Castro indole synthesis

What is Castro indole synthesis?

Castro was the first to report the reaction in 1966, which involves the cuprous halide-catalyzed intramolecular cyclization of o-ethynylanilines or the coupling between o-haloaniline and cuprous mono-substituted acetylide. This reaction is commonly known as the Castro indole synthesis and is a suitable method for producing 2-substituted indoles, serving as an alternative to the Fischer indole synthesis.

Castro indole synthesis - general reaction scheme
Castro indole synthesis

The o-ethynylanilines can be easily obtained through the Castro-Stephens coupling or Sonogashira coupling of o-haloanilines with acetylene or mono-substituted acetylenes. During the coupling, the reactivity of o-haloanilines follows the order:

I > Br > Cl >> F

while the catalytic efficiency of cuprous salts varies with the counteranions and decreases in the sequence of:

Cl > Br > I > CN > SPh > SCN

The solvent used has a significant impact on the reaction’s outcome; for instance, (o-amino)phenylacetylide readily cyclizes intramolecularly in dimethylformamide DMF to give indole exclusively, but in pyridine, it only produces either uncyclized acetylene or tolane. Furthermore, o-aminotolane does not undergo cyclization when treated with CuI or cuprous phenylacetylide in pyridine, but the reaction proceeds smoothly when treated with CuI in DMF. The synthesis of indoles can be accomplished in two steps: Castro-Stephens coupling in pyridine and Castro indole synthesis in DMF.

The Castro indole synthesis is commonly used for the synthesis of indoles, particularly 2-substituted indoles.

References

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