Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Cláudia Alves; Carla Grosso; Pedro Barrulas; José A. Paixão; Ana L. Cardoso; Anthony J. Burke; Américo Lemos; Teresa M. V. D. Pinho e Melo

doi:10.1055/s-0039-1691533

Synlett, Table of Contents

Synlett 2020; 31(06): 553-558
DOI: 10.1055/s-0039-1691533

cluster

Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Authors

Cláudia Alves

^aCQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal, Email: tmelo@ci.uc.pt
Carla Grosso

^aCQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal, Email: tmelo@ci.uc.pt
Pedro Barrulas

^bCentro de Química de Évora and Department of Chemistry, University of Évora, 7000 Évora, Portugal

^cHERCULES Laboratory, Évora University, Largo Marquês de Marialva 8, 7000-809 Évora, Portugal
José A. Paixão

^dCFisUC and Department of Physics, University of Coimbra, Coimbra 3004-516, Portugal
Ana L. Cardoso

^aCQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal, Email: tmelo@ci.uc.pt
Anthony J. Burke

^bCentro de Química de Évora and Department of Chemistry, University of Évora, 7000 Évora, Portugal
Américo Lemos

^aCQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal, Email: tmelo@ci.uc.pt

^eFCT, University of Algarve, Campus Gambelas, 8005-139 Faro, Portugal
Teresa M. V. D. Pinho e Melo ∗

^aCQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal, Email: tmelo@ci.uc.pt

Abstract

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Published as part of the ISySyCat2019 Special Issue

Abstract

A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.

Key words

2H-azirines - asymmetric Neber reaction - organocatalysis - tetrazoles - thiourea - 6β-aminopenicillanic acid

Full Text

References

References and Notes
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21 General Procedure for the Optimized Asymmetric Synthesis of 2H-azirines 7, 14a, and 14b To a solution of the appropriate β-ketoxime 5 or 13a,b (0.15 mmol), K₂CO₃ (1.50 mmol, 10 equiv), and tosyl chloride (0.17 mmol, 1.1 equiv) in toluene (4 mL) under a nitrogen atmosphere was added the organocatalyst (18 or 20 mol%) in toluene (1 mL). The mixture was stirred for 48 h at the appropriate temperature. The solvent was evaporated under reduced pressure, and the crude reaction was dissolved in ethyl acetate (20 mL) and washed with water (3 × 10 mL). The organic layer was dried over anhydrous Na₂SO₄ and filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (ethyl acetate/hexane, 1:1). The characterization data for 7, 14a, and 14b agreed with those previously reported.¹⁹

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26 Procedure for the Synthesis of (2S,6R)-Benzhydryl 6β-{3-[3,5-bis(trifluoromethyl)phenyl] thioureido}-aminopenicillanate (12) To a solution of benzhydryl 6β-aminopenicillanate 10b (1.94 mmol, 0.74 g) under inert atmosphere in dry THF (3.5 mL) was added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate (11, 1.94 mmol, 0.35 mL). After stirring for 3 h at room temperature, the solvent was evaporated, and the crude product was purified by flash chromatography (eluting with ethyl acetate/hexane, 1:2) and recrystallized with diethyl ether/hexane; yield 48%; white solid; mp 77.0–78.0 °C. IR (KBr): ν = 682, 697, 1128, 1251, 1175, 1276, 1491, 1735, 2968, 2933, 3032, 3066, 3271, 3291 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (s, 1 H), 7.84 (s, 2 H), 7.50 (s, 1 H), 7.35–7.31 (m, 11 H), 6.96 (s, 1 H), 5.19 (d, J = 2 Hz, 1 H), 4.25 (dd, J = 3.2 Hz and J = 1.2 Hz, 1 H), 3.92 (s, 1 H), 1.64 (s, 3 H), 1.00 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 182.8, 170.6, 167.3, 139.1, 138.9, 133.9, 132.4 (q, J = 34.0 Hz, 2 C), 128.8, 128.9, 128.6, 128.5, 128.2, 127.9, 127.7, 126.9, 126.8, 126.6, 124.1, 122.9 (m, 1 C), 121.4, 78.7, 73.3, 66.5, 65.5, 65.1, 60.6, 26.3, 26.1 ppm. ¹⁹F NMR (376 MHz CDCl₃): δ = 62.8 (s, 6 F). HRMS (ESI): m/z calcd for C₃₀H₂₆F₆N₃O₃S₂ [MH⁺]: 654.1314; found: 654.1301.

Supplementary Material

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