Regioselective Nucleophilic Opening of Azetidinium Ions

Abstract

Azetidinium ions bearing different substitution patterns were reacted with nitrogen nucleophiles (sodium azide and benzylamine) and oxygenated nucleophiles (sodium acetate and alkoxides). High regioselectivity of nucleophilic opening was observed in both cases: the nucleophile reacting on the unsubstituted carbon in the case of α-substituted azetidinium salts and on the carbon bearing an ester or cyano moiety in the case of α,α′-substituted azetidinium salts.

azetidiniums - nitrogen - heterocycles - ring opening - asymmetric synthesis

References

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All new compounds were characterized by ¹H NMR, ¹³C NMR spectroscopy, mass spectra analysis, and for most relevant compounds, by elementary analysis. Typical procedure for the preparation of an azetidinium salt is given below:
To a solution of the azetidine (2.0 mmol) in CH₂Cl₂ (10 mL), cooled at 0 °C, was added dropwise methyltrifluoromethanesulfonate (0.45 mL, 4 mmol). The reaction mixture was stirred for 1 h at r.t., and the solvent was evaporated under reduced pressure. The crude salt was washed thoroughly with small quantities of dry Et₂O, and dried under vacuum.
Compound 2: yield 99%; [α] -34 (c 0.5, acetone); mp 116 °C. MS (ESI Pos): m/z = 263.2 [M - Otf]⁺. ¹H NMR [300 MHz, (CD₃)₂CO]: δ = 7.89-7.82 (m, 2 H, Ph), 7.67-7.42 (m, 8 H, Ph), 6.34 (d, J = 9.3 Hz, 1 H, H-2), 5.31-5.14 (m, 4 H, H-3, H-4, H-6, H-6′), 4.91-4.81 (m, 1 H, H-4′), 3.70 (s, 3 H, H-5) ppm. ¹³C NMR [75 MHz, (CD₃)₂CO]: δ = 133.9 (C _ipso Ph), 133.1, 131.9, 130.5, 129.9, 129.8, 128.4 (CH Ph), 128.3 (C _ipso Ph), 112.3 (CN), 69.3, 69.2 (C-4, C-6), 65.3 (C-2), 46.9 (C-5), 39.6 (C-3) ppm. Anal. Calcd for C₁₉H₁₉F₃N₂O₃S: C, 55.33; H, 4.64; N, 6.79. Found: C, 55.23; H, 4.66; N, 6.74.
Typical procedure for the reaction of an azetidinium salt with sodium azide is given below: To a solution of azetidinium triflate (2.0 mmol) in DMF (10 mL) was added sodium azide (650 mg, 10.0 mmol) and the suspension was stirred overnight at r.t. Partition between Et₂O and H₂O was followed by usual work-up. The crude residue was examined by NMR, and the major compound was purified by flash chromatography.
Compound 11: purified by flash chromatography (Et₂O-cyclohexane, 10:90, 20:80, 40:60); yield 93%; clear oil; R _f = 0.61 (Et₂O-petroleum ether, 3:7); [α] -90 (c 0.75, CH₂Cl₂). MS (IC NH₃ Pos): m/z = 353 [M + H]⁺. ¹H NMR [300 MHz, (CD₃)₂CO]: δ = 7.38-7.19 (m, 10 H, Ph), 4.67 (d, J = 4.2 Hz, 1 H, H-2), 4.17 (q, J = 7.1 Hz, 2 H, H-7), 3.66 (d, J = 13.1 Hz, 1 H, H-6), 3.54-3.47 (m, 2 H, H-3, H-6′), 3.01 (t, J = 11.9 Hz, 1 H, H-4), 2.47 (dd, J = 4.2, 12.3 Hz, 1 H, H-4′), 2.28 (s, 3 H, H-5), 1.22 (t, J = 7.1 Hz, 3 H, H-8) ppm. ¹³C NMR [75 MHz, (CD₃)₂CO]: δ = 170.2 (C-1), 138.9, 138.1 (C _ipso Ph), 129.2, 128.9, 128.5, 128.4, 127.6, 127.3 (CH Ph), 64.3 (C-2), 62.9 (C-6), 61.7 (C-7), 59.3 (C-4), 45.2 (C-3), 42.5 (C-5), 14.2 (C-8) ppm. Anal. Calcd for C₂₀H₂₄N₄O₂: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.03; H, 6.91; N, 15.80.