed dehydrogenative coupling of N-pyrimidine-protected indoles using aldehydes as the source of acyl reagent and tert-butyl hydroperoxide as the oxidant. 2-Indole carboxylates can be synthesized when aldehydes are substituted by ethyl glyoxylate.

Key words

palladium - dehydrogenative coupling - aldehyde - acylation - indoles

• References and Notes

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• 17 General Procedure: To a 25-mL sealed tube were added indole (0.3 mmol), aldehyde (0.45 mmol), Pd(OAc)₂ (6.72 mg, 10 mmol%), anhydrous TBHP (ca. 5 M in decane, 4 equiv), and EtOAc (2.0 mL). The tube was capped and stirred under N₂ at 125 °C for 24 h. The reaction mixture was cooled to room temperature and diluted with CH₂Cl₂, filtered through a short pad of Celite, and washed with brine and CH₂Cl₂. The combined organic extracts were dried over Na₂SO₄, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography to afford the desired product. [3-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3as): Yield: 82%; white solid; mp 153–154 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.63 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 4.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.48–7.40 (m, 2 H), 7.32 (q, J = 8.0 Hz, 3 H), 6.84 (t, J = 4.0 Hz, 1 H), 2.37 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 189.4, 157.5, 157.0, 139.2, 136.4, 133.2, 132.2, 130.2, 128.5, 128.3, 126.1, 122.5, 121.7, 120.1, 116.1, 115.2, 9.3; HRMS: m/z [M]⁺ calcd for C₂₀H₁₅N₃O: 313.1207; found: 313.1210. [7-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3at): Yield: 80%; yellow solid; mp 36–37 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 4.0 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 2 H), 7.60–7.55 (m, 2 H), 7.48–7.45 (m, 2 H), 7.39 (t, J = 4.0 Hz, 1 H), 7.20 (s, 1 H), 7.13–7.11 (m, 2 H), 1.96 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 187.0, 159.7, 158.1, 138.3, 138.2, 136.0, 132.4, 129.6, 129.2, 128.2, 127.2, 122.4, 121.9, 121.1, 120.1, 116.4, 19.3. HRMS: m/z [M]⁺ calcd for C₂₀H₁₅N₃O: 313.1207; found: 313.1210. (4-Methoxyphenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (3au): Yield: 76%; white solid; mp 39–40 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.61 (d, J = 4.0 Hz, 2 H), 8.39 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 7.02 (t, J = 4.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 2 H), 3.83 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 186.4, 163.3, 157.9, 157.2, 138.0, 137.2, 131.8, 130.7, 127.9, 126.1, 122.6, 122.2, 117.3, 114.5, 114.1, 113.5, 55.4; HRMS: m/z [M]⁺ calcd for C₂₀H₁₅N₃O₂: 329.1152; found: 329.1159. N-{4-[1-(Pyrimidin-2-yl)-1H-indole-2-carbonyl]phenyl}acetamide (3av): Yield: 67%; yellow solid; mp 138–139 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.11 (s, 1 H), 8.56 (d, J = 4.0 Hz, 2 H), 8.37 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.68–7.61 (m, 3 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 6.99 (t, J = 4.0 Hz, 1 H), 2.09 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 186.8, 169.4, 157.8, 157.0, 142.9, 138.0, 136.9, 132.7, 130.7, 127.8, 126.4, 122.7, 122.3, 118.7, 117.3, 115.1, 114.1, 24.28; HRMS: m/z [M]⁺ calcd for C₂₁H₁₆N₄O₂: 356.1273; found: 356.1268.
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