Reactions of Indole with Nucleophiles

  • Tara L. S. KishbaughEmail author
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 26)


While indole naturally tends to act as a nucleophile, there are numerous examples of nucleophilic substitutions as well as nucleophilic additions to the indole ring system.


Indole Nucleophilic addition Nucleophilic substitution 


  1. 1.
    Donskaya OV, Dolgushin GV, Lopyrev VA (2002) Vicarious nucleophilic substitution of hydrogen in nitro-substituted pyrroles, azoles, and benzannelated systems based on them. Chem Heterocycl Comp 38:371–384CrossRefGoogle Scholar
  2. 2.
    Ma̧kosza M, Wojciechowski K (2004) Nucleophilic substitution of hydrogen in heterocyclic chemistry. Chem Rev 104:2631–2666CrossRefGoogle Scholar
  3. 3.
    Somei M (2006) A Frontier in indole chemistry: 1-hydroxyindoles, 1-hydroxytryptamines, and 1-hydroxytryptophans. In: Topics in heterocyclic chemistry. Springer, Berlin/Heidelberg, pp 77–111Google Scholar
  4. 4.
    Joule JA (1999) Nucleophilic substitution of C-hydrogen on the five-membered ring of indoles. Prog Heterocycl Chem 11:45–65CrossRefGoogle Scholar
  5. 5.
    Szmuszkovicz J (1962) The reaction of 3-acylindoles with Grignard reagents. J Org Chem 27:511–514CrossRefGoogle Scholar
  6. 6.
    Bartoli G, Bosco M, Baccolini G (1980) Conjugate addition of RMgX to nitroarenes. A very useful method of alkylation of aromatic nitro compounds. J Org Chem 45:522–524CrossRefGoogle Scholar
  7. 7.
    Pelkey ET, Gribble GW (1999) Synthesis and reactions of N-protected 3-nitroindoles. Synthesis 1117–1122Google Scholar
  8. 8.
    Gribble GW, Saulnier MG, Pelkey ET, Kishbaugh TLS, Liu Y, Jiang J, Trujillo HA, Keavy DJ, Davis DA, Conway SC, Switzer FL, Roy S, Silva RA, Obaza-Nutaitis JA, Sibi MP, Moskalev NV, Barden TC, Chang L, Habeski WM, Pelcman B, Sponholtz Iii WR, Chau RW, Allison BD, Garaas SD, Sinha MS, McGowan MA, Reese MR, Harpp KS (2005) Novel indole chemistry in the synthesis of heterocycles. Curr Org Chem 9:1493–1519CrossRefGoogle Scholar
  9. 9.
    Bruni P, Giorgini E, Tommasi G, Greci L (1998) Nucleophilic attack on the nitrone tautomeric form of 1-hydroxy-2-phenylindole. Tetrahedron 54:5305–5314CrossRefGoogle Scholar
  10. 10.
    Nicolaou KC, Estrada AA, Freestone GC, Lee SH, Alvarez-Mico X (2007) New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems. Tetrahedron 63:6088–6114CrossRefGoogle Scholar
  11. 11.
    Nicolaou KC, Sang HL, Estrada AA, Zak M (2005) Construction of substituted N-hydroxyindoles: synthesis of a nocathiacin I model system. Angew Chem Int Ed 44:3736–3740CrossRefGoogle Scholar
  12. 12.
    Myers AG, Herzon SB (2003) Identification of a novel Michael acceptor group for the reversible addition of oxygen- and sulfur-based nucleophiles. Synthesis and reactivity of the 3-alkylidene-3H-indole 1-oxide function of Avrainvillamide. J Am Chem Soc 125:12080–12081CrossRefGoogle Scholar
  13. 13.
    Feldman KS, Karatjas AG (2004) Extending Pummerer reaction chemistry. Application to the oxidative cyclization of tryptophan derivatives. Org Lett 6:2849–2852CrossRefGoogle Scholar
  14. 14.
    Feldman KS, Vidulova DB (2004) Extending Pummerer reaction chemistry. Application to the oxidative cyclization of indole derivatives. Org Lett 6:1869–1871CrossRefGoogle Scholar
