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Synlett 2017; 28(17): 2335-2339
DOI: 10.1055/s-0036-1588491
DOI: 10.1055/s-0036-1588491
letter
Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates
Acknowledgement is made to the Donors of the American Chemical Society Petroleum Research Fund for a New Directions award in support of this research (54823-ND1). The National Institute of General Medical Sciences (R15-GM116054) also provided financial support. NMR spectra were obtained at Syracuse University using instrumentation acquired with the assistance of the National Science Foundation (CHE-1229345). L. R. thanks the Laboratoire d’Excellence Multiscale Integrative Chemistry (LabEx MiChem) for a travel grant to facilitate study in the USA.Further Information
Publication History
Received: 09 May 2017
Accepted after revision: 13 June 2017
Publication Date:
11 July 2017 (online)
Abstract
Trichloroacetimidates function as effective electrophiles for the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3′-disubstituted indolenines. These indolenines are common synthetic intermediates that are often utilized in the synthesis of complex molecules. Effective reaction conditions utilizing Lewis acid catalysts have been determined, and the scope of the reaction with respect to indole and imidate reaction partner has been investigated. This chemistry provides an alternative to base promoted and transition-metal-catalyzed methods that are more commonly utilized to access similar indolenines.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1588491.
- Supporting Information
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- 17 Representative Procedure for C3-Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates In a flame-dried flask allyl trichloroacetimidate 7 (121 mg, 0.60 mmol) was dissolved in 4 mL of anhydrous DCE. 2,3-Dimethylindole (6, 130 mg, 0.90 mmol) was then added followed by freshly distilled TMSOTf (20 mol%, 27 μL, 0.12 mmol). After 3 h at rt the reaction mixture was quenched with the addition of 10 mL of 1 M NaOH. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc/70% hexanes) to provide 2,3-dimethyl-3-(prop-2-en-1-yl)-3H-indole (8) as a yellow oil (82.0 mg, 74%). TLC Rf = 0.11 (10% EtOAc/90% hexanes). IR (neat): 3079, 3009, 2966, 2827, 2869, 1579 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.0 Hz, 1 H), 7.33–7.21 (m, 2 H), 7.19 (td, J = 7.2, 0.8 Hz, 1 H), 5.21–5.11 (m, 1 H), 4.98–4.85 (m, 2 H), 2.66–2.60 (m, 1 H), 2.42 (dd, J = 14.0, 8.0 Hz, 1 H), 2.26 (s, 3 H), 1.31 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 186.6, 154.2, 143.4, 132.5, 127.7, 125.0, 121.8, 119.8, 118.0, 57.5, 41.2, 21.8, 15.9. This compound has been reported previously.8f
A combination of photochemistry and a weak amine base has also been employed, see:
For other routes to similar communensin core structures, see ref. 8b and: