Wednesday, November 4, 2009

C-3 arylation of indole

Challenging chemical architectures of natural origin often point to gaps in synthetic methodology. For instance, there is a shortage of methods for C-3 quaternization of indoles with an aryl appendage. A number of natural products including haplophytine,1 bipleiophylline,2 hodgkinsine,3 and leptosin D4 (Fig. 1) contain a quaternary indole C-3 with an aryl appendage or a structure theoretically derived from such a motif as with haplophytine.1h Recent efforts by Nicolaou and co-workers,5 and Fukuyama and coworkers6 in the context of haplophytine have demonstrated the feasibility of the synthetic union of a substituted indole C-3 with an
aryl nucleophile,6 or a pseudo-aryl electrophile,5 however, both approaches were highly substrate specific and proceed in less than 25% yield.
In a much simpler context, Barton and co-workers have shown that treatment of skatole with tert-butyl tetramethylguanidine (BTMG) in the presence of 1.5 equiv of Ph4BiOTs results in
95% conversion to the C-3 disubstituted indolenine 1 (Fig. 2).7 This approach suffers from the required use of 4 equiv of aryl donor for each aryl group transfer. Additionally, extensive studies in these laboratories have shown that this bismuth mediated protocol does not have broad substrate scope and requires a tedious five-step reagent preparation.8

Baran reaported this method:
Tetrahedron 65 (2009) 3149–3154

The strategy has been generalized and performs well with a wide variety of substrate and reagent combinations. While this strategy is somewhat limited with respect to efficiency in appending very electron rich arene rings to C-3 of indole substrates, other than highly substrate dependent cases of Nicolaou5 and Fukuyama,6 there are no comparable methods in the
literature that allow for the direct C-3 quaternization of indoles with an arene ring.

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