Trifluoroacetic acid mediated synthesis of 2,3,4,9-tetrahydro-1H-carbazole via an in-situ generated hydrazone

Indoles are aromatic heterocyclic organic compounds that contain a 5-membered pyrrole, which occur naturally in the form of tryptophan, the essential amino acid and metabolic precursor to serotonin and melatonin and find widespread inclusion in synthetically derived biologically active molecules such as the non-steroidal anti-inflammatory indomethacin and antimigraine agent sumatripan. Owing to the anti-cancer, inhibition of blood platelet aggregation, antifungal and osteoporosis therapeutic activity, significant research has been centred om the development of efficient methods for the synthesis and derivatisation of the indole core motif includingthe Leimgruber-Batcho, Fischer, Bartoli, Mischler-Möhlau and Nenitzescu indole syntheses.
With the Fischer indolisation representing one of the oldest and most reliable routes to 2-/3-substitiuted indoles, the acid-promoted technique was investigated under flow conditions, as a means of identifying if there are any advantages associated with this mode of operation.
With the ability to readily pressurise micro reactors utilising Labtrix® Start Flex (20 bar), we are able to employ volatile reaction solvents and reagents at elevated reaction temperatures (up to 195°C) allowing the reaction to be assessed in MeCN. With this in mind, the TFA promoted Fischer Indole synthesis of 2,3,4,9-tetradydro-1H-carbazole was evaluated under continuous flow, using both a pre-prepared and an in-situ generated hydrazone.