Synthesis of 2-Substituted Aziridine-2-Carboxylic Esters via Michael-Induced Ring-Closure Strategy

Abstract

A Michael-induced ring-closure (MIRC) strategy allowing the synthesis of 2-substituted aziridine-2-carboxylic esters is presented. A broad spectrum of nucleophiles can be applied, leading to large diversity of products which can be subjected to further structural modifications. Diastereoselective ring closure is observed in the case of chiral substrates.

Key words

MIRC - Michael additions - ring closure - aziridines - diastereoselective aziridination - N-heterocycles

• References and Notes

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• 9 Diffraction-quality crystals of 13a were grown from t-BuOMe and pentane. X-ray data were collected on an Oxford Diffraction Xcalibur PX Ultra diffractometer using Cu Kα radiation. The structure was solved by full-matrix least squares refinement using CRYSTALS. Empirical formula: C₁₉H₂₅NO₆; formula weight: 363.41; T = 100.0(2) K; crystal system: monoclinic; space group: P2(1)/n; Z = 4; cell parameters: a = 8.8078(5) Å, b = 8.1927(4) Å, c = 25.9170(13) Å, β = 93.874(6)°; V = 1865.90(17) ų; R1 = 0.1070; wR2 = 0.1726; max shift/e.s.d. = 0.00014. CCDC 1528523 contains the supplementary crystallographic data for 13a. The data can be obtained free of charge from The ­Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 10 Computational calculations of energy profiles (M06-2X/6-311G**, kcal/mol) of aziridine formation for the S,S pathway, the S,R pathway and the interconversion between the pro-S and the pro-R conformer reactants, see the Supporting Information for details.
• 11 Representative Procedure for MIRC Reactions A two-necked flask (10 mL) was charged with DMF (2 mL) and solid NaH (65% dispersion in oil) (23 mg, 0.52 mmol, 1.10 equiv). The mixture was cooled in ice bath and selected nucleophile (0.49 mmol, 1.05 equiv) was added. The reaction mixture was stirred for 30 min at 0 °C, then 10 min at r.t. Then, the reaction mixture was cooled in ice bath, and a solution of starting material 3 (150 mg, 0.47 mmol, 1.0 equiv) in DMF (2 mL) was added dropwise by means of a syringe. The ice bath was removed, and stirring was continued overnight at r.t. The reaction mixture was cooled in ice bath. Saturated NH₄Cl (aq, 10 mL) was added first dropwise, then in one portion (pH after quenching 8–9). The resulting mixture was extracted with Et₂O (3 × 25 mL). Combined organic extracts were washed with water (2 × 30 mL), sat. NaHCO₃ (aq, 10 mL), dried over Na₂SO₄ (anhydrous), filtered, and evaporated to dryness. The crude product was purified by chromatographic separation on R_f machine yielding the corresponding product 4 as a colorless to yellow oil. Dimethyl 2-{[1-Benzyl-2-(ethoxycarbonyl)aziridin-2-yl]methyl} Malonate (4b) Yield 71%, R_f = 0.54 (1:1 cyclohexane/EtOAc), t _R (LCMS): 1.04 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.20 (m, 5 H, C(Ar)H), 4.17 (m, 2 H, C (b)HH′), 3.77 (ap s, 2 H, C (f)HH′), 3.69 (ap s, 6 H, C (j)H₃ and C′ (j)H₃), 3.58 (ap t, J = 8 Hz, 1 H, C (h)H), 2.45 (ap d, J = 4 Hz, 2 H, C (g)HH′), 2.26 (s, 1 H, C (e)HH′), 2.02 (s, 1 H, C (e)HH′), 1.23 (ap t, J = 6 Hz, 3 H, C (a)H₃). ¹³C NMR (100 MHz, CDCl₃): δ = 169.7 (C (c) or C (i)), 169.6 (C (c) or C(i)), 139.2 (C(Ar)ipso), 128.3 (C(Ar)H), 128.0 (C(Ar)H), 127.0 (C(Ar)H), 61.6 (C (b)HH′), 56.0 (C (f)HH′), 52.6 (C (j)H₃), 52.6 (C′ (j)H₃), 48.9 (C (h)H), 42.2 (C (d)), 40.1 (C (e)HH′), 32.7 (C (g)HH′), 14.2 (C (a)H₃). HRMS (ESI/FT-Orbitrap): m/z calcd for: C₁₈H₂₄NO₆; found: 350.160; deviation = 0.800 mμ.
• 12 Detailed procedures along with full analytical data are available in the Supporting Information.