Leimgruber–Batcho Indole Synthesis

The relatively new Leimgruber-Batcho indole synthesis has rapidly emerged as a key weapon in the arsenal of the synthetic organic chemist. Willy Leimgruber and Andrew Batcho synthesized a large number of indoles and employed several reduction conditions with and without the isolation of the nitroenamine 2. The initial step takes advantage of the enhanced acidity of the benzylic methyl hydrogens, similar to what was observed in the Reissert reaction. Heating N,N-dimethylformamide dimethyl acetal (4) generates iminium ion 5 and methoxide, which deprotonates o-nitrotoluene to give anion 6. Subsequent condensation of 6 with 5 and elimination of methoxide (methanol) affords nitroenamine 7. The addition of pyrrolidine can intervene in this pathway at this point or earlier. Reduction of 7 leads to aminoenamine 8, which cyclizes to 2-aminoindoline 10, presumably via iminium ion 9. Final elimination of dimethylamine gives indole.