Iron-Catalyzed C3-Formylation of Indoles with Formaldehyde and Aqueous Ammonia under Air

Abstract

An efficient iron-catalyzed C3-selective formylation of free (N–H) or N-substituted indoles was developed by employing formaldehyde and aqueous ammonia, with air as the oxidant. This new method gave 3-formylindoles in moderate to excellent yields with fairly short reaction times. Moreover, this procedure for catalytic formylation of indoles can be applied to gram-scale syntheses.

Key words

iron catalysis - formylation - indoles - indolecarbaldehydes - formaldehyde

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• 13 Indolecarbaldehydes 2a–2aa; General Procedure A 50 mL round-bottomed flask equipped with a magnetic stirring bar was charged with the appropriate indole 1 (0.5 mmol, 1.0 equiv), 37% aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25% aq NH₃ (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl₃ (0.01 mmol, 0.0016 g, 2 mol%), and DMF (2 mL). The flask was fitted with a reflux condenser, and the mixture was stirred at 130 °C under open air. When the reaction was complete (TLC), the mixture was cooled to r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL), and extracted with EtOAc (3 x 7 mL). The organic layers were combined, washed with sat. aq NaHCO₃ (10 mL) and sat. aq NaCl (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane–EtOAc). 1H-indole-3-carbaldehyde (2a)^7f Pale-yellow solid; yield: 0.0676 g (93%); mp 190–192 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.07 (s, 1 H), 8.36 – 8.28 (m, 1 H), 7.86 (d, J = 3.0 Hz, 1 H), 7.48 – 7.41 (m, 1 H), 7.36 – 7.31 (m, 2 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 185.01, 138.30, 137.05, 124.08, 123.49, 122.15, 120.83, 118.13, 112.38. EI-MS: m/z (%) = 63(30), 90(60), 116(18), 144(100), 145(84) [M⁺]