  15. 15.
    Feldman KS, Vidulova DB (2004) Use of Stang’s reagent, PhI(CN)OTf, to promote Pummerer-like oxidative cyclization of 2-(phenylthio)indoles. Tetrahedron Lett 45:5035–5037CrossRefGoogle Scholar
  16. 16.
    Feldman KS, Skoumbourdis AP (2005) Extending Pummerer reaction chemistry. Synthesis of (±)-dibromophakellstatin by oxidative cyclization of an imidazole derivative. Organic Lett 7:929–931CrossRefGoogle Scholar
  17. 17.
    Feldman KS, Vidulova DB, Karatjas AG (2005) Extending Pummerer reaction chemistry. Development of a strategy for the regio- and stereoselective oxidative cyclization of 3-(ω-nucleophile)-tethered indoles. J Org Chem 70:6429–6440CrossRefGoogle Scholar
  18. 18.
    Feldman KS (2006) Modern Pummerer-type reactions. Tetrahedron 62:5003–5034CrossRefGoogle Scholar
  19. 19.
    Feldman KS, Karatjas AG (2006) Extending Pummerer reaction chemistry. Asymmetric synthesis of spirocyclic oxindoles via chiral indole-2-sulfoxides. Organic Lett 8:4137–4140CrossRefGoogle Scholar
  20. 20.
    Feldman KS, Nuriye AY (2009) Extending Pummerer reaction chemistry. Examination of the prospects for forming vicinal quaternary carbon centers. Tetrahedron Lett 50:1914–1916CrossRefGoogle Scholar
  21. 21.
    Marsili L, Palmieri A, Petrini M (2010) Reaction of carbon nucleophiles with alkylideneindazolium and alkylideneindolium ions generated from their 3-(1-arylsulfonylalkyl) indazole and indole precursors. Org Biomol Chem 8:706–712CrossRefGoogle Scholar
  22. 22.
    Khdour O, Skibo EB (2007) Chemistry of pyrrolo[1,2-a]indole- and pyrido[1,2-a]indole-based quinone methides. Mechanistic explanations for differences in cytostatic/cytotoxic properties. J Org Chem 72:8636–8647CrossRefGoogle Scholar
  23. 23.
    Wojciechowski K, Makosza M (1989) Reactions of organic anions. Part 158. Vicarious nucleophilic substitution of hydrogen in 5- and 6-nitroindole derivatives. Synthesis 106–109Google Scholar
  24. 24.
    Makosza M, Kwast E (1995) Vicarious nucleophilic substitution of hydrogen in nitro derivatives of five-membered heteroaromatic compounds. Tetrahedron 51:8339–8354CrossRefGoogle Scholar
  25. 25.
    Macor JE, Froman JT, Post RJ, Ryan K (1997) Synthesis and reactivity of pyrrolo[3,2-e]indole: removal of a N-BOM group from an unactivated indole. Tetrahedron Lett 38:1673–1676CrossRefGoogle Scholar
  26. 26.
    Yamada K, Yamada F, Shiraishi T, Tomioka S, Somei M (2009) Nucleophilic substitution reaction in indole chemistry: 1-methoxy-6-nitroindole-3-carbaldehyde as a versatile building block for 2,3,6-trisubstitute indoles. Heterocycles 77:971–982CrossRefGoogle Scholar
  27. 27.
    Rozhkov VV, Kuvshinov AM, Shevelev SA (2000) Transformations of 2-aryl-4, 6-dinitroindoles. Heterocycl Commun 6:525–528CrossRefGoogle Scholar
  28. 28.
    Bastrakov MA, Starosotnikov AM, Kachala VV, Nesterova EN, Shevelev SA (2007) Synthesis of 3-R-2-aryl-4, 6-dinitroindoles and specific features of their reactions with anionic nucleophiles. Russ Chem Bull 56:1603–1607CrossRefGoogle Scholar
  29. 29.
    Arnold RD, Nutter WM, Stepp WL (1959) Indoxyl acetate from indole. J Org Chem 24:117–118CrossRefGoogle Scholar
  30. 30.
