Synlett 2017; 28(16): 2115-2120
DOI: 10.1055/s-0036-1590806
letter
© Georg Thieme Verlag Stuttgart · New York

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

Ewa Pietrasiak
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland   Email: [email protected]
,
Grit Schade
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland   Email: [email protected]
,
Myriam Baalouch
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland   Email: [email protected]
,
Daniel Emery
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland   Email: [email protected]
,
Syngenta Crop Protection AG, Chemical Research, Schaffhauserstrasse 101, 4332 Stein, Switzerland   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 19 April 2017

Accepted after revision: 22 May 2017

Publication Date:
12 July 2017 (online)


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.

Supporting Information

 
  • 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) Å3; 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 Rf 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%, Rf = 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.