Diastereoselective Synthesis of Morpholine Derivatives from Grignard Reagents and N-Sulfinyl Imines

Abstract

The stereoselective synthesis of substituted morpholine derivatives has been achieved through a two-step process involving diastereoselective addition of a Grignard reagent to a sulfinyl imine, followed by cyclization.

Key words

morpholines - stereoselectivity - chiral auxiliaries - sulfinyl imines - Grignard reaction

Publication History

Received: 19 May 2021

Accepted after revision: 15 June 2021

Accepted Manuscript online:
15 June 2021

Article published online:
06 July 2021

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• 25 3-Substituted Morpholine Derivatives 4a–n; General Procedure AlMe₃ (0.12 mL, 0.24 mmol, 1.1 equiv) was added dropwise to a stirred solution of sulfinyl imine 1 (50 mg, 0.22 mmol, 1.0 equiv) in MTBE (1.1 mL) at –78 °C, and the mixture was stirred for 30 minutes at –78 °C. The appropriate Grignard reagent (1.5 equiv) was then added dropwise and the mixture was stirred at –78 °C for 6 h. The reaction was quenched with sat aq NH₄Cl and the mixture was diluted with H₂O and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was dissolved in THF (7.5 mL), and 18-crown-6 (29 mg, 0.11 mmol, 0.5 equiv) and a 60% dispersion of NaH in mineral oil (27 mg, 0.67 mmol, 3.0 equiv) were added. The mixture was then stirred at rt for 2 h before the reaction was quenched with sat aq NH₄Cl. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography [silica gel, heptane–EtOAc (9:1 to 0:1)]. (3S)-4-[(R)-tert-Butylsulfinyl]-3-phenylmorpholine (4a) White solid; yield: 45.0 mg (76%). ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.27 (m, 5 H), 4.22 (dd, J = 8.7, 3.4 Hz, 1 H), 3.99 (dtd, J = 11.4, 3.4, 1.0 Hz, 1 H), 3.87 (ddd, J = 11.7, 3.4, 1.0 Hz, 1 H), 3.84–3.73 (m, 2 H), 3.27–3.10 (m, 2 H), 1.14 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 138.0, 129.2, 128.6, 128.4, 72.9, 66.7, 64.4, 58.5, 43.0, 24.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₂₁NNaO₂S: 290.1191; found: 290.1194.