    Roy S, Gribble GW (2005) A convenient synthesis of 2-nitroindoles. Tetrahedron Lett 46:1325–1328CrossRefGoogle Scholar
  31. 31.
    Coppola GM, Hardtmann GE (1977) Fused indoles. 1. Synthesis of the 1, 9-dihydrothiazino[3, 4-b]indole ring system. J Heterocycl Chem 14:1117–1118CrossRefGoogle Scholar
  32. 32.
    Comber MF, Moody CJ (1992) 2-Chloro-1-methoxymethylindole-3-carboxaldehyde: introduction of nucleophiles into the indole 2-position and an approach to the unusual TrpHis fragment of moroidin. Synthesis 731–733Google Scholar
  33. 33.
    Young SD, Amblard MC, Britcher SF, Grey VE, Tran LO, Lumma WC, Huff JR, Schleif WA, Emini EE et al (1995) 2-Heterocyclic indole-3-sulfones as inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 5:491–496CrossRefGoogle Scholar
  34. 34.
    Schkeryantz JM, Woo JCG, Danishefsky SJ (1995) Total synthesis of gypsetin. J Am Chem Soc 117:7025–7026CrossRefGoogle Scholar
  35. 35.
    Schkeryantz JM, Woo JCG, Siliphaivanh P, Depew KM, Danishefsky SJ (1999) Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: novel constructions of 2, 3-disubstituted indoles. J Am Chem Soc 121:11964–11975CrossRefGoogle Scholar
  36. 36.
    Roy S, Gribble GW (2007) Nucleophilic amination of 2-iodo-3-nitro-1-(phenylsulfonyl)indole. Tetrahedron Lett 48:1003–1005CrossRefGoogle Scholar
  37. 37.
    Bastrakov MA, Starosotnikov AM, Shakhnes AK, Shevelev SA (2008) Functionalization of 4, 6-dinitro-2-phenylindole at position 7. Russ Chem Bull 57:1539–1542CrossRefGoogle Scholar
  38. 38.
    Barraja P, Diana P, Carbone A, Cirrincione G (2008) Nucleophilic reactions in the indole series: displacement of bromine under phase transfer catalysis. Tetrahedron 64:11625–11631CrossRefGoogle Scholar
  39. 39.
    Cooper MM, Hignett GJ, Newton RF, Joule JA, Harris M, Hinchley JD (1977) Nucleophilic substitutions at an indole beta-position. J Chem Soc Chem Commun 432–434Google Scholar
  40. 40.
    Cooper MM, Lovell JM, Joule JA (1996) Indole-beta-nucleophilic substitution. Part 9. Nitrogen nucleophiles. Syntheses of hydroxycryptolepine, cryptolepine, and quindoline. Tetrahedron Lett 37:4283–4286CrossRefGoogle Scholar
  41. 41.
    Pelkey ET, Barden TC, Gribble GW (1999) Nucleophilic addition reactions of 2-nitro-1-(phenylsulfonyl)indole. A new synthesis of 3-substituted-2-nitroindoles. Tetrahedron Lett 40:7615–7619CrossRefGoogle Scholar
  42. 42.
    Yamada F, Fukui Y, Shinmyo D, Somei M (1993) Introduction of nucleophiles or ethyl group to the indole nucleus through nucleophilic substitution and/or radical reactions of 1-methoxyindole-3- and -2-carboxaldehyde. Heterocycles 35:99–104CrossRefGoogle Scholar
  43. 43.
    Yamada K, Yamada F, Somei M (2002) Reactions of 1-methoxy-3-(2-nitrovinyl)indole with nucleophiles: an interesting solvent effect and a novel preparation of 3-substituted 1-methoxyindoles. Heterocycles 57:1231–1234CrossRefGoogle Scholar
  44. 44.
    Alford PE, Kishbaugh T, Gribble GW (2010) Nucleophilic addition of hetaryllithium compounds to 3-nitro-1-(phenylsulfonyl)indole: synthesis of tetracyclic thieno[3, 2-c]-g-carbolines. Heterocycles 80:831–840CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Eastern Mennonite UniversityHarrisonburgUSA

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