Halogenated-2-pyrones in Sonogashira cross-coupling:: limitations, optimisation and consequences for GC analysis of Pd-mediated reactions

The Sonogashira couplings of 4-bromo-6-methyl-2-pyrone (5) with phenylacetylene, mediated by Pd(PPh3)(2)Cl-2 in the presence of a CuI co-catalyst, have been investigated in detail. The concentration of Pd dramatically influences the product yield, with lower Pd-loadings favouring higher conversions and purer cross-coupled product. A post reaction time-dependence in product conversion is seen in samples quenched solely on silica-gel (eluted with CH2Cl2). The effect is mirrored in reactions employing 4-nitro-bromobenzene (14) and to a lesser extent (E) and (Z)-ethyl 3-iodo-2-propenonate (16) under similar conditions. A more efficient quenching system (using excess dppe) has been developed to enable accurate determinations in product conversions. Alternatively, solvent and base (Et3N) removal in vacuo, or quench with saturated aqueous ammonium chloride, prevents further turnover in Sonogashira coupling. An ESI-MS study on samples eluted through silica was undertaken to probe the nature of the soluble Pd/Cu species. The Sonogashira cross-coupling of 4-chloro- and 6-chloro-2-pyrone (18 and 20, respectively) has further been investigated. The former undergoes successful coupling, however the latter decomposes in polar aprotic and protic solvents under standard conditions, through a chlorine substitution process, making Pd-mediated reactions problematic.