Benzoquinone, Nenitzescu condensation

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. 

This reaction was first reported by Nenitzescu in 1929. It is the synthesis of a 5-hydroxyindoie derivative involving the condensation between a 1,4-benzoquinone and a /3-amino-a ,/3-unsaturated compound and subsequent cyclization. Therefore, this reaction is generally known as the Nenitzescu indole synthesis, Nenitzescu reaction, j or Nenitzescu synthesis.Occasionally, it is also referred to as the Nenitzescu cyclization, Nenitzescu condensation, s.2i qj. Nenitzescu process. It should be pointed out that the synthesized indole derivatives by this reaction are restricted to those with an electron-withdrawing group at position 3, such as an ester or a carbonyl group. In addition, the completion of this reaction requires an appropriate oxidizing agent to convert the initial adduct into the indole derivative. i From monosubstituted quinone, 4-, 6- and 7-substituted 5-hydroxyindole derivatives all are possible products, but 6-substituted isomer is the one normally obtained. ... 

Gong and co-workers employed an intermolecular Nenitzescu reaction, a type lice transformation, for the condensation of a P-amino-a,(3-unsaturated ester with 1,4-benzoquinone to afford a 5-hydroxyindole derivative <06BMC911>. 

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... 

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

Two kinds of mechanisms are possible for the Nenitzescu indole synthesis, depending on the order of carbon-carbon bond and carbon-nitrogen bond formation. " However, the one involving the initial carbon-carbon condensation is more plausible as illustrated here for the reaction between 2-methyl 1,4-benzoquinone and 0-amino methyl crotonate. ... 

Given the typical low to modest yields of the aforementioned Nenitzescu indole syntheses, several improvements have been reported. Patrick and Saunders found that nitfomethane solvent greatly improved the efficiency of the condensation between p-aminoCTOtonates and 1,4-benzoquinones (Scheme 8) [22]. More remarkable is the... 

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