Indole synthesis Nenitzescu

5-Hydroxy-2-methyl-1 H-indole-3-carboxylic acid ethyl ester 

0-aikyi, 0-aryi, Ci, Br, CF3, C02-alkyl, etc. R = H, alkyl, cycloalkyl, aryl, benzyl R = alkyl, aryl, CO2-alkyl, 0-alkyl R = alkyl, aryl, O-alkyl, NH2, NR2 solvent acetone, EtOH, MeN02, AcOH, CHCI3 

The synthesis of the first potent and selective secretory phospholipase Az (S-PLA2) inhibitor, LY311727, was carried out in the laboratory of M.J. Martinelli. The indole core of the target was prepared by the Nenitzescu indole synthesis, which proceeded in high yield. The enamine component was readily prepared from methyl propionylacetate (3-oxo-pentanoic acid methyl ester) and benzylamine in the presence of catalytic amounts of TsOH. A thorough screening of various solvents pinpointed nitromethane as the optimal solvent for the transformation, since the product crystallized from the reaction mixture and was easily removed by filtration. 

An interesting variant of the Nenitzescu indole synthesis, involving the Lewis acid-directed coupling of enol ethers with benzoquinone mono- and b/s-imides, was developed by T.A. Engler et al. for the synthesis of substituted - and -tetrahydrocarbolines.  

The Nenitzescu indole synthesis involves the condensation of a quinone 1 and an enamine 2 to generate a hydroxyindole 3. 

In 1929, Nenitzescu reported that p-benzoquinone (4) was treated with ethyl 3-aminocrotonate (5) in boiling acetone to yield ethyl 5-hydroxy-2-methylindole-3-carboxylate (6).  

The procedure was largely ignored until the 1950s when interest in melanin-related substances and recognition of serotonin as a 5-hydroxy derivative stimulated exploration of the scope of the reaction. Nowadays, the Nenitzescu reaction is one of the most efficient processes for the preparation of 5-hydroxyindoles. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted. Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

The Nenitzescu reaction generally occurs under relatively mild reaction conditions. Moreover mono-, di-, and tri-substituted quinones react with equal facility. Many enamines including p-aminoacrylonitriles, p-aminoacrylamides, and p-amino-a,p-unsaturated ketones react with quinones to form indole nuclei as well. The mild reaction conditions and the availability of the starting material render it attractive even in those instances where the yield of the product is low.  

The Nenitzescu indole synthesis is the formation of a 5-hydroxylindole from the condensation of p-benzoquinone and P-aminocrotonate. 

The bona fide mechanism of the Nenitzescu indole synthesis involves complicated, multiple redox cycles. A simplified version is shown below  

The Nenitzescu indole synthesis was employed to synthesize LY311727, an indole acetic acid-based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) by Eli Lilly as a potential treatment for sepsis. The Nenitzescu condensation of benzoquinone with the P-aminoacrylate was carried out in CH3NO2 to provide the desired 5-hydroxylindole. An additional seven steps then afforded LY311727. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 178, Springer-Verlag Berlin Heidelberg 2009 

Nenitzescu indole synthesis. In Name Reactions in Heterocyclic Chemistry Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, pp 145-153. (Review). 

Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 513). 

Ponaras, A. A. Zain, O. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed. Wiley Sons New York, 1995,2174-2176. (Review). 

Li Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 191, Springer International Publishing Switzerland 2014 

The internal oxidation-reduction process might involve a bimolecular face-to-face electronic transfer complex (in nitromethane) [3]  

Kinugawa, M. Arai, H. Nishikawa, H. Sakaguchi, A. Ogasa, T. Tomioka, S. Kasai, M. J. Chem. Soc., Perkin Trans. 11995, 2677. 

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NENITZESCU Indole Synthesis Indole synthesis trom quinones and amino crotonates... 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

As an extension of the Nenitzescu indole synthesis, p-benzoquinone (521) was condensed with various electron-withdrawing anilines 522 in the presence of trifluoroacetic acid (TFA) to give 6-hydroxycarbazoles 523. Besides the low )deld of... 

Related reactions Fischer indole synthesis, Larock indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis ... 

Related reactions Bartoli indole synthesis, Fischer Indole synthesis, Larock Indole synthesis, Nenitzescu Indole synthesis ... 

Aggarwal, V., Kumar, A., Ila, H., Junjappa, H. Polarized ketene N,N- and S,N-acetals as novel enamine components for the Nenitzescu indole synthesis. XV. Synthesis 1981, 157-158. 

Ketcha, D. M., Wilson, L. J., Portlock, D. E. The solid-phase Nenitzescu indole synthesis. Tetrahedron Lett. 2000,41, 6253-6257. 

Nenitzescu indole synthesis. Hydrogenative acylation of cycloolefins with acid chlorides in the presence of aluminum chloride with five- and six-membered rings, no change in ring size occurs, but with seven-membered rings, rearrangement takes place with formation of a cyclohexane derivative. 

NENITZESCU Indole Synthesis Synthesis of indoles by reductive cyclisation of o, co-dinitrostyrenes. 

NENITZESCU Indole Synthesis Indole synthesis from quinones and amino croto nates... 

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