The indole ring is built into the essential amino acid tryptophan which is a key constituent of most proteins and is the building block of widely distributed tryptamines and other indole containing secondary metabolites. For this and other reasons indole moiety is regarded as a 'privileged scaffold' and plays an important role in the discovery of new leads in medicinal chemistry. Although numerous methods have been devised to synthesize substituted indoles, new methodologies have yet to emerge to address the issues of obtaining difficult substitution patterns. The Hemetsberger-Knittel (HK) indole synthesis is a popular method used to obtain indole-2-carboxylates that involves Knoevenagel condensation of an aryl aldehyde with an azidoacetate and subsequent thermal cyclization of the resulting azidocinnamate to afford indole-2-carboxylates. We are investigating the HK reaction using microwave and microreactor technology to make differentially substituted indoles and other heterocycles as important pharmaceutical building blocks. We have successfully adopted the HK route to synthesize 2-unsbustitued indoles and derivatives using microwave, flow and hybrid methodologies and have illustrated a route to analogs of the antitumor agent PLX-4032. Moreover, the versatility of the HK substrates is demonstrated in bioconjugation reactions via Huisgen type [3+2] cycloaddition chemistry, followed by ring closure and fluorine labeling to form peptoid adducts.

Microwave and flow assisted synthesis of medicinally relevant indoles, N-heterocyles and peptide adducts using Hemetsberger-Knittel route

246th National Meeting (2013)

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