Fukuyama indole synthesis

The Fukuyama indole synthesis is a name reaction of organic chemistry and was discovered in 1994 by the Japanese chemist Tohru Fukuyama (* 1948).

Overview reaction

The reaction is used for the synthesis of indoles by radical cyclization of ο -Isocyano styrene - derivatives -Reaktionsschema:

In the Fukuyama indole synthesis, the tin reagents tributyltin hydride ( n -Bu ₃ SnH) and azobis (isobutyronitrile) (AIBN) are used as radical initiators or triethylborane . With these reagents ο -Isocyano styrene derivatives can be converted to indoles, with the addition of acid a 3-substituted indole and with addition of haloalkanes and palladium (0) 2,3-disubstituted indoles.

mechanism

A possible mechanism for this radical cyclization is described in the scientific publications by Tohru Fukuyama et al. presented. The addition of the AIBN to the tributyltin hydride creates a tributyltin radical that attacks a mesomerically stable ο -iso styrene 1 radical. An α- stannoimidoyl radical 2 is formed , which reacts to radical 3 through intramolecular ring closure and intramolecular proton migration . Further addition of tributyltin hydride stops the radical processes and 2-stannyl indole 4 remains as the main product. Depending on which reagents are added to 4 , a 3- or a 2,3-disubstituted indole is formed. The 3-substituted indole is obtained by protonating 4 by adding an acid. Then a tributyltin cation splits off and the desired indole derivative 5 is formed .

The synthesis of the 2,3-disubstituted indole ( 6 ) instead requires a halogen compound ( R ² radical = cyclohexenyl , phenyl and butyl group ) and palladium as a catalyst.

Various esters , but also alkyl groups , can be used as the R ¹ radical . It is a one-pot reaction in which the triethylborane is only used for cis isomers and, just like when using AIBN, gives an indole yield of 93%.

Individual evidence

1. ↑ Gordon W. Gribble: Recent developments in indole ring synthesis — methodology and applications . In: Journal of the Chemical Society, Perkin Transactions 1 . No. 7 , 2000, pp. 1045-1075 , doi : 10.1039 / A909834H .
2. ↑ ^{a b c} Tohru Fukuyama, Xiaoqi Chen, Ge Peng: A Novel Tin-Mediated Indole Synthesis . In: Journal of the American Chemical Society . tape 116 , no. 7 , April 1994, pp. 3127-3128 , doi : 10.1021 / ja00086a054 .
3. ↑ ^{a b} Hidetoshi Tokuyama, Tohru Yamashita, Matthew T. Reding, Yosuke Kaburagi, Tohru Fukuyama: Radical Cyclization of 2-Alkenylthioanilides: A Novel Synthesis of 2,3-Disubstituted Indoles . In: Journal of the American Chemical Society . tape 121 , no. 15 , April 1999, p. 3791-3792 , doi : 10.1021 / ja983681v .