Tandem Palladium/Charcoal-Copper(I) Iodide (Pd/C-CuI) Catalyzed Sonogashira Coupling and Intramolecular Cyclization from 2-Bromonicotinic Acid (=2-Bromopyridine-3-carboxylic Acid) and Ethynylarenes to 4-Azaphthalides (=Furo[3,4-b]pyridin-5(7H)-ones) and 5-Azaisocoumarins (=5H-Pyrano[4,3-b]pyridin-5-ones)

Several 4-azaphthalides (=furo[3,4-b]pyridin-5(7H)-ones) and 5-azaisocoumarins (=5H-pyrano[4,3-b]pyridin-5-ones) were prepared through a tandem heterogeneous Pd/C-mediated Sonogashira coupling and a 5-exo-dig or 6-endo-dig intramolecular cyclization of 2-bromonicotinic acid (=2-bromopyridine-3-carboxyclic acid) with various ethynylarenes or 3-ethynylthiophene. In the presence of Pd/C-Ph3P-CuI and Et3N in dry dioxane under Ar at 908, a mixture of 4-azaphthalides (usually the major product) and 5-azaisocoumarins was obtained after 3.5 h under normal heating (Schemes 3 and 4; Tables 1 and 2). This mixture of compounds was also obtained with the same catalytic system under microwave (MW) irradiation in only 25 min (Tables 3 and 4). The 1-ethynyl-3-methoxybenzene gave on heating only the corresponding 4-azaphthalide (Table 2), while under MW irradiation, both the 5-exo-dig and the 6-endo-dig products were obtained (Table 4). For the 3-ethynylthiophene, the regioselectivity for the corresponding 4-azaphthalide was achieved with both methods (Tables 2 and 4). Although the yields and the regioselectivity of the reaction generally remained the same with both methods, the use of MW allowed us to obtain the corresponding products in a shorter reaction time. From 4-ethynyl-N,N-dimethylaniline (=4-ethynyl-N,N-dimethylbenzenamine), the corresponding 4-azaphthalide and 5-isocoumarin were only obtained under MW irradiation (Tables 2 and 4). To the best of our knowledge, it is the first time that this kind of tandem reaction was applied to a pyridine derivative giving the corresponding 4-azaphthalides and 5-azaisocoumarins which are easily separated and may both show biological activity.