The Nenitzescu indole synthesis is a chemical reaction that forms 5-hydroxyindole derivatives from benzoquinone and β-aminocrotonic esters.
center|400px|The Nenitzescu indole synthesis
This reaction was named for its discoverer, Costin Nenițescu, who first reported it in 1929. It can be performed with a number of different combinations of R-groups, which include methyl, methoxy, ethyl, propyl, and H substituents. There is also a solid-state variation in which the reaction takes place on a highly cross-linked polymer scaffold. 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.
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.
center|800px|Mechanism for the Nenitzescu indole synthesis
The reaction was first published by Nenitzescu in 1929, 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. They report that the catalyzing effect originates from enamine activation through a diketodienamine-ZnCl<sub>2</sub> 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. 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.
Variations and related reactions
One of the most common variations of the Nenitzescu reaction is the solid phase variant. This reaction, first reported by Ketcha et al., is shown below.
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.