Flow Synthesis of Muscone‐Macrocycles Using the Eschenmoser Rearrangement as a Key Step

Abstract

ABSTRACT Hydrazone formation followed by Eschenmoser fragmentation are key steps in the synthesis of muscone‐type macrocycles. However, these require long reaction times and typically result in many side reactions leading to complex reaction mixtures requiring extensive separation. In the present work, we report a two‐step flow sequence, which telescopes the hydrazone formation with the subsequent Eschenmoser fragmentation. The use of flow processing allowed for a substantially improved sequence with respect to yield and reduction in reaction time. Overall, access to the exaltone precursor can be achieved in 89% and a space‐time yield of 6.39 g/(L*h), and the corresponding muscone precursor in a yield of 50% and a space‐time yield of 3.81 g/(L*h). These results pave the way to develop efficient industrial processes to muscone and exaltone, respectively.