A Broadened Scope for the Use of Hydrazones as Neutral Nucleophiles in the Presence of H-Bonding Organocatalysts

Daniel Pettersen; Raquel P. Herrera; Luca Bernardi; Franscesco Fini; Valentina Sgarzani; Rosario Fernandez; José M. Lassaletta; Alfredo Ricci

doi:10.1055/s-2005-922791

LETTER

A Broadened Scope for the Use of Hydrazones as Neutral Nucleophiles in the Presence of H-Bonding Organocatalysts

Daniel Pettersen*^a, Raquel P. Herrera*^a, Luca Bernardi^a, Franscesco Fini^a, Valentina Sgarzani^a, Rosario Fernandez^b, José M. Lassaletta^c, Alfredo Ricci^a
^a Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento N°4, 40136 Bologna, Italy
Fax: +39(051)2093654; e-Mail: dap@chem.gu.se, rph@alu.ua.es;
^b Dpto. de Quimica Organica, Universidad de Sevilla, Apdo. de Correos 553, 41071 Seville, Spain
^c Instituto de Investigaciones Quimicas (CSIC-Use), Isla de la Cartuja, Americo Vespucio s/n, 41092 Seville, Spain

Abstract

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Abstract

Using thioureas as H-bonding organocatalysts, nitroalkenes can be activated for the conjugate addition of hydrazones as neutral nucleophiles. Formaldehyde derivatives react at the azomethine carbon as expected, whereas hydrazones from enolizable aldehydes behave as ene-hydrazines and react at the α-carbon instead. Ionic liquids were found to decrease the reaction times considerably compared to commonly used solvents, whereas alternative activation by Lewis acids resulted in decomposition of reactants.

Key words

catalysis - ionic liquids - hydrazones - nucleophiles - addition reactions

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References

References and Notes

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Experimental Procedure.
To a mixture of thiourea 1 (0.02 mmol, 10 mg) and nitroalkene (0.1 mmol) in CH₂Cl₂ (100 µL) was added hydrazone (0.15 mmol). The reaction was then stirred for the time stated at ambient temperature. The product was isolated as an oil using column chromatography (EtOAc-hexane, 1:4). All compounds gave satisfactory analytical and spectral data.
Typical data for representative compounds:
Compound 4ca (19.2 mg, 77%): Major diastereomer: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (3 H, d, J = 6.87 Hz, CH₃), 2.62 (1 H, m, J = 6.87, 7.11, 10.2 Hz, CH₃CH), 2.75 [6 H, s, N(CH₃)₂], 3.41 (1 H, dt-like, J = 5.27, 10.20 PhCH), 4.53 (1 H, dd, J = 9.87, 12.9 Hz, CHNO₂), 4.76 (1 H, dd, J = 5.07, 12.9 Hz, CHNO₂), 6.39 (1 H, d, J = 7.11, HC=N), 7.08-7.37 (5 H, m, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 17.96, 41.14, 43.18, 48.79, 79.94, 127.9, 128.3, 129.1, 136.7, 138.7. ESI-MS: m/z = 272 [M + Na⁺]. HRMS: m/z calcd for C₁₃H₁₉N₃O₂: 249.1477; found: 249.1475.
Compound 4de (24.7 mg, 82%): Major diastereomer: ¹H NMR (300 MHz, CDCl₃): δ = 2.80 [6 H, s, N(CH₃)₂], 3.89 (1 H, dd, J = 5.84, 10.3 Hz, PhCH), 4.26 (1 H, m, CH), 4.77 (1 H, dd, J = 8.96, 12.9, CHNO₂), 4.95 (1 H, dd, J = 5.01, 12.9, CHNO₂), 5.83 (1 H, m, furyl), 6.08 (1 H, m, furyl), 6.62 (1 H, d, J = 5.84 Hz, HC=N), 7.05-7.38 (5 H, m, Ph and 1H, furyl). ¹³C NMR (75 MHz, CDCl₃): δ = 41.99, 43.11, 51.07, 77.25, 108.8, 110.3, 127.2, 128.3, 128.4, 129.3, 139.6, 142.1, 151.2. ESI-MS: m/z = 324 [M + Na⁺]. HRMS: m/z calcd for C₁₆H₁₉N₃O₃: 301.1426; found: 301.1424.

Formation of adducts derived from attack by the azo-methine carbon was not observed for any of the studied hydrazones 2b-f.

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Other H-bonding catalysts such as tartaric acid or mandelic acid were unsuccessfully tried. Furthermore, no decomposition of hydrazones or nitroalkenes in presence of thiourea 1 was observed after one week in CH₂Cl₂.

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