Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Given the importance and beneficial
characteristics of decorated
azetidines in medicinal chemistry, efficient strategies for their
synthesis are highly sought after. Herein, we report a facile synthesis
of the elusive all-carbon quaternary-center-bearing azetidines. By
adopting a well-orchestrated polar-radical relay strategy, ring strain
release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB)
can be harnessed for nickel-catalyzed Suzuki Csp2–Csp3 cross-coupling with commercially available boronic acids
in broad scope (>50 examples), excellent functional group tolerance,
and gram-scale utility. Preliminary mechanistic studies provided insights
into the underlying mechanism, wherein the ring opening of ABB with
a catalytic quantity of bromide accounts for the conversion of ABB
into a redox-active azetidine, which subsequently engages in the cross-coupling
reaction through a radical pathway. The synergistic bromide and nickel
catalysis could intriguingly be derived from a single nickel source
(NiBr2). Application of the method to modify natural products,
biologically relevant molecules, and pharmaceuticals has been successfully
achieved as well as the synthesis of melanocortin-1 receptor (MC-1R)
agonist and vesicular acetylcholine transporter (VAChT) inhibitor
analogues through bioisosteric replacements of piperidine with azetidine
moieties, highlighting the potential of the method in drug optimization
studies. Aside from the synthesis of azetidines, we demonstrate the
ancillary utility of our nickel catalytic system toward the restricted
Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic
acids to construct all-carbon quaternary centers.