The reaction of a 2-haloketone with aniline to give either a 2-, or 3-substituted indole is known as the Bischler-Möhlau indole synthesis . The reaction also occurs with the use of a 2-haloaldehyde to give unsubstituted indole. This reaction was named after its discoverer, Möhlau, in 1881, and the elucidation of its mechanisms in 1893 by Bischler.
The reaction gives 2-substitued indole proucts when an excess of aniline is used (typically 2 equiv.). The excess reagent is regenerated in situ, and so lesser excesses can be used.
The reaction gives 3-substitued indoles when stoichiometric amounts of aniline is used (and stirred well).
1. General Scheme
Scheme B1: Scheme of Bischler-Möhlau indole synthesis:
2-substituted indole products (top) are given when an excess of aniline is used. 3-substituted indoles are given when 1:1 ratio of reagents is used.
The first step of the mechanism is the nucleophilic attack from the aniline. Normally the carbonyl carbon would be the site of attack, but in this case we have a carbon-halogen bond, which is polarised to a larger extent than the carbon-oxygen (given that halogens are more electronegative than oxygen). To this end, the nitrogen forms a bond with the halo-carbon, which then eliminates the halogen.
Scheme B2: Synthesis of 3-substituted indoles
The electron rich ring attacks the slightly positive carbonyl carbon, which forms the 5 membered ring. The oxygen picks up a hydrogen from the acidic environment, and the loss of a hydrogen at the terminus of the new sigma bond, results in the 6 membered ring regaining its aromaticity. The hydrogen α to the nitrogen is given up to form a double bond at the 2,3-position which results in the elimination of a hydroxyl group, to render the 3-substitued indole product.
Scheme B3: Synthesis of 2-bustitued indoles
As explained, the route that this reaction takes is largely dependant on the amount of aniline added. By careful manipulation of how the reagents are added in relation to heat, it is possible to get good selectivity - given that the actual indolisation from the phenylaminoketone intermediate requires heat, whereas the additions of the aniline to the haloketone generally occur at room temperature (or very mild heat).
Practically, I have found that dropwise addition of the aniline to a vigorously stirring heated solution of the haloketone allows the intermediate phenylaminoketone to form and then indolise rapidly to give the 3-substituted indole product in near exclusivity. The 2-substituted product can be formed selectively by the addition of an excess of aniline rapidly to a stirred solution of haloketone, which is not heated until TLC or GCMS demonstrates that the di-(phenylamino)- material is formed (or that there is no phenylaminoketone remaining in solution). The solution is then heated, providing the driving energy to indolise to the 2-substitued product.
Substitution on the phenyl side of the ring (e.g. positions 4, 5, 6 and 7) is less likely due to the electrophilically preferred pyrollic ring sites (2 and 3 positions), however functionality can be built into the phenyl side of the indole by using a substituted aniline as a starting material.