Bartoli G,
*,
Palmieri G,
Bosco M,
Dalpozzo R.
University of Camerino, Italy
The Reaction of Vinyl Grignard Reagents with 2-Substituted Nitroarenes: A New Approach
to the Synthesis of 7-Substituted Indoles.
Tetrahedron Lett. 1989;
30: 2129-2132
DOI:
10.1016/S0040-4039(01)93730-X
Key words
vinyl Grignard reagents - nitroarenes - indoles
Significance
In 1989, Bartoli et al. reported an indole synthesis starting from substituted nitroarenes
and vinyl Grignards. Satisfactory yields are obtained only for ortho-substituted nitroarenes; 4-substituted nitroarenes gave the corresponding anilines
as major products. The versatile behavior of the vinyl Grignards is notable. The use
of styryl magnesiumbromide in place of the vinyl magnesiumbromide leads to a mixture
of desired indole, phenylacetaldehyde and styrene in a ratio of 1:1:1. The procedure
allows for the efficient synthesis of 7-substituted indoles.
Review: For a review on the Bartoli indole synthesis and its applications, see: G. Bartoli,
R. Dalpozzo, M. Nardi Chem. Soc. Rev.
2014, 43, 4728–4750.
Comment
The result of the styryl magnesiumbromide reaction is discussed in another publication
of the same group concerning the mechanism of the reaction (J. Chem. Soc., Perkin Trans. 2
1991, 657). According to the proposed mechanism, the first equivalent of Grignard reduces
the nitro group to a nitroso functionality, ultimately leading to the phenylacetaldehyde
shown in the scheme above. The second equivalent attacks the oxygen atom of the nitroso
group in a SET-triggered reaction. The formed product undergoes [3,3]-sigmatropic
rearrangement forming the ortho-substituted indole scaffold. The third equivalent deprotonates the nitrogen, which
induces rearomatization of the six-membered ring and subsequent formation of the five-membered
ring. In the reaction sequence shown in the scheme, this equivalent ends up as styrene.
Quenching with NH4Cl leads to dehydration and rearomatization of the five-membered ring.
