Visible Light Promoted Synthesis of Indoles in DMSO

Visible Light Promoted Synthesis of Indoles in DMSO

Indole ring is widely found in pharmaceutical compounds, agrochemicals and natural products. Therefore, the methods to form this heterocycle are important. Traditional methods of synthesizing indole rings often suffer from the need for exotic starting materials, from poor functional group tolerance, and from the generation of significant amounts of undesirable byproducts. Therefore, greener, more sustainable synthetic methods for making indoles are desirable.

With this in mind, the Wu group has recently published an account of synthesizing indoles using a single photosensitizer. [fac-Ir(ppy)3] and blue LED lights to promote the cyclization of easily prepared enamine substrates in DMSO.1 This reaction produces highly substituted indoles for excellent yields (58–99%, 23 examples). Additionally, this reaction does not require any special additives or environments and works well when run under air.

This reaction R. was tolerant to a variety of electron-withdrawing and electron-donating substances for1 in all positions in the ring. Similarly, the Ar position tolerated electron-donating and substituting in all cases except for the para-nitro substitution, in which there was no product. The reaction was also unaffected by the change in the ester part, R. was giving comparable yields with2 = et and i.

Several control experiments found that the enamine starting material in solvents other than DMSO readily decomposed after irradiation with blue LEDs. Mechanical studies indicate that the excited photosensitizer reacts with oxygen to produce superoxide radical anion (O.)2,,) in DMSO, and it is the species involved in the cyclization reaction. It was also found that DMSO is unique in that it is the only solvent to effectively increase the oxidation potential of the enamine starting material such that it can undergo a cyclic reaction.

With experimental evidence of superoxide radical anion, along with other mechanistic studies (for example, the inclusion of a radical scavenger does not produce a product) the authors proposed the following mechanism.

In this system, Irthird Excited by the blue LED light *Irthird, Oxygen then *Ir. interacts withthird Species to form superoxide radical anion. The superoxide radical ion enamine abstracts a hydrogen atom from the starting material. 1 to form radical intermediates a, It undergoes radical rotation to produce intermediate b, cyclic intermediate b Then Ir. is oxidized byIV Species for making indole products 2,

This direct path to indole is driven under air and requires only a photosensitizer [fac-Ir(ppy)3] And the light from blue LEDs. Therefore, it is extremely lightweight. DMSO, due to its unique ability to increase the oxidation potential of the starting material, is the only solvent that can be used for this reaction. Compared to conventional indole synthesis, this route is simple to perform and does not require foreign reagents or generate undesirable side products. This seems like an excellent and green way to make indole rings.

Debra D. Dolliver, Ph.D.

References:

1Liu, W-Q.; Lei, T.; Song, Z-Q.; Yang, X.-L.; Wu, C.-J.; Jiang, X.; Chen, B.; Tung, C.-H.; Wu, L-Z. Organization late. 2017, 193251-3254.

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