TY - JOUR
T1 - Radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach
AU - Kim, Seonyoung
AU - Hwang, Keon Ha
AU - Park, Hyeong Gyu
AU - Kwak, Jaesung
AU - Lee, Hyuk
AU - Kim, Hyunwoo
N1 - Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) [NRF-2021R1C1C1004605 and NRF-2021R1A4A3022415]. This work was also supported by the R&D program of the Institutional Research Program of the KRICT (KK2232-10). This study made use of the NMR facility supported by Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (NRF-2020R1A6C101B194). Dedicated to Professor Sukbok Chang on the occasion of his 60th birthday.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Due to its superior ability in controlling pharmaceutical activity, the installation of difluoromethyl (CF2H) functionality into organic molecules has been an area of intensive research. In this context, difluoromethylation of C−C π bonds mediated by a CF2H radical have been pursued as a central strategy to grant access to difluoromethylated hydrocarbons. However, early precedents necessitate the generation of oxidative chemical species that can limit the generality and utility of the reaction. We report here the successful implementation of radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach. Preliminary mechanistic investigations suggest that the key distinction of the present strategy originates from the reconciliation of multiple redox processes under highly reducing electrochemical conditions. The reaction conditions can be chosen based on the electronic properties of the alkenes of interest, highlighting the hydrodifluoromethylation of both unactivated and activated alkenes. Notably, the reaction delivers geminal (bis)difluoromethylated products from alkynes in a single step by consecutive hydrodifluoromethylation, granting access to an underutilized 1,1,3,3-tetrafluoropropan-2-yl functional group. The late-stage hydrodifluoromethylation of densely functionalized pharmaceutical agents is also presented.
AB - Due to its superior ability in controlling pharmaceutical activity, the installation of difluoromethyl (CF2H) functionality into organic molecules has been an area of intensive research. In this context, difluoromethylation of C−C π bonds mediated by a CF2H radical have been pursued as a central strategy to grant access to difluoromethylated hydrocarbons. However, early precedents necessitate the generation of oxidative chemical species that can limit the generality and utility of the reaction. We report here the successful implementation of radical hydrodifluoromethylation of unsaturated C−C bonds via an electroreductively triggered two-pronged approach. Preliminary mechanistic investigations suggest that the key distinction of the present strategy originates from the reconciliation of multiple redox processes under highly reducing electrochemical conditions. The reaction conditions can be chosen based on the electronic properties of the alkenes of interest, highlighting the hydrodifluoromethylation of both unactivated and activated alkenes. Notably, the reaction delivers geminal (bis)difluoromethylated products from alkynes in a single step by consecutive hydrodifluoromethylation, granting access to an underutilized 1,1,3,3-tetrafluoropropan-2-yl functional group. The late-stage hydrodifluoromethylation of densely functionalized pharmaceutical agents is also presented.
UR - http://www.scopus.com/inward/record.url?scp=85135775867&partnerID=8YFLogxK
U2 - 10.1038/s42004-022-00697-1
DO - 10.1038/s42004-022-00697-1
M3 - Article
AN - SCOPUS:85135775867
SN - 2399-3669
VL - 5
JO - Communications Chemistry
JF - Communications Chemistry
IS - 1
M1 - 96
ER -