Nenitzescu indole synthesis
{{Short description|Chemical reaction}}
{{Reactionbox
| Name = Nenitzescu indole synthesis
| Type = Ring forming reaction
| NamedAfter = Costin Nenițescu
}}
The Nenitzescu indole synthesis is a chemical reaction that forms 5-hydroxyindole derivatives from benzoquinone and β-aminocrotonic esters.
File:Nenitzescu Indole Synthesis Scheme.png
This reaction was named for its discoverer, Costin Nenițescu, who first reported it in 1929.{{cite journal|last=Nenitzescu|first=C.D.| title=Derivatives of 2-methyl-5-hydroxyindole | journal= Bull. Soc. Chim. Romania |year=1929|volume=11|pages=37–43}} It can be performed with a number of different combinations of R-groups, which include methyl, methoxy, ethyl, propyl, and H substituents.{{cite journal|last=Allen|first=G.|author2=Pidacks, C. |author3=Weiss, M. |title=The Mitomycin Antibiotics. Synthetic Studies|journal=J. Am. Chem. Soc. |date=5 June 1996|volume=88|issue=11|pages=2536–2544|doi=10.1021/ja00963a032|pmid=5941382}} There is also a solid-state variation in which the reaction takes place on a highly cross-linked polymer scaffold.{{cite journal|last=Ketcha|first=Daniel M.|author2=Wilson, L.J. |author3=Portlock, D.E. |title=The solid-phase Nenitzescu indole synthesis|journal=Tetrahedron Letters |date=2000|volume=41|pages=6253–6257|doi=10.1016/S0040-4039(00)00697-3|issue=33}} The synthesis is particularly interesting because indoles are the foundation for a number of biochemically important molecules, including neurotransmitters and a new class of antitumor compounds.{{cite journal|last=Schenck|first=Lothar Werner|author2=Kuna, K. |author3=Frank, W. |author4=Albert, A. |author5=Asche, C. |author6= Kucklaender, U. |title=1,4,9,10-Anthradiquinone as precursor for antitumor compounds|journal=Bioorganic & Medicinal Chemistry|date=10 January 2006|volume=14|pages=3599–3614|doi=10.1016/j.bmc.2006.01.026|issue=10 |pmid=16458517}}
Mechanism
The mechanism of a Nenitzescu reaction consists of a Michael addition, followed by a nucleophilic attack by the enamine pi bond, and then an elimination.{{cite book|last=Li|first=Jie Jack|title=Name Reactions, 4th ed.|url=https://archive.org/details/namereactions00jjli|url-access=limited|year=2009|publisher=Springer-Verlag|location=Berlin|pages=[https://archive.org/details/namereactions00jjli/page/n408 391]–392|isbn=978-3642010521}}
File:Nenitzescu Mechanism 3.png
The reaction was first published by Nenitzescu in 1929, and has since been refined by Allen et al. In his 1996 publication, Allen and coworkers investigated the effects that different substituents on the benzoquinone starting material had on the arrangement of the final product. These steric effects also gave evidence that one of the two current proposed mechanisms was more likely than the other, which led to the publication of the mechanism shown above.
Conditions
A preliminary study conducted by Katkevica et al. investigated the reaction conditions for a Nenitzescu synthesis, and reported on the behavior of the reaction when it takes place in various solvents.{{cite journal|last=Katkevica|first=Daze|author2=Trapencieris, P. |author3=Boman, A. |author4=Kalvins, I. |author5= Lundstedt, T. |title=The Nenitzescu reaction: an initial screening of experimental conditions for improvement of the yield of a model reaction|journal= J. Chemometrics |date=2004|volume=18|issue=34|pages=1883–187|doi=10.1002/cem.863|s2cid=95058789}} Their results indicated that the reaction performs best in a highly polar solvent, and further kinetic studies involving variation of the substrate, reagents, solvents, and the presence of Lewis acids and bases were proposed. Two years later, Velezheva et al. went on to report an alternative version of the synthesis using a Lewis acid catalyst.{{cite journal|last=Velezheva|first=Valeriya S.|author2=Sokolov, A.I. |author3=Kornienko, A.G. |author4=Lyssenko, K.A. |author5=Nelyubina, Y.V. |author6=Godovikov, I.A. |author7=Peregudov, A.S. |author8= Mironov, A.F. |title=The orle of a Lewis acid in the Nenitzescu indole synthesis|journal=Tetrahedron Letters |date=15 September 2008|volume=49|pages=7106–7109|doi=10.1016/j.tetlet.2008.09.087|issue=50}} They report that the catalyzing effect originates from enamine activation through a diketodienamine-ZnCl2 complex.
However, despite improvements in the conditions, the traditional Nenitzescu synthesis was not suitable for use on a manufacturing scale because of a relatively low yield and polymerization under normal reaction conditions. Originally, it was believed that the benzoquinone had to be used in 100% excess to drive the reaction to completion on this scale, but Huang et al. reported that a 20–60% excess is most effective.{{cite journal|last=Huang|first=Yun-Sheng|author2=Zhang, W. |author3=Zhang, X. |author4= Wang, J. |title=Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole|journal= Research on Chemical Intermediates |date=2010|volume=36|pages=975–983|doi=10.1007/s11164-010-0210-x|issue=8|s2cid=94168531}} Furthermore, they reported that for the ideal conditions for a large-scale reaction, there should be a 1:1.2-1.6 mole ratio between the benzoquinone and the ethyl 3-aminocrotonate, and the reaction should take place around room temperature. These conditions are sufficient for producing batches of 100 kg or more.
Applications
The 5-hydroxyindole skeleton is the foundation for a number of biochemically important molecules. Among them are serotonin, a neurotransmitter; indometacin, a non-steroidal anti-inflammatory agent; L-761,066, a COX-2 inhibitor; and LY311727, an inhibitor of secretory phospholipase. Currently, one of the most interesting applications of the Nenitzescu synthesis is its ability to produce a precursor to antitumor compounds. This synthesis, reported in 2006, involves the reaction of 1,4,9,10-anthradiquinone with various enamines. The products of this reaction constitute a new class of lead structures for anticancer drug design.
References
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{{Organic reactions}}
Category:Indole forming reactions