Opposite Regioselectivity in the Sequential Ring-Opening of 2-(Alkanoyloxymethyl)aziridinium Salts by Bromide and Fluoride in the Synthesis of Functionalized β-Fluoro Amines

Matthias D’hooghe; Norbert De Kimpe

doi:10.1055/s-2006-947359

LETTER

Opposite Regioselectivity in the Sequential Ring-Opening of 2-(Alkanoyloxymethyl)aziridinium Salts by Bromide and Fluoride in the Synthesis of Functionalized β-Fluoro Amines

Matthias D’hooghe, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;

Abstract

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Abstract

1-Arylmethyl-2-(bromomethyl)aziridines were converted into the corresponding 2-(alkanoyloxymethyl)aziridines upon treatment with potassium 2-methylpropanoate or potassium 2-methylbutyrate in DMSO in excellent yields, following regioselective ring-opening towards N-(2-bromo-3-alkanoyloxypropyl)amines using allyl bromide or an arylmethyl bromide in acetonitrile. Treatment of the latter β-bromo amines with tetrabutylammonium fluoride in acetonitrile afforded 2-amino-1-fluoropropanes as the major compounds (72-86%) besides the isomeric 1-amino-2-fluoropropanes in minor quantities (14-28%). The ring-opening of the intermediate aziridinium salts by bromide and fluoride in acetonitrile resulted in a different regioselectivity with a preferential attack of bromide at the more hindered carbon atom and of fluoride at the less hindered carbon atom of the aziridinium ion.

Key words

2-(bromomethyl)aziridines - aziridinium salts - β-fluoro amines - ring-opening - substitution

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References and Notes

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As a representative example, the synthesis of 1-(3-methyl-benzyl)aziridin-2-ylmethyl 2-methylpropanoate 4a is described. To a solution of isobutyric acid (0.88 g, 1.0 equiv) in DMSO (15 mL) was added K₂CO₃ (2.76 g, 2 equiv), and the resulting suspension was stirred for 30 min at r.t. Subsequently, 2-(bromomethyl)-1-(3-methylbenzyl)-aziridine (3a, 2.40 g, 0.01 mol) was added, and the mixture was heated at 80 °C for 15 h. The reaction mixture was poured into H₂O (20 mL) and extracted with Et₂O (3 × 15 mL). The combined organic extracts were washed with H₂O (2 × 15 mL) and brine (20 mL). Drying (MgSO₄), filtration of the drying agent and evaporation of the solvent afforded 1-(3-methylbenzyl)aziridin-2-ylmethyl 2-methylpropanoate (4a), which was purified by filtration through silica gel (hexane-EtOAc, 5:3).
1-(3-Methylbenzyl)aziridin-2-ylmethyl 2-methylpropanoate (4a): R _f = 0.25; light-yellow oil; yield 85%. ¹H NMR (300 MHz, CDCl₃): δ = 1.10 and 1.11 [6 H, 2 d, J = 6.9 Hz, (CH ₃)₂CH], 1.51 [1 H, d, J = 6.3 Hz, (H _cisCH)N], 1.77 [1 H, d, J = 3.3 Hz, (HCH _trans)N], 1.82-1.89 (1 H, m, NCH), 2.34 (3 H, s, CH₃Ar), 2.47 [1 H, sept, J = 7.0 Hz, (CH₃)₂CH], 3.30 and 3.53 [2 H, 2 d, J = 13.3 Hz, N(HCH)Ar], 3.81 and 4.20 [2 H, 2 × dd, J = 11.6, 7.4, 4.5 Hz, (HCH)O], 7.06-7.24 (4 H, m, CH_arom). ¹³C NMR (68 MHz, CDCl₃): δ = 18.89 [(CH₃)₂CH], 21.39 (CH₃Ar), 31.76 [(H_cisCH_trans)N], 33.86 [(CH₃)₂ CH], 37.21 (CHN), 64.40 (NCH₂Ar), 66.55 (CH₂O), 125.14, 127.87, 128.27 and 128.85 (HC_arom), 137.93 and 138.73 (2 × C_arom,quat), 176.99 (CO). IR (NaCl): 1733 cm^-1 (C=O). MS (70 eV): m/z (%) = 247 (19) [M⁺], 160 (38), 158 (17), 105 (100), 72 (21), 71 (38). Anal. Calcd for C₁₅H₂₁NO₂: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.97; H, 8.74; N, 5.50.

