The Bartoli indole synthesis uses an alkenyl Grignard reagent in excess at low temperatures and an acid work-up to convert a substituted nitroarene to an indole. The mechanism is not clear in every detail, but the main steps have been elucidated. The first equivalent of the Grignard reagent attacks the oxygen atom of the nitro group, forming a nitrosoarene, which is attacked by the second equivalent. A [3,3]-sigmatropic rearrangement then produces an aldehyde intermediate that undergoes intramolecular nucleophilic attack by the nitrogen. The third equivalent of the Grignard reagent removes the proton in the ring junction and an acid work-up generates the final indole.
- Reagents: Alkenyl Grignard Reagent, Solvent (THF, Bu2O, or Et2O), Acid Work-Up
- Reactant: Ortho-Substituted Nitroarene or Nitrosoarenes
- Product: 7-Substituted Indole
- Type of Reaction: Heterocycle Formation
Lab Tips
- When the nitroarene does not have an ortho substituent, the reaction provides low or no yield of the desired indole. Moreover, sterically more demanding ortho substituents usually provide higher yields of product.
- A wide variety of ortho substituents may be used (alkyl, aryl, F, Cl, Br, I, OSiR3, O-benzyl, O-sec-alkyl, or CH(OR)2 group).
- Alkenyl Grignard reagents that are substituted produce corresponding indoles with substituents at the C2 or C3 positions, while simple vinyl reagents produce indoles with no substituents at C2 or C3.
- Only two equivalents of the Grignard reagent are necessary when nitrosoarene is used as the substrate.
Mechanism
Original Paper
Top Citations
Related Reactions
- Leimgruber-Batcho Indole Synthesis
Related Compounds
- Vinyl/Alkenyl Grignard Reagent
- Acid Work-Up
