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Synlett 2008(3): 399-401  
DOI: 10.1055/s-2007-1000864
LETTER
© Georg Thieme Verlag Stuttgart · New York

Barbier Conditions for Reformatsky and Alkylation Reactions on Trifluoromethyl Aldimines

Mickael Dos Santos, Benoit Crousse*, Danièle Bonnet-Delpon
BioCIS-CNRS, Faculté de Pharmacie, Université Paris-Sud, 5 rue J. B. Clément, 92296 Châtenay-Malabry cedex, France
Fax: 33(1)46835740; e-Mail: benoit.crousse@u-psud.fr;
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Publication History

Received 3 October 2007
Publication Date:
21 December 2007 (online)

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Abstract

β-Trifluoromethyl β-amino acids and α-trifluoromethyl α-alkyl amines can be easily prepared under Barbier conditions from trifluoromethyl aldimines in moderate to good yields. β-Tri­fluoromethyl β-amino acids were obtained in good enantioselectivity from the chiral trifluoromethyl aldimine starting material.

Key words

Barbier reaction - Reformatsky - fluoroalkyl amines - amino acids

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Addition of EtMgBr (1.3 equiv, 1 N THF) to CF3 aldimine 2 led to a mixture of products [CF3CH(Et)NHBn: 42%; CF3CH2NHBn: 13%; 2: 33%, side products: 13%].

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Typical Procedure for the Synthesis of 4,4,4-Trifluoro-3-(2-methoxy-1-phenylethylamino)butyric Acid Ethyl Ester (9): The methyl ether of the (R)-phenylglycinol trifluoromethyl aldimine 7 (1 mmol, 231 mg) was dissolved in THF (5 mL) and kept under argon. Ethyl bromoacetate (6 equiv, 6 mmol, 1 g) and granular zinc (5 equiv, 5 mmol, 327 mg) were then introduced, followed by a few drops of TMSCl. After being stirred at reflux for 3 h, the reaction mixture was quenched with a sat. NH4Cl solution (15 mL) and extracted with Et2O (3 × 5 mL). The organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (cyclohexane-Et2O, 80:20) to afford a mixture of two diastereomers of 9 (80%, 255 mg).
Major Diastereomer: yellow oil; yield: 69%; [α]D 22 -25.0 (c = 0.20, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H), 2.10 (br s, 1 H), 2.56 (dd, J = 6.5, 15.7 Hz, 1 H), 2.72 (dd, J = 4.3, 15.8 Hz, 1 H), 3.38 (s, 3 H), 3.40 (dd, J = 5.3, 7.9 Hz, 1 H), 3.52 (m, 1 H), 4.11 (dd, J = 5.5, 7.8 Hz, 2 H), 4.18 (q, J = 7.0 Hz, 2 H), 7.36 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 14.1, 34.6, 54.2 (q, J CF = 29 Hz, CHCF3), 58.7, 60.0, 61.0, 77.8, 125.8 (q, J CF = 281 Hz, CF3), 127.8, 128.0, 128.5, 139.4, 170.1. 19F NMR (188 MHz, CDCl3):
δ = -76.30 (d, J = 7.6 Hz, CF3). IR: 2984, 1735 cm-1. Minor Diastereomer: yellow oil; yield: 10%; [α]D 22 +12.5 (c = 0.16, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.19 (t, J = 7.0 Hz, 3 H), 2.87 (dd, J = 2.6, 15.0 Hz, 1 H), 3.05 (dd, J = 5.6, 14.9 Hz, 1 H), 3.31 (s, 3 H), 3.53 (dd, J = 4.9, 9.8 Hz, 1 H), 3.85 (m, 1 H), 4.03 (t, J = 9.9 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.53 (dd, J = 5.3, 9.9 Hz, 1 H), 7.27 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 13.8, 49.5, 51.5 (q, J CF =35 Hz, CHCF3), 58.7, 60.0, 61.4, 72.2, 124.1 (q, J CF = 278.8 Hz, CF3), 127.7, 128.0, 128.6, 135.8, 165.5. 19F NMR (188 MHz, CDCl3): δ = -76.0 (d, J = 5.9 Hz, CF3). IR: 2932, 1768 cm-1.