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Synlett 2022; 33(01): 84-87
DOI: 10.1055/a-1666-9533
letter

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

Esha Sharma
a   SRF Limited Block C, Greenwood City, Sector 45, Gurugram Haryana 122003, India
,
Manjot Kaur
b   Mehr Chand Mahajan DAV College for Women, Sector-36, Chandigarh, India
c   Department of Chemistry, Panjab University, Chandigarh, India
,
Babaldeep Kaur
c   Department of Chemistry, Panjab University, Chandigarh, India
,
Amarjit Kaur
c   Department of Chemistry, Panjab University, Chandigarh, India
,
Paramjit Singh
c   Department of Chemistry, Panjab University, Chandigarh, India
,
Kamal Nain Singh∗
c   Department of Chemistry, Panjab University, Chandigarh, India
› Author AffiliationsWe acknowledge financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, through Scheme number 02(0131)/13/EMR-II.
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1666-9533.
  • Supporting Information


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.