Recently we disclosed a scalable and efficient synthesis of the 6-azaindole scaffold from the trifluoroacetamide of 3-amino-4-methyl pyridine (Scheme 1, A). In this research, we report on our determination of the scope and limitation of the recent transformation (Scheme 1, B) towards pyridine and electrophilic components. Firstly, we modified the procedure to a one-pot option starting from the corresponding free amine. The substrate screen of the pyridine components using TFAA as model electrophile allow us to divide these components into three groups. In the first group (Scheme 1, C1) are 4-methylpyridines bearing in one β-position NH2, OH or NHMe group and substituents in another β-position as well as 3-amino-4-methyl quinoline. All these substrates give corresponding fused pyrrolo-/furano- derivatives in preparative yields. In the second group (Scheme 1, C2) corresponding pyridines bearing α-substituents or strong σ-acceptors in the β-position have been proved. In this case, the reaction stopped on the step of the corresponding trifluoroacetamide. The shifting from pyridine to diazine derivatives (Scheme 1, C3) leads to an undefined mixture of products using standard reaction protocol. Among electrophilic components DFAA, TCAA and Vilsmeier-Haack reagent (VHR) were tested. DFAA and VHR give results similar to TFAA. Meanwhile, TCAA using afford the double NH2 / Me trichloroacylation without expected cyclization. X-ray investigations proved the structure of key final products and intermediates. The superposition of the obtained results provided an understanding of the cyclization mechanism and gave the prediction ability of the substrates' activity.

Synthesis of 6-azaindoles via electrophilic [4+1]-cyclization of 3-amino-4-methyl pyridines: Scope and limitations

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