Intermolecular Nucleophilic Addition Reaction of a C-7 Anion from N-[Bis(dimethylamino)phosphoryl]indole to Electrophiles/Arynes: Synthesis of 7-Substituted Indoles

Abstract

A novel approach to the C-7 substitution of N-[bis(dimethylamino)phosphoryl]indole by nucleophilic addition of the corresponding C-7 carbanion to electrophiles or arynes is described. The directing group can be easily removed, providing a simple route to the synthesis of 7-functionalized indoles.

Key words

indoles - lithiation - arylation - substitution - directing groups

Publication History

Received: 25 August 2021

Accepted after revision: 11 October 2021

Accepted Manuscript online:
11 October 2021

Article published online:
03 November 2021

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• 12 C-7 Substitution of N-[Bis(dimethylamino)phosphoryl] indole (1); General Procedure A flame-dried, two-necked, round-bottomed flask equipped with a magnetic stirrer bar, a septum cap, and a bubbler was charged with a solution of protected indole 1 (0.5 g, 1 equiv) in anhyd THF (10 mL) under an inert atmosphere. The solution was cooled to –78 °C and BuLi (2.2 equiv) was added dropwise. An orange-red color appeared immediately, and the solution was stirred at –78 °C for 15 minutes. The appropriate electrophile (2.2 equiv) was then added, and the reaction mixture was stirred at –78 °C for another 30 min. The reaction was then quenched with sat. aq NH₄Cl (20 mL), and the mixture was added to Et₂O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et₂O (2 × 10 mL). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to obtain a crude product that was purified by flash chromatography [silica gel (230–400 mesh), hexane–EtOAc]. N-[Bis(dimethylamino)phosphoryl)-7-methylindole (3a) Clear viscous oil; yield: 0.52 g (99%). ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.61 (m, 1 H,), 7.46–7.44 (m, 1 H), 7.17–7.10 (m, 2 H), 6.36–6.35 (m, 1 H), 2.69 (s, 6 H), 2.66 (s, 6 H), 2.55 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 140.3, 140.2, 139.4, 139.3, 130.6, 130.5, 122.9, 121.3, 119.5, 113.7, 107.5, 107.4, 36.6, 36.5, 16.0. HRMS (ES⁺): m/z [M + H]⁺calcd for C₁₃H₂₁N₃OP: 266.1422; found: 266.1316. Deprotection of C-7-Functionalized N-[Bis(dimethylamino)phosphoryl)indoles; General Procedure A single-necked round-bottomed flask equipped with a magnetic stirrer bar and drying tube was charged with a solution of the appropriate C-7-substituted protected indole 3 (1 equiv) in anhyd THF (10 mL), and LAH (1.1 equiv) was added at 0 °C. After completion of the addition of LAH, the ice bath was removed and the mixture was stirred at rt for 2 h. The mixture was then cooled to 0 °C and the reaction was quenched with 15% aq NaOH (5 mL). The mixture was extracted with CHCl₃ (3 × 10 mL). The organic layer was washed with brine, dried, and concentrated under reduced pressure to afford a crude product that was purified by column chromatography [silica gel (60–120 mesh) hexane–EtOAc (4:1)]. 7-Methyl-1H-indole (4a) Light-brown solid; yield: 0.12 g (99%); mp 84–86 °C (Lit.¹¹ 85 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (br s, 1 H), 7.51 (d, J = 7.56 Hz, 1 H), 7.25–7.22 (m, 1 H), 7.19–7.03 (m, 2 H), 6.20 (s, 1 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.0, 129.0, 124.1, 122.0, 120.9, 119.8, 119.6, 102.6, 13.7.