The Mitomycin Antibiotics. Synthetic Studies. XIV.<sup>1</sup> The Nenitzescu Indole Synthesis. Formation of Isomeric Indoles and Reaction Mechanism

Allen, George R.; Pidacks, C.; Weiss, Martin J.

doi:10.1021/ja00963a032

Cited by 64 publications

(30 citation statements)

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“…The generally accepted mechanism includes a Micheal addition of ethyl 3-aminocrotonate to the 1,4-benzoquinone to form a substituted 1,4-diphenol, oxidation of the diphenol to 1,4-benzoquinone, condensation/cyclization, and reduction to give the indole product [42]. Due to the relatively low yield, Nenitzescu reaction has not been extensively applied in indole synthesis, especially for manufacturing purpose.…”

Section: Resultsmentioning

confidence: 99%

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Huang

Zhang

et al. 2010

Res Chem Intermed

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The manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole is described and two synthetic methods were used and the results discussed. Two small and three large runs with Nenitzescu's method were analyzed and results reported with different reaction conditions. Manufacturing issues encountered were discussed. Production scale of more than 60 kg of the 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester and over 20 kg of the 5-hydroxy-2-methyl-1H-indole were achieved. Based on these results, larger scale manufacturing of this product or similar products based on the optimized conditions is feasible.

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Section: Resultsmentioning

confidence: 99%

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Huang

Zhang

et al. 2010

Res Chem Intermed

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“…The alternative is realized when the reactions are conducted in low-polar solvents in the presence of weak Lewis acids. Thus we have defined experimental conditions for the realization of the Nenitzescu reaction via a second, non-redox mechanism that was first theoretically proposed by G. R. Allen in 1966 [27]. On the basis of the latter, we offer a simple and rapid method to afford polysubstitited 5-hydroxyindoles in good to excellent yields based on a catalytic version of the Nenitzescu reaction and applicable to a variety of enamines; the method does not require expensive solvents.…”

Section: Discussionmentioning

confidence: 97%

Lewis acid catalyzed nenitzescu indole synthesis

Velezheva

Kornienko

Topilin

et al. 2006

Journal of Heterocyclic Chem

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A novel method for Lewis acid catalyzed Nenitzescu indole syntheses of 5‐hydroxyindoles bearing different substituents in positions 1 )Alk, Bn, Ar), 2 )Me, Et, Ph), and 3 )COOEt, COMe, CONHPh) as well as tricyclic derivatives are reported. The method is simple, rapid, efficient, and allows preparation of hydroxyindoles from 1,4‐benzoquinone and enamines in good to excellent yields with the use of low‐polar solvents in the presence of weak Lewis acids catalysts. The formation of 5‐hydroxyindoles under such mild conditions is explained in terms of a non‐redox mechanism.

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“…These are of considerable interest because of their various physiological activities. The mechanism of the reaction has been discussed recently by Allen, Pidacks, and Weiss (15). The essential steps appear to include addition of the enamine to the electrophilic quinone, aromatization, oxidation, cyclization, and reduction.…”

Section: Indoles From the Reactions Of Enamines With Quinones: Thementioning

confidence: 99%

“…4-Substituted indoles are then obtained. When, as in the case of C24, the initial adduct has stereochemistry inappropriate for direct cyclization, indolization can be accomplished by an oxidant in the presence of an acid (15,17,157). The acid effects configurational equilibration of the enamine via its carbon conjugate acid.…”

Section: Indoles From the Reactions Of Enamines With Quinones: Thementioning

confidence: 99%

“…The oxidant is necessary to convert the hydroquinone C25 to the quinone oxidation state. The 3-carbethoxy substituent can be removed efficiently by hydrolysis (15,24). The Nenitzescu reaction thus provides a route to indoles unsubstituted in the 3-position and these can then be elaborated by appropriate synthetic procedures.…”

Section: Indoles From the Reactions Of Enamines With Quinones: Thementioning

confidence: 99%

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Synthesis of the Indole Ring

