One-Pot Synthesis of 1,4-Bridged Dihydroisoquinoline-3-ones from Isoquinolinium Salts and Cyclic 1,3-Diketones

Bridged isoquinoline derivatives play an important role in various bioactive molecules. The cascade dearomatizative annulation of isoquinolinium salts with bis-nucleophiles is a straightforward strategy to construct bridged isoquinoline skeletons because isoquinolinium ions have two electrophilic sites. However, the reported examples only focused on the synthesis of 1,3-bridged cyclic skeletons. In the previous work, it was reported the first synthesis of 1,4-bridged dihydroisoquinolin-3-ones from isoquinolinium salts and 4-hydroxycoumarins. When cyclic 1,3-diketones were used instead of 4-hydroxycoumarins, isoquinoline-1,3,4(2H)-triones, instead of the expected 1,4-bridged dihydroisoquinolin-3-ones, were unexpectedly yielded. Experimental evidence by high resolution mass spectroscopy supports that the generation of isoquinoline-1,3,4(2H)-triones was initiated via an O-nucleophilic substitution of the cyclic 1,3-diketone, followed by an elimination of the 2-bromo-cyclic 1,3-diketone to give intermediate 4-bromoisoquinolin-3(2H)-one, which subsequently underwent dual hydrolyses and aerobic oxidations. Based on this mechanism, the O-nucleophilic substitution of cyclic 1,3-diketones was successfully inhibited by the addition of a catalytic amount of trifluoromethanesulfonic acid (TfOH). The desired 1,4-bridged dihydroisoquinolin-3-ones were then obtained. This method provides a facile access to 1,4-bridged isoquinoline skeletons under mild reaction conditions (33 examples). The general procedure is as following: under an argon atmosphere, a 5 mL Schlenk flask was charged with isoquinolinium salt 6 (0.2 mmol), phenyliodine(III) diacetate (0.6 mmol), KBr (0.2 mmol), H2O (3.6 mu L), and dry dichloroethane (2 mL). The mixture was continually stirred at room temperature until 6 was consumed as indicated by thin-layer chromatography (TLC). TfOH (5 mu L) and cyclic 1,3-diketone 7 (0.4 mmol) were sequentially added. The reaction mixture was heated at 50 degrees C in the oil bath until the intermediate was consumed as indicated by TLC, then cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (5 mLx3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc as the eluent) to give the 1,4-bridged product 8.

Automated summary

Bridged isoquinoline derivatives are important in bioactive molecules. Previous studies have focused on the synthesis of 1,3-bridged cyclic skeletons, but we report the first synthesis of 1,4-bridged dihydroisoquinolin-3-ones. We successfully inhibited the O-nucleophilic substitution of cyclic 1,3-diketones and obtained the desired product.