Iron-Catalyzed Diastereoselective Synthesis of Disubstituted Morpholines via C–O or C–N Bond Formation

In expression of our deepest gratitude to Prof. Barry M. Trost.

Abstract

The diastereoselective synthesis of 2,6- and 3,5-disubstituted morpholines was achieved from 1,2-amino ethers and 1,2-hydroxy amines substituted by an allylic alcohol using an iron(III) catalyst. The morpholines were obtained either by C–O or C–N bond formation. A plausible mechanism is suggested, involving a thermodynamic equilibrium to explain the formation of the cis diastereoisomer as the major product.

Key words

morpholine - iron - diastereoselective - thermodynamic equilibrium

• References and Notes

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• 18 Measured by GC/MS analysis of the crude mixture.
• 19 Experimental Procedure for the Synthesis of 2,6- or 3,5-Disubstituted Morpholines In a tube was added the amino alcohol in CH₂Cl₂. FeCl₃·6H₂0 was then added to the solution, the tube was sealed, and the mixture was heated at the specified temperature for 1–2 h. After cooling, the suspension was filtered through a short plug of silica gel, and elution was achieved with CH₂Cl₂ to remove the iron salts. The filtrate was concentrated under vacuum to afford the morpholine which was in most cases recovered as a pure product. Purification by flash chromatography on silica gel was performed if needed. cis-(E)-2-Isopropyl-6-styryl-4-tosylmorpholine (10c) ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.40–7.18 (m, 7 H), 6.73–6.59 (m, 1 H), 6.06 (dd, J = 16.1, 5.6 Hz, 1 H), 4.29–4.19 (m, 1 H), 3.68 (d_app, J = 11.3 Hz, 2 H), 3.41–3.29 (m, 1 H), 2.43 (s, 3 H), 2.05 (dd_app, J = 21.7, 10.8 Hz, 2 H), 1.77–1.65 (m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 136.3, 132.3, 132.1, 129.8 (2 C), 128.6 (2 C), 128.0, 127.8 (2 C), 126.6 (2 C), 126.1, 80.1, 75.6, 50.0, 47.7, 31.6, 21.6, 18.6, 18.4. MS (EI, 70 eV): m/z (abundance) = 385 (3, M^+•), 281 (14), 230 (29), 130 (16), 129 (12), 115 (10), 98 (100), 91 (30), 69 (16), 56 (16). HRMS: m/z calcd for C₂₂H₂₈NO₃S [M + H]⁺: 386.1784; found: 386.1789. cis-(E)-3-Isopropyl-5-styryl-4-tosylmorpholine (12c) ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.38–7.19 (m, 7 H), 6.67 (dd, J = 16.2, 1 H), 6.56–6.41 (m, 1 H), 4.45–4.35 (m, 1 H), 3.92 (d, J = 11.8 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.38 (dd, J = 10.9, 3.4 Hz, 1 H), 3.20 (dd, J = 11.9, 4.0 Hz, 1 H), 3.11 (dd, J = 12.0, 3.6 Hz, 1 H), 2.43 (s, 3 H), 2.32–2.23 (m, 1 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.4, 138.7, 136.6, 132.8, 130.0 (2 C), 128.7 (2 C), 127.9, 127.7, 127.0 (2 C), 126.5 (2 C), 69.1, 66.6, 59.6, 52.9, 28.4, 21.6, 20.6, 20.2. MS (EI, 70 eV): m/z (abundance) = 342 (23), 268 (19), 187 (11), 171 (16), 156 (12), 155 (37), 130 (16), 129 (26), 128 (11), 117 (33), 115 (27), 91 (100), 69 (14), 65 (15). HRMS: m/z calcd for C₂₂H₂₇NNaO₃S [M + Na]⁺: 408.1604; found: 408.1606.