Reductive Fischer Indole Synthesis from N-Aryl Conjugated Hydrazones

doi:10.1055/s-0035-1562088

Paper

Reductive Fischer Indole Synthesis from N-Aryl Conjugated Hydrazones

Published May 1, 2016 · V. Snieckus, Sahaj Gupta

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Abstract

Significance: A tert-butyl iodide mediated synthesis of substituted indoles 2 from N-aryl-conjugated hydrazones 1 is reported. In this reaction, tert-butyl iodide acts as a source of anhydrous HI, which plays the dual role of reducing agent and Brønsted acid for the Fischer indolization step. A study of the substrate scope demonstrated that compounds 1 (R = para-electron-withdrawing group, F, Br) were well tolerated, whereas 1 (R = 4CN) showed no reaction due to its electron-withdrawing nature, which disfavors the sigmatropic rearrangement step. Modest regioselectivity was observed for hydrazone 1 (R = 3-Me), which gave mixture of 2b and 2b′ in a 1.2:1 ratio. The reaction conditions were also compatible with 1 (R4 = ester, aliphatic, aromatic, hetaromatic), which gave the corresponding indoles in moderate to excellent yields. A plausible mechanism is proposed based on experimental observations. Comment: The indole framework is ubiquitous in modern organic chemistry involving pharmaceuticals, agrochemicals, over-the-counter drugs, dyes, vitamin supplements, flavor enhancers/perfumery, and material sciences (see first Review below). Methods for the synthesis of indoles are well known (see second Review below). The current method is complementary to the classical Fischer indole method for those cases in which indolization cannot be achieved due to instability of aldehydes, hydrazones, or enehydrazines. The stable N-aryl-conjugated hydrazones 1 were readily prepared by reaction of N-arylhydrazines with suitable chalcones. The utility of the method was demonstrated by the synthesis of biologically important indomethacin on a gram scale and of esermethole, an intermediate that can be converted into the alkaloid physostigmine by known methods.

Study Snapshot

Tert-butyl iodide-mediated Fischer indole synthesis is a useful method for synthesising stable N-aryl-conjugated hydrazones, useful in pharmaceuticals and agrochemicals.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Reductive Fischer Indole Synthesis from N-Aryl Conjugated Hydrazones

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References

Citations

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Indole synthesis methods have evolved from classical to contemporary strategies, enabling the creation of biologically active compounds and offering insights into future synthetic applications.

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