A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry

Abstract

Photoredox-transition metal dual catalysis provides a unique platform for constructing sp 3 -rich chemical matter. Here, we report a nickel-catalyzed cross-coupling of commercially available or easily prepared redox-active NHP azetidine-2carboxylates with commercially available heteroaryl iodides to yield 2-heteroaryl azetidines. This "off-the-shelf" approach yielded products amenable to diversification giving access to novel saturated heterocyclic scaffolds useful for medicinal chemistry programs. An alternative mechanism for Hantzsch ester within nickel-catalyzed cross-coupling of heteroaryl halides and α-amino radicals is also presented.

Decarboxylative, Radical C–C Bond Formation with Alkyl or Aryl Carboxylic Acids: Recent Advances

“…Using a zinc-packed bed, the reaction could also be scaled up in continuous flow with a 45 min residence time (Scheme 5 ). Similar decarboxylative XEC reactions with strained carbo- or heterocycles have also recently been described, including for cyclopropylamine 32 and azetidine 33 NHPI esters, greatly expanding the 3D chemical space that is accessible using XEC reactions.…”

Nickel‐Catalysed Decarboxylative Coupling Reactions – An Overview

“…Brewster, Hinklin and co-workers developed a method to synthesize 2-heteroaryl azetidines 64 by Ni-catalysed decarboxylative coupling reaction. [39] Under the optimized condition of 10 mol % Ni-catalyst, 12 mol % of bipyridine based ligand, NaHCO 3 as base and redox active Hantzsch ester under room temperature and 395 nm light irradiation, azetidine-2-N-hydroxyphthalimide esters (NHP) 63 and heteroaryl iodides 37 were effectively coupled to yield 2-heteroaryl azetidines 64 (Scheme 16). Differently substituted heteroaryl iodides including pyridine, pyrimidine and quinoline were found effective under the reaction conditions.…”