Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

Utilising the intrinsic fluorescence of pomalidomide for imaging applications.

Optimisation of protein degraders requires balancing multiple factors including potency, cell permeability and solubility. Here we show that the fluorescence of pomalidomide can be used in high-throughput screening assays to rapidly assess cellular penetration of degrader candidates. In addition, this technique can be paired with endocytosis inhibitors to gain insight into potential mechanisms of candidates entering a target cell. A model library of pomalidomide conjugates was synthesised and evaluated using high-throughput fluorescence microscopy. This technique based on intrinsic fluorescence can be used to guide rational design of pomalidomide conjugates without the need for additional labels or tags.

Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles.

Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired product in 4 steps from commercially available starting materials.