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Synlett 2005(11): 1666-1670  
DOI: 10.1055/s-2005-871537
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Nucleophilic Opening of Azetidinium Ions

François Couty*, François Durrat, Gwilherm Evano
SIRCOB, UMR 8086, Université de Versailles, 45, Avenue des Etats-Unis, 78035, Versailles Cedex, France
e-Mail: couty@chimie.uvsq.fr;
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Publication History

Received 14 April 2005
Publication Date:
14 June 2005 (online)

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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.

Key words

azetidiniums - nitrogen - heterocycles - ring opening - asymmetric synthesis

10

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.