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

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

References

• 1a Aziridines, Azirines and Fused-ring Derivatives: Padwa A. Woolhouse AD. In Comprehensive Heterocyclic Chemistry   Vol. 7:  Katritzky AR. Rees CW. Lwowski W. Pergamon Press; Oxford: 1984.  p.80-93  
• 1b Aziridines: Deyrup JA. In The Chemistry of Heterocyclic Compounds   Vol. 42:  Weissberger A. Taylor EC. Hassner A. Wiley; New York: 1983.  p.11-83  
• 1c Tanner D. Angew. Chem., Int. Ed. Engl.  1994,  33:  599 
• 1d Kametani T. Honda T. Adv. Heterocycl. Chem.  1986,  39:  181 
• 2 Chao B. Dittmer DC. Tetrahedron Lett.  2001,  42:  5789 
• 3 Bergmeier SC. Fundy SL. Seth PP. Tetrahedron  1999,  55:  8025 
• 4a Bergmeier SC. Seth PP. J. Org. Chem.  1997,  62:  2671 
• 4b Sweeney JB. Cantrill AA. Tetrahedron  2003,  59:  3677 
• 5 Axenrod T. Watnick C. Yazdekhasti H. Dave PR. J. Org. Chem.  1995,  60:  1959 
• 6 Axenrod T. Watnick C. Yazdekhasti H. Dave PR. Tetrahedron Lett.  1993,  34:  6677 
• 7 Chiu IC. Kohn H. J. Org. Chem.  1983,  48:  2857 
• 8 Deyrup JA. Moyer CL. J. Org. Chem.  1970,  35:  3424 
• 11 De Kimpe N. Jolie R. De Smaele D. J. Chem. Soc., Chem. Commun.  1994,  1221 
• 12 Gaertner VR. J. Org. Chem.  1970,  35:  3952 

9

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, H_b), 1.57 (1 H, d, J = 6.3 Hz, H_a), 1.84-1.91 (1 H, m, H_c), 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): ν_max = 2970, 2930, 2875, 1364, 1110, 734 cm^-1. MS (70 eV): m/z (%) = 144 (100)
[M⁺ + 1], 88(23). TLC: R_f = 0.40 (hexane/EtOAc 1:1).

10

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, H_a), 1.63-1.70 (1 H, m, H_c), 1.86 (1 H, d, J = 3.6 Hz, H_b), 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 (CH_c), 37.45 (CH₃CH), 58.44 (CH₃O), 69.80 (CHMe), 74.03 (CH₂O), 126.75 (C_para), 127.02 and 128.28 (2 × C_ortho and 2 × C_meta), 144.49 (C_quat). IR (NaCl): ν_max = 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: R_f = 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, H_a), 1.66-1.73 (1 H, m, H_c), 1.79 (1 H, d, J = 3.3 Hz, H_b), 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, CH_arom). ¹³C NMR (75 MHz, CDCl₃): δ = 21.74 (CH₃Ar), 23.37 (CH₂N), 32.33 (CH_c), 35.95 (CH₃CH), 69.43 (CHMe), 72.17 (CH₂O), 126.67, 127.28, 127.98, 128.47 and 129.86 [CH(Me)CH_para, 4 × C_ortho and 4 × C_meta], 133.06 (CCH₃), 144.09 and 144.78 (2 × C_quat). IR (NaCl): ν_max = 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: R_f = 0.36 (hexane/EtOAc 1:1).