@misc{9246840,
  abstract     = {{Five-membered heterocycles are a crucial moiety in medicinal chemistry and are widely present in drugs due to its broad biological profile. Disubstituted 1,2,4-triazoles are used in a variety of therapeutic applications such as anti-cancer drugs, although the synthesis can be challenging. Previously, synthetic routes required harsh conditions and small range of reagents, which limits the scope of triazoles. By utilizing metal catalysis skeletal editing of oxadiazoles, triazoles can be synthesized through late-stage modification. The focus of this project is to further assess and develop reaction conditions for skeletal editing of di-substituted 1,2,4-oxadiazoles including FDA-approved drug structures to highlight the utility for medicinal chemists. 
High-Throughput Experimentation (HTE) was utilized to optimize reaction conditions by screening different pre-catalysts, ligands and solvents. The optimized conditions included a less sterically hindered ligand P(4-FPh)3 with a Ni(0) pre-catalyst, Ni(4-CF3stb)3 and a polar aprotic solvent. While DMA and DMSO gave similar conversion, the greener solvent DMSO was further investigated. Scale-up reactions confirmed the observed trends from the screen, although the results also highlighted limitations of using HTE as a predictive optimization tool. 
Kinetic studies revealed that elevated temperatures were essential to efficiently achieve full conversion. Control experiments further demonstrated that both the pre-catalyst and phosphine ligand were necessary for the reaction to proceed, while four equivalents of hydrazine was significant to reach full conversion. From investigating the scope of oxadiazoles, electron-donating substituents generally increased the yield, where nitrogen containing functional groups hampered the reaction due to catalyst poisoning. Additionally, substituted hydrazine reagent was investigated to explore the opportunity to introduce further substitution on the triazole ring, although steric effects impacted the reactivity significantly.
Overall, this project demonstrated the potential of using late-stage skeletal editing for synthesizing 1,2,4-triazoles under relatively mild conditions. It also provides an insight of electronic and steric effects on nickel catalysed reactions for further optimization and expanding the scope further.}},
  author       = {{Jönsson, Ebba}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Skeletal editing of substituted 1,2,4-oxadiazoles}},
  year         = {{2026}},
}