Mechanistic studies, divergent chemoselectivity, and electrophilic additions for Birch-type reductions

The Birch reduction remains largely non-chemoselective, limiting synthetic applications. Electrophilic additions to radical anion and anion intermediates of electron-rich monoarenes have also been found to be unfeasible. These shortcomings have persisted because the traditional Birch reduction conditions are not tunable. In 2021, we reported our Birch-type method using Li(0), ethylenediamine (EDA), and tBuOH in THF at 0–25 °C. We plan to develop unprecedented chemoselectivity for this Birch-type method to reduce one arene group over other arenes and even alkynes. Our preliminary work has indicated that the reactivity is tunable with various proton sources and amines. We will determine the structure-activity relationships of amines, substrates, and proton sources in order to predict optimal conditions for desired chemoselectivity. Moreover, this project will allow us to develop a silyl Birch-type reduction method to intercept the radical anion and anion intermediates, affording 3,6- disilylated 1,4-cyclohexadienes. The oxidative rearomatization of these products will generate anti-Friedel-Crafts products. The long-term goal of this study is to develop unprecedented chemodivergence and complexity- building strategies through Birch-type reductions to synthesize therapeutic agents. Aim 1 is to determine the roles of amines and proton sources in Birch-type reduction. The traditional Birch reduction proceeds through an electron transfer (ET) step to form a radical anion, followed by a proton transfer (PT) step to generate a dearomatized radical (ET-PT mechanism). We hypothesize that a proton-coupled electron transfer (PCET) involving π-hydrogen bonding, under our reaction conditions, is a viable alternative mechanism as the PCET process can bypass the higher-energy radical anion intermediate. We will investigate the mechanism experimentally and computationally to study the structures of Li-ligand complexes and the roles of proton donors. A mechanistic model from this aim will be used to rationally develop new chemoselective Birch- type reductions. Aim 2 is to develop chemodivergent Birch-type reductions. While chemoselective Birch(-type) reduction has not yet been developed, our preliminary studies have indicated that the judicious choice of proton sources in combination with the use of diamines besides EDA can achieve new chemoselectivity. Specifically, this aim will explore the chemodivergent Birch-type reduction of an arene in the presence of other arenes and alkynes. This aim will also inform Aim 1, which seeks to determine whether more acidic proton sources promote the PCET mechanism, selectively accelerating the reduction of more electron-rich arenes. Aim 3 is to develop Birch-type reduction-silylation with electron-rich monoarenes, previously impossible. This aim will overcome this barrier through the discovery of Li(0)-resistant electrophiles and non-nucleophilic amines to form solvated electrons. We recently determined that N-trimethylsilyl-imidazole met these requirements and plan to develop new synthetic methods, turning the Birch-type reaction into a complexity-building transformation, including a synthetic platform for anti-Friedel-Crafts products. Project Number: 1R01GM160810-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: KAZUNORI KOIDE | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $371,175 | Activity Code: R01 | Study Section: Chemical Synthesis and Biosynthesis Study Section[CSB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367580