反应详情

温度

70 °C

Morpholine 17 was prepared using a modification of the procedure outlined by Froyen and coworkers (Froyen et al. (1995) Tetrahedron Lett. 36:9555). To a solution of 2-methyl-3-penten-1-ol (1.3 g, 13 mmol) and triphenylphosphine (3.6 g, 14 mmol) in THF (10 mL) was added N-bromosuccinimide (2.5 g, 14 mmol). After 15 min, morpholine (2.7 mL, 31 mmol) was added dropwise and the resulting brown solution was heated to 70° C. for 2.5 h. Upon cooling to rt, the reaction mixture was diluted with Et2O (25 mL) and filtered through a pad of Celite©. The filtrate was then extracted with aqueous 1N HCl (100 mL). The product containing aqueous layer was then washed with Et2O (3×100 mL), and then made alkaline by the addition of NaOH (4 g). The aqueous solution was then extracted with Et2O (3×100 mL), the combined organic layers dried (Na2SO4), and then concentrated by rotary evaporation at 0° C. under reduced pressure. The resulting residue was then distilled (110° C., 20 mm) to afford (E)-N-(3-ethyl-3-methyl-2-propenyl)-morpholine (16) as a colorless oil in 49% yield (1.0 g, 6.0 mmol); IR 2968, 1455, 1293, 1116, 1004, 907 cm−1; 1H NMR(400 MHZ) δ5.21-5.25 (m, 1H, CH═CCH3), 3.65-3.77 (m, 4H, O(CH2)2), 2.96 (d, J=7.0 Hz, 2H, CH2C═CH), 2.44 (m, 4H, N(CH2)2), 2.01 (q, J=7.3 Hz, 2H, CH3CH2), 1.63 (s, 3H, CH3C═CH), 0.97-1.04 (m, 3H, CH3CH2); 13C NMR (100 MHZ) δ141.1, 118.7, 67.0, 56.0, 53.5, 32.4, 16.4, 12.5; LRMS (FAB) m/z 169 (M)+; HRMS (FAB) exact mass calcd for (C10H19NO)+ requires m/z 169.1467, found m/z 169.1464. (b) Preparation of (2R*,3R*)-N-(2,3-Dimethyl-3-ethyl4-pentenoyl)-morpholine (18): Prepared according to general procedure B from (E)-N-(3-ethyl-3-methyl-2-propenyl)-morpholine 17 (135 mg, 0.80 mmol), TiCl4.(THF)2, (27 mg, 81 μmol), i-Pr2NEt (0.56 mL, 3.2 mmol), and propionyl chloride (2.4 mL, 1 M solution in CH2Cl2, 2.4 mmol) in CH2Cl2 (2.7 mL) to provide the pure product as a yellow oil in 72% yield (130 mg, 0.58 mmol); >99:1 syn:anti. Syn isomer: IR (CH2Cl2) 2972, 1633, 1459, 1432, 1235 cm−1; 1H NMR (400 MHZ) δ5.88 (dd, J=10.9 Hz, 17.6 Hz, 1H, CH═CH2), 5.03 (dd, J=1.5, 10.9 Hz, 1H, CH═CH2), 4.88 (dd, J=1.4, 17.6 Hz, 1H, CH═CH2), 3.49-3.64 (m, 8H, N(CH2CH2)2), 2.63 (q, J=6.9 Hz, 1H, CHC═O), 1.32-1.49 (m, 2H, CH2CH3), 1.02 (d, J=6.9 Hz, 3H, CH3CHC═O), 0.99 (s, 3H, CHC3C), 0.73 (t, J=7.5 Hz, 3H, CH3CH2); 13C NMR (100 MHZ) δ174.1, 143.8, 67.0, 66.7, 66.6, 46.8, 42.7, 42.2, 41.8, 30.9, 18.7, 13.3, 8.3; LRMS (FAB) m/z 225 (M)+; HRMS (FAB) exact mass calcd for (C13H23NO2)+ requires m/z 225.1710, found m/z 225.1727.

1. customMorpholine 17 was prepared
2. temperatureUpon cooling to rt
3. filtrationfiltered through a pad of Celite©
4. extractionThe filtrate was then extracted with aqueous 1N HCl (100 mL)
5. additionThe product containing aqueous layer
6. washwas then washed with Et2O (3×100 mL)
7. additionby the addition of NaOH (4 g)
8. extractionThe aqueous solution was then extracted with Et2O (3×100 mL)
9. dry with materialthe combined organic layers dried (Na2SO4)
10. concentrationconcentrated by rotary evaporation at 0° C. under reduced pressure
11. distillationThe resulting residue was then distilled (110° C., 20 mm)