Synlett 2018; 29(14): 1857-1860
DOI: 10.1055/s-0037-1609551
letter
© Georg Thieme Verlag Stuttgart · New York

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

Patience Mukashyaka
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: Hamilton.gregory@gene.com
,
Gregory L. Hamilton*
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA   Email: Hamilton.gregory@gene.com
› Author Affiliations
Further Information

Publication History

Received: 17 May 2018

Accepted after revision: 10 June 2018

Publication Date:
10 July 2018 (online)


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.

Supporting Information

 
  • References and Notes

  • 3 Allyl Grignards are well-known to be particularly nucleophilic and less basic, reacting with even very hindered electrophiles. See for example: DeMeester WA. Fuson RC. J. Org. Chem. 1965; 30: 4332
  • 7 Notte GT. Leighton JL. J. Am. Chem. Soc. 2008; 130: 6676
  • 11 Nishino T. Miyaji K. Iwamoto S. Mikashima T. Saruhashi K. Kishikawa Y. WO 2012074067, 2012
  • 12 Johns AM. Liu Z. Hartwig JF. Angew. Chem. Int. Ed. 2007; 46: 7259
  • 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.