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

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.

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

References and Notes

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See also:

28b

Ref. 15b.

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29

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.

30 Acetalization of ketones under weakly acidic conditions (1a, pK _a = 14.75 in DMSO) in the absence of any dehydrating agents is quite unique, and we are currently performing experiments to explore the general scope of this reaction. See also: Kumamoto K. Ichikawa Y. Kotsuki H. Synlett  2005,  2254 

31

All new compounds gave satisfactory analytical and spectral data.

32

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.

33

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.

For recent examples of imidazole-catalyzed Morita-Baylis-Hillman reactions, see:

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35

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).