A Fluorenyl Activating Group Enables Addition of Simple Grignard Reagents to C=N Electrophiles

Abstract

Nucleophilic addition of organometallic reagents to ketimines and hydrazones can be a challenging transformation. Here we report the use of fluorenone-derived mixed azines which promote facile addition of Grignard reagents. The fluorenylidene activating group is easily installed and removed, thereby offering practical access to highly substituted amines and hydrazines.

Key words

amines - Grignard reaction - hydrazones - imines - nucleophilic addition - organometallic reagents

• References and Notes

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Addition of carbon radicals to hydrazones is possible when the substrate is quite electrophilic, e.g., 1,2-dicarbonyl- or aldehyde-derived. See for example:
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• 13 General Procedure for Reactions of Azine Substrates with Grignard ReagentsTo a solution of azine substrate in anhydrous THF (ca. 0.2 M) cooled to 0 °C was added slowly a solution of Grignard reagent (1–5 equiv). After addition, the reaction mixture was allowed to warm to room temperature and stir for 16 h. After this time, the reaction was quenched with 5% aqueous citric acid, and the mixture was extracted with isopropyl acetate (3×). The combined organics were washed with water and brine, dried over sodium sulfate, and concentrated. The resulting crude material was purified by column chromatography. NOTE: The azine substrates were generally found to be hygroscopic. Therefore, best yields were obtained when the azines were dried overnight in a vacuum dessicator over anhydrous calcium sulfate prior to use.
• 14 Analytical Data for Example Azine 1b ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.6 Hz, 1 H), 7.86 (d, J = 7.4 Hz, 1 H), 7.61 (dd, J = 11.1, 7.5 Hz, 2 H), 7.39 (tt, J = 7.5, 1.3 Hz, 2 H), 7.34–7.21 (m, 2 H), 4.05–3.93 (m, 4 H), 2.81–2.69 (m, 4 H), 2.04–1.95 (m, 2 H), 1.87–1.78 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.25, 155.11, 142.27, 141.01, 136.86, 131.54, 131.06, 130.55, 129.43, 128.01, 127.99, 122.48, 119.96, 119.75, 108.00, 64.56, 34.70, 33.73, 32.15, 25.06. LRMS: m/z [M + H]⁺ calcd for C₂₁H₂₁N₂O₂ ⁺: 333; found: 333.
• 15 Analytical Data for Example Product 2b ¹H NMR (400 MHz, CDCl₃): δ = 7.83–7.73 (m, 3 H), 7.71–7.62 (m, 1 H), 7.40 (td, J = 7.5, 1.1 Hz, 1 H), 7.34 (td, J = 7.5, 1.3 Hz, 1 H), 7.33–7.23 (m, 2 H), 6.68 (s, 1 H), 3.96 (s, 3 H), 2.16–2.06 (m, 2 H), 1.96–1.85 (m, 2 H), 1.82–1.72 (m, 3 H), 1.72–1.62 (m, 4 H), 0.84 (t, J = 7.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃); δ = 140.63, 138.76, 138.47, 137.30, 130.35, 128.47, 127.46, 127.37, 127.10, 123.87, 120.48, 120.25, 119.35, 108.96, 64.28, 64.28, 57.78, 32.77, 31.55, 30.61, 7.55. LRMS: m/z [M + H]⁺ calcd for C₂₃H₂₇N₂O₂ ⁺: 363; found: 363.