Madelung indole synthesis

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The Madelung indole synthesis , which is also known as the Madelung synthesis , Madelung reaction or Madelung cyclization , is a name reaction in organic chemistry . It was named after the German chemist Walter Madelung (1879–1963), who published the reaction in 1912. The reaction enables the synthesis of indole derivatives from ortho- alkyl- N- acyl anilines .

Overview reaction

Substituting ortho alkyl N -acylaniline at high temperatures with a strong base (for example, potassium alkoxides ) in a way, formed under dehydration indole derivatives.

R 1 = hydrogen , alkyl group , aryl group ; R 2 = hydrogen, alkyl group, aryl group

Instead of potassium alcoholates, bases such as sodium amide or alkyl and aryl lithium (such as butyl lithium ) can also be used. In the first case, the required temperature is considerably lower, and in the case of the reaction with butyllithium, the reaction can even be carried out at room temperature.

mechanism

The mechanism of the Madelung indole synthesis is shown here using the example of the reaction of N - (2-methylphenyl) acetamide ( 1 ) with ethanolate as the base:

Mechanism of the Madelung indole synthesis

First the base (here ethanolate) deprotonates the nitrogen atom of the N - (2-methylphenyl) acetamide ( 1 ). In the resulting anion 2 , a 1,3 proton shift takes place with the formation of the carbanion 3 . This intramolecularly attacks the carbon atom of the carbonyl group and thus forms a heterocyclic intermediate 4 . Its protonation yields the alcohol 5 , which, with elimination of water and the formation of a C = C double bond, leads to the indole 6 , here 2-methyl-1 H -indole.

This method is suitable for producing unsubstituted indole or indoles substituted in position 2. On the other hand, there are difficulties in the synthesis of halogen-substituted indoles.

Individual evidence

  1. ↑ a b c d e f Z. Wang: Comprehensive Organic Name Reactions and Reagents, 3 Volume Set . John Wiley & Sons, Hoboken, New Jersey 2009, ISBN 978-0-471-70450-8 , pp. 1791-1792.
  2. ↑ W. Madelung: About a new way of representing substituted indoles. I . In: Ber. German Chem. Ges. Volume 45 , no. 1 , 1912, p. 1128–1134 , doi : 10.1002 / cber.191204501160 .
  3. ↑ WJ Houlihan, Y. Uike, VA Parrino: Novel cycloaddition products FORMED by the modified Madelung indole synthesis . In: J. Org. Chem. Band 46 , no. 22 , 1981, pp. 4515-4517 , doi : 10.1021 / jo00335a039 .
  4. ↑ a b L. Kürti , B. Czakó: Strategic Applications of Named Reactions in Organic Synthesis . Elsevier Academic Press, Amsterdam 2005, ISBN 978-0-12-429785-2 , pp. 270-271.
  5. ^ WJ Houlihan: The Chemistry of Heterocyclic Compounds. Indoles Part One . John Wiley & Sons, Inc., New York 1972, ISBN 0-471-37500-4 , pp. 385-396.
  6. ^ WJ Houlihan, VA Parrino, Y. Uike: Lithiation of N- (2-alkylphenyl) alkanamides and related compounds. A modified Madelung indole synthesis . In: J. Org. Chem. Band 46 , no. 22 , 1981, pp. 4511-4515 , doi : 10.1021 / jo00335a038 .