Exploration of Aberrant Behaviour of Grignard Reagents with Indole-3-carboxaldehyde: Application to the Synthesis of Turbomycin B and Vibrindole A Derivatives

Abstract

An aberrant reaction of Grignard reagents with N-alkylated indole-3-carboxaldehyde has been observed. Contrary to the usual formation of an alcohol, it afforded an unusual bis(indolyl)methane product. A systematic study on this new mode of reactivity and its application to a synthesis of the potent antibiotic turbomycin B and vibrindole A derivatives is reported.

Key words

Grignard - vibrindole - turbomycin

• References and Notes

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• 15 Procedure for the Synthesis of Representative Substrate Turbomycin B Reductant {3-[(1H-indol-3-yl)(phenyl)methyl]-1H-indole} Indole-3-carboxaldehyde was dissolved in a Et₂O–THF (2:1) mixture and the solution cooled to 0 °C. The Grignard reagent (PhMgBr, 2.5 equiv) was added dropwise to the solution. After addition, the reaction mixture was stirred at the same temperature for 50 min. After completion of the reaction (monitored by TLC), sat. aq NH₄Cl was added to quench the reaction, and the reaction mixture was allowed to warm to r.t. The resultant mixture was then extracted with EtOAc or CH₂Cl₂ (3×) and dried over anhydrous Na₂SO₄. The resultant solution was filtered and concentrated under vacuum to obtain the crude product, which was then purified by column chromatography using a hexane–EtOAc solvent system to give turbomycin B. Note: If the above-mentioned reaction was performed in just THF, exclusively the alcohol product was formed in the given time. It was observed that the crude mixture must be purified within 1 h of completion of the reaction, and the concentration of the reaction mixture must be carried out at moderate temperatures (30–35 °C) under vacuum. CH₂Cl₂ (a low boiling solvent) was preferred over EtOAc for extraction purposes. White solid; mp 125–127 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.76 (s, 2 H) 7.30 (d, 2 H, J = 8.2 Hz), 7.27–7.24 (m, 4 H), 7.20–7.16 (m, 2 H), 7.14–7.06 (m, 3 H), 6.92 (t, 2 H, J = 6.9 Hz), 6.54 (d, 2 H, J = 2.1 Hz), 5.80 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 143.9, 136.6, 128.7, 128.2, 127.0, 126.1, 123.6, 121.9, 120.0, 119.7, 119.2, 111.0, 40.1.