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Pd(II)-Catalyzed Enantioselective γ‑C(sp3)–H Functionalizations of Free Cyclopropylmethylamines
journal contribution
posted on 2020-07-07, 14:37 authored by Zhe Zhuang, Jin-Quan YuPrized
for their ability to reliably forge stereocenters with precise
regiocontrol from simple and abundant starting materials, substrate-directable
enantioselective reactions are widely used in modern organic synthesis.
As such, enantioselective C(sp3)–H functionalization
reactions directed by innate functional groups could provide new routes
to introduce molecular complexity within the inert hydrocarbon moiety,
but to date this approach has been met with little success. While
free primary aliphatic amines are common, versatile intermediates
in synthesis, they are traditionally unreactive in C(sp3)–H activation reactions. Herein we report the Pd-catalyzed
enantioselective C(sp3)–H functionalization of free
aliphatic amines (cyclopropylmethylamines) enabled by a chiral bidentate
thioether ligand. This ligand’s privileged bidentate coordination
mode and thioether motif favor the generation of the requisite mono(amine)-Pd(II)
intermediate, thus enabling the enantioselective C–H activation
of free amines. The resulting C–Pd(II) species could engage
in either Pd(II)/Pd(IV) or Pd(II)/Pd(0) catalytic cycles, enabling
access to a diverse range of products through (hetero)arylation, carbonylation,
and olefination reactions. Consequently, this versatile reactivity
offers medicinal chemists a general strategy to rapidly prepare and
functionalize biologically relevant amines.