Copper-Mediated Direct Aromatic ortho-C–H Cyanation by AIBN

Abstract

We have developed a copper-mediated chelation-assisted direct aromatic ortho-C–H cyanation that uses AIBN as a safe cyanation reagent. The substrate scope included indoles, pyrroles, a carbazole, and a thiophene.

Key words

copper catalysis - cyanation - C–H bond activation - AIBN - radical reaction - safety

• References and Notes

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• 17 Heterocyclic Nitriles 2a–s; General ProcedureAn oven-dried Schlenk tube equipped with a magnetic stirring bar was charged sequentially with the appropriate heterocycle 1a–s (0.1 mmol), AIBN (82.1 mg, 0.5 mmol), Cu(OAc)₂ (27.2 mg, 0.15 mmol), DMF (0.5 mL), and MeCN (1.5 mL). After evacuation and backfilling with O₂ three times, the Schlenk tube was attached to an O₂ balloon, and the mixture was stirred at 135 °C (oil bath) for 48 hours then cooled to r.t. The resultant mixture was poured into H₂O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic phase was dried (Na₂SO₄; White solid; yield: 15.5 mg (85%), R_f = 0.5 (PE–EtOAc, 5:1). ¹H NMR (400 MHz, CDCl₃)), filtered, and concentrated under reduced pressure to give a residue that was purified by flash column chromatography [silica gel, PE–EtOAc (10:1)].1-Pyrimidin-2-yl-1H-indole-2-carbonitrile (2a) ¹¹White solid; yield: 15.5 mg (85%), R_f = 0.5 (PE–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 4.8 Hz, 2 H), 8.68 (d, J = 8.6 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.34–7.30 (m, 1 H), 7.24–7.21 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ = 158.4, 156.6, 136.6, 127.8, 127.6, 123.6, 122.0, 121.0, 118.0, 116.2, 114.3, 108.9