Barbier Conditions for Reformatsky and Alkylation Reactions on Trifluoromethyl Aldimines

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.

Barbier reaction - Reformatsky - fluoroalkyl amines - amino acids

References and Notes

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12

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%].

13

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.

14 Fukuhara K. Okamoto S. Sato F. Org. Lett.  2003,  5:  2145