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Recent Advances on the C2-Functionalization of Indole via Umpolung

Abstract

Heterocyclic compounds having a nitrogen atom in the ring exhibit very interesting biological activities. Indole is the core structure of many bioactive compounds owing to its high affinity to bind with most biological targets. Indole is an electron-rich compound and generally prefers electrophilic rather than nucleophilic substitution. Hence, many important indole derivatives are difficult to synthesize through the conventional reactivity of indole. This limitation can be avoided by using the umpolung, from the German word meaning polarity inversion. In umpolung, the indole molecule, especially the C2 and C3 positions, behave as an electrophile. As C2-functionalized indoles have substantial importance in synthetic and pharmaceutical chemistry, this review focuses on the C2 umpolung of indoles via the indirect approach which is less explored. Unlike direct approaches of indole umpolung, indirect methods have several advantages and therefore a number of research articles have been published in this field. But no review is available up till now. This is the first review on this topic and we believe that it will surely motivate the readers to work in this area further.

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Abbreviations

Ac:

Acyl

AcOH:

Acetic acid

Ar:

Aryl

BHT:

Butylated hydroxytoluene

Bn:

Benzyl

Boc:

tert-Butyloxycarbonyl

CAN:

Ceric ammonium nitrate

DCE:

Dichloroethane

DCM:

Dichloromethane

DIB:

(Diacetoxyiodo)benzene

DMDO:

Dimethyldioxirane

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

DTBP:

Di-tert-butyl peroxide

EDG:

Electron-donating group

EWG:

Electron-withdrawing group

Eq.:

Equivalent

LG:

Leaving group

NCS:

N-Chlorosuccinimide

NIS:

N-Iodosuccinimide

Nu:

Nucleophile

PPTS:

Pyridinium p-toluenesulfonate

rt:

Room temperature

TBHP:

tert-Butyl hydrogen peroxide

TBAI:

Tetrabutyl ammonium iodide

TEMPO:

2,2,6,6-Tetramethylpiperidin-1-oxyl

TFA:

Trifluoroacetic acid

pTSA:

p-Toluenesulfonic acid

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Acknowledgements

MLD is thankful to the Science and Engineering Research Board (SERB), India [Grant no. SB/FT/CS-073/2014] for the financial support under the “Fast Track” Scheme. BD acknowledges MHRD, Govt of India for research fellowship under the TEQIP-III Project.

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Correspondence to Mohit L. Deb or Pranjal K. Baruah.

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Deka, B., Deb, M.L. & Baruah, P.K. Recent Advances on the C2-Functionalization of Indole via Umpolung. Top Curr Chem (Z) 378, 22 (2020). https://doi.org/10.1007/s41061-020-0287-7

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Keywords

  • C-2 functionalization
  • Umpolung
  • Electrophilic indole
  • Dearomatization
  • C–X bond formation