1970

Organic Chemistry

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H A8 H R NH 2 A7arrangements. One line of effort has involved attempts to detect or trap the intermediates proposed for the various steps in the reaction. The hydrazonevinylhydrazine equilibrium in the first step of the reaction is analogous to ketone-enol and imine-enamine equilibria, but no firm physical evidence for the existence of measurable concentrations of the vinylhydrazine has been found to date (25a, 137a, 182, 183).Refluxing the phenylhydrazone of methyl ethyl ketone in acetic anhydride gives the diacylated vinylhydrazine A10. This can be considered to consti tute t r a p p i n g " of the first intermediate in the Fischer cyclization. Heating A9 /Et + Ac 2 0 H "Me H+ A10 A13 H NHAc A12 Me A14 H Ac 1 N / N v y A M e Ac I Me OH Me Ac H Me a V^M e NHAc NH 2 Me All D HI. SYNTHESIS OF THE INDOLE RINGA10 with dilute mineral acids gives 2,3-dimethylindole (259). These trans formations appear to constitute the closest analogy observed to date for the first step in the Robinson mechanism. Alkaline hydrolysis of A10 gave a substance formulated as A l l (259). This material gave 2,3-dimethylindole and acetamide on heating. Reexamination (72a) of the structure of this material has shown that it is actually A12. The formation of A l l can no longer be cited as an analogy for the second stage of the Robinson mechan ism. There are, however, products formed during Fischer reactions in certain cyclic systems which correspond to interruption of the reaction after the ortho substitution step. Plieninger (203,206) has reported the isolation of A16 by treatment of A15 with hydrochloric acid in acetic acid. Subsequent nmr spectral evi dence (185) has shown that the substance actually exists as the tautomer A17. It has been suggested that A17 is isolated because the enamine is very weakly basic and therefore the iminium species A18 is not generated in sufficient concentration to lead to indolization (185).Southwick and co-workers (238) have recorded isolation of compounds of structure A21. Structure A21 corresponds to interruption of the normal Fischer sequence at the aromatization stage. It has been suggested that ring A. THE FISCHER INDOLE SYNTHESIS □ 145 A20 N -I^< N R H ΝΗ 2^Ό A21 NH 3 R •N : NR A22 O strain effects are responsible for the failure of A21 to lose ammonia. Ring C of structure A22 contains three sp 2 atoms, representing considerable angle strain. Carlin and co-workers have examined the behavior of 2,6-disubstituted arylhydrazones under conditions of the Fischer synthesis (51, 54, 57, 59). Diortho substitution prevents the tautomerization A6 -> A7 in the Robinson mechanism. Heating the 2,6-dimethylphenylhydrazone of acetophenone in the presence of zinc chloride gives as the main product A24, as well as 4,7-dimethyl-2-phenylindole and cleavage products (54). The intermediate A26 can account for the formation of A24 and A25. / M e / V-NH-N < Ph Me Me A23The key step in the formation of the atomic skeleton of A24 is the trans formation A26 -> A29 which is analogous to a nucleophilic addition to a cyclohexadien...

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The Mitomycin Antibiotics. Synthetic Studies. XIV.¹ The Nenitzescu Indole Synthesis. Formation of Isomeric Indoles and Reaction Mechanism

Cited by 64 publications

References 5 publications

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Lewis acid catalyzed nenitzescu indole synthesis

Synthesis of the Indole Ring

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The Mitomycin Antibiotics. Synthetic Studies. XIV.1 The Nenitzescu Indole Synthesis. Formation of Isomeric Indoles and Reaction Mechanism

Cited by 64 publications

References 5 publications

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Lewis acid catalyzed nenitzescu indole synthesis

Synthesis of the Indole Ring

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Product

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The Mitomycin Antibiotics. Synthetic Studies. XIV.¹ The Nenitzescu Indole Synthesis. Formation of Isomeric Indoles and Reaction Mechanism