Weix Group

Congratulations Dr. Lauren Ehehalt on a fantastic thesis defense! We're so excited to see all your future work at Eastman Chemical Co.! 🥳🎉🎓

Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

Another #OPRD asap to highlight is this one from #PfizerChemistry showing a kilo scale route to complex API with all kinds of cool - small hets (pyrazoles!) cyBu, Weix cross electrophile coupling, key synthesis improvements driven by reaction safety…so much to discover in this one #ChemSky

Translation of Nickel-Catalyzed C(sp2)–C(sp3) Cross-Electrophile Coupling to Non-Amide Solvents The cross-electrophile coupling of organobromides is widely utilized in organic synthesis but generally requires undesirable amide solvents (e.g., DMF, DMA, and NMP). We report that the combination of...

Our work on the translation of Nickel-Catalyzed C(sp2)–C(sp3) Cross-Electrophile Coupling to Non-Amide Solvents is now online in Org. Lett.! @pubs.acs.org Congrats to Brett, Julianna, Michelle, and wonderful collaborators at @novartis.bsky.social Check it out! doi.org/10.1021/acs.orglett.5c01011

Congrats to Julianna for receiving an Outstanding Chemistry Teaching Assistant Award for your work with Chem 636 and the NMR facilities! Well deserved! 🎉

Cross-Electrophile Coupling to Form Sterically Hindered C(sp2)–C(sp3) Bonds: Ni and Co Afford Complementary Reactivity The formation of sterically hindered C(sp2)–C(sp3) bonds could be a useful synthetic tool but has been understudied in cross-electrophile coupling. Here, we report two methods that couple secondary alkyl bromides with aryl halides that contain sterically hindered C–X bonds: 1) ortho-substituted aryl bromides with nickel catalysts and 2) di-ortho-substituted aryl iodides with cobalt catalysts. Stoichiometric experiments and deuterium labeling studies show that 1) [Co] is better than [Ni] for oxidative addition of di-ortho-substituted Ar–I and 2) [Co] is better than [Ni] for radical capture/reductive elimination steps with di-ortho-substituted arenes. For both metals, Ar–H side products observed in reactions with low-yielding di-ortho-substituted aryl iodides appear to arise from Ar• formation and hydrogen-atom transfer from the solvent. While the origins of the differences in scope are not yet understood, these studies demonstrate a previously unknown complementarity between nickel and cobalt in cross-electrophile coupling.

Our work on Ni- and Co-catalyzed Cross-Electrophile Coupling to Form Sterically Hindered C(sp2)–C(sp3) Bonds is now online at J.A.C.S.! @pubs.acs.org Congrats to Tianrui, Anthony, Kasturi, and our collaborators Madeline (@kozlowskigroup.bsky.social) and @novartis.bsky.social doi.org/10.1021/jacs...

Our work on in-situ generation of alkyl chlorides using Ghosez’s reagent and coupling with aryl chlorides is now online at Org. Lett. Congrats Ben! @pubs.acs.org Check it out! doi.org/10.1021/acs.orglett.4c04676 #chemsky

Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Alkyl Halides: Mechanism-Informed Design of More General Conditions Aryl triflates make up a class of aryl electrophiles that are available in a single step from the corresponding phenol. Despite the known reactivity of nickel complexes for aryl C–O bond activation of phenol derivatives, nickel-catalyzed cross-electrophile coupling using aryl triflates has proven challenging. Herein, we report a method to form C(sp2)–C(sp3) bonds by coupling aryl triflates with alkyl bromides and chlorides using phenanthroline (phen) or pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN)-ligated nickel catalysts. The scope of the reaction is demonstrated with 38 examples (61 ± 14% average yield). Mechanistic studies provide a rationale for the conditions used and a roadmap for further applications of cross-electrophile coupling. First, the rate of alkyl radical generation is controlled by maintaining the majority of alkyl halide as the alkyl chloride, which is unreactive, and utilizing a dynamic halide exchange process to adjust the concentration of reactive alkyl bromide or iodide. Second, the challenge of using electron-rich aryl triflates appears to be due to off-cycle transmetalation to form unproductive aryl zinc reagents. The optimal PyBCamCN ligand together with LiCl avoids this deleterious transmetalation step.

Our work on Ni-Catalyzed Cross-Electrophile Coupling of Aryl Triflates with Alkyl Halides is now online at JACS @pubs.acs.org. Congrats to Seoyoung, Matt, Ben, and Daniel! doi.org/10.1021/jacs.4c14769

Welcome to Abi! We're excited to see all your awesome work in the group! 🥳✌️

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous liga...

4a/ #12DaysofPapers #ChemSky. This 2024 favorite is a #PfizerChemistry collab with the Weix (Wisconsin) and Sigman (Utah) labs towards computationally designed ligands for Ni-catalyzed cross electrophile coupling. Improvements in selectivity up to 300% #ChemCollabs

We're incredibly proud to say that our review of Cross-Electrophile Coupling: Principles, Methods, and Applications in Synthesis is now online and open access at Chem Rev! Congrats to the team for this labor of love (and data!) pubs.acs.org/doi/10.1021/...