Knochel indole synthesis

This new indole ring synthesis should find utility for the preparation of 2-aryUndoles with electron-withdrawing substituents in the indole ring. Furthermore, as we see in equations 1-3, the bromine atom is impervious to attack by the Grignard reagent. The starting ortfto-nitrostilbenes were prepared in the standard fashion from the appropriate ortho-nitrotoluene and aryl aldehyde with piperidine as base. 

Indole Ring Synthesis Fmm Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

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Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Koradin, C. Dohle, W. Rodriguez, A. L. Schmid, B. Knochel, P. Synthesis of polyfunctional indoles and related heterocydes mediated by cesium and potassium bases. Tetrahedron 2003, 59, 1571-1587. 

Dohle, W. Staubitz, A. Knochel, P. Mild synthesis of polyfunctional benzimidazoles and indoles by the reduction of functionalized nitroarenes with PhMgCl. Chem. Eur. J. 2003, 9, 5323-5331. 

A similar approach was used by Knochel and coworkers for the first synthesis of unsubstituted b-SFs-indole (7) (12CEJ10234). They directly used unprotected 2-bromo-5-SF5-aniline (8) in reaction with trimethylsilylacetylene under Sonogashira cross-coupling conditions, which provided SFs-substituted 2-ethynyl(trimethylsilyl)aniline (9). Subsequent cychzation using KH in 1-methyl-2-pyrrolidinone afforded the b-SFs-indole (7) in 83% yield (Scheme 3). 

The author expected that a reaction with a chiral ligand which coordinates to a copper atom could produce optically active 2-(aminomethyl)indoles. Knochel recently developed a novel asymmetric synthesis of chiral propargylamines with excellent ee values through a copper-catalyzed asymmetric Mannich-type reaction of alkynes with an aldehyde and a secondary amine using QUINAP as a chiral ligand (up to 98% ee) [1-3]. Carreira reported the similar synthesis of propargylic amine in up to 99% ee with PINAP [4, 5]. The author initially examined the... 

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