Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch, Microwave, and Continuous Flow Strategies

The renewable macrocyclic musk 3-methylcyclohexadec-6-enone was prepared via macrocyclic olefin metathesis on gram scale using two different protocols: a room temperature batch process which afforded a 57% yield of the desired macrocycle, but required long reaction times (5 d). In contrast, a continuous flow strategy provided a lower yield of 32% of macrocycle, although the short reaction times (150 degrees C, 5 min) improve throughput (1 g/4.8 h). Batch and continuous flow protocols were also tested on other macrocyclizations involving substrates bearing trisubstituted olefins.