3.13. General Procedure for the Synthesis of 4-[(2R)-(–)-2-Chloropropyl]morpholine (R)-(–)-5 or 4-[(2S)-(+)-2-Chloropropyl]morpholine (S)-(+)-5

Method A: To a stirred solution of the respective optically active alcohol (S)-(+)-3 (99% ee) or (R)-(–)-3 (98% ee) (10 g, 68.87 mmol) in CHCl₃ (100 mL), a solution of SOCl₂ (16.4 g, 0.14 mol, 10 mL) in CHCl₃ (50 mL) was added dropwise at 0–5 °C under nitrogen atmosphere within a period of 1 h. Next, the resultant reaction mixture was stirred for 2 h at room temperature (ca. 25 °C) until hydrochloride of morpholino derivative precipitated as a heavy-pasty white solid. Then, the solution was refluxed (the solid has been dissolved meantime) until completion of starting material (followed by TLC, approx. 2 h) and stopped by quenching the content of the flask with saturated NaHCO₃ (2 × 100 mL). The water phase was extracted with CHCl₃ (3 × 100 mL), the combined organic layer was dried over anhydrous MgSO₄, the drying agent was filtered off, and the permeate was concentrated in a vacuum. The crude reaction mixture was purified on silica gel column chromatography eluting with a mixture of CHCl₃/MeOH (95:5, v/v) to afford (R)-(–)-5 (8.05 g, 71% yield, >99% ee, [α]_D²² = –19.87 (c 2.3, CHCl₃); obtained from (S)-(+)-3] or (S)-(+)-5 [7.78 g, 69%, 98% ee, [α]_D²² = +23.00 (c 1.3, CHCl₃); obtained from (R)-(–)-3) as pale amber oil, respectively. The enantiomeric excesses (% ee) of (R)-(–)-5 and (S)-(+)-5 were determined after thioetherification of the respective chloro-derivative with sodium thiophenolate (for details, see Section 3.14).

Method B: A solution of (S)-(+)-5 (5 g, 34.4 mmol) and CCl₄ (7.95 g, 51.6 mmol) in dry CH₂Cl₂ (30 mL) was cooled to 0–5 °C. Next, triphenylphosphine (Ph₃P, 13.5 g, 51.6 mmol) was added portion-wise via a powder funnel over 30 min with vigorous stirring. Upon addition of the phosphine, the colorless solution turned a pale brown color and was stirred for an additional 6 h at room temperature (ca. 25 °C). Next, EtOAc (50 mL) was added to the remaining mixture with vigorous stirring until the formation of white precipitate, which was filtered off, and washed with cold EtOAc (10 mL). The combined solutions were concentrated in a vacuum, and the remaining oil was subjected to silica gel column chromatography using a mixture of n-hexane/EtOAc (50:50, v/v) to afford (R)-(–)-5 (3.2 g, 57% yield, >99% ee) as a yellowish oil. The enantiomeric excesses (% ee) of (R)-(–)-5 and (S)-(+)-5 were determined after thioetherification of chloro-derivatives with sodium thiophenolate (for details, see Section 3.14).

4-[(2R)-(–)-2-Chloropropyl]morpholine [(R)-(–)-5] or 4-[(2S)-(+)-2-chloropropyl]morpholine ((S)-(+)-5). R_f (CHCl₃/MeOH 95:5, v/v) 0.75 or R_f (n-hexane/EtOAc 50:50, v/v) 0.55; ¹H NMR (CDCl₃, 400 MHz) δ: 1.51 (d, J = 6.6 Hz, 3H, CH₃), 2.42–2.55 (m, 5H, CH₂N(CH₂)CH₂ and partially NCH₂CH), 2.65 (dd, J = 13.0, 7.0 Hz, 1H, one of NCH₂CH), 3.65–3.74 (m, 4H, CH₂OCH₂), 4.02–4.12 (m, 1H, CH); ¹³C NMR (CDCl₃, 100 MHz) δ: 23.3 (CH₃), 53.9 (2C, CH₂N(CH₂)CH₂), 54.1 (CH), 66.8 (NCH₂CH), 66.8 (2C, CH₂OCH₂); FT-IR (neat) ν_max (cm⁻¹): 2961, 2931, 2856, 2812, 1454, 1373, 1298, 1277, 1144, 1115, 1070, 1035, 1011, 934, 903, 864, 800, 684, 635, 622, 472; UV/VIS: λ_max = 208 nm (EtOH); MS (ESI) m/z [M+H]⁺ calcd for C₇H₁₅ClNO⁺ 164.0842, found 164.0877; GC (80–260 (10 °C/min)): t_R = 4.66.