Highly Stereoselective Addition of Organomagnesium Reagents to Aziridinyl-2-carboxaldimine: Preparation of Enantiopure 2-Aminomethylaziridines and 4,5-Disubstituted Imidazolidin-2-ones

Abstract

The addition of alkyl- and arylmagnesium reagents to chiral [1′(R)-α-methylbenzyl]aziridine-2(R)-carboxaldimines was carried out in a highly stereoselective manner to give 2-aminomethylaziridine. Further treatment of 2-aminomethylaziridines with triphosgene and NaH afforded enantiopure 5-alkyl- or 5-aryl-4-chloromethylimidazolidin-2-ones.

stereoselectivity - addition reactions - organometallic reagents - aziridines - imines

References

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9

General Procedure for the Addition Reactions of Alkyl or Aryl Magnesium Bromide: Into the solution of (p-methoxyphenyl)-{[1′(R)-α-methylbenzyl]aziridine-2(R)-ylmethylene}amine (280 mg, 1 mmol) in of Et₂O (10 mL) was added ethereal solution of alkyl or aryl magnesium bromide (3 mmol) and BF₃·OEt₂ (0.15 mL, 0.8 mmol) under N₂ atmosphere. The resultant solution was stirred at -10 °C for the reaction to be completed before being quenched by adding ice-water. The reaction product was isolated with Et₂O (15 mL × 4). The ethereal solution was washed with brine twice. The organic layer was dried over anhyd MgSO₄, filtered and concentrated under reduced pressure. Purification by silica gel flash column chromatography provided the analytically pure addition product. Compound 2a: colorless oil, [α]_D 33.5 (c 2.0 in EtOAc). ¹H NMR (200 MHz, CDCl₃): δ = 1.12 (d, J = 6.0 Hz, 1 H), 1.14 (d, J = 4.2 Hz, 3 H), 1.22 (d, J = 6.2 Hz, 3 H), 1.54-1.62 (m, 2 H), 2.36 (q, J = 6.6 Hz, 1 H), 3.32-3.41 (m, 1 H), 3.63 (s, 3 H), 6.52-6.71 (m, 4 H), 7.14-7.31 (m, 5 H). ¹³C NMR (50.3 MHz, CDCl₃): δ = 19.5, 23.5, 30.4, 44.2, 48.9, 55.6, 69.3, 114.6, 114.6, 126.6, 126.7, 128.1, 141.8, 144.6, 151.6. HRMS (EI) calcd for C₁₉H₂₄N₂O: 296.1889. Found: 296.1883. Anal. Calcd. for C₁₉H₂₄N₂O: C, 77.0; H, 8.16; N, 9.45. Found: C, 76.8; H, 8.09; N, 9.42. Compound 2f: colorless oil, [α]_D 18.9 (c 3.0 in EtOAc). ¹H NMR (200 MHz, CDCl₃): δ = 1.08 (d, J = 6.8 Hz, 3 H), 1.19 (d, J = 6.2 Hz, 1 H), 1.66-1.78 (m, 2 H), 2.25 (q, J = 6.6 Hz, 1 H), 3.55 (s, 3 H), 4.04-4.08 (m, 1 H), 6.35-6.57 (m, 4 H), 7.10-7.33 (m, 10 H). ¹³C NMR (50.3 MHz, CDCl₃): δ = 23.6, 31.5, 45.4, 55.6, 58.9, 69.1, 114.6, 114.8, 126.5, 126.7, 127.0, 127.1, 128.3, 128.5, 141.5, 142.8, 144.3, 151.7. HRMS (EI) calcd for C₂₄H₂₆N₂O: 358.2045. Found: 358.2049.

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14

General Procedure for the Synthesis of 5-Aalkyl or 5-Aryl-4-chloromethylimidazolidin-2-one: To a solution of {1-[1′(R)-α-methylbenzyl]aziridin-2(R)-yl}-methylamine (310 mg, 1.05 mmol) in 15 mL of THF under nitrogen atmosphere was added NaH (144 mg, 6 mmol) at -10 °C. The mixture was stirred for 1 h at -10 °C. To the mixture was slowly added triphosgene solution (0.356 g, 1.2 mmol) in THF (5 mL) at -10 °C. The mixture was stirred for 2 h at -10 °C. The reaction was quenched with H₂O at -10 °C and warmed to r.t. The aqueous layer was extracted with CH₂Cl₂ (10 mL × 5). The combined organic extract was dried over MgSO₄ and the solvent was evaporated in vacuo to give the crude product as a white solid which was purified by silica gel flash chromatography to give analytically pure product. Compound 6a: colorless oil. ¹H NMR (200 MHz, CDCl₃):
δ = 0.82 (d, J = 6.2 Hz, 3 H), 1.50 (d, J = 7.4 Hz, 3 H), 2.92 (dt, J = 7.0 Hz, 3.2 Hz, 1 H), 3.32 (dd, J = 11.4 Hz, 7.6 Hz, 1 H), 3.42 (dd, J = 11.4 Hz, 3.2 Hz, 1 H), 3.65 (s, 3 H), 3.90 (qd, J = 6.2 Hz, J = 3.2 Hz, 1 H), 5.25 (q, J = 7.4 Hz, 1 H), 6.72-6.78 (m, 2 H), 7.11-7.27 (m, 7 H). ¹³C NMR (50.3 MHz, CDCl₃): δ = 18.7, 19.4, 45.5, 51.2, 54.6, 55.4, 58.8, 114.1, 123.1, 127.3, 127.7, 128.6, 131.4, 139.8, 156.2, 156.8. HRMS (EI) calcd for C₂₀H₂₃ClN₂O₂: 358.1448. Found: 358.1453.

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