Nenitzescu indole synthesis

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The Nenitzescu indole synthesis is a name reaction in organic chemistry . It is also called Nenitzescu reaction , Nenitzescu synthesis , Nenitzescu cyclization or Nenitzescu condensation . This reaction was named after the Romanian chemist Costin Nenitzescu (1902-1970), who published it in 1929. The reaction can be used to synthesize 5-hydroxy indoles from 1,4-benzoquinone and β-amino-α, β-unsaturated carbonyl compounds (e.g. β-amino crotonic acid esters ).

Overview reaction

A substituted 1,4-benzoquinone reacts with a β- amino-substituted -α, β-unsaturated carbonyl compound with ring closure to form a 5-hydroxyindole.

R 1 = H , alkyl group , aryl group ; R 2 = H, alkyl group, aryl group; R 3 = H, alkyl group; R 4 = H, alkyl group, alkoxy group

The reaction also works with alkoxy , aryloxy , and hydroxyl groups substituted on the benzoquinone , as well as with chlorine , bromine or ester substituents . The following groups are permitted for the other residues:

mechanism

The exact mechanism of the reaction is not known. A plausible mechanism is described here based on the reaction between 2-methyl-1,4-benzoquinone and β-amino acrylic acid methyl ester :

Mechanism of the Nenitzescu indole synthesis

In the first step, the C = C double bond of the β-aminoacrylic acid methyl ester ( 2 ) attacks 2-methyl-1,4-benzoquinone ( 1 ), which leads to molecule 3 . A proton is rearranged to alcoholate group 3 , which also leads to the iminium ion 3 becoming an amino group 4 again. The latter now attacks the carbonyl group of the benzoquinone intramolecularly, which results in the formation of a five-membered ring 5 . The resulting negative oxygen atom is protonated by the ammonium group and thus to hydroxyl group 6 . With elimination of water, the six-membered ring aromatizes to the product 7 , a 5-hydroxy-6-methyl-3-methylcarboxylate-1 H -indole.

This reaction is particularly important in the production of 5-hydroxyindole derivatives.

Individual evidence

  1. ↑ Sorin Rosca: COSTIN D. NENITESCU. 2002, accessed June 5, 2013 .
  2. ↑ CD Nenitzescu: Nenitzescu indole synthesis . In: Bull. Soc. Chim. Romania . tape 11 , 1929, pp. 37 .
  3. ^ A b c d e Z. Wang: Comprehensive Organic Name Reactions and Reagents. 3 volumes. John Wiley & Sons, Hoboken, New Jersey 2009, ISBN 978-0-471-70450-8 , pp. 2042-2043.
  4. ↑ G. Domschke: The 5-hydroxy-indole synthesis according to CD Nenitzescu . In: Journal of Chemistry . tape 6 , no. 2 , 1966, p. 41-51 , doi : 10.1002 / zfch.19660060202 .
  5. ↑ SA Monti: The Nentizescu Condensation of Ethyl 3-Aminocrotonate and 1,4-Benzoquinone . In: J. Org. Chem. Band 31 , no. 8 , 1966, pp. 2669-2672 , doi : 10.1021 / jo01346a503 .
  6. ↑ a b J. J. Li: Name Reactions. A Collection of Detailed Reaction Mechanisms . 3rd expanded edition, Springer-Verlag, Berlin, Heidelberg 2006, ISBN 978-3-540-30030-4 , pp. 391-392.
  7. ↑ DM Ketcha, LJ Wilson, DE Portlock: The solid-phase Nenitzescu indole synthesis . In: Tetrahedron Letters . tape 41 , no. 33 , 2000, pp. 6253-6257 , doi : 10.1016 / S0040-4039 (00) 00697-3 .
  8. ↑ a b c d L. Kürti , B. Czakó: Stratigic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press, Amsterdam 2005, ISBN 978-0-12-429785-2 , p. 312.
  9. ^ R. Littell, GO Morton, GR Allen: Observations on the mechanism of the nenitzescu indole synthesis . In: J. Chem. Soc. D . tape 19 , 1969, p. 1144-1144 , doi : 10.1039 / C29690001144 .