TY - JOUR
T1 - Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction
AU - Biallas, Phillip
AU - Yamazaki, Ken
AU - Dixon, Darren J.
N1 - Funding Information:
The authors thank Daniel Matheau-Raven, Yaseen Almehmadi, Daniel Rozsar, and Andrew Maitland, as well as former group members (Chemistry Research Laboratory, Department of Chemistry, University of Oxford), for starting material synthesis and enriching discussions. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 892540.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/18
Y1 - 2022/3/18
N2 - An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1-2 mol % of Vaska's complex (IrCl(CO)(PPh3)2), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF2R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N-aryl- and N-heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.
AB - An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1-2 mol % of Vaska's complex (IrCl(CO)(PPh3)2), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF2R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N-aryl- and N-heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.
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U2 - 10.1021/acs.orglett.2c00438
DO - 10.1021/acs.orglett.2c00438
M3 - Article
C2 - 35258311
AN - SCOPUS:85126586990
SN - 1523-7060
VL - 24
SP - 2002
EP - 2007
JO - Organic Letters
JF - Organic Letters
IS - 10
ER -