Heterocycle synthesis — indole via nitro reduction
Reissert indole synthesis
How the Reissert indole synthesis works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: o-Nitrotoluene, (CO₂Et)₂, KOEt; then Zn/AcOH (or H₂, Pd/C). Conditions: EtOH/Et₂O, 25 °C; reduction 25–80 °C. Bonds formed: C–C (Claisen); N–H₂; C=N then C=C–N (indole ring); bonds broken: benzylic C–H; N–O (×2); C=O. Stereochemistry: None (aromatic). Rate and selectivity: Condensation limited by CH acidity (pKa ≈ 20).
At a glance
Step 1: Benzylic carbanion, Claisen condensation
Base deprotonates the acidic methyl group of an ortho-nitrotoluene, and the resulting benzylic carbanion attacks diethyl oxalate's electrophilic carbonyl carbon — an ordinary Claisen-condensation-type nucleophilic acyl substitution.
Step 2: Reduce NO₂ to NH₂
The nitro group is then selectively reduced (commonly with Sn/HCl or catalytic hydrogenation) to an amine, generating a nucleophile positioned right next to the newly installed ketoester chain.
Step 3: Imine formation closes the ring
That amine condenses intramolecularly with the nearby ketone (ordinary Schiff-base imine formation) and tautomerizes, closing and aromatizing the five-membered ring to give an indole-2-carboxylate ester — this route builds the ring by installing the side chain before reducing the nitro group, the reverse order from most other indole syntheses in this library.
Abbreviations and terms
- Et2O
- Diethyl ether. Low-boiling ether solvent, classic for Grignard reagents.
- EtOH
- Ethanol. Polar protic solvent.
- AcOH
- Acetic acid. Weak acid and polar protic solvent.
- Pd/C
- Palladium on carbon. Heterogeneous hydrogenation catalyst.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- HCl
- Hydrochloric acid / hydrogen chloride. Strong acid; chloride is the nucleophile in additions/substitutions.
- pKa
- Acid-dissociation constant (–log). Lower pKa = stronger acid; used to judge which proton a base removes.
How it compares with related reactions
| Reissert indole synthesis | Bischler indole synthesis | Leimgruber-Batcho indole synthesis | |
|---|---|---|---|
| Reagents | o-Nitrotoluene, (CO₂Et)₂, KOEt; then Zn/AcOH (or H₂, Pd/C) | Aniline (excess), α-haloketone (PhCOCH₂Br) | DMF-DMA (Me₂NCH(OMe)₂), pyrrolidine; then H₂, Pd/C or Raney Ni |
| Conditions | EtOH/Et₂O, 25 °C; reduction 25–80 °C | Step 1: 25–80 °C; step 2: acid (or aniline·HBr), 150–200 °C | DMF, 110 °C; then H₂ (1 atm), EtOAc or MeOH, 25 °C |
| Stereochemistry | None (aromatic) | None | None at the product; enamine is the E isomer |
| Rate / selectivity | Condensation limited by CH acidity (pKa ≈ 20) | Cyclisation (high T) is slow; SN2 alkylation is fast | Condensation is slow but drives off MeOH; cyclization is fast |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Reissert indole synthesis?
o-Nitrotoluene, (CO₂Et)₂, KOEt; then Zn/AcOH (or H₂, Pd/C). Conditions: EtOH/Et₂O, 25 °C; reduction 25–80 °C.
Which bonds are formed and which are broken?
Formed: C–C (Claisen); N–H₂; C=N then C=C–N (indole ring). Broken: benzylic C–H; N–O (×2); C=O.
What is the stereochemical outcome?
None (aromatic)
What controls the rate or the selectivity?
Condensation limited by CH acidity (pKa ≈ 20)
Study guides that help with this reaction
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go
- How to answer mechanism questions in an exam