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Synlett 2008(9): 1402-1406  
DOI: 10.1055/s-2008-1072594
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Method for the High-Pressure-Promoted, Uncatalyzed Aza-Michael Reaction of Nitrogen Heterocycles with Enones in Water [1]

Md. Imam Uddin, Keiji Nakano, Yoshiyasu Ichikawa, Hiyoshizo Kotsuki*
Laboratory of Natural Product Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax: +81(888)448359; e-Mail: kotsuki@kochi-u.ac.jp;
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Publication History

Received 14 January 2008
Publication Date:
07 May 2008 (online)

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Abstract

A new green chemical method for the aza-Michael reaction of nitrogen heterocycles with enones in water as a solvent without the use of any catalysts under high-pressure conditions is described.

Key words

aza-Michael reaction - nitrogen heterocycles - enones - water - high-pressure reaction

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General Procedure A mixture of N-heterocycle (1, 1.1 mmol) and enone (2, 1.0 mmol) in distilled H2O (ca. 3.0 mL) was placed in a Teflon reaction vessel, and the mixture was allowed to react at 0.6 GPa and 60 °C for 20 h. After the mixture was cooled and the pressure was released, the mixture was extracted with CH2Cl2. The extracts were dried, concentrated, and purified by silica gel column chromatography (elution with CH2Cl2-i-PrOH) to afford the pure adduct 3.

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All new compounds gave satisfactory analytical and spectral data.

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The higher reactivity of purine (1g) at the N9 position is well established. For example, see ref. 6.
Compound 3q: mp 123-125 °C (hexane-CH2Cl2). FT-IR (KBr): ν = 1698, 1595, 1576, 1496, 1413 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.85 (1 H, dddd, J = 14.0, 12.0, 5.4, 3.6 Hz), 2.16-2.23 (1 H, m), 2.32-2.39 (1 H, m), 2.48-2.62 (3 H, m), 2.95 (1 H, ddt, J = 14.1, 4.9, 1.7 Hz), 3.26 (1 H, dd, J = 14.1, 11.7 Hz), 4.89 (1 H, tt, J = 11.5, 4.2 Hz), 8.13 (1 H, s), 8.98 (1 H, s), 9.17 (1 H, s). 13C NMR (100 MHz, CDCl3): δ = 22.0, 30.7, 40.5, 46.9, 54.4, 134.6, 143.2, 149.1, 150.9, 152.4, 206.3.
Compound 3r: mp 143-144 °C (hexane-CH2Cl2). FT-IR (KBr): ν = 1708, 1606, 1559, 1488, 1412 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.83-1.96 (1 H, m), 2.17-2.26 (1 H, m), 2.37 (1 H, ddt, J = 14.6, 11.2, 3.6 Hz), 2.45-2.57 (2 H, m), 2.58-2.66 (1 H, m), 2.96 (1 H, ddd, J = 14.2, 11.0, 1.0 Hz), 3.03 (1 H, ddt, J = 14.2, 5.1, 1.7 Hz), 4.79 (1 H, ddt, J = 10.9, 5.1, 3.9 Hz), 8.33 (1 H, s), 9.04 (1 H, s), 9.18 (1 H, s). 13C NMR (100 MHz, CDCl3): δ = 21.9, 31.3, 40.4, 47.6, 55.7, 124.4, 140.0, 145.5, 153.7, 161.0, 205.3.

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Compound 3d: mp 69-70 °C (hexane-CH2Cl2). FT-IR (KBr): ν = 1685, 1596, 1521, 1448 cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.60 (2 H, t, J = 6.4 Hz), 4.65 (2 H, t, J = 6.4 Hz), 7.47 (2 H, m), 7.59 (1 H, tt, J = 7.3, 1.2 Hz), 7.91-7.95 (3 H, m), 8.23 (1 H, s). 13C NMR (100 MHz, CDCl3): δ = 37.9, 44.0, 128.0 (2×), 128.7 (2×), 133.7, 136.0, 144.0, 152.0, 196.5.
Compound 3e: mp 87-89 °C (hexane-CH2Cl2). FT-IR (KBr): ν = 1687, 1538 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 3.50 (2 H, t, J = 6.1 Hz), 4.55 (2 H, t, J = 6.1 Hz), 7.50 (2 H, t, J = 7.8 Hz), 7.62 (1 H, m), 7.93 (2 H, m), 8.34 (2 H, s). 13C NMR (100 MHz, CDCl3): δ = 39.2, 39.7, 128.0 (2×), 128.9 (2×), 134.2, 135.6, 143.2 (2×), 195.8.

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α,β-Unsaturated esters were found to be mostly unreactive as Michael acceptors under the standard conditions (in H2O, 0.6 GPa, 60 °C, 20 h), except for methyl acrylate (87% conversion yield).