Reissert indole synthesis explained

The Reissert indole synthesis is a series of chemical reactions designed to synthesize indole or substituted-indoles (4 and 5) from ortho-nitrotoluene 1 and diethyl oxalate 2.^{[1] [2]}

Potassium ethoxide has been shown to give better results than sodium ethoxide.^[3]

Reaction mechanism

The first step of the synthesis is the condensation of o-nitrotoluene 1 with a diethyl oxalate 2 to give ethyl o-nitrophenylpyruvate 3. The reductive cyclization of 3 with zinc in acetic acid gives indole-2-carboxylic acid 4. If desired, 4 can be decarboxylated with heat to give indole 5.

Variations

Butin modification

In an intramolecular version of the Reissert reaction, a furan ring-opening provides the carbonyl necessary for cyclization to form an indole. A ketone side chain is present in the final product, allowing further modifications.^[4]

See also

• Leimgruber-Batcho indole synthesis

References

1. Reissert, A. . 10.1002/cber.189703001200. Einwirkung von Oxalester und Natriumäthylat auf Nitrotoluole. Synthese nitrirter Phenylbrenztraubensäuren. 1897. . 30. 1030–1053.
2. Noland, W. E.; Baude, F. J. Organic Syntheses, Coll. Vol. 5, p. 567 (1973); Vol. 43, p. 40 (1963). (Article)
3. Johnson, J. R.. Hasbrouck, R. B.. Dutcher, J. D.. Bruce, W. F.. amp . . 1945. 67. 423. 10.1021/ja01219a023. Gliotoxin. V. The Structure of Certain Indole Derivatives Related to Gliotoxin1,2. 3.
4. Butin . Alexander . Stroganova . Tatyana . Lodina . Irina . Krapivin . Gennady . 2001 . Furan ring opening—indole ring closure: a new modification of the Reissert reaction for indole synthesis . Tetrahedron Letters . 42 . 10 . 2031–3 . 10.1016/S0040-4039(01)00066-1.