doi: 10.1021/acs.orglett.9b00111. Epub 2019 Jan 31.
Replacement of Stoichiometric DDQ with a Low Potential o-Quinone Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermediates
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- PMID:30702297
- PMCID: PMC6413530
- DOI: 10.1021/acs.orglett.9b00111
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Replacement of Stoichiometric DDQ with a Low Potential o-Quinone Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermediates
Bao Li et al. Org Lett..
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Abstract
A transition-metal/quinone complex, [Ru(phd)3]2+ (phd = 1,10-phenanthroline-5,6-dione), is shown to be effective for aerobic dehydrogenation of 3° indolines to the corresponding indoles. The results show how low potential quinones may be tailored to provide a catalytic alternative to stoichiometric DDQ, due to their ability to mediate efficient substrate dehydrogenation while also being compatible with facile reoxidation by O2. The utility of the method is demonstrated in the synthesis of key intermediates to pharmaceutically important molecules.
Conflict of interest statement
The authors declare no competing financial interest.
Figures
Conditions (A): 1.0 mmol scale, 2.5 mol % [Ru(phd)3](PF6)2, 1 mol % Bu4NI, MeCN (0.1 M), O2, room temperature. Conditions (B): 1.0 mmol scale, 2.5 mol % [Ru(phd)3](PF6)2, 5 mol % Co(salophen), MeOH (0.1 M), O2, 65 °C. Isolated yields.aReactions were run at 65 °C.bReactions were run at 40 °C.
Competition Studies with Oxidatively Sensitive Molecules
(Note: The deuterium labels in the C3 position of2a-d3 are a by-product of the synthetic protocol; NaBD3CN/DOAc mediated reduction of the indole leads to full H/D exchange at the C3 position. Then, partial H-incorporation from MeOH occurs at the C3 position during the dehydrogenation reaction.) a) Kinetic isotope effects by independent rate measurements b) Kinetic isotope effects by intramolecular competition
Quinone-Catalyzed Dehydrogenation of Amines
Quinone-Catalyzed Aerobic Dehydrogenation Process Using Electron-Transfer Mediators (ETMs)
Quinone-Catalyzed Dehydrogenation of Pharmaceutical Intermediates
a1.0 mmol scale. Yields were determined by1H NMR. Isolated yields in parentheses.
References
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- Sleath PR; Noar JB; Eberlein GA; Bruice TC Synthesis of 7,9-Didecarboxymethoxatin (4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f] quinoline-2-carboxylic acid) and Comparison of Its Chemical Properties with Those of Methoxatin and Analogous o-Auinones. Model Studies Directed Toward the Action of PQQ Requiring Bacterial Oxidoreductases and Mammalian Plasma Amine Oxidase. J. Am. Chem. Soc 1985, 107, 3328–3338.
- Mure M; Klinman JP Model Studies of Topaquinone-Dependent Amine Oxidases. 1. Oxidation of Benzylamine by Topaquinone Analogs. J. Am. Chem. Soc 1995, 117, 8698–8706.
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