Synthetic Applications of the Pyrolysis of Meldrum's Acid Derivatives

Abstract

The pyrolysis of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) 1 derivatives in solution and in the gas-phase takes place by loss of acetone and carbon dioxide to provide ketene intermediates. In particular, methylene Meldrum's acid derivatives 7 often provide methyleneketenes 8, which act as substrates for internal hydrogen transfer leading to cyclisation reactions. The availability of versatile synthetic routes to 7 (in particular R = heteroatom) has led to the efficient preparation of a diverse range of cyclic compounds such as quinolinones, 3-hydroxythiophenes, naphthols, azepin-3(2H)-ones or pyrrolizin-3-ones initiated respectively by 1,3-1,4-1,5-1,6-or 1,7-prototropic shifts. These reactions are discussed in the context of a rigorous understanding of the chemistry of the ketene intermediates involved. Most of the work was published in the period 1980-2000 but important references to earlier literature are also included.

Synthesis and Antiparasitic Activity Against Trypanosoma cruzi and Leishmania amazonensis of Chlorinated 1,7- and 1,8-Naphthyridines

“…Thermocyclization of 1 in refluxing diphenylether at 250°C during 5 minutes according to the method reported by Cassis et al [20] was accompanied by spontaneous elimination of CO 2 and propanone to give the bicycle 6,8-Dichloro-1,7-naphthyridin-4(1H)-one (2). This transformation proceeds via electrocyclization of the corresponding aminoketene derivative generated upon thermolysis [21]. The 1 H NMR spectrum of 2 showed two singlets at 7.93 ppm (aromatic proton) and 12.10 ppm (NH) and two doublets at 6.33 and 8.01 (J= 5.7 Hz) related to pyridone system.…”

Solution-Phase Parallel Synthesis of Dissymmetric Disubstituted Malonamides Carrying Amino Ester Residues

“…11 Moreover, it is necessary to work at a temperature high enough to remove the acetone generated by the decomposition of 1, but avoiding the possible formation of the Knoevenagel adduct 6 with 1 itself. 12 Optimal reaction conditions required that a first a-amino ester hydrochloride A and Et 3 N in equimolar amounts reacted with a twofold excess 13 of 1 under reflux of THF.…”

Gas-Phase Synthesis of Pyrazolo[3,4-b]pyridin-4-ones

“…First, 3 (R 1 = alkyl or aryl) were synthesized and pyrolyzed to ensure that, in the absence of the pyrazole NH, cyclization onto the adjacent carbon atom to give 1 (R = 1-alkyl or 1-aryl) would take place (Scheme 1), as observed in many related systems. 6 Second, we explored the design of a thermal N-protecting group, which would remain at low furnace temperatures, but be selectively removed at higher furnace temperatures to provide N-unsubstituted pyrazolopyridinones 1 (R 1 = H). If the previous stages were successful, we aimed finally to functionalize the 4-position of the pyrazolo [3,4-b]pyridin-4-ones to establish that the route has significant potential for the synthesis of pyrazolo [3,4-b]pyridines 2.…”