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Naturally occurring benzoxanthenones which belongs to the vast family of lignans, are promising biologically relevant targets. They are biosynthetically produced by the oxidative dimerization of 2-propenyl phenols. In this manuscript, we disclose a powerful automated flow-based strategy for identifying and optimizing a cobalt-catalyzed oxidizing system for the bio-inspired dimerization of 2-propenyl phenols. We designed a reconfigurable flow reactor associating on-line monitoring and process-control instrumentation. Our machine was first configured as an automated screening platform to evaluate a matrix of 4 catalysts (plus the blank) and 5 oxidant (plus the blank) at two different temperatures, resulting in an array of 50 reactions. The automated screening was conducted on micromole scale at a rate of one fully characterized reaction every 26 minutes. After having identified the most promising cobaltcatalyzed oxidizing system, the automated screening platform was straightforwardly reconfigured to an autonomous self-optimizing flow reactor by implementation of an optimization algorithm in the closed-loop system. The optimization campaign allowed the determination of very effective experimental conditions in a limited number of experiments which allowed to prepare natural products carpanone and polemannone B as well as synthetic analogues.

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The hazardous nature of molecular oxygen can be mitigated with the use of flow reactors of small size which, in turn, accelerate the gas to liquid mass transfer rate. In this contribution, we describe a reconfigurable automated flow platform integrating an online HPLC monitoring for the cobalt-catalyzed aerobic oxidative dimerization of desmethoxycarpacine 1 to carpanone 2. The flow platform was configured for aerobic oxidation under either a gas-liquid segmented or tube-in-tube strategy. An extensive optimization study concluded that the tubein-tube device was penalized by the use of expensive and fragile Teflon AF-2400 tubing while the gas-liquid segmented setup featured higher yields (62% vs. 48%), faster reaction rates (5 min vs. 20 minutes) and better robustness.