Total synthesis of indoles from Tricholoma species via Bartoli/heteroaryl radical methodologies

Dobbs, Adrian (2001). Total synthesis of indoles from Tricholoma species via Bartoli/heteroaryl radical methodologies. Journal of Organic Chemistry, 66(2) pp. 638–641.

DOI: https://doi.org/10.1021/jo0057396

Abstract

[Introduction] The Bartoli indole synthesis is the treatment of an ortho-substituted nitro-aromatic compound with 3 equiv of vinylmagnesium bromide to give the 7-substituted indole,1,2 and this method has rapidly become the shortest and most flexible synthesis for indoles of this substitution pattern.1-5 We have recently reported an extension to this methodology, suggesting that it may not be limited exclusively to the synthesis of 7-substituted indoles but that modest yields of other substitution patterns may also be obtained via this methodology.6 However, there is no doubt that the best yields are obtained when the nitro-aromatic compound possesses an ortho substituent, enforcing selectivity in the 3,3-sigmatropic rearrangement and subsequent cyclization step. This ortho substituent is, of course, undesirable in the synthesis of many indoles when a Bartoli approach may be advantageous.

We have also been interested in the generation and use of heteroaryl free radicals for some time now and have reported the radical reactions and cyclizations of indoles bearing halogen substituents at both the 2- and 7-positions.3,7,8

We envisaged a combination of these two methodologies, whereby a range of o-bromonitrobenzenes are treated under Bartoli conditions with various vinyl Grignard reagents (using the o-bromine atom to direct the cyclization) and then subsequently reduced using the heteroaryl radical methodology to replace the halogen and give a 7-unsubstituted indole, i.e., effectively using the bromine as a labile protecting group (Scheme 1). This method could give a significant reduction in the number of steps required for the synthesis of many complex indoles and also offers the advantage that many functionalities are tolerant to radical-generating conditions without the need for protection.

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