Site-selective transformation of benzylic C−H bonds into diverse functional groups is achieved via Cu-catalyzed C−H fluorination with N-fluorobenzenesulfonimide (NFSI), followed by substitution of the resulting fluoride with various nucleophiles. The benzyl fluorides generated in these reactions are reactive electrophiles in the presence of hydrogen-bond donors or Lewis acids, allowing them to be used without isolation in C−O,
A copper catalyst
in combination with N-fluorobenzenesulfonimide
(NFSI) has been reported to functionalize benzylic C–H bonds
to the corresponding benzylic sulfonimides via C–N coupling.
Here, we reported a closely related Cu-catalyzed method with NFSI
that instead leads to C–F coupling. This switch in selectivity
arises from changes to the reaction conditions (Cu/ligand ratio, temperature,
addition of base) and further benefits from inclusion of MeB(OH)2 in the reaction. MeB(OH)2 is shown to serve as
a “redox buffer” in the reaction, responsible for rescuing
inactive Cu(II) for continued promotion of fluorination reactivity.
Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N−H/C−H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N−H heterocycles with substrates bearing (hetero)benzylic C−H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N−H heterocycle and benzylic C−H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.
Copper-catalyzed radical-relay reactions provide a versatile
strategy
for selective C–H functionalization; however, reactions with
peroxide-based oxidants often require excess C–H substrate.
Here, we report a photochemical strategy to overcome this limitation
by using a Cu/2,2′-biquinoline catalyst that supports benzylic
C–H esterification with limiting C–H substrate. Mechanistic
studies indicate that blue-light irradiation promotes carboxylate-to-copper
charge transfer, reducing resting-state CuII to CuI, which activates the peroxide to generate an alkoxyl radical
hydrogen-atom-transfer species. This “photochemical redox buffering”
introduces a unique strategy to sustain the activity of Cu catalysts
in radical-relay reactions.
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