Demonstration of a Multikilogram-Scale Birch Reduction and Evaluation of Alternative Synthetic Routes to a Ketalized Cyclohexene Derivative
Adam E. Goetz, Joel T. Arcari, Scott W. Bagley, Robert W. Hicklin, Liangxue Jin, Zuxi Jin, Xinnan Li, Zhiqing Liu, J. Christopher McWilliams, Mihir D. Parikh, Tyler J. Potter, William Smith, Lijie Sun, John I. Trujillo, Pan Wang, Xin Zhao
Abstract
We report the successful manufacture of several >50 kg batches of a key intermediate via a Birch reduction that utilized liquified ammonia as well as lithium metal. With an eye toward continued scalability, we explored two alternative procedures to obtain the same intermediate: (1) an electrochemical reduction performed using continuous flow technology and (2) a ketalization approach that proceeds with olefin migration to give the target molecule. Both options were explored in detail and then demonstrated on a ≥100 g scale to assess the overall robustness. Ultimately, the olefin migration route appeared to be more promising and was demonstrated on a >1 kg scale to show the potential to avoid several unattractive aspects of the Birch reduction for future scale-up needs.