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Skeletal editing of substituted 1,2,4-oxadiazoles

Jönsson, Ebba LU (2026) KEMR10 20261
Department of Chemistry
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... (More)
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. (Less)
Popular Abstract (Swedish)
Många läkemedel innehåller heterocykliska strukturer, vilket är ringformade molekyler som består av både kol och andra atomer, så som syre och kväve. En viktig grupp inom heterocykler är 1,2,4-triazoler som förekommer i flera läkemedel tack vare sina biologiska egenskaper. De används för behandlingar av en mängd områden, där bland behandling av till exempel humant immunbristvirus (HIV). Trots dess stora betydelse är syntesen av triazoler ofta komplicerad och kräver flera reaktionssteg, vilket begränsar möjligheten att snabbt utveckla nya läkemedelskandidater.
Detta projekt kommer undersöka en alternativ metod för att framställa 1,2,4-triazoler genom så kallad ”skeletal editing”, metamorfos. Metoden innebär att en atom i en molekyl byts... (More)
Många läkemedel innehåller heterocykliska strukturer, vilket är ringformade molekyler som består av både kol och andra atomer, så som syre och kväve. En viktig grupp inom heterocykler är 1,2,4-triazoler som förekommer i flera läkemedel tack vare sina biologiska egenskaper. De används för behandlingar av en mängd områden, där bland behandling av till exempel humant immunbristvirus (HIV). Trots dess stora betydelse är syntesen av triazoler ofta komplicerad och kräver flera reaktionssteg, vilket begränsar möjligheten att snabbt utveckla nya läkemedelskandidater.
Detta projekt kommer undersöka en alternativ metod för att framställa 1,2,4-triazoler genom så kallad ”skeletal editing”, metamorfos. Metoden innebär att en atom i en molekyl byts ut mot en annan utan att förändra resten av den ursprungliga molekylstrukturen. I detta fall, har en syre atom i en heterocyklisk struktur, kallad 1,2,4-oxadiazole ersättas med en kväveatom för att bilda motsvarande triazol, innehållande tre kväven. Reaktionen utförs med hjälp av nickel, som agerar katalysator vilket är mer hållbart än andra traditionellt använda metaller inom läkemedelssyntes.
För att effektivt optimera reaktionen används ”High-Throughput Experimentation” (HTE), som är en metod där många småskaliga reaktioner kan genomföras parallellt under flera olika förhållanden. På så sätt kan flera katalysatorer, lösningsmedel och ligander testas samtidigt för att identifiera de mest effektiva reaktionsförhållandena. Syftet med detta projekt är att utveckla metoden för att omvandla oxadiazoler till triazoler genom metamorfos samt att optimera reaktionen med hjälp av HTE. Arbetet kommer även fokusera på att undersöka hur olika substituenter påverkar reaktionen och metodens relevans inom läkemedelskemi. (Less)
Please use this url to cite or link to this publication:
author
Jönsson, Ebba LU
supervisor
organization
course
KEMR10 20261
year
type
H2 - Master's Degree (Two Years)
subject
keywords
HTE, Skeletal editing, Oxadiazoles, Triazoles, 1, 2, 4-oxadiazoles, Metal-catalysis, Nickel catalysis, Organic chemistry
language
English
id
9246840
date added to LUP
2026-08-13 10:29:19
date last changed
2026-08-13 10:29:19
@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}},
}