Byron K Peters1, Kevin X Rodriguez1, Solomon H Reisberg1, Sebastian B Beil1, David P Hickey2, Yu Kawamata1, Michael Collins3, Jeremy Starr3, Longrui Chen4, Sagar Udyavara5, Kevin Klunder2, Timothy J Gorey2, Scott L Anderson2, Matthew Neurock6, Shelley D Minteer7, Phil S Baran8. 1. Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA. 2. Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA. 3. Discovery Sciences, Medicine Design, Pfizer Global Research and Development, Groton, CT 06340, USA. 4. Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, China. 5. Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA. 6. Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA. pbaran@scripps.edu minteer@chem.utah.edu mneurock@umn.edu. 7. Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA. pbaran@scripps.edu minteer@chem.utah.edu mneurock@umn.edu. 8. Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA. pbaran@scripps.edu minteer@chem.utah.edu mneurock@umn.edu.
Abstract
Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.
Reductive electrosynthesis has faced long-standing chn class="Chemical">allenpan>ges inpan> applicationpan>s to pan> class="Chemical">complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology [tris(pyrrolidino)phosphoramide] can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemicalconditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.
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