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As a representative example, the synthesis of 3-[allyl-(3-methylbenzyl)amino]-2-bromopropyl 2-methylpropanoate (6a) is described. To a solution of 1-(3-methylbenzyl)-aziridin-2-ylmethyl 2-methylpropanoate (4a, 2.47 g, 10 mmol) in MeCN (50 mL) was added allyl bromide (1.45 g, 1.2 equiv) under stirring, and the resulting mixture was heated for 6 h under reflux. Evaporation of the solvent afforded 3-[allyl(3-methylbenzyl)amino]-2-bromopropyl 2-methylpropanoate (6a), which was purified by means of column chromatography (hexane-EtOAc, 49:1) on silica gel in order to obtain an analytically pure sample.
3-[Allyl(3-methylbenzyl)amino]-2-bromopropyl 2-methyl-propanoate (6a): colorless liquid; yield 90%; R _f = 0.04 (hexane-EtOAc, 49:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.17 [6 H, d, J = 7.2 Hz, (CH ₃)₂CH], 2.34 (3 H, s, CH₃Ar), 2.54 [1 H, sept, J = 7.0 Hz, (CH₃)₂CH], 2.84 and 2.93 [2 H, 2 × dd, J = 13.7, 8.8, 5.9 Hz, N(HCH)CHBr], 3.06 and 3.17 [2 H, 2 × dd, J = 14.0, 6.9, 6.1 Hz, N(HCH)CH=CH₂], 3.53 and 3.67 [2 H, 2 d, J = 13.5 Hz, N(HCH)Ar], 4.07-4.16 (1 H, m, CHBr), 4.27 and 4.50 [2 H, 2 × dd, J = 11.9, 6.3, 3.7 Hz, (HCH)O], 5.15-5.22 (2 H, m, CH=CH ₂), 5.79-5.92 (1 H, m, CH=CH₂), 7.05-7.26 (4 H, m, CH_arom). ¹³C NMR (68 MHz, CDCl₃): δ = 18.87 and 18.96 [(CH₃)₂CH], 21.41 (CH₃Ar), 33.94 [(CH₃)₂ CH], 48.77 (CHBr), 57.50, 57.67 and 59.12 (3 × CH₂N), 65.70 (CH₂O), 118.07 (CH=CH₂), 125.93, 127.95, 128.25 and 129.61 (HC_arom), 135.23 (CH=CH₂), 137.90 and 138.70 (2 × C_arom,quat), 176.48 (CO). IR (NaCl): 1736 cm^-1 (C=O). MS (70 eV): m/z (%) = 368, 370 (23) [M⁺ + 1], 288 (100) [M⁺ - Br]. Anal. Calcd for C₁₈H₂₆BrNO₂: C, 58.70; H, 7.12; N, 3.80. Found: C, 58.91; H, 7.31; N, 3.66.

As a representative example, the synthesis of 2-[allyl(3-methylbenzyl)amino]-3-fluoropropyl 2-methylpropanoate (7a) and 3-[allyl(3-methylbenzyl)amino]-2-fluoropropyl 2-methylpropanoate (8a) is described. To a solution of 3-[allyl(3-methylbenzyl)amino]-2-bromopropyl 2-methyl-propanoate (6a, 3.68 g, 10 mmol) in MeCN (50 mL) was added TBAF·3H₂O (4.73 g, 1.5 equiv) under stirring and the resulting mixture was heated for 7 h under reflux. Extraction with H₂O (40 mL) and Et₂O (3 × 30 mL), drying (MgSO₄), filtration of the drying agent and evaporation of the solvent afforded a mixture of 2-[allyl(3-methylbenzyl)amino]-3-fluoropropyl 2-methylpropanoate (7a, 72%) and 3-[allyl(3-methylbenzyl)amino]-2-fluoropropyl 2-methylpropanoate (8a, 28%). Both isomers were separated by means of column chromatography (hexane-ethyl acetate, 34:1) in order to obtain analytically pure samples.
2-[Allyl(3-methylbenzyl)amino]-3-fluoropropyl 2-methyl-propanoate (7a): colorless liquid; R _f = 0.16 (hexane-EtOAc, 34:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.18 and 1.19 [6 H, 2 d, J = 6.9 Hz, (CH ₃)₂CH], 2.34 (3 H, s, CH₃Ar), 2.57 [1 H, sept, J = 7.0 Hz, (CH₃)₂CH], 3.20-3.35 (3 H, m, CHN and NCH ₂CH=CH₂), 3.73 and 3.76 [2 H, 2 d, J = 14.3 Hz, N(HCH)Ar], 4.20 [1 H, dd, J = 11.4, 6.5 Hz, (HCH)O], 4.30 [1 H, ddd, J = 11.4, 6.5, 1.2 Hz, (HCH)O], 4.50 and 4.66 [2 H, dd, J = 47.5, 5.1 Hz, (HCH)F], 5.09-5.24 (2 H, m, CH=CH ₂), 5.73-5.86 (1 H, m, CH=CH₂), 7.04-7.32 (4 H, m, CH_arom). ¹³C NMR (68 MHz, CDCl₃): δ = 19.06 [(CH₃)₂CH], 21.52 (CH₃Ar), 34.12 [(CH₃)₂ CH], 54.06 and 54.81 (2 × CH₂N), 56.85 (d, J = 18.5 Hz, CHN), 61.55 (d, J = 5.8 Hz, CH₂O), 82.34 (d, J = 171.9 Hz, CH₂F), 117.28 (CH=CH₂), 125.57, 127.82, 128.26 and 129.22 (HC_arom), 136.84 (CH=CH₂), 137.94 and 139.87 (2 × C_arom,quat), 176.92 (CO). ¹⁹F (CCl₃F): δ = -227.42 (td, J = 46.0, 22.4 Hz, CH₂F). IR (NaCl): 1738 cm^-1 (C=O). MS (70 eV): m/z
(%) = 307 (1) [M⁺], 274 (5) [M⁺ - CH₂F], 206 (45), 174 (40), 105 (100). Anal. Calcd for C₁₈H₂₆FNO₂: C, 70.33; H, 8.53; N, 4.56. Found: C, 70.50; H, 8.70; N, 4.41.
3-[Allyl(3-methylbenzyl)amino]-2-fluoropropyl 2-methyl-propanoate (8a): colorless liquid; R _f = 0.09 (hexane-EtOAc, 34:1). ¹H NMR (300 MHz, CDCl₃): δ = 1.16 [6 H, d, J = 7.2 Hz, (CH ₃)₂CH], 2.34 (3 H, s, CH₃Ar), 2.55 [1 H, sept, J = 7.0 Hz, (CH₃)₂CH], 2.74 (2 H, dd, J = 19.8, 5.5 Hz, NCH ₂CHF), 3.15 (2 H, d, J = 6.3 Hz, NCH ₂CH=CH₂), 3.62 (2 H, s, NCH₂Ar), 4.11-4.34 (2 H, m, CH₂O), 4.76 (1 H, dddd, J = 48.8, 11.7, 5.8, 3.0 Hz, CHF), 5.14-5.23 (2 H, m, CH=CH ₂), 5.85-5.93 (1 H, m, CH=CH₂), 7.04-7.25 (4 H, m, CH_arom). ¹³C NMR (68 MHz, CDCl₃): δ = 18.92 [(CH₃)₂CH], 21.42 (CH₃Ar), 33.88 [(CH₃)₂ CH], 53.39 (d, J = 23.1 Hz, NCH₂CHF), 57.82 (NCH₂CH=CH₂), 59.13 (NCH₂Ar), 64.42 (d, J = 21.9 Hz, CH₂O), 90.33 (d, J = 173.1 Hz, CHF), 117.96 (CH=CH₂), 125.95, 127.89, 128.22 and 129.61 (HC_arom), 135.43 (CH=CH₂), 137.90 and 138.83 (2 × C_arom,quat), 176.80 (CO). ¹⁹F (CCl₃F): δ = -189.50 to
-189.34 (m, CHF). IR (NaCl): 1736 cm^-1 (C=O). MS
(70 eV): m/z (%) = 307 (3) [M⁺], 174 (99), 105 (100). Anal. Calcd for C₁₈H₂₆FNO₂: C, 70.33; H, 8.53; N, 4.56. Found: C, 70.54; H, 8.72; N, 4.32.

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