Iridium(I)-Catalyzedα‑C(sp3)–H Alkylation of SaturatedAzacycles
2020
Saturated azacycles
are commonly encountered in bioactive compounds
and approved therapeutic agents. The development of methods for functionalization
of the α-methylene C–H bonds of these highly privileged
building blocks is of great importance, especially in drug discovery.
While much effort has been dedicated toward this goal by using a directed
C–H activation approach, the development of directing groups
that are both general as well as practical remains a significant challenge. Herein, the design and development
of novel amidoxime directing groups is described for Ir(I)-catalyzed
α-C(sp3)–H alkylation of saturated azacycles
using readily available olefins as coupling partners. This protocol
extends the scope of saturated azacycles to piperidines, azepane,
and tetrahydroisoquinoline that are incompatible with our previously
reported directing group. A variety of olefin coupling partners, including
previously unreactive disubstituted terminal olefins and internal
olefins, are compatible with this transformation. The selectivity
for a branched α-C(sp3)-alkylation product is also
observed for the first time when acrylate is used as the reaction
partner. The development of practical, one-step installation and removal
protocols further adds to the utility of amidoxime directing groups.
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