TY - JOUR
T1 - Protecting Group-Controlled Regioselective Synthesis for Unsymmetrical 3,5-Disubstituted Pyridones
AU - Kwon, Yong Ju
AU - Kim, Won Suk
N1 - Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (NRF‐2019M1A2A2072417, NRF‐2021R1H1A2014525, NRF‐2021R1A6A1A10039823).
Publisher Copyright:
© 2022 Wiley-VCH GmbH.
PY - 2022/4/12
Y1 - 2022/4/12
N2 - 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.).
AB - 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.).
KW - 2-pyridone derivatives
KW - Amrinone
KW - Continuous flow chemistry
KW - Milrinone
KW - Regioselective Suzuki-Miyaura reaction
KW - Selective halogen-lithium exchange
UR - http://www.scopus.com/inward/record.url?scp=85126542258&partnerID=8YFLogxK
U2 - 10.1002/adsc.202101514
DO - 10.1002/adsc.202101514
M3 - Article
AN - SCOPUS:85126542258
SN - 1615-4150
VL - 364
SP - 1440
EP - 1449
JO - Advanced Synthesis and Catalysis
JF - Advanced Synthesis and Catalysis
IS - 8
ER -