Sugasawa indole synthesis

What is Sugasawa indole synthesis?

The Sugasawa indole synthesis was initially documented by Sugasawa et al. in 1979 and represents a general approach to synthesize 2,3-unsubstituted indoles. The reaction involves the reaction between anilines and chloroacetonitrile ClCH2CN in the presence of boron trichloride BCl3 and titanium tetrachloride TiCl4 (or aluminium trichloride AlCl3), followed by reduction using NaBH4 and treatment with NaH or NaOMe.

Sugasawa indole synthesis - general reaction scheme
Sugasawa indole synthesis

The specific ortho-substitution of aniline during the reaction produces indole derivatives, making it comparable to the Gassman indole synthesis.

Sugasawa indole synthesis is an extension of the Sugasawa reaction and can produce the desired indole even in the absence of NaH or NaOMe by reducing o-amino-α-chloroacetophenone to o-(2-chloro-1-hydroxyl) aniline, which then undergoes cyclization and dehydration.

The Sugasawa indole synthesis is also a viable approach to prepare N-acyl-3-indolinones through acylation of o-amino-α-chloroacetophenone followed by dehydrochlorination. Nonetheless, anilines with strong electron-withdrawing substituents, such as nitroaniline and carboalkoxyaniline, are not suitable for this reaction.

References

Aminohaloborane in organic synthesis. 2. Simple synthesis of indoles and 1-acyl-3-indolinones using specific ortho α-chloroacetylation of anilines
Tsutomu Sugasawa, Makoto Adachi, Kazuyuki Sasakura, and Akiko Kitagawa
The Journal of Organic Chemistry 1979 44 (4), 578-586
DOI: 10.1021/jo01318a021

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