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Synlett
DOI: 10.1055/a-2593-6446
letter

Nucleophilic Additions of Organolithium Reagents to Heterocyclic Aldimines

Justin Baek
,
Walker A. Hoisington
,
Evelyn S. Galgano
,
Ethan H. Schneider
,
Timothy J. Barker∗

We gratefully acknowledge financial support from the South Carolina IDeA Networks of Biomedical Research Excellence (SC INBRE) for a Developmental Research Project grant (2022–2025) funded by grants from the National Center for Research Resources (5 P20 RR016461) and the National Institute of General Medical Sciences (8 P20 GM103499) from the National Institutes of Health. We additionally acknowledge financial support from the College of Charleston Department of Chemistry and Biochemistry, College of Charleston Faculty Research and Development fund, and the School of Natural and Environmental Sciences at the College of Charleston.
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Abstract

The addition of alkyllithium reagents to heterocyclic aldimines is described. This method is a straightforward two-step procedure from the starting aldehyde and amine with one purification. The ability to use unprotected indole carboxaldehydes as substrates is a key feature of this method that makes it an attractive way to synthesize the corresponding amine products.

Key words

alkyllithium - aldimine - indole - heterocycles - amine

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2593-6446.
  • Supporting Information


Publication History

Received: 07 March 2025

Accepted after revision: 23 April 2025

Accepted Manuscript online:
23 April 2025

Article published online:
20 June 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 35 General Procedure for Nucleophilic Addition to IminesTo a 25 mL round-bottomed flask containing 4 Å molecular sieves (0.5 g), heterocyclic aldehyde (0.50 mmol), and aniline (56 mg, 0.60 mmol), pyrrolidine (10 μL, 0.1 mmol) and dichloromethane (2 mL) were added.27 The solution was left to stir overnight at room temperature. The molecular sieves were removed by vacuum filtration, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was examined by 1H NMR spectroscopy to confirm conversion into the imine had occurred. In a separate 25 mL round-bottomed flask under argon, cooled to –78 ℃, phenethyl iodide (220 μL, 1.5 mmol) dissolved in 2 mL diethyl ether was added. To this solution, tert-butyllithium (1.9 mL, 3.3 mmol, 1.7 M in pentane) was added. The solution was stirred and allowed to warm to room temperature over 1 h, so following lithium–halogen exchange, the excess tert-butyllithium would react with the diethyl ether.28 The phenethyl lithium solution was then chilled back to –78 ℃, and the unpurified imine product was added as a solution in 3 mL of THF. The solution was slowly allowed to warm to room temperature over 1 h, then quenched with water (10 mL). The product was extracted with ethyl acetate (3 × 10 mL), dried with Na2SO4, and concentrated under reduced pressure. The product was then purified either with a manual flash column or with an automated flash chromatography system.[1-(5-Indolyl)-3-phenylpropyl]aniline (2)The product was prepared according to the general procedure and purified with a silica column with a gradient of 5–15% ethyl acetate in hexanes providing 2 as a light brown oil in 53% yield (87 mg, 0.27 mmol). 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.51 (s, 1 H), 7.31–6.82 (m, 10 H), 6.52 (t, J = 7.3 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 2 H), 6.40 (s, 1 H), 4.34 (t, J = 6.8 Hz, 1 H), 4.03 (br s, 1 H), 2.69–2.48 (m, 2 H), 2.23–1.93 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 147.65, 141.91, 135.24, 135.18, 129.18, 128.59, 128.52, 128.11, 126.01, 124.65, 120.91, 118.59, 117.19, 113.55, 111.37, 102.65, 58.30, 40.54, 32.87. HRMS (ESI): m/z [M + H]+ calcd for C23H23N2: 327.1855; found: 327.1852.