A Journey through Hemetsberger–Knittel, Leimgruber–Batcho and Bartoli Reactions: Access to Several Hydroxy 5‐ and 6‐Azaindoles

• Published in: Helvetica chimica acta Vol. 105; no. 3
• Main Authors: Radix, Sylvie, Hallé, François, Mahiout, Zahia, Teissonnière, Amélie, Bouchez, Grégoire, Auberger, Ludovic, Barret, Roland, Lomberget, Thierry
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.03.2022; Wiley Subscription Services, Inc
• Subjects: azaindole; Bartoli reaction; Catalysts; Chemistry; Chemistry, Multidisciplinary; cyclization; Hemetsberger-Knittel reaction; heterocycles; Leimgruber-Batcho reaction; Molecular structure; Oxidation; Oxygen; Physical Sciences; Science & Technology; Substitution reactions; SUBSTITUTION; DESIGN; Leimgruber-Batcho reaction; Hemetsberger-Knittel reaction; Bartoli reaction; 5-AZAINDOLES; PYRIDINE; AZAINDOLES; REACTIVITY; N-OXIDES; cyclization; azaindole; heterocycles; AMINATION REACTIONS; INHIBITORS; SELECTIVITY
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.202100211

The preparation of various 5‐ and 6‐azaindoles, heterocyclic structures that are frequently part of molecules in clinical development, and their monohydroxy analogues were described. Different strategies, relying on the de novo pyrrole ring formation, were investigated and, thanks to Hemetsberger–Knittel, Bartoli and Leimgruber–Batcho approaches, 4‐ and 7‐monohydroxy 5‐ and 6‐azaindoles were obtained. The crucial introduction of the oxygen atom was carried out from halogen derivatives, using nucleophilic substitution reactions under basic conditions with or without a copper catalyst. Some preliminary oxidation reactions have shown that it was yet not possible to synthesize the azaquinone indole structure from monohydroxy azaindole, using molecular oxygen in the presence of salcomine as a catalyst.