Protecting Group-Controlled Regioselective Synthesis for Unsymmetrical 3,5-Disubstituted Pyridones

Protecting group-controlled regioselective functionalization of 3,5-dibromo-2-pyridones has been studied for preparation of unsymmetrical 3,5-disubstituted 2-pyridones. A bulky di-tert-butyl(isobutyl)silyl (BIBS) group was utilized for C5 regioselective arylation in Suzuki-Miyaura reactions. Meanwhile, the p-toluenesulfonyl (Ts) group was used to maximize C3 selective halogen-lithium exchange employing flow chemistry. Most of the reactions proceeded well, with yields of 76 to 95% and excellent regioselectivity. A one-pot synthesis of unsymmetrical 3,5-diaryl-2-pyridones starting from 3,5-dibromo-2-silyloxypyridine was conducted to demonstrate the practical convenience. Further functionalization onto the remaining bromine group, such as transition metal-catalyzed C-C and C-N bond-forming reactions and retro-Brook rearrangement for C-Si bond formation, was accomplished for synthesis of biologically relevant 3,5-disubstituted 2-pyridones. Finally, amrinone and milrinone, commonly used for congestive heart failure, were synthesized in three steps from 3,5-dibromo-2-pyridones in 41% and 56% overall yields, respectively.

Automated summary

This study investigated the regioselective functionalization of protected compounds to synthesize unsymmetrical molecules. Different protecting groups were used to achieve selective functionalization at specific positions, leading to the synthesis of biologically active compounds.