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Synlett 2004(2): 0271-0274  
DOI: 10.1055/s-2003-45001
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Mechanism of Nucleophilic Substitution of 1-Alkyl-2-(tosyloxymethyl)-aziridines

Matthias D’hooghe, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;
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Publication History

Received 8 October 2003
Publication Date:
18 December 2003 (online)

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Abstract

The stereochemical course of nucleophilic substitution of 1-alkyl-2-(tosyloxymethyl)aziridines has been elucidated by a study using a chiral substrate, which confirmed that no initial ring opening and subsequent ring closure occurred but that instead direct substitution at the exocyclic methylene function took place. Consequently, these N-alkylaziridines exhibit a totally different reactivity towards nucleophiles as compared to the corresponding activated aziridines with an electron-withdrawing group at nitrogen, which has important stereochemical implications.

Key words

2-(bromomethyl)aziridines - nucleophilic substitution - diastereoselectivity - nitrogen - heterocycles

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The synthesis of 1-tert-butyl-2-(methoxymethyl)aziridine 7, starting from 1-tert-butyl-2-(tosyloxymethyl)aziridine 8, has been reported in the past. [8] This substitution was accomplished using methanolic sodium hydroxide (1 N) upon a prolonged reaction time (2 d). The procedure reported here with 2 equiv of sodium methoxide in MeOH
(1 N) was much more effective, resulting in the desired compound in 88% yield after reflux for 4 h. Furthermore, the reported 1H NMR data are partially incorrect and incomplete, [8] [12] and for that reason all obtained spectroscopic data are mentioned here. Spectroscopic data of 1-tert-butyl-2-(methoxymethyl)aziridine 7: 1H NMR (300 MHz, CDCl3): δ = 0.99 [9 H, s, (CH3)3C], 1.41 (1 H, d, J = 3.0 Hz, Hb), 1.57 (1 H, d, J = 6.3 Hz, Ha), 1.84-1.91 (1 H, m, Hc), 3.31 and 3.37 [2 H, 2 × d × d, J = 10.5, 5.6, 5.2 Hz, (HCH)O]; 3.38 (3 H, s, CH3O). 13C NMR (75 MHz, CDCl3): δ = 24.94 (CH2N), 26.52 [(CH3)3C], 30.94 (CHN), 52.67 [(CH3)3C], 58.85 (CH3O), 75.58 (CH2O). IR (NaCl): νmax = 2970, 2930, 2875, 1364, 1110, 734 cm-1. MS (70 eV): m/z (%) = 144 (100)
[M+ + 1], 88(23). TLC: Rf = 0.40 (hexane/EtOAc 1:1).

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Method a: To an ice-cooled solution of (1R,2S)-1-(α-methylbenzyl)-2-(hydroxymethyl)aziridine 9 (0.27 g, 1.5 mmol) in THF (2 mL) was added NaH (0.09 g, 1.5 equiv, 60% dispersion in mineral oil) and the mixture was stirred for 30 min at r.t. Subsequently, MeI (0.23 g, 1.1 equiv) was added dropwise to the ice-cooled reaction mixture, which was then refluxed for 3 h. Extraction with Et2O (3 × 10 mL), drying (MgSO4), filtration of the drying agent and removal of the solvent in vacuo afforded (1R,2S)-1-(α-methylbenz-yl)-2-(methoxymethyl)aziridine 10 (0.27 g, 93%).
Method b: To a solution of (1R,2S)-1-(α-methylbenzyl)-2-(tosyloxymethyl)aziridine 11 (0.50 g, 1.5 mmol) in MeOH (2.25 mL), prepared from the commercially available (1R,2S)-1-(α-methylbenzyl)-2-(hydroxymethyl)aziridine 9 via a standard tosylation reaction with 1.1 equiv TosCl, 1.1 equiv Et3N and 0.1 equiv DMAP in 98% yield, was added sodium methoxide in MeOH (0.75 mL, 4 N in MeOH, 2 equiv) at r.t. and the reaction mixture was refluxed for 4 h. Extraction with CH2Cl2 (3 × 10 mL), drying (MgSO4), filtration of the drying agent and removal of the solvent in vacuo afforded (1R,2S)-1-(α-methylbenzyl)-2-(methoxy-methyl)aziridine 10 (0.26 g, 91%).
Spectroscopic data of (1R,2S)-1-(α-methylbenzyl)-2-(methoxymethyl)aziridine 10: 1H NMR (300 MHz, CDCl3): δ = 1.43 (3 H, d, J = 6.6 Hz, CH3CH), 1.49 (1 H, d, J = 6.6 Hz, Ha), 1.63-1.70 (1 H, m, Hc), 1.86 (1 H, d, J = 3.6 Hz, Hb), 2.49 (1 H, q, J = 6.6 Hz, CHMe), 3.18 (3 H, s, CH3O), 3.24 and 3.38 [2 H, 2 × d × d, J = 10.6, 5.8, 5.2 Hz, (HCH)O], 7.22-7.39 (5 H, m, C6H5). 13C NMR (75 MHz, CDCl3): δ = 23.15 (CH2N), 32.07 (CHc), 37.45 (CH3CH), 58.44 (CH3O), 69.80 (CHMe), 74.03 (CH2O), 126.75 (Cpara), 127.02 and 128.28 (2 × Cortho and 2 × Cmeta), 144.49 (Cquat). IR (NaCl): νmax = 2977, 2927, 1494, 1450, 1109, 701 cm-1. MS (70 eV): m/z (%) = 191 (1) [M+], 176 (3), 146 (100), 118 (8), 105 (79), 104 (11), 103 (13), 91 (16), 86 (40), 79 (13), 77 (20). [α]D +22.0 (c 1, MeOH). TLC: Rf = 0.28 (hexane/EtOAc 1/1). Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.47; H, 9.11; N, 7.20.
Spectroscopic data of (1R,2S)-1-(α-methylbenzyl)-2-(tosyloxymethyl)aziridine 11: 1H NMR (300 MHz, CDCl3): δ = 1.37 (3 H, d, J = 6.6 Hz, CH3CH), 1.52 (1 H, d, J = 6.3 Hz, Ha), 1.66-1.73 (1 H, m, Hc), 1.79 (1 H, d, J = 3.3 Hz, Hb), 2.43 (3 H, s, CH3Ar), 2.48 (1 H, q, J = 6.6 Hz, CHMe), 3.84 and 3.93 [2 H, 2 × d × d, J = 10.7, 6.2, 6.1 Hz, (HCH)O], 7.22-7.36 and 7.63-7.66 (7 H and 2 H, 2 × m, CHarom). 13C NMR (75 MHz, CDCl3): δ = 21.74 (CH3Ar), 23.37 (CH2N), 32.33 (CHc), 35.95 (CH3CH), 69.43 (CHMe), 72.17 (CH2O), 126.67, 127.28, 127.98, 128.47 and 129.86 [CH(Me)CHpara, 4 × Cortho and 4 × Cmeta], 133.06 (CCH3), 144.09 and 144.78 (2 × Cquat). IR (NaCl): νmax = 3061, 3030, 2972, 2927, 2869, 1599, 1494, 1450, 1363, 958 cm-1. MS (70 eV): m/z (%) = 331 (1) [M+], 316 (8), 226 (11), 176 (3), 160 (10), 144 (8), 105 (100), 91 (27), 79 (9), 77 (13), 55 (10). [α]D +7.5 (c 1.2, MeOH). TLC: Rf = 0.36 (hexane/EtOAc 1:1).