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Synthesis of Indazoles via N-N Bond-Forming Oxidative Cyclization from 2-Aminomethyl-phenylamines

Anna Schoeggl Toledano, Jacqueline Bitai, David Covini, Jale Karolyi-Oezguer, Christian Dank, Helmut Berger, Andreas Gollner*

*Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria, Email: a_gollnerhotmail.com

A. S. Toledano, J. Bitai, D. Covini, J. Karolyi-Oezguer, C. Dank, H. Berger, A. Gollner, Org. Lett., 2024, 26, 1229-1232.

DOI: 10.1021/acs.orglett.4c00036


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Abstract

A N-N bond-forming oxidative cyclization enables the synthesis of all three tautomeric forms of indazoles from readily available 2-aminomethyl-phenylamines. The method selectively gives access to various 2-substituted 2H-indazoles which are frequently used in drug design, and to less studied 3H-indazoles.


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proposed mechanism



Details

The document details a method for synthesizing indazoles from 2-aminomethyl-phenylamines via N−N bond-forming oxidative cyclization. This method, inspired by previous observations by N. Coskun et al., allows for the selective formation of various 2-substituted 2H-indazoles, 1H-indazoles, and 3-disubstituted 3H-indazoles, which are significant in drug design. The researchers optimized the reaction conditions, finding that using (NH4)2MoO4 and H2O2 at room temperature yielded the best results, achieving up to 89% yield. The method tolerates various substituents, including alkyl, halogen, and methoxy groups, although electron-withdrawing groups generally result in lower yields. The study also explored the synthesis of 3H-indazoles, achieving a 94% yield for 3,3-dimethyl-3H-indazole. The proposed mechanism involves the oxidation of the anilinic nitrogen to a nitroso compound, followed by nucleophilic addition and cyclization. This new protocol offers a valuable and broadly applicable method for indazole synthesis, complementing existing reductive N−N bond-forming methods. The findings are supported by experimental procedures, characterization data, and NMR spectra available in the supporting information. The study was conducted by researchers from Boehringer Ingelheim RCV GmbH & Co KG and published in Organic Letters in 2024.


General procedure for indazole synthesis:

To a solution of the aniline substrate (40 to 100 mg; 1.00 equiv., as free base or salt) in MeOH (3 ml) at 0 °C were added ammonium molybdate (1.00 equiv.) and aqueous H2O2 30% (10.00 equiv.). The mixture was stirred for a minimum of 1 h, or until the reaction was completed (1-24 h) at RT which was monitored by HPLC/MS. After completion, the reaction mixture was cooled again to 0 °C and quenched with aq. 10% Na2S2O3 solution (2 ml). The mixture was diluted with water and neutralized with sat. aq. NaHCO3 solution. The mixture was extracted with DCM (3 x). The combined organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified using preparative chromatography. The yields are preparative yields after chromatography.


Key Words

1H-indazoles, 2H-indazoles, hydrogen peroxide


ID: J54-Y2024