General methods for the synthesis and late-stage diversification of 2,4-substituted 7-azaindoles

• Published in: Tetrahedron letters Vol. 57; no. 42; pp. 4718 - 4722
• Main Authors: Varnes, Jeffrey G., McGuire, Thomas, Meadows, Rebecca E., Barlaam, Bernard, Clark, Jemma, Cook, Calum R., Davison, Gemma, Dishington, Allan, De Savi, Chris, Donald, Craig, Grebe, Tyler, Hande, Sudhir, Hawkins, Janet, Hird, Alexander W., Holmes, Jane, Lister, Andrew, Lucas, Simon, Moore, Jane, Moore, Esther, Patel, Anil, Pike, Kurt G., Roberts, Bryan, Stark, Andrew, Stead, Darren, Thakur, Kumar, Turner, Paul, Vasbinder, Melissa, Yang, Bin
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 19-10-2016
• Subjects: 1H-Pyrrolo[2,3-b]pyridine; 2-(Piperidin-4-yl)-7-azaindole; 7-Azaindole; Miyaura borylation; Suzuki–Miyaura reaction; 1H-Pyrrolo[2,3-b]pyridine; 7-Azaindole; 2-(Piperidin-4-yl)-7-azaindole; Miyaura borylation; Suzuki–Miyaura reaction
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2016.09.029

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•Methods for preparing 2,4-substituted 7-azaindoles are compared.•An iterative catalyst screen was used to optimize borylation conditions.•A scalable synthesis of 4-bromo-2-(piperidin-4-yl)-7-azaindole is described.
As part of a medicinal chemistry program, we adapted known synthetic methods for the late-stage diversification of 2,4-substituted 7-azaindoles. The strengths and weaknesses of these strategies are discussed. In the course of this work, three optimized conditions were identified from an iterative catalyst screen for the conversion of Boc-protected 4-chloro-2-(piperidin-4-yl)-7-azaindole to the corresponding pinacol borate ester. Additionally, a scalable route to previously unreported Boc-protected 4-bromo-2-(piperidin-4-yl)-7-azaindole and efficient conversion to the corresponding pinacol borate ester in 72% isolated yield are also disclosed.