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Synthesize a Variety of 3-arylthioindoles in Less than 4 Minutes

October 24, 2012

Microwave irradiation has been utilized to accelerate a wide variety of different chemical transformations. Until recently, those transformations have been limited to rapid heating under pressure, with no way to alleviate excess pressure without stopping the reaction, or at atmospheric pressure, with no way to contain a small amount of pressure for a short period of time. La Regina and coworkers have recently been able to take advantage of technological advances in microwave chemistry to synthesize 3-arylthioindoles using venting-while-heating, or ActiVent™ Technology. This technology is available exclusively in the Discover® SP System. The process by La Regina and coworkers was recently published in ACS Combinatorial Science (ACS Comb. Sci., 2012, 14, 258).

Scheme 1. 3-arylindoles

There are several different pathways to access 3-arylthioindoles, but the group was looking for a generalized procedure that would allow them to quickly synthesize a library. They were able to determine that, while conditions do exist to access these compounds, there is no easy way to access a variety of them.

After some work, the group was able to determine that an indole could be reacted with the corresponding disulfide in the presence of NaH, using DMF as the solvent. The use of NaH prevented the use of traditional sealed vessel microwave vials, as a truly sealed vessel would quickly overpressurize with the release of H2. The authors noted:
The result could be explained by taking into account that the venting of the reaction mixture allows the release of the internal pressure of the vial during the experiment and maintain[s] a high power of microwave irradiation for all reaction time.

The group was able to optimize microwave conditions and reduce the reaction time to 2 minutes. The optimized microwave conditions of 120 Watts, 130 °C, with ActiVent™ on, gave a 98% yield of the desired compound.  Higher temperatures or longer reaction times resulted in lower yields of the desired arylthioindole. In comparison, the same conditions in an oil bath required 12 hours to generate 90% of the model product.  

Longer reaction times were required for the 2-carboxylate derivatives. These longer reaction times did not, however, increase the amount of thioanisole, as has been previously-observed. The authors propose the venting not only releases excess hydrogen gas, but also the thiol, reducing the unwanted side reaction.  

The authors were able to expand the scope of the reaction to accommodate both electron withdrawing and electron donating substituents on the 3-arylthio moiety, as well as at the 2- and 5-positions on the indole. Electron-withdrawing substituents at the 2-position on the indole did, however, require larger amounts of NaH to ensure reaction completion and a slightly longer reaction time (4 minutes at 130 °C instead of the standard 2 minutes).  

activent_small.pngThe combination of the Discover® SP and ActiVent™, or venting-while-heating, allowed the authors easy access to a variety of 3-arylthioindoles in less than 4 minutes. The venting allowed excess hydrogen gas to be released, as well as possibly unwanted byproducts, thus ensuring the microwave power was maintained at a high level throughout the course of the reaction, driving the reaction to completion. The conditions were amenable to a variety of different substituents, illustrating the power of the overall synthesis.

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