A Domino Microwave-Assisted Protocol for the Synthesis of 2,6-Disubstituted Pyrimidinones

Abstract

A practical microwave-assisted protocol for the synthesis of 2,6-disubstituted pyrimidinones has been developed. This approach is based on a domino Michael addition-cyclocondensation reaction between substituted thioureas/guanidines and acetylenecarboxylates. The application of such protocol for the synthesis of not easily accessible N-DABO derivatives as potential antiviral agents is also reported.

Key words

microwave - pyrimidinones - acetylenecarboxylates - ­S-DABO - N-DABO

References and Notes

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1

These authors contributed equally to this work.

18

Typical Experimental Procedure: In a microwave sealed tube, S-methylisothiourea sulfate (1; 79 mg, 0.283 mmol), ethyl 4-(tetrahydro-2H-pyran-2-yloxy)but-2-ynoate (2; 50 mg, 0.236 mmol) and Na₂CO₃ (60 mg, 0.566 mmol) in DMF or t-BuOH (3 mL) were irradiated for 20 min in a self-tunable CEM microwave synthesizer at 120 ˚C and finally allowed to cool to r.t. When DMF was used as solvent, H₂O was added and the aqueous layer was extracted with EtOAc (2 ×). The organic layers were collected, washed with brine, dried over Na₂SO₄ and concentrate under reduced pressure. When t-BuOH was used as solvent, the reaction mixture was directly evaporated to dryness to give a solid crude material. The residue was purified by flash chromatography (petroleum ether-EtOAc) to obtain 2-(methylthio)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]pyrimidin-4(3H)-one (3; 52-54%) as a white solid. ^¹H NMR (400 MHz, CDCl₃): δ = 12.68 (br s, 1 H), 6.34 (s, 1 H), 4.68 (s, 1 H), 4.52 (d, J = 16.0 Hz, 1 H), 4.32 (d, J = 16.0 Hz, 1 H), 3.77 (m, 1 H), 3.47 (m, 1 H), 2.48 (s, 3 H), 1.40-1.90 (m, 8 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 166.33, 165.29, 161.36, 105.81, 98.12, 67.81, 61.91, 30.33, 25.36, 18.93, 13.19. MS (ESI): m/z = 257.3 [M + H]⁺.

23

Data not shown.