Piperazine as Leaving Group in A3 Adducts: Fast Access to Alkynyl Indoles

Abstract

The A3 coupling between N-ethylpiperazine and electron-rich aromatic aldehydes forms adducts that may be easily used as electrophiles towards electron-rich heterocycles such as indoles. The removal of the piperazine moiety is triggered by the addition of 1,2-dibromoethane. Overall, the reaction provides efficient access to alkynyl indoles and pyrroles.

Key words

A3 reaction - alkyne - piperazine - indoles

• References and Notes


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• 8 Synthesis of 1a; Typical Procedure: To a stirred solution of 4-methoxybenzaldehyde (5 mmol, 0.6 mL), N-ethylpiperazine (1 equiv, 5 mmol, 0.64 mL), and 1-hexyne (2 equiv, 10 mmol, 1.16 mL) in toluene (1 mL, 5 M) was added CuI (0.1 equiv, 95 mg) and the mixture was heated at 130 °C under microwave irradiation for 60 min. Purification by flash chromatography (EtOAc–EtOH) gave 1a (1.09 g, 69%) as a yellow oil. R_f = 0.16 (EtOAc–EtOH, 90:10). FTIR: 2930, 2872, 2809, 1508, 1158, 1145, 1002, 834 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.44 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 4.49 (s, 1 H), 3.80 (s, 3 H), 2.57 (br s, 8 H), 2.4 (q, J = 7.2 Hz, 2 H), 2.27 (td, J = 7.1, 2 Hz, 2 H), 1.53 (m, 2 H), 1.41 (m, 2 H), 1.07 (t, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 159.0, 131.0, 129.8, 113.4, 88.2, 76.1, 60.8, 55.3, 53.1, 52.5, 31.2, 22.2, 18.7, 13.8, 12.1. HRMS (ESI+/TOF): m/z calcd for C₂₀H₃₀N₂O: 314.2358; found: 314.2365. Synthesis of 3a; Typical Procedure: To a solution of 1a (1.2 equiv, 0.36 mmol, 113 mg) in acetonitrile (1.5 mL), was added 1,2-dibromoethane (1.5 equiv, 0.45 mmol, 0.04 mL) and N-methylindole 2a (1 equiv, 0.3 mmol, 0.04 mL). Purification by flash chromatography (petroleum ether–Et₂O) gave 3a (73 mg, 73%) as a brownish oil. R_f = 0.34 (petroleum ether–Et₂O, 90:10). FTIR: 2953, 2929, 1607, 1507, 1462, 1243, 1172, 1012, 879, 841 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.56 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 1 H), 7.21 (m, 1 H), 7.05 (m, 1 H), 6.90 (s,1 H), 6.85 (d, J = 8.5 Hz, 2 H), 5.18 (s, 1 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 2.28 (td, J = 7.0, 2.3 Hz, 2 H), 1.55 (m, 2 H), 1.46 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 158.3, 137.6, 134.5, 128.9, 127.1, 126.6, 121.7, 119.9, 119.0, 116.6, 113.8, 109.3, 83.2, 81.2, 55.4, 34.1, 32.8, 31.3, 22.2, 18.8, 13.8. HRMS (ESI+/TOF): m/z calcd for C₂₃H₂₅NO: 331.1936; found: 331.2296.