Bartoli Indole Synthesis

Bartoli Indole Synthesis (o-Nitroarene + Vinyl Grignard)

Bartoli Indole Synthesis (o-Nitroarene + vinyl Grignard → indole)

The Bartoli indole synthesis uses three equivalents of a vinyl Grignard reagent, added to an ortho-substituted nitroarene at cryogenic temperature, to forge a 7-substituted indole after acidic workup. The sequence passes through nitroso and [3,3]-sigmatropic rearrangement stages before cyclization and rearomatization deliver the indole. Ortho substitution is mandatory: it raises yields, enforces the rearrangement trajectory, and ensures the benzenoid substituent maps onto the indole’s C-7 position.


Key Emphasis (Teaching Pivots)

  • Substrate gate: Reliable only for ortho-substituted nitroarenes; simple nitrobenzene is unreactive and low-yielding. Bulky o-groups (Me, Br, t-Bu) raise yields.
  • Three equivalent logic: For nitroarenes, 3 eq vinyl RMgX are consumed—(1) sacrificed as a carbonyl after fragmentation, (2) installs the indole C-2 substituent via rearrangement, (3) serves as base before quench.
  • Mechanistic spine: Addition → nitroso formation → second addition → [3,3] sigmatropic rearrangement → cyclization/rearomatization → acid workup.
  • Outcome map: o-Substituent from the nitroarene becomes C-7 on the indole; the vinyl Grignard delivers the C-2 substituent.

Quick Summary

  • Reagents & conditions: o-Nitroarene, vinyl-MgX (3 eq for nitro; 2 eq for nitroso substrates) in dry THF/Et₂O at −78→−20 °C; quench with NH₄Cl or dilute acid.
  • Outcome: 7-substituted indole containing the vinyl fragment at C-2; a carbonyl byproduct arises from the first equivalent.
  • Mechanism class: Polar organometallic additions followed by an aza-Claisen [3,3]-shift and intramolecular cyclization.
  • Scope: o-Me, o-OMe, o-halogen, and related ortho groups perform best; nitrosoarenes follow a similar but shorter stoichiometry.
  • Limitations: Moisture-sensitive; electron-poor or unsubstituted rings fail; Grignard-incompatible functional groups must be masked.

Mechanism — Addition, Rearrangement, Cyclization, Workup (9 Steps)

Step 1: vinyl Grignard addition to the nitro group
Step 1 — First equivalent: nitro addition → nitroso. Vinyl‑MgX adds to the nitro group to form a nitronate adduct that fragments into a nitrosoarene plus a magnesium enolate (carbonyl byproduct on workup).
Step 2: second vinyl Grignard addition to the nitroso
Step 2 — Second equivalent: nitroso capture. Another vinyl‑MgX equivalent adds to the nitroso N/O manifold, forming an anionic adduct whose geometry is set for the upcoming [3,3]-sigmatropic shift.
Step 3: second vinyl Grignard addition
Step 3 — Second vinyl Grignard addition. The nitroso intermediate captures another vinyl‑MgX equivalent, setting up the vinyl fragment on nitrogen/oxygen.
Step 4: alignment for the rearrangement
Step 4 — Align for the [3,3]-shift. Bond rotations position the vinyl fragment and ortho carbon perfectly for the ensuing aza‑Claisen move.
Step 5: [3,3]-sigmatropic rearrangement and ring closure
Step 5 — [3,3]-sigmatropic rearrangement & cyclization. The concerted aza‑Claisen event plus intramolecular attack forge the indoline core and anchor the vinyl fragment at C-2.
Step 6: acidic protonation and rearomatization
Step 6 — Acidic protonation and water-assisted rearomatization. Acid adds at nitrogen while water removes the β‑hydrogen, restoring the benzenoid π-system and pushing the aniline stage forward.
Step 7: third vinyl Grignard setup
Step 7 — Intermediate reset for the third vinyl Grignard equivalent. The protonated nitrogen transfers H to the new vinyl Grignard while the lone pair coordinates Mg, prepping the final reduction block.
Step 8: acidic workup eliminates water
Step 8 — Acidic workup eliminates water. H₃O⁺ drives off the remaining oxygen substituent as water and strips the MgBr adducts, revealing the protonated indolide.
Step 9: final Bartoli indole product
Step 9 — Final indole product. After aqueous workup the neutral indole appears with the vinyl fragment at C-2 and the original ortho substituent at C-7.

Mechanistic Checklist

  • Demand an ortho substituent (bulky = better) for productive rearrangement.
  • Account for all three equivalents of vinyl RMgX when starting from a nitroarene (only two for nitroso substrates).
  • Identify the key pericyclic step as a [3,3]-sigmatropic rearrangement (aza-Claisen type).
  • Map substituents: o-R → C-7; vinyl fragment → C-2 of the indole.
  • Finish with an acidic quench to unveil the neutral indole.

Worked Examples

Example A: o-tert-butylnitrobenzene Bartoli workflow
Example A — o-tert-Butylnitrobenzene. Reactant → Bartoli reagent button → solver product, highlighting the 7-tert-butyl-2-vinyl indole outcome.
Example B: 6-nitro-2-methylpyridine Bartoli workflow
Example B — 6-Nitro-2-methylpyridine. Shows a heteroarene substrate (2 eq vinyl‑MgX) flowing through the same reactant/reagent/product layout to an azaindole.

Scope & Limitations

  • Favored substrates: o-Me, o-OMe, o-Br, o-t-Bu nitroarenes; related heteroaryl nitro substrates for azaindoles.
  • Vinyl partners: Vinyl-/propenyl-MgX (Br, Cl). Fresh, titrated reagents give the best conversions.
  • Temperature: Maintain −78→−40 °C for additions/rearrangement; warm only after the cascade completes.
  • Functional-group tolerance: Avoid protic, electrophilic, or strongly electron-withdrawing groups that quench Grignards; protect them first.
  • Poor performers: Unsubstituted nitrobenzene, electron-poor rings, highly hindered or moisture-contaminated reaction mixtures.

Edge Cases & Exam Traps

  • Assuming nitrobenzene works—ortho substitution is essential.
  • Skipping the [3,3] rearrangement explanation; it accounts for regiochemistry.
  • Miscounting RMgX equivalents (3 for nitro, 2 for nitroso).
  • Forgetting the carbonyl byproduct originating from the first equivalent.
  • Neglecting acidic workup (without it, you isolate metalated indolides).

Practical Tips

  • Scrupulously dry glassware, solvent, and vinyl-MgX; titrate the reagent when possible.
  • Charge the nitroarene at −78 °C, then add vinyl-MgX slowly to control the exothermic addition/fragmentation steps.
  • After rearrangement/cyclization, warm cautiously before quenching with NH₄Cl or dilute acid.
  • Expect a carbonyl byproduct; plan the workup/extraction to remove it cleanly.
  • Consider the Dobbs o-bromo variant for stubborn substrates; debrominate or cross-couple later.

Exam-Style Summary

o-Substituted nitroarene + 3 eq vinyl-MgX (−78→−20 °C, THF) undergoes nitro addition/fragmentation → nitroso capture → [3,3]-sigmatropic rearrangement → cyclization → metalated indole. Acidic workup releases the 7-substituted indole; the vinyl fragment defines C-2. Nitrosoarenes need only two equivalents.


Interactive Toolbox

  • Mechanism Solver — animate the Bartoli cascade (nitro vs. nitroso, 3 eq vs. 2 eq) with narrated overlays and the newest protonation steps.
  • Reaction Solver — screen ortho substituents, stoichiometry, and Grignard compatibility while comparing Bartoli to tin/acid or catalytic hydrogenation routes.
  • IUPAC Namer — double-check nomenclature for substituted indole products and their nitro/nitroso precursors.