Demonstration of a Multikilogram-Scale Birch Reduction and Evaluation of Alternative Synthetic Routes to a Ketalized Cyclohexene Derivative

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.