Bartoli indole synthesis

The Bartoli indole synthesis (also called the Bartoli reaction) is the chemical reaction of ortho-substituted nitroarenes with vinyl grignard reagents to form substituted indoles.Ref|Bartoli1989Ref|Bartoli1991Ref|Dobbs1999Ref|Dalpozzo2005

The reaction is unsuccessful without substitution ortho to the nitro group. Three equivalents of the vinyl grignard reagent are also necessary for good yields.

This method has become one of the shortest and most flexible routes to 7-substituted indoles.Ref|Dobson1991Ref|Dobson1992 The Leimgruber-Batcho indole synthesis gives similar flexibility and regiospecificity to indole derivatives. One advantage of the Bartoli indole synthesis is the ability to produce indoles substituted on both the carbocyclic ring "and" the pyrrole ring, which is difficult to do with the Leimgruber-Batcho indole synthesis.

Reaction mechanism

The reaction mechanismRef|Bosco1991 of the Bartoli indole synthesis is illustrated below using o-nitrotoluene (1) and propenyl grignard (2) to form 3,7-dimethylindole (13).

The mechanism begins by the addition of the grignard reagent (2) onto the nitroarene (1) to form intermediate 3. Intermediate 3 spontaneously decomposes to form a nitrosoarene (4) and a magnesium salt (5). (Upon reaction workup, the magnesium salt will liberate a carbonyl compound (6).) Reaction of the nitrosoarene (4) with a second equivalent of the grignard reagent (2) forms intermediate 7. The steric bulk of the ortho group causes a [sigmatropic rearrangement| [3,3] -sigmatropic rearrangement] forming the intermediate 8. Cyclization and tautomerization give intermediate 10, which will react with a third equivalent of the grignard reagent (2) to give a dimagnesium indole salt (12). Reaction workup eliminates water and gives the final desired indole (13).

Therefore, three equivalents of the grignard reagent are necessary, as one equivalent becomes a carbonyl compound (6), one equivalent gets protonated forming an alkene (11), and one equivalent gets incorporated into the indole ring.

The nitroso intermediate (4) has been isolated from the reaction. Additionally, reaction of the nitroso intermediate (4) with two equivalents of the grignard reagent produces the expected indole.

Variations

Dobbs modification

Adrian Dobbs greatly enhanced the scope of the Bartoli indole synthesis by using an ortho-bromine as a directing group, which is subsequently removed by AIBN and tributyltin hydride.Ref|Dobbs2001

The synthesis of 4-methylindole (3) highlights the ability of this technique to produce highly substituted indoles.

References

# Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. "Tetrahedron Lett." 1989, "30", 2129-2132. (DOI|10.1016/S0040-4039(01)93730-X)
# Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. "J. Chem. Soc., Perkin Trans. 1" 1991, 2757-2761.
# Dobbs, A. P.; Voyle, M.; Whitall, N. "Synlett" 1999, 1594-1596.
# Dalpozzo, R.; Bartoli, G. "Curr. Org. Chem." 2005, "9", 163-178. (Review) ( [http://www.bentham.org/coc/sample/coc9-2/0003D.pdf Article] )
# Dobson, D.; Todd, A.; Gilmore, J. "Synth. Commun." 1991, "21", 611-617.
# Dobson, D. R.; Gilmore, J.; Long, D. A. "Synlett" 1992, 79-80.
# Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. "J. Chem. Soc. Perkin Trans. 2" 1991, 657-663.
# Dobbs, A. "J. Org. Chem." 2001, "66", 638-641. (doi|10.1021/jo0057396)

ee also

* Fischer indole synthesis