Synthesis of molecular block “two-sided” indole
01 The Double Magic of Indole
Remember the faint scent of jasmine on your first love, which you once thought was the smell of love, but in fact, this nice scent comes from a chemical called indole. However, it also has a familiar name - fecal odorant. As it turns out, indole and its derivatives almost always have this double-smelling magic. It has a pleasant, floral scent at very low concentrations, and an odor that's unpleasant at very high concentrations.
Indole is a compound of pyrrole and benzene, containing a bipyrrole ring system, also known as benzopyrrole. It has special biological activities. Some natural substances, such as alkaloids and plant growth factors, are derivatives of indole. Indoles and their homologues and derivatives are found everywhere in nature, and their chemical syntheses and applications are countless and have been studied for over a century, with more than two million syntheses in Reaxys.
02 The Path to Indole Synthesis
The synthesis of indole compounds has always been a challenge in the field of organic synthesis, as well as an inspiration for organic synthetic chemists. In recent years, scientists have conducted a comprehensive categorization of known indole synthesis reactions, presenting the synthetic routes of indoles and their classifications, and identifying a total of nine major types of strategies:
Figure 1. 9 Types of Indole Synthesis
1. Classical Fischer indole synthesis: This method produces 3-hydroxypropyl indole by reacting arylhydrazine with dihydropyrane. This is an ancient but still actively developing method for introducing substituents directly onto the aromatic ring.
2. Introduction of substituents by Heck reaction: Substituents can be introduced at the 2,3 position of the indole by utilizing the Heck reaction. This is done by cross coupling reaction to introduce substituents on the aromatic ring, which in turn produces the target indole compound.
3. Generation of indoles from azacyclopentadiene: In this method, azacyclopentadiene is heated and cyclized to form an indole ring.
4. Metal-catalyzed cyclization amination reactions: Using the action of a metal catalyst, an amination reagent can be reacted with a suitable starting material to form an indole ring.
5. Formation of C-N bond followed by ring closure: This method starts with the formation of a C-N bond by reaction followed by further reaction cyclization to form an indole ring.
6. Formation of C-C bond followed by ring closure: In this method, the C-C bond is first formed by a reaction, followed by the introduction of other functional groups, and finally the indole ring is formed by a cyclization reaction.
7. Construction of pyrrole rings from cyclohexane derivatives: Using appropriate reaction conditions, such as oxidation and cyclization reactions, pyrrole rings can be constructed from cyclohexane derivatives, which then undergo further reactions to form indole rings.
8. Construction of a benzene ring on a pyrrole ring: This method allows the construction of indole compounds containing a benzene ring by introducing a substituent group on the pyrrole ring followed by a cyclization reaction.
9. Direct synthesis of two rings in one go: This method allows the direct synthesis of indole compounds from two rings in one go by means of appropriate reaction conditions and intermediates, thus increasing the efficiency of synthesis and yield.
03 Main Applications of Indole
Indoles also have a pivotal role in the field of medicine. Indoles exhibit important pharmacological properties by modulating signaling pathways and targeting specific molecules and cells, and the following are some of the major applications of indoles in the field of medicine:
1. Anti-cancer drugs:
Indoles are widely used in the development and treatment of anticancer drugs, inhibiting the growth and proliferation of cancer cells through different mechanisms For example, the thiourea drugs Zoerythromycin (Etoposide) and Paclitaxel contain indole structures.
2. Immunomodulators:
Indoles can be immunomodulators. For example, a compound called indole-3-carboxylic acid modulates T-cell activity in the immune system and has anti-inflammatory and immunosuppressive effects.
3. Antidepressants:
Indole compounds can affect neurotransmitter systems, modulate mood and mental states, and reduce depressive symptoms.The SSRI (selective 5-hydroxytryptamine reuptake inhibitor) drugs Paroxetine and Trazodone both contain indole structures.
Indoles have also been studied and applied in the field of anti-inflammatory drugs. Some indole derivatives have anti-inflammatory and antioxidant activities and are used in the treatment of inflammatory diseases such as arthritis and inflammatory bowel disease.
Overall, indoles have a wide range of applications. With further research development, we believe that more innovative strategies will be added to the above synthetic "dictionary" in the future, which provides a valuable reference for us to design new indole synthesis reactions. The research of indole compounds still has a long way to go, let's wait and see!
References
1. Douglass F. Taber a, Pavan K. Tirunahari b. Indole synthesis: a review and proposed classification. Tetrahedron 67 (2011) 7195e7210. doi:10.1016/j.tet.2011.06.040. https://doi.org/10.1016/j.tet.2011.06.040
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