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Published on: July 17, 2020
Indazoles: regioselective protection and subsequent amine coupling reactions
David J Slade1, Nicholas F Pelz, Wanda Bodnar
1Department of Chemistry, Inspire Pharmaceuticals, Inc., 4222 Emperor Boulevard, Durham, North Carolina 27713, USA. drslade@gmail.com
The Journal of Organic Chemistry
|July 22, 2009
Summary
Protecting indazoles selectively is key. Mild acid conditions favor N-2 protection, while thermodynamic control yields N-1 protected indazoles, enabling further derivatization via Buchwald reactions.
Area of Science:
- Organic Chemistry
- Heterocyclic Chemistry
Background:
- Indazoles are important heterocyclic compounds with diverse applications.
- Unselective N-protection of indazoles complicates synthetic strategies.
- Controlling regioselectivity in indazole functionalization is crucial for developing novel derivatives.
Purpose of the Study:
- To investigate regioselective protection strategies for indazoles under varying conditions.
- To explore the utility of protected indazoles in cross-coupling reactions.
- To synthesize novel indazole derivatives through Buchwald amination.
Main Methods:
- Treatment of indazoles with different acidic and basic conditions to achieve regioselective N-protection.
- Utilizing protected 5-bromoindazoles in palladium-catalyzed Buchwald-Hartwig amination reactions.
- Characterization of synthesized indazole derivatives using spectroscopic techniques.
Main Results:
- Mild acidic conditions regioselectively protect indazoles at the N-2 position.
- Thermodynamic conditions favor regioselective protection at the N-1 position.
- Protected 5-bromoindazoles successfully undergo Buchwald reactions with various amines, yielding novel derivatives.
Conclusions:
- Regioselective N-protection of indazoles can be achieved by controlling reaction conditions (acidic vs. thermodynamic).
- This controlled protection strategy is applicable to a range of substituted indazoles.
- The synthesized novel indazole derivatives hold potential for further chemical exploration and application.
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