Fukuyama Indole Synthesis

• General Characteristics

The Fukuyama indole synthesis is a powerful way to synthesize 3-substituted or 2,3-disubstituted indoles using a radical initiator and tributyltin hydride.

The second generation conditions are particularly useful to introduce a wide scope of substituents. Introducing sp³ carbons at the 2-position is possible, which is usually difficult by cross coupling reactions.

The isothiocyanate starting materials can be prepared readily by the cleavage of quinoline mediated by thiophosgene. The reactions can be run on large scales.

• General References

・Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127. DOI: 10.1021/ja00086a054
・Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. DOI: 10.1021/ja983681v

• Reaction Mechanism

Under both the first and second generation conditions, the reaction proceeds by free radical-based cyclization mechanism. When the olefin geometry is trans, the formation of the tetrahydroquinoline (the thermodynamic product) increases.

<1st Generation Conditions>

<2nd Generation Conditions>

• Examples

The total synthesis of (+)-vinblastine is one of the landmark achievements in organic synthesis. It utilized the Fukuyama indole synthesis as key steps.^[1]

• Experimental Procedure

• Experimental Tips

• References

[1] Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.J. Am. Chem. Soc. 2002, 124, 2137. DOI:10.1021/ja0177049

• Related Books

[amazonjs asin=”9057022680″ locale=”US” title=”Indole Alkaloids (Frontiers in Natural Product Research)”]

[amazonjs asin=”B0000EHLJH” locale=”US” title=”Advances in heterocyclic natural product synthesis”]

[amazonjs asin=”0471302155″ locale=”US” title=”Name Reactions in Heterocyclic Chemistry”]

alkaloid, free radical, heterocycle, synthesis of indoles