Potassium Hydroxide Catalysed Intermolecular Aza-Michael Addition of 3-Cyanoindole to Aromatic Enones

Abstract

Indole is one of the utmost important heterocycles as it is an essential nucleus of many pharmaceutical compounds. Its aza-Michael reaction, however, is underdeveloped because of the moiety’s inherent characteristics. Here, a potassium hydroxide catalysed intermolecular aza-Michael reaction of 3-cyanoindole with aromatic enones is described. A variety of chalcone derivatives are well tolerated and afford the corresponding N-adducts in moderate to high yields. The use of a cheap catalyst, low catalyst loading, mild reaction temperature, and good substrate tolerance make this procedure a direct and facile method for the preparation of N1-functionalized indoles.

Key words

Michael addition - enones - 3-cyanoindole - nitrogen heterocycles - regioselectivity

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• 33 1-(3-Oxo-1,3-diphenylpropyl)-1H-indole-3-carbonitrile (2a) – Typical Procedure Enone 1a (62.5 mg, 0.3 mmol), 3-cyanoindole (51.2 mg, 0.36 mmol, 1.2 equiv), KOH (0.8 mg, 0.015 mmol, 5.0 mol%), and CH₂Cl₂ (3.0 mL) were sequentially charged into a dry round-bottomed flask (25 mL). The reaction mixture was stirred at 25 °C until the reaction complete (monitored by TLC). The reaction mixture was diluted with CH₂Cl₂ (3.0 mL), and washed with brine (3 × 4.0 mL). The aqueous phase was extracted with CH₂Cl₂ (4.0 mL). The organic phase was combined, dried with anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE–EtOAc, 6:1) to afford the pure product 2a. White solid; yield 71.4 mg (68%); mp 123–125 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.93 (d, J = 7.8 Hz, 2 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.71 (s, 1 H), 7.62–7.59 (m, 1 H), 7.49–7.47 (m, 3 H), 7.36–7.27 (m, 5 H), 7.24 (d, J = 7.2 Hz, 2 H), 6.42 (t, J = 6.6 Hz, 1 H), 3.99 (d, J = 6.6 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 195.2, 138.4, 136.0, 135.3, 134.0, 132.6, 129.2, 128.9, 128.6, 128.1, 128.0, 126.4, 124.1, 122.4, 120.0, 115.7, 111.3, 86.8, 56.1, 43.3. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₄H₁₉N₂O: 351.1492; found: 351.1494.
• 34 CCDC 1510327 contains the supplementary crystallographic data for compound 2m. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.