Overcoming limitations in decarboxylative arylation via Ag-Ni electrocatalysis TeYu Chen 2 , Maximilian D. Palkowitz 7 , Gabriele Laudadio 7 , Simon Kolb 7 , Jin Choi 7 , Martins S. Oderinde 1 , Tamara El- Hayek Ewing 7 , Philippe Bolduc 2 , Hao Zheng 1 , Peter Cheng 1 , Benxiang Zhang 7 , Michael Mandler 1 , Jeremy M. Richter 1 , Michael Collins 6 , Ryan Schioldager 6 , Murali Dhar 1 , Benjamin Vokits 1 , Yeheng Zhu 1 , Pierre-Georges Echeverria 5 , Michael Poss 1 , Scott Shaw 1 , Sebastian Clementson 4 , The radical applications in organic synthesis have a rich history, 1,2 , and the modern manifestation of radical retrosynthesis has the potential to transform conventional logic, enable dramatically simplified routes to seemingly trivial structures, and prevent the need for otherwise arduous multistep synthetic sequences that are wedded to polar disconnections. 3,4 Such approaches significantly impact medicinal chemistry efforts, where practical and modular access to a broad range of analogs is critical for exploring key biological hypotheses. 5 A practicable protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is hereby reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined surprisingly simply: open to the air, technical grade solvents, an inexpensive ligand, and nickel source, sub-stoichiometric silver nitrate, proceeding at room temperature in about two hours with a simple commercial potentiostat. This practical method to overcome the limitations of decarboxylative arylation features a broad scope amongst challenging real-world substrates, extreme operational simplicity, and a versatile scale regime ranging from parallel mg-based synthesis to decagram recirculating flow. Most importantly, benchmarking with state-of-the-art methods puts the results into context for achieving the same transformation and is conducted in collaboration with a diverse array of practitioners across five different pharmaceutical partners (the typical end user of this method).Manuscript under review by J. Am. Chem. Soc. References 1. Romero, K. J.; Galliher, M. S.; Pratt, D. A.; Stephenson, C. R. J., Radicals in natural product synthesis. Chemical Society Reviews 2018, 47 (21), 7851-7866. 2. Jasperse, C. P.; Curran, D. P.; Fevig, T. L., Radical reactions in natural product synthesis. Chemical Reviews 1991, 91 (6), 1237-1286. 3. Smith, J. M.; Harwood, S. J.; Baran, P. S., Radical Retrosynthesis. Accounts of Chemical Research 2018, 51 (8), 1807- 1817. 4. Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S., Radicals: Reactive Intermediates with Translational Potential. Journal of the American Chemical Society 2016, 138 (39), 12692- 12714. 5. Smith, J. M.; Dixon, J. A.; deGruyter, J. N.; Baran, P. S., Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery. Journal of Medicinal Chemistry 201, 62 (5), 2256-2264. Nadia Nasser Petersen 4 , Pavel Mykhailiuk 3 and Phil S. Baran 1 BMS, 2 Biogen, 3 Enamine, 4 LEO Pharma, 5 Minakem, 6 Pfizer, 7 Scripps
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