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

Yong Ju Kwon, Won Suk Kim

Research output: Contribution to journalArticlepeer-review

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. (Figure presented.).

Original languageEnglish
Pages (from-to)1440-1449
Number of pages10
JournalAdvanced Synthesis and Catalysis
Volume364
Issue number8
DOIs
StatePublished - 12 Apr 2022

Keywords

  • 2-pyridone derivatives
  • Amrinone
  • Continuous flow chemistry
  • Milrinone
  • Regioselective Suzuki-Miyaura reaction
  • Selective halogen-lithium exchange

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