Manganese-Mediated N-Heteroarylation of Indoles and Indazoles in Water

Abstract

A convenient strategy for the N-heteroarylation of indoles and indazoles using MnF₂/trans-1,2-diaminocyclohexane as catalyst and cesium carbonate as the base in water has been developed. The protocol afforded the corresponding N-heteroarylated products in moderate to good yields (up to 90%).

Key words

cross-coupling - manganese - N-heteroarylation - indoles - indazoles - heteroaryl iodides - water

• References and Notes

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• 14 Representative Characterization Data
  5-Bromo-1-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (4a) ¹H NMR (400 MHz, CDCl₃): δ = 8.98 (d, J = 2.2 Hz, 1 H), 8.61 (d, J = 3.9 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.22–8.25 (m, 1 H), 8.12 (d, J = 2.3 Hz, 1 H), 7.56 (d, J = 3.7 Hz, 1 H), 7.47–7.50 (m, 1 H), 6.65 (d, J = 3.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.9, 147.6, 144.6, 144.4, 134.8, 131.4, 131.0, 128.3, 123.9, 123.3, 110.8, 102.3. Anal. Calcd for C₁₂H₈BrN₃: C, 52.58; H, 2.94; N, 15.33. Found: C, 52.66; H, 3.25; N, 15.41. 5-Bromo-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (4b) ¹H NMR (400 MHz, CDCl₃): δ = 8.80 (d, J = 8.8 Hz, 1 H), 8.48 (d, J = 6.3 Hz, 1 H), 8.38–8.41 (m, 2 H), 8.06 (d, J = 2.3 Hz, 1 H), 7.86 (t, J = 8.8 Hz, 1 H), 7.18 (t, J = 6.1 Hz, 1 H), 6.59 (d, J = 11.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.4, 148.3, 145.8, 143.6, 138.4, 131.1, 128.0, 124.9, 120.7, 115.6, 113.1, 102.0. Anal. Calcd for C₁₂H₈BrN₃: C, 52.58; H, 2.94; N, 15.33. Found: C, 52.58; H, 3.14; N, 15.42. 5-Bromo-1-(pyridin-2-yl)-1H-indazole (7a) ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (d, J = 9.0 Hz, 1 H), 8.52 (d, J = 5.2 Hz, 1 H), 8.13 (s, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 7.91 (s, 1 H), 7.84 (t, J = 8.7 Hz, 1 H), 7.59 (d, J = 10.5 Hz, 1 H), 7.16–7.19 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.0, 147.7, 138.4, 137.6, 135.7, 130.9, 127.5, 123.1, 120.8, 116.9, 115.6, 113.4. Anal. Calcd for C₁₂H₈BrN₃: C, 52.58; H, 2.94; N, 15.33. Found: C, 52.58; H, 3.13; N, 15.41. 6-Bromo-1-(pyridin-2-yl)-1H-indazole (8a) ¹H NMR (400 MHz, CDCl₃): δ = 9.09 (s, 1 H), 8.53 (d, J = 4.8 Hz, 1 H), 8.14 (s, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.82 (t, J = 8.8 Hz, 1 H), 7.61 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 10.0 Hz, 1 H), 7.17 (t, J = 6.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 147.8, 139.4, 138.4, 136.6, 126.1, 124.7, 122.4, 121.7, 120.3, 118.3, 113.4. Anal. Calcd for C₁₂H₈BrN₃: C, 52.58; H, 2.94; N, 15.33. Found: C, 52.62; H, 3.18; N, 15.19.
• 15 Representative Procedure for N-Heteroarylation of Indoles and Indazoles A mixture of MnF₂ (Sigma-Aldrich, 98% purity, 0.074–0.147 mmol), N-heterocycles (0.735 mmol), Cs₂CO₃ (1.470 mmol), heteroaryl halide (1.103 mmol), trans-1,2-diamino-cyclohexane (0.147–0.294 mmol), and H₂O (0.1 mL) were added to a reaction vial, and a screw cap was fitted to it. The reaction mixture was stirred under air in a closed system at 130 °C for 24 h. After cooling to r.t., the mixture was diluted with CH₂Cl₂ and filtered through a pad of Celite^®. The combined organic extracts were dried with anhyd Na₂SO₄, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to afford the N-heteroarylated product. The identity and purity of known products were confirmed by ¹H NMR and ¹³C NMR spectroscopic analysis. Following the general procedure using 7-azaindole (87 mg, 0.735 mmol) and 3-iodopyridine (226 mg, 1.1025 mmol) provided 129 mg (90% yield) of the coupling product 3a as a brown solid after purification by flash chromatography (hexane–EtOAc = 70:30) of the crude oil.