The Highly Diastereoselective Synthesis of Oxazolidines Derived from Ketones and Pseudoephedrine or Ephedrine

Abstract

2,2-Dialkyl-3,4-dimethyl-5-phenyloxazolidines and 2-alkyl-2-aryl-3,4-dimethyl-5-phenyloxazolidines are formed with high diastereoselectivity from ketones and pseudoephedrine or ephedrine in the presence of scandium triflate and 4 Å molecular sieves.

Key words

amino alcohols - heterocycles - ketones - scandium - ­stereoselective

References

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(+)-(2 S ,4 S ,5 S )-2-Isopropyl-2,3,4-trimethyl-5-phenyl-oxazolidine. Pseudoephedrine (0.5 g, 3.0 mmol), scandium triflate (0.22 g, 0.5 mmol), and 3-methylbutanone (0.26 g, 3.0 mmol) were added to a suspension of flame dried 4 Å molecular sieves in CH₂Cl₂ (7.0 mL). The mixture was then heated under reflux for 48 h, allowed to cool to r.t., and solid NaHCO₃ (1.0 g) added, the mixture was then stirred for a further 2 h at r.t. The solution was filtered, washed with H₂O (2 × 5 mL) and the organic layer was dried over anhyd MgSO₄. Solvents were removed under reduced pressure to afford a colourless oil (0.67 g, 96%). [α]_D +39.0 (c 1.00, CCl₄). IR (neat): ν_max = 3130, 2924, 2761, 1459, 1373, 1326, 1189, 1135 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.00
(3 H, d, J = 6.8 Hz), 1.01 (3 H, d, J = 6.9 Hz), 1.04 (3 H, d, J = 6.0 Hz), 1.29 (3 H, s), 1.83 (1 H, m), 2.24 (3 H, s), 2.50 (1 H, m), 4.33 (1 H, d, J = 8.9 Hz), 7.27-7.34 (5 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.6, 17.1, 17.4, 18.6, 33.3, 36.4, 65.8, 85.9, 98.7, 126.8, 127.7, 128.3, 140.4 ppm. MS (FAB): m/z calcd for C₁₅H₂₄NO [M + 1]: 234.1852; found: 234.1801.

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¹H NMR (400 MHz, CDCl₃): δ = 1.16 (3 H, d, J = 5.9 Hz), 1.82 (3 H, s), 2.48 (3 H, s), 2.78 (1 H, m), 4.67 (1 H, d, J = 8.9 Hz), 7.35-7.47 (5 H, m), 7.20-8.58 (4 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.5, 19.3, 32.8, 65.9, 86.0, 96.8, 119.6, 122.4, 126.7, 127.9, 128.3, 136.6, 139.5, 148.1, 163.9 ppm. MS (FAB): m/z calcd for C₁₇H₂₁N₂O [M + 1]: 269.1648; found: 269.1656.

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¹H NMR (400 MHz, CDCl₃): δ = 1.14 (3 H, d, J = 6.0 Hz), 1.72 (3 H, s), 2.36 (3 H, s), 2.76 (1 H, m), 4.52 (1 H, d, J = 8.7 Hz), 7.30-7.67 (10 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.7, 20.7, 33.1, 65.8, 85.2, 96.2, 125.9, 126.5, 127.4, 127.7, 127.9 (2 × CH), 139.5, 145.3 ppm. MS (FAB): m/z calcd for C₁₈H₂₂NO [M + 1]: 268.1696; found: 268.1702.

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(-)-(2 R ,4 S ,5 R )-2-Methoxycarbonylmethyl-3,4-dimethyl-5-phenyl-oxazolidine-2-carboxylic Acid Methyl Ester.
Scandium triflate (0.22 g, 0.5 mmol) and but-2-ynedioic acid dimethyl ester (0.43 g, 3.0 mmol) were added to a solution of ephedrine (0.50 g, 3.0 mmol) in MeCN (10.0 mL). The mixture was then heated under reflux for 24 h, allowed to cool to r.t. and solid NaHCO₃ (1.0 g) added, the mixture was stirred for a further 2 h at r.t. The solution was filtered, washed with H₂O (2 × 5 mL) and the organic layer dried over anhyd MgSO₄. Solvents were removed under reduced pressure to afford an orange oil, crystallisation from MeOH afforded colourless prisms (0.82 g, 89%). Mp 71-73 °C (lit. [6a] 72 °C); [α]_D -27.6 (c 1.16, CHCl₃). IR (film): ν_max = 3026, 2952, 1751, 1730, 1437, 1346, 1151, 1073 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 0.61 (3 H, d, J = 6.4 Hz), 2.28 (3 H, s) 2.83 (1 H, d, J = 16.1 Hz), 3.17-3.24 (1 H, m), 3.43 (1 H, d, J = 16.1 Hz), 3.69 (3 H, s), 3.82 (3 H, s), 5.39 (1 H, d, J = 8.1 Hz), 7.20-7.45 (5 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.3, 33.5, 41.0, 51.8, 51.9, 60.0, 83.3, 95.3, 127.7, 127.8, 127.9, 139.3, 169.8, 170.1 ppm.

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CCDC 264414-264416 contain the supplementary crys-tallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].