Fukuyama indole synthesis

What is Fukuyama indole synthesis?

The synthesis of 3-substituted or 2,3-disubstituted indole derivatives, known as the Fukuyama indole synthesis, was first reported in 1994 by Fukuyama. This reaction utilizes tributyltin-based intramolecular radical cyclization of o-alkenylphenylisocyanides and has been upgraded to a second generation (see Scheme 2).

The initial reaction protocol involves the treatment of 2-isocyanostyrene derivatives with tributyltin hydride in the presence of a radical initiator, giving a (2-alkenyl)phenylstannoimidoyl radical, which cyclizes intramolecularly and tautomerizes to afford 3-substituted-2-tributylstannyl indoles. Acidic treatment of the indole tin derivatives will afford simple 3-alkyl-substituted indole derivatives, and in conjunction with the Stille coupling, 2-alkenyl (or alkynyl, aryl)-3-alkyl-indole derivatives can be obtained in a one-pot manner. This reaction allows for the preparation of indoles with both acid- and base-sensitive functionalities at positions 2 and 3 from readily accessible phenylisonitriles. However, it would be challenging to form 2-alkyl-substituted indoles directly. The reaction from 2-isocyanostyrenes with a trans-β-alkyl group might be complicated with the formation of tetrahydroquinolines, while 2-isocyanostyrenes with a cis-β-alkyl group will give much less tetrahydroquinolines.

Fukuyama indole synthesis - general reaction scheme
Fukuyama indole synthesis (first generation)
  • R = alkyl, aryl
  • R’ = acyl, alkenyl, allyl, aryl, benzyl, vinyl
  • X = Br, I, etc.
  • X’ = Br, I, OTs, Ms, OAc, etc. (see list of acronyms)

The second generation of the Fukuyama indole synthesis (Scheme 2) involves the intramolecular radical cyclization of 2-alkenylthioanilides that can be accessed through three different methods. In the first method, tetrahydropyran-protected o-(3-hydroxyallyl)thioanilides are synthesized from quinolines by decomposition of thiophosgene, NaBH4 reduction, tetrahydropyran protection, and nucleophilic addition on the isothiocyanate moiety. In the second modular reaction, quinolines are treated similarly with thiophosgene and NaBH4, then o-(3-hydroxyallyl)phenyl isothiocyanates are converted into o-(3-hydroxyallyl)anilines, which are acylated with acyl chloride and treated with Lawesson’s reagen. The third method involves Sonogashira coupling of 2-iodoaniline with terminal alkynes, followed by reduction with activated zinc to give exclusively o-aminostyrenes with a β-substituent in cis-configuration. The anilines are transformed into thioanilides by acylation and subsequent treatment with Lawesson’s reagent. The thioanilides can be easily converted into various 2-substituted and 2,3-disubstituted indoles by tributyltin hydride followed by desulfurization with Raney nickel.

Fukuyama indole synthesis - general reaction scheme
Fukuyama indole synthesis (second generation)
  • R = alkyl, aryl
  • R’ = alkyl, aryl
  • R” = CH2OTHF, CH2OAc
  • R”’ = R, R’
  • X = Cl, Br, I

Triethylborane (Et3B) has been shown to be a reliable radical initiator that can introduce a wide variety of acid- and base-sensitive groups, including ester, THP ether, and β-lactam, at the 2- or 3-position of indole. Racemization has not been observed for thioanilides derived from chiral α-amino acids under radical reaction conditions. In addition to tin hydride, hypophosphorous acid has been used as a radical reducing reagent.

The Fukuyama indole synthesis has been successfully applied to the total synthesis of various natural alkaloids containing indole moieties, such as aspidophytine, haplophytine, catharanthine, vindoline, and the antineoplastic agent (+)-vinblastine.


A Novel Tin-Mediated Indole Synthesis
Tohru Fukuyama, Xiaoqi Chen, and Ge Peng
Journal of the American Chemical Society 1994 116 (7), 3127-3128
DOI: 10.1021/ja00086a054