Diversity-Oriented Synthesis {1} (DOS) and cascade rearrangement reactions represent powerful strategies that, when combined, can significantly accelerate drug discovery by providing a rapid access to a large variety of complex compounds from simple precursors. The Doyle-Kirmse [2,3]-sigmatropic rearrangement represents a good example of such a strategy, yielding complex compounds with various points of diversification starting from readily available thioethers and diazo compounds.{2} However, despite the high interest for this reaction only few post-Doyle-Kirmse reactions have been developed, especially when an allene is obtained as the |2,3] rearrangement product.{3}

In this context, a modular and divergent approach toward thiophene-derived structures has been developed using flow chemistry involving cascade reactions starting from a unique precursor, obtained through a rhodium-catalysed rearrangement. The corresponding allenes were heated at high temperatures in tert-amyl alcohol to trigger multiple cascade sequences yielding three different benzothiophene derivatives, depending on the conditions used and substrate structures. Overall, this strategy allowed a swift and direct access to complex molecular structures containing S-heterocyclic scaffolds of interest in drug discovery.{4}

References

1. Galloway, W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 80 

2. a) Peng, L.; Zhang, X.; Wang, J. Angew. Chem. Int. Ed. 2007, 46, 1905-1908; b) West, T. H.; Spoehrle, S. S. M.; Kasten, K.; Taylor, J. E.; Smith, A. D. ACS Catal. 2015, 5, 7446−7479.

3. a) Peng, L.; Zhang, X.; Ma, J.; Zhong, Z.; Wang, J. Org. Lett. 2007, 9, 1445-1448; b) Peng, L.; Zhang, X.; Ma, J.; Wang, J. J. Organomet. Chem. 2011, 1, 118-122.

4. a) Keri, R. S.; Chand, K.; Budagumpi, S.; Somappa, S. B.; Patil, S. A.; Nagaraja, B. M. Eur. J. Med. Chem. 2017, 138, 1002-1033; b) Pathania, S.; Narang, R. K.; Rawal, R. K. Eur. J. Med. Chem. 2019, 180, 486-508.