Solid-phase synthesis of 2,3,5-trisubstituted indoles
1Department of Chemistry, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Organic Letters
|November 27, 2001
Summary
A new three-step synthesis enables the creation of diverse 2,3,5-trisubstituted indoles. This method utilizes palladium-catalyzed reactions and solid-phase synthesis for efficient indole core formation and diversification.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Medicinal Chemistry
Background:
- Indole derivatives are crucial scaffolds in pharmaceuticals and materials science.
- Efficient and versatile synthetic routes to polysubstituted indoles are highly sought after.
Purpose of the Study:
- To develop a novel, efficient, and modular synthetic strategy for 2,3,5-trisubstituted indoles.
- To enable rapid diversification at multiple positions of the indole core.
Main Methods:
- Solid-phase synthesis starting from resin-bound aniline.
- Palladium-catalyzed Sonogashira and Suzuki coupling reactions.
- Intramolecular cyclization for indole core formation.
- Acylation and post-cleavage N-alkylation for further functionalization.
Main Results:
- Successful synthesis of 2,3,5-trisubstituted indoles in three steps.
- Demonstration of modularity through diversification at C-3, C-5, and N-1 positions.
- High yields and purity of the target indole compounds.
Conclusions:
- The developed synthetic route provides a powerful tool for accessing diverse indole libraries.
- This methodology is applicable for the discovery of new bioactive compounds and functional materials.
More Related Videos
Related Concept Videos
02:37Disubstituted Cyclohexanes: cis-trans Isomerism
Depending upon the different spatial orientation of the substituents, the disubstituted cycloalkanes exhibit two types of stereoisomers. The cis isomers have the substituents on the same side of the ring, whereas the trans isomers have the substituents on the opposite sides. These stereoisomers exhibit different physical properties and cannot be interconverted without breaking the carbon-carbon bonds.
In cyclohexane, the substituents can occupy different positions generating distinct isomers.
In cyclohexane, the substituents can occupy different positions generating distinct isomers.
01:26Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
01:11ortho–para-Directing Activators: –CH3, –OH, –NH2, –OCH3
All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
01:18Directing and Steric Effects in Disubstituted Benzene Derivatives
When disubstituted benzenes undergo electrophilic substitution, the product distribution depends on the directing effect of both substituents. When the directing effects of both substituents reinforce each other, a single product is obtained. For example, bromination of p-nitrotoluene occurs ortho to the methyl group and meta to the nitro group, which is the same position, resulting in a single product. However, if the directing effects of the two groups oppose each other, the more strongly...
01:20Diazonium Group Substitution with Halogens and Cyanide: Sandmeyer and Schiemann Reactions
Arenediazonium substitution reactions occur when the diazonium group is substituted by various functional groups such as halides, hydroxyl, nitrile, etc. For instance, arenediazonium salts react with copper(I) salts of chloride, bromide, or cyanide to form corresponding aryl chlorides, bromides, and nitriles. These reactions are named Sandmeyer reactions. Although the mechanism of this reaction is complicated, as illustrated in Figure 1, they are believed to progress via an aryl copper...
01:13Electrophilic Aromatic Substitution: Fluorination and Iodination of Benzene
Bromination and chlorination of aromatic rings by electrophilic aromatic substitution reactions are easily achieved, but fluorination and iodination are difficult to achieve. Fluorine is so reactive that its reaction with benzene is difficult to control, resulting in poor yields of monofluoroaromatic products. To address this, Selectfluor reagent is used as a fluorine source in which a fluorine atom is bonded to a positively charged nitrogen.