Solid-Phase Fischer Indole Synthesis

Further examples of the Fischer indole synthesis have been reported in the recent literature [412]. 

---

A solid phase library synthesis method based on the Fischer indole synthesis was developed (Scheme A resin-capture-release method... 

Several modern adaptations of the Fischer indole synthesis have been devised, employing for instance solid-phase-<1996TL4869, 2005TL911> or dendrimer- <1996PNA10012> supported ketones, as well as immobilized hydrazines... 

The thermal conversion of arylhydrazones in the presence of a protic acid or a Lewis acid to form an indole ring. See OweUen, R.J., Fitzgerald, J.A., Fitzgerald, B.M. et al.. The cyclization phase of the Fischer indole synthesis. The structure and significance of Pleininger s intermediate. Tetrahedron Lett. 18, 1741-1746, 1967 Kim, R.M., Manna, M., Hutchins, S.M. et al., Dendrimer-supported combinatorial chemistry, Proc. Natl. Acad. Sci. USA 93, 10012-10017, 1996 Brase, S., Gil, C., and Knepper, K., The recent impact of solid-phase synthesis on medicinally relevant... 

Rosenbaum, C., Katzka, C., Marzinzik, A., Waldmann, H. Traceless Fischer indole synthesis on the solid phase. Chem. Commun. 2003, 1822-1823. 

Solid-phase-bound phenylhydrazones can also be reduced to the corresponding phenylhydrazines, which can then be used for a traceless Fischer indole synthesis on the solid support [150]. 

To obtain neurokinin-1 (NKi) receptor antagonists. Cooper and co-workers [410] synthesized a series of variously substituted indoles by means of a Fischer indole synthesis on a solid phase. Thus, EUman resin [411], based on Kenner s safety-catch Hnker [318], was first reacted with 4-(4-chlorobenzoyl)butyric acid affording (598) and then treated with differently substituted phenyUiydrazines, affording the required indoles (599). These compounds were then cleaved from the resin using bromoacetonitrile, and subsequently coupled in solution with the desired amines under standard conditions (600) (Scheme 125). 

As we will see in the Applications section to follow, solid-phase synthesis of indoles has assnmed an important role in all of synthetic organic chemistry, including Fischer... 

A number of excellent variations on the classic Fischer indolization are known that fall outside of the previous three categories. Like solid-phase synthesis, multicomponent and domino reactions are of major interest to organic chemists. Ganem reported a three-component Fischer indole variation that embraces the union of nitriles or carboxylic acids with organometaUics followed by the addition of arylhydrazine. This exquisite method is summarized in Scheme 16 [117]. In both variations, in situ formation of the requisite arylhydrazones culminates in indolization. The presence of sufficient arylhydrazine hydrochloride... 

---