5- Hydroxyindole Nenitzescu synthesis

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

Even though the proposed mechanism does not preclude formation of 4-alkyl-5-hydroxyindoles, no examples were known until Allen and Weiss isolated ethyl 4-carbomethoxy-5-hydroxy-2-methylindole-3-carboxy-late (22) from the reaction of 2-carbomethoxy-l,4-benzo-quinone (20) with ethyl 3-aminocrotonate, following 

Allen and colleagues studied the effect of halogen-substitution on the Nenitzescu indolization, and their results are summarized in Table 1 [14,15]. The reactions of 2-halo-1,4-benzoquinones with ethyl 3-aminocrotonate gave poor to low yields of indoles, with the initial Michael 

With the invention of several variations on the basic Nenitzescu indole synthesis, both the scope and efficiency of this method have been greatly expanded and 

Menendez and colleagues used a ibree-component cerium(rV) anunonium nitrate (CAN) domino reaction to effect the synthesis of 5-hydroxybenzo[g]indoles and 5-hydroxyindoles in yields up to 96% (equations 2, 3) [50], The reaction presumably proceeds via enaminone 54 and activation of the quinone by CAN. The diphenylcarbinol unit serves as a source of the C-2 methyl group following loss of benzophenone. 

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NENITZESCU 5-Hydroxyindole Synthesis 5-Hydroxyindole synthesis from quinones and p-aminocrotonates (see 1st edition). 

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

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. 

Kucklaender, U. Mechanism of the Nenitzescu reaction, IV. Synthesis of benzindole derivatives. Liebigs Ann. Chem. 1978,129-139. Kucklaender, U. Mechanism of the Nenitzescu reaction, V. Synthesis of naphthofuran derivatives. Liebigs Ann. Chem. 1978, 140-149. Kucklaender, U., Huehnermann, W. Studies on the mechanism of the Nenitzescu reaction. Synthesis of 6-hydroxyindole derivatives. Arch. Pharm. (Weinheim, Ger.) 1979, 312, 515-526. 

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. ... 

Although Nenitzescu is best known for his 5-hydroxyindole synthesis (Chapter 15), he and his colleagues pioneered the reduction and cyclization of ort/jo-p-dinitrostyrenes to indoles. This classic reaction paved the way for other indole ring syntheses involving the reduction of nitroarenes. Nenitzescu described the inaugural reaction in 1925 as shown in Scheme 1, equation 1 [1], The o,p-dinitrostyrene was prepared by the base-catalyzed condensation of... 

The choice of experimental conditions exerts a major influence on the course of Nenitzescu procedure and thereby determines the structure of the major product. The mechanism demonstrated to be operative for the method can be employed to understand the genesis of certain anomalous products and suggests ways to avoid them, thus increasing the efficiency of the synthesis of 5-hydroxyindoles. 

Synthesis of 5- and 6-hydroxyindoles using the Nenitzescu reaction 93KFZ(6)37. 

Patrick, J. B., Saunders, E. K. Studies on the Nenitzescu synthesis of 5-hydroxyindoles. Tetrahedron Lett. 1979, 4009-4012. 

In the Nenitzescu synthesis of 5-hydroxyindoles, an A-aryl substituted amino-propenoic ester may be used, albeit with a low yield of product [2343]. Better yields may be obtained by reacting the quinone at ambient temperature with an enaminonitrile [3246]. The methylthio group may be removed by heating with Raney nickel. Magnesium methyl carbonate is sometimes used to carboxylate a methyl ketone but when it is warmed with the methyl ketone (35.3), it causes cyclization of the keto side-chain [2747]. A dioxopyrimidine aldehyde (35.4) is cyclized in moderate yield by heating with carbonate in DMF [2668]. 

Only a few indole syntheses make use of building blocks in which the N-atom is not directly bonded to an arene. The Nenitzescu synthesis is of this type. In this synthesis, 1,4-quinones are condensed with 3-aminoacrylic esters to give 5-hydroxyindole-3-carboxylic esters 44. The mechanism of this synthesis has not been completely clarified. It includes a Michael addition (-> 41) and a cyclodehydration (42 43) as well as a redox transformation (41 42 and 43 44) [53] ... 

The Nenitzescu synthesis is another process about which some of the mechanistic details remain unclear, but which can be used for the efficient synthesis of certain 5-hydroxyindoles. ... 

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