Synthesis of (R)- and (S)-Oxymethylmorpholine Derivatives

References

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• Procedure for the synthesis of (R)- and (S)-oxymethylmorpholine derivatives: A suspension of ditosylate (1 mmol), benzylamine (1 mmol) and anhydrous Na2C3 (3 mmol) in MeCN (12 mL) was refluxed for 40 h with vigorous stirring. The reaction mixture, cooled at room temperature, was filtered, and the filtered solution was dried over MgSO4 and concentrated. Purification of the residue by flash chromatography (4:1, hexanes-ethyl acetate) afforded the desired product
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• Spectral data for compound (2): [α]23 D –7.65 (c 10.09, CHCl3); 1H NMR (CDCl3) δ 1.05 (s, 9H), 3.43–3.75 (m, 5H), 4.08 (s, 1H), 4.09 (s, 1H), 4.54 (s, 2H), 5.11–5.27 (m, 2H), 5.84–5.88 (m, 1H), 7.26–7.42 (m, 11H), 7.65–7.68 (m, 4H); 13C NMR (CDCl3) δ 19.1, 26.7, 63.4, 70.1, 71.2, 73.3, 78.6, 116.5, 127.4, 127.5, 127.6, 128.2, 129.6, 133.3, 133.4, 135.1, 135.5, 138.3; FAB-MS m/z 461.2 ([M + H]+, calcd 461.2); for compound (3): [α]23 D –10.94 (c 10.05: CHCl1); 1H NMR (CDCl3) δ 1.06 (s, 9H), 3.60–3.74 (m, 9H), 4.55 (s, 2H), 7.33–7.45 (m, 11H), 7.66–7.70 (m, 4H); 13CNMR (CDCl3) δ 19.1, 26.7, 62.0, 63.7, 70.3, 71.9, 73.4, 80.0, 127.6, 127.7, 128.3, 129.7, 133.1, 133.2, 135.5, 137.7; FAB-MS m/z 465.1 ([M + H]+, calcd 465.2); for compound (4): [α]23 D –17.6 (c 2.10: CHCl3); 1H NMR (CDCl3) δ 1.09 (s, 9H), 3.57–3.81 (m, 11H), 7.39–7.46 (m, 6H), 7.69–7.72 (m, 4H); 13C NMR (CDCl3) δ 19.1, 26.7, 61.9, 62.7, 63.5, 71.6, 81.2, 127.7, 129.7, 133.05, 133.13, 135.5; FAB-MS m/z 375.12 ([M + H]+, calcd 375.20); for (S)-N-benzyl-3-tert-butyldiphenylsilyloxymethylmorpholine (5): [α]23 D +2.2 (c 5.2: CHCl3); 1H NMR (CDCl3) δ 1.14 (s, 9H), 1.99–2.06 (m, 1H), 2.19–2.28 (m, 1H), 2.70–2.74 (m, 1H), 2.99–3.03 (m, 1H), 3.60 (s, 2H), 3.68–3.93 (m, 5H), 7.40–7.49 (m, 11H), 7.73–7.77 (m, 4H); 13C NMR (CDCl3) δ 19.2, 26.8, 53.1, 55.9, 63.4, 65.2, 66.6, 76.0, 127.0, 127.6, 128.2, 129.1, 129.6, 133.4, 135.49, 135.53, 137.6; FAB-MS m/z 446.25 ([M + H]+ calcd 446.01); for compound (6): [α]23 D +6.23 (c 1.61: CHCl3); 1H NMR (CDCl3) δ 3.52–3.79 (m, 11H), 4.54 (s, 2H), 7.25–7.36 (m, 5H); 13C NMR (CDCl3) δ 61.8, 62.5, 70.0, 71.6, 73.4, 79.6, 127.6, 127.8, 128.3, 137.7; for compound (7): [α] 23 D +3.45 (c 5.56: CHCl3); 1H NMR (CDCl3) δ 2.40 (s, 6H), 3.40–3.42 (m, 2H), 3.65–3.70 (m, 3H), 3.96–4.12 (m, 4H), 4.41 (s, 2H), 7.21–7.33 (m, 9H), 7.73–7.76 (m, 4H); 13C NMR (CDCl3) δ 22.0, 68.5, 69.1, 69.7, 69.9, 73.8, 78.0, 128.0, 128.2, 128.3, 130.3, 130.4, 133.0, 133.3, 1385.1, 145.3, 145.5; for (R)-N-benzyl-3-benzyloxymethylmorpholine (8): [α] 23 D–11.5 (c 2.5: CHCl3); 1H NMR (CDCl3) δ 1.99–2.06 (m, 1H), 2.19–2.28 (m, 1H), 2.68–2.82 (m, 2H), 3.43–3.56 (m, 4H), 3.70–3.95 (m, 3H), 4.54–4.64 (m, 2H), 7.28–7.40 (m, 10H),; 13C NMR (CDCl3) δ 52.9, 55.3, 63.2, 66.7, 71.4, 73.3, 74.8, 127.1, 127.5, 127.6, 128.2, 128.3, 129.1, 137.6, 138.0; FAB-MS m/z 298.12 ([M + H]+, calcd 298.18)
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