At first glance this may seem like an extension to the installments (there are 5) on microwave methods toward the construction of indoles — but it has a bit more of a story than that. I found a minireview out of Northeastern University by Graham Jones and Nadeesha Ranasinghe that I posted on my flow chemistry resource blog — mainly because the journal article emphasis both continuous flow, microwave and the combination thereof. So some of the introduction and historical perspective can be found there. For this I will stick closer to the theme: microwave methods and show a few more examples that one can dig into off-line.

Although it would be the place to start – the Fisher Indole synthesis is one of the most published methods around and there are some examples using microwave to speed up the reaction — I think this is one that can be done in a large microwave batch reactor easily. But the emphasis here is on indoles, and their rightful place in the top 2-3 of the heterocyles researched in drug discovery.

The first example shows a movement away from solvent into a solvent-free approach using p-TSA and several enolizable ketones from Horaguchi in J Het Chem 2011.

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In keeping with a similar theme, Barluenga reported (Chem Eur J 2010) a heterogeneous Pd-sequential coupling of arenes to a number of imine starting materials in aqueous media to reduce reaction times from 24-48 hours to 30-60 min in high yield (no organic solvents and sequential steps).

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Moving over to drug targets, Thirupathi Reddy reported (Bioorg Med Chem 2010) an approach to marine natural product mimics of aplysinopsin, with the preparation of indole-2-imidazoline-2,4-diones under microwave heating and a comparison to conventional heating.

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A multi-step combinatorial approach to a library of compounds was reported with indole-2-carboxylic acid, ethyl pyruvate with amines and isocyanides as a four component, 2-step Ugi and subsequent cyclization in TL 2009.

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An approach to antitubercular activity was reported in a library of compounds made in a modified Fisher indole synthesis to 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles using microwave heating for 3-6 min at 90C (Biorg Med Chem Lett 2009).

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And we can end on an approach I mentioned in my 4th installment of microwave indole construction, Peter Wipf’s usage of an intramolecular diels alder with a pendant amino furan (IMDAF) as a tandem diels-alder rearrangement sequence to provide an array of substituted indoles under microwave heating (JOC 2013).

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And for those us who enjoy the arrows, you can see the release of H2O in the cycloadduct to form the indole.

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Several examples have been shown where microwave technology has been a key step in the formation of indoles as targets in basic research and in the formation of medicinally important compounds, either in the form of analog libraries or mimics to compounds hitting targets of interest. This certainly indicates to me that we have a number of current approaches to indole targets and microwave synthesis can be used as a tool to rapidly provide compounds for testing or quickly decide the relevance of a target class. I end by pointing back to the minireview as a source of information and inspiration. Happy Reading!

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