Chem. Pharm. Bull. 53(1) 67—71 (2005)

Chart 1) were reported to inhibit colon and lung tumors in a patent literature. Subsequently, we found that 3-aryl b-carbolin-1-ones (2) inhibit the proliferation of HeLa cells with IC50 values in the low micromolar range and that the aromatic substitution on C3 in 2 proved to be essential for their biological activity. To broaden the scope of previous studies, aryl-substituted 2-pyridone-containing derivatives, such as pyrido[2,1-a]isoindole-4-one (3) and 1H-indeno[1,2b]pyridine-2-one (4), were designed as our synthetic targets to make it possible to probe their structure–activity relationships. Some alkaloids having frameworks of 3 and 4 occur in nature, whose analogues were synthesized more often in laboratories for their potent bioactivities as receptor ligands, enzyme inhibitors or anti-tumor agents. Since 3 and 4 are a pair of structural isomers, it is reasonable to expect that they could be prepared from a common precursor, which should have a structure of 6-substituted 2-pyridone allowing a disconnection between methylene and Cring in 3 and 4 (Chart 1). However, neither such precursor nor procedure has been employed for this purpose so far. Since the methods for preparation of 3-unsubstituted 2-pyridone have been well established in recent years, herein we report a novel synthetic route to 3 and 4 as shown in Chart 2. The route starts from an aldol condensation between 2-acetylbenzoic acid (5) and aryl aldehyde (6) to yield chalcone (7), which subsequently undergoes a [3 3] annulation to give 2-(2-pyridon-6-yl)benzoic acid (8). Serving as a common precursor, 8 goes through an intramolecular N-acylation to produce 2-aryl pyrido[2,1a]isoindole-4,6-diones (9), or carries out an intramolecular C-acylation to yield 4-aryl 1-methyl-1H-indeno[1,2-b]pyridine-2,5-diones (11) regioselectively. Results and Discussion Preparation of 2-Aryl Pyrido[2,1-a]isoindole-4,6-diones (9a—j) Following the known procedure, the mixtures of 2-acetylbenzoic acid (5) and aryl aldehydes 6a—j were treated respectively with NaOH in aqueous EtOH at room temperature for 20 h. As shown in Table 1, the corresponding products 2-(3-aryl acryloyl)benzoic acids (7a—j) were yielded conveniently in high yields. However, the aryl aldehydes bearing an electron-withdrawing group, such as o-, m-, January 2005 Chem. Pharm. Bull. 53(1) 67—71 (2005) 67