Regioselective Ring Opening of N-H-Aziridines with Sulfur Nucleophiles in Liquid SO₂

Abstract

N-H-Aziridines undergo efficient ring-opening reactions with aromatic and aliphatic thiols in liquid sulfur dioxide as reaction medium. Due to the Lewis acidic nature of SO₂, these reactions do not require any other catalytic additives. The expected β-alkyl/arylthio-amines (β-amino thioethers) are obtained with excellent β-regioselectivity. The developed reaction conditions are compatible with chiral starting materials the enantiomeric purity of which is conserved in the corresponding products. This method is also useful for direct synthesis of carbohydrate–amino acid conjugates and 2-iminothiazolidine derivatives.

Key words

aziridines - thiols - ring opening - sulfur dioxide - β-amino thioethers

• References and Notes

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• 27 General Procedure for Aziridine Ring Opening at –10 °C (S)-Aziridine-2-carboxamide (1; 0.10 g, 1.17 mmol, 1 equiv) and 4-chlorobenzenethiol (2a; 0.34 g, 2.35 mmol, 2 equiv), were placed into a two-neck round-bottom flask equipped with dry ice condenser under inert atmosphere. Sulfur dioxide (35 ± 5 mL) was condensed into the flask at –78 °C. The resulting reaction mixture was allowed to warm up to the boiling point of SO₂ (–10 °C), and the reaction was performed in liquid SO₂ under the same temperature for 5 h. Then the flask was connected to SO₂-collecting vessel cooled at –78 °C, and the excess of SO₂ was transferred. The solid residue was purified by column chromatography (4% EtOH–CH₂Cl₂) and (R)-2-amino-3-[(4-chlorophenyl)thio]propanamide (3a, 149 mg, 55%) was obtained as an amorphous powder; [α]_D ²⁵ –53.5 (c 1.0, CHCl₃). IR (KBr): 3380, 3330, 3075, 3185, 1655, 1635, 1575, 1540, 1505, 1495, 1475, 1425, 1390, 1095, 1010, 815, 810, 730, 705, 675 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.41 (br s, 1 H, CONH), 7.40–7.31 [m, 4 H, H-C(Ar)], 7.10 (br s, 1 H, CONH), 3.33–3.19 [m, 2 H, Ha-C(3), H-C(2)], 2.98 [dd, 1 H, ² J = 12.4 Hz, ³ J = 7.0 Hz, Hb-C(3)], 1.99 [br s, 1 H, H₂N-C(2)]. ¹³C NMR (75.5 MHz, DMSO-d ₆): δ = 175.1, 135.6, 130.1, 129.7, 128.8, 54.0, 38.4. HRMS: m/z calcd [C₉H₁₁ClN₂OS + H⁺]: 231.0354; found: 231.0355.
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• 28b Romanchikova N, Trapencieris P, Zemitis J, Turks M. J. Med. Chem. Enz. Inhib. 2014; 29: 765
• 29 General Procedure for Aziridine Ring Opening at 25 °C 1-(Aziridin-2-ylmethyl)-4-[4-(trifluoromethyl)phenyl]-1H-1,2,3-triazole (6; 0.05 g, 0.19 mmol, 1 equiv) and dodecane-1-thiol (2b; 89 μL, 0.37 mmol, 2 equiv) were placed into a stainless steel vessel. Three vacuum/nitrogen cycles were accomplished via Schlenk line. Sulfur dioxide (25 ± 2 g) was transferred into the vessel at –78 °C. Reaction was carried out under pressure (4 bar) at 25 °C for 14 h. Then the SO₂-collecting vessel was cooled to –78 °C, connected to the reaction vessel, and the excess of SO₂ was transferred. The resulting residue was purified by column chromatography (3% EtOH–CH₂Cl₂), and compound 9b (83 mg, 95%) was obtained as an amorphous powder. IR (KBr): 3385, 3315, 3135, 3115, 2965, 2920, 2850, 1620, 1470, 1335, 1230, 1190, 1170, 1125, 1065, 845, 825, 720, 695, 600 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.99 [s, 1 H, H-C(triaz)], 7.95 [d, ³ J = 8.2 Hz, 2 H, H-C(Ar)], 7.67 [d, ³ J = 8.2 Hz, 2 H, H-C(Ar)], 4.56 (dd, ² J = 13.7 Hz, ³ J = 4.2 Hz, 1 H, Ha-C(3)], 4.34 [dd, ² J = 13.7 Hz, ³ J = 7.3 Hz, 1 H, Hb-C(3)], 3.53–3.40 [m, 1 H, H-C(2)], 2.67 [dd, ² J = 13.4 Hz, ³ J = 5.4 Hz, 1 H, Ha-C(1)], 2.58–2.44 [m, 3 H, Hb-C(1), CH₂-S], 1.66–1.49 (m, 4 H, CH₂, NH₂), 1.44–1.14 (m, 18 H, 9 CH₂), 0.87 (t, ³ J = 6.6 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃): δ = 146.2, 134.0, 130.0 (q, ² J _C–F = 32 Hz), 125.8 (q, ³ J _C–F = 4 Hz), 125.8, 124.5 (q, ¹ J _C–F = 272 Hz), 121.6, 55.7, 50.9, 37.5, 32.7, 31.9, 29.6, 29.6, 29.6, 29.5, 29.5, 29.3, 29.2, 28.8, 22.6, 14.1. HRMS: m/z calcd [C₂₄H₃₇F₃N₄S + H⁺]: 471.2759; found: 471.2780.
• 30 CCDC 1479668 (for compound 11) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.