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

Abstract 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. magnified image