Continuous-flow retro-Diels-Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

Abstract

The syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-Diels-Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to rapidly screen a selection of conditions and quickly confirm the viability of preparing the desired pyrimidinones in short reaction times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved.

Keywords: continuous-flow; desulfurisation; norbornene-fused heterocycles; pyrimidinones; retro-Diels–Alder reaction.

Scheme 1

Flow synthesis for the preparation of fused pyrimidinones 9–14 by rDA reaction. Solvent and conditions (F_R is the flow rate): (i) MeCN, toluene, F_R = 0.5 mL min⁻¹, 230–250 °C; (ii) MeOH, F_R = 0.5 mL min⁻¹, 120–150 °C; (iii) MeCN, F_R = 0.5 mL min⁻¹, 220–250 °C.

Figure 1

Schematic outline of the continuous-flow reactor.

Scheme 2

Synthesis of tricyclic ethanoquinazolin-4(3H)-one 15b; (i) MeCN, F_R = 0.5 mL min⁻¹, 220–250 °C; (ii) EtOH/H₂O = 2:1, F_R = 0.5 mL min⁻¹, 250 °C; (iii) MeCN, F_R = 0.5 mL min⁻¹, 250 °C.