Synlett 2021; 32(05): 525-531
DOI: 10.1055/s-0040-1707902
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The Power of Transition Metals: An Unending Well-Spring of New Reactivity
© Georg Thieme Verlag Stuttgart · New York

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

,
Alexandre Dupas
,
Tian Zeng
,
Further Information

Publication History

Received: 28 April 2020

Accepted after revision: 23 June 2020

Publication Date:
23 July 2020 (online)


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.

Supporting Information

 
  • References and Notes

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      This has been observed on piperidines substrates. See for example:
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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 (dapp, J = 11.3 Hz, 2 H), 3.41–3.29 (m, 1 H), 2.43 (s, 3 H), 2.05 (ddapp